[House Hearing, 107 Congress]
[From the U.S. Government Publishing Office]
EVALUATING THE EFFECTIVENESS OF THE FOOD AND DRUG ADMINISTRATION
MODERNIZATION ACT
=======================================================================
HEARING
before the
SUBCOMMITTEE ON HEALTH
of the
COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED SEVENTH CONGRESS
FIRST SESSION
__________
MAY 3, 2001
__________
Serial No. 107-51
__________
Printed for the use of the Committee on Energy and Commerce
Available via the World Wide Web: http://www.access.gpo.gov/congress/
house
__________
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COMMITTEE ON ENERGY AND COMMERCE
W.J. ``BILLY'' TAUZIN, Louisiana, Chairman
MICHAEL BILIRAKIS, Florida JOHN D. DINGELL, Michigan
JOE BARTON, Texas HENRY A. WAXMAN, California
FRED UPTON, Michigan EDWARD J. MARKEY, Massachusetts
CLIFF STEARNS, Florida RALPH M. HALL, Texas
PAUL E. GILLMOR, Ohio RICK BOUCHER, Virginia
JAMES C. GREENWOOD, Pennsylvania EDOLPHUS TOWNS, New York
CHRISTOPHER COX, California FRANK PALLONE, Jr., New Jersey
NATHAN DEAL, Georgia SHERROD BROWN, Ohio
STEVE LARGENT, Oklahoma BART GORDON, Tennessee
RICHARD BURR, North Carolina PETER DEUTSCH, Florida
ED WHITFIELD, Kentucky BOBBY L. RUSH, Illinois
GREG GANSKE, Iowa ANNA G. ESHOO, California
CHARLIE NORWOOD, Georgia BART STUPAK, Michigan
BARBARA CUBIN, Wyoming ELIOT L. ENGEL, New York
JOHN SHIMKUS, Illinois TOM SAWYER, Ohio
HEATHER WILSON, New Mexico ALBERT R. WYNN, Maryland
JOHN B. SHADEGG, Arizona GENE GREEN, Texas
CHARLES ``CHIP'' PICKERING, KAREN McCARTHY, Missouri
Mississippi TED STRICKLAND, Ohio
VITO FOSSELLA, New York DIANA DeGETTE, Colorado
ROY BLUNT, Missouri THOMAS M. BARRETT, Wisconsin
TOM DAVIS, Virginia BILL LUTHER, Minnesota
ED BRYANT, Tennessee LOIS CAPPS, California
ROBERT L. EHRLICH, Jr., Maryland MICHAEL F. DOYLE, Pennsylvania
STEVE BUYER, Indiana CHRISTOPHER JOHN, Louisiana
GEORGE RADANOVICH, California JANE HARMAN, California
CHARLES F. BASS, New Hampshire
JOSEPH R. PITTS, Pennsylvania
MARY BONO, California
GREG WALDEN, Oregon
LEE TERRY, Nebraska
David V. Marventano, Staff Director
James D. Barnette, General Counsel
Reid P.F. Stuntz, Minority Staff Director and Chief Counsel
______
Subcommittee on Health
MICHAEL BILIRAKIS, Florida, Chairman
JOE BARTON, Texas SHERROD BROWN, Ohio
FRED UPTON, Michigan HENRY A. WAXMAN, California
JAMES C. GREENWOOD, Pennsylvania TED STRICKLAND, Ohio
NATHAN DEAL, Georgia THOMAS M. BARRETT, Wisconsin
RICHARD BURR, North Carolina LOIS CAPPS, California
ED WHITFIELD, Kentucky RALPH M. HALL, Texas
GREG GANSKE, Iowa EDOLPHUS TOWNS, New York
CHARLIE NORWOOD, Georgia FRANK PALLONE, Jr., New Jersey
Vice Chairman PETER DEUTSCH, Florida
BARBARA CUBIN, Wyoming ANNA G. ESHOO, California
HEATHER WILSON, New Mexico BART STUPAK, Michigan
JOHN B. SHADEGG, Arizona ELIOT L. ENGEL, New York
CHARLES ``CHIP'' PICKERING, ALBERT R. WYNN, Maryland
Mississippi GENE GREEN, Texas
ED BRYANT, Tennessee JOHN D. DINGELL, Michigan,
ROBERT L. EHRLICH, Jr., Maryland (Ex Officio)
STEVE BUYER, Indiana
JOSEPH R. PITTS, Pennsylvania
W.J. ``BILLY'' TAUZIN, Louisiana
(Ex Officio)
(ii)
C O N T E N T S
__________
Page
Testimony of:
Applebaum, Rhona S., Executive Vice President, Scientific and
Regulatory Affairs, National Food Processors Association... 38
Ben-Maimon, Carole, President and CEO, Proprietary Research
and Development, Barr Laboratories......................... 71
Franson, Timothy R., Vice President, Clinical Research and
Regulatory Affairs, U.S., Lilly Research Laboratories,
accompanied by Stephen Spielberg, Vice President, Drug
Development, Janssen Research Foundation................... 94
Gorman, Richard, Incoming Chair, American Academy of
Pediatrics Committee on Drugs, American Academy of
Pediatrics................................................. 75
Kearns, Gregory L., Professor and Chief, Division of Clinical
Pharmacology and Medical Toxicology, Children's Mercy
Hospital and Clinics....................................... 65
Meyers, Abbey S., President, National Organization for Rare
Disorders.................................................. 81
Northrup, Stephen J., Executive Director, Medical Device
Manufacturers Association.................................. 30
Plunkett, Travis B., Legislative Director, Consumer
Federation of America...................................... 88
Suydam, Linda A., Senior Associate Commissioner, Food and
Drug Administration........................................ 20
Material submitted for the record by:
Advanced Medical Technology Association, prepared statement
of......................................................... 131
Applebaum, Rhona S., Executive Vice President, Scientific and
Regulatory Affairs, National Food Processors Association,
letter dated June 12, 2001, enclosing response for the
record..................................................... 142
Clemente, Frank, Director, Public Citizen's Congress Watch,
prepared statement of...................................... 135
Collins, Arthur, Chief Executive Officer, Medtronic, prepared
statement of............................................... 139
Franson, Timothy R., Vice President, Clinical Research and
Regulatory Affairs, U.S., Lilly Research Laboratories,
letter dated June 7, 2001, enclosing response for the
record..................................................... 153
Giuli, Steve, Director of Government Affairs, Generic
Pharmaceutical Association, letter dated June 13, 2001,
enclosing response for the record.......................... 144
Kearns, Gregory L., Professor and Chief, Division of Clinical
Pharmacology and Medical Toxicology, Children's Mercy
Hospital and Clinics, letter dated June 7, 2001, enclosing
response for the record.................................... 151
Meyers, Abbey S., President, National Organization for Rare
Disorders, letter dated June 11, 2001, enclosing response
for the record............................................. 165
Northrup, Stephen J., Executive Director, Medical Device
Manufacturers Association, letter dated June 7, 2001,
enclosing response for the record.......................... 146
Plaisier, Melinda K., Associate Commissioner for Legislation,
Department of Health and Human Services, letter dated June
29, 2001, to Hon. Michael Bilirakis, enclosing response for
the record................................................. 154
(iii)
EVALUATING THE EFFECTIVENESS OF THE FOOD AND DRUG ADMINISTRATION
MODERNIZATION ACT
----------
THURSDAY, MAY 3, 2001
House of Representatives,
Committee on Energy and Commerce,
Subcommittee on Health,
Washington, DC.
The subcommittee met, pursuant to notice, at 10 a.m., in
room 2322, Rayburn House Office Building, Hon. Michael
Bilirakis (chairman) presiding.
Members present: Representatives Bilirakis, Upton,
Greenwood, Deal, Burr, Whitfield, Ganske, Norwood, Bryant,
Buyer, Brown, Waxman, Strickland, Barrett, Capps, Pallone,
Deutsch, Eshoo, Stupak, Engel, Wynn, and Green.
Also present: Representatives Harman and McCarthy.
Staff present: Brent DelMonte, majority counsel; Marc
Wheat, majority counsel; Kristi Gillis, legislative clerk; and
John Ford, minority counsel.
Mr. Bilirakis. Let's get started, please. I am advised that
we will have votes constantly today. Apparently there will be
an awful lot of procedural votes called. I'll ask all the
witnesses to forgive us in advance, but that is the way it is.
In the interests of time too, I would hope that the opening
statements can be kept very brief so that we can do as much as
possible before that first vote is called.
Today we are here to consider whether the Food and Drug
Administration Modernization Act, which we fondly refer to as
FDAMA, has revitalized the FDA for the benefit of patients,
consumers, and industry. The purposes of the law were clear:
Congress wanted the FDA and industry to work collaboratively in
the consideration of applications for safe, effective drugs and
devices. We wanted to ensure that food consumers would have
access to legitimate health and nutrition content claims.
Clearly, however, no one advocated that the FDA sacrifice
its safety and efficacy requirements to achieve these goals. To
the contrary, our intent was to create a consistent process and
enable all stakeholders to know precisely what is expected of
them.
Today we will learn more about whether the hope represented
in the FDA Modernization Act has been realized. Of particular
interest to me is the pediatric exclusivity section of the act
and the authorization for these provisions, the fact that the
authorizations for these provisions expires this year.
Because so few drugs taken by children are labeled for
pediatric uses, Congress created an incentive for drug makers
to conduct tests which could increase pediatric labelling.
In exchange for conducting pediatric studies at the request
of the FDA, drug makers received 6 months of additional patent
exclusivity. The response to this provision has been
overwhelmingly positive. The FDA has issued 188 written
requests for the industry to conduct 411 pediatric studies.
There have been 18 label changes for the benefit of children,
with more to come.
This is not a partisan concern, I like to think. In fact,
the Clinton Administration noted just this past January, ``The
pediatric exclusivity provision has been highly effective in
generating pediatric studies on many drugs and in providing
useful new information in product labeling.''
While the pediatric research incentives have clearly worked
well, some have argued for changes in the law. For example, to
promote testing on drugs with no patent protection or
exclusivity remaining. I believe that this is a legitimate
problem which we should consider in our discussions of a
reauthorization measure. At the same time, we must avoid
changing the incentives in a way which results in fewer
pediatric studies.
I am also interested in learning more about how FDAMA has
worked to improve the availability of medical devices for
patients. What is it, a vote?
Mr. Pallone. Adjournment.
Mr. Bilirakis. Adjournment?
How would you handle that, Mr. Waxman?
Mr. Waxman. Keep going.
Mr. Bilirakis. Keep going. Under the law, FDA was directed
to work with industry in creating a least burdensome standard
to demonstrate the effectiveness of devices. On Tuesday, more
than 3 years after the act's passage, this standard was finally
issued. We need to understand why the FDA took so long to
accomplish its task, whether the result will be beneficial for
patients, and how the FDA plans to ensure that the standard is
properly articulated to device reviewers.
I again want to thank all of our witnesses for taking their
valuable time to join us and share their expertise. I know we
all look forward to their testimony and their continued input
and guidance as the subcommittee works to advance the
reauthorization measure.
I will now recognize Mr. Pallone.
Mr. Pallone. I was going to ask Mr. Waxman to go first.
Mr. Bilirakis. Mr. Waxman. I think I should always start
with Mr. Waxman, because you all seem to want to yield to him,
which is okay with me.
Mr. Waxman?
Mr. Waxman. Thank you very much, Mr. Chairman, and Mr.
Pallone. There is a meeting of another subcommittee on the
California energy problems, so I asked if I could go first in
making my opening statement.
This is an issue I care a great deal about. At the end of
this calendar year, the pediatric exclusivity authorities of
the FDA expire. With my colleague from Pennsylvania, Mr.
Greenwood, I was the original author of this legislation. We
proposed it because we were convinced that the regular drug
development marketplace was not working in the best interests
of children. At that time, 80 percent of all drugs on the
market had not been tested for safety in children. Many of the
most important drugs for childhood diseases had never been
studied in children, and children were often left waiting years
to be able to take advantage of research progress.
For almost 30 years, child health advocates, pediatricians,
and the FDA had appealed to the pharmaceutical manufacturers
for health, but nothing happened. The industry said nice things
about child health, but they were uninterested in using their
research powers and their financial clout to do anything real.
So finally we developed a market incentive to pay manufacturers
to do what many of us thought they should be doing as a matter
of course. That is, produce results.
Pediatric research on some pharmaceuticals is happening
now. I am pleased that industry has turned its attention to
children's health. But it is still not clear to me that we are
getting what we bargained for. Most obviously, it is not clear
that the drugs that most need study are being studied. Many of
the most important drugs for serious and life-threatening
pediatric diseases are still not under review. Many of the
drugs that are under review are not the most important ones for
children.
Also, obviously we are often paying vastly more than we
should for the research. Studies that cost hundreds of
thousands of dollars are resulting in hundreds of millions in
windfall profits. These windfalls total billions of dollars.
These windfalls come out of Americans' pockets because of this
legislation as surely as they would if we had increased taxes
and paid billions for pediatric trials directly. One of five
pharmaceutical dollars is paid directly through government
programs. The rest by private insurance companies and by
patients themselves.
Each time we extend patents or exclusivity, however
laudable the purpose, we spend the public's money. I stand
ready and willing to do whatever we must to improve pediatric
research on pharmaceuticals. It is a good and important goal. I
expect that we will ultimately reauthorize the pediatric
exclusivity, but as we consider reauthorizing this legislation,
I want to know if we are getting the research we need and if we
are purchasing this research prudently.
Thank you very much, Mr. Chairman.
Mr. Bilirakis. I thank you, Mr. Waxman.
Dr. Norwood?
Mr. Norwood. Thank you very much, Mr. Chairman. I do
appreciate this hearing very much. In consideration of the
witnesses, I will simply ask you to put my opening statement in
the record and move us on.
[The prepared statement of Hon. Charlie Norwood follows:]
Prepared Statement of Hon. Charlie Norwood, a Representative in
Congress from the State of Georgia
Thank you Mr. Chairman. I thank you for calling this hearing, and
applaud your efforts to further the review of the Food and Drug
Administration Modernization Act. I am particularly interested in the
pediatric exclusivity provision, included under Title I of the Act.
In January of last year, the FDA report on pediatric exclusivity
reported that between the years of 1991-1996, prior to pediatric
exclusivity, only 11 requests for studies were honored by the
pharmaceutical industry. Since 1998, when the pediatric provision was
implemented, the pharmaceutical industry has agreed to perform 411 drug
studies. The report went further to suggest that the absence of
appropriate labeling poses significant risks to the children of
America; and, that the Secretary projected that the additional costs to
the nation's pharmaceutical bill due to pediatric exclusivity amounts
to only one-half of one percent.
While there are some out there that feel that the costs to sponsor
study requests by the FDA are unacceptable, I am far from convinced
those costs are unacceptably high where the health of our children is
concerned. To make pediatric exclusivity contingent only on a positive
label change will deter the pharmaceutical industry from further
studies. If exclusivity is not to be granted, or revoked, based on a
negative label change; then, what incentives have we presented the
industry to further research?
I thank all of the witnesses for attending the hearing this morning
and I look forward to hearing from each of the witnesses. Again, Mr.
Chairman, I commend you for calling these hearings and leading the
efforts to insure the safety of America's children, and I yield back
the balance of my time.
Mr. Bilirakis. Mr. Pallone, an opening statement?
I thank the gentleman from Georgia.
Mr. Pallone. Thank you, Mr. Chairman, for holding this
hearing on the evaluation of the effectiveness of the FDA
Modernization Act. There are several FDA issues that concern
me, including the need to promote generic drugs as a method to
hold down prescription drug prices, the lack of progress on
dietary supplement regulations, and the current
administration's inadequate attention to food safety.
I want to mention several things Congress can do to
increase access to low-cost generic alternatives to name-brand
products. The first is to stop a practice being used by some in
the brand industry to prevent generics from reaching the
consumer. These restrictive laws are being advanced despite a
scientific finding by the FDA that the generic drug is
equivalent and substitutable to the brand name product.
Congress needs to pass legislation prohibiting keeping
generics off the market once the FDA has determined they are
therapeutically equivalent to a brand name product. I have
introduced legislation titled the Generic Drugs Access Act of
2001, which would accomplish just that. I hope, in light of the
well-documented price discrimination that seniors face today,
this committee would consider this legislation.
The second issue I wanted to mention concerns the lack of
generic competition in the biotechnology industry. In my view,
the lack of a clear regulatory framework for approving generic
biotech products promises to become yet another obstacle
blocking consumer access to lower cost alternatives. Indeed,
the patents on a number of giant biotech products have already
expired, and many more will expire in the next few years.
Mr. Chairman, there is no scientific reason why biologics
should be exempt from the Hatch Waxman Act. Actually, I told
Mr. Waxman I was going to say Waxman Hatch Act. We will save
enormous sums of money if an explicit framework for approving
generic biologics can be established through statutory
language. Generic competition in the pharmaceutical industry
has been an incentive for innovation at the same time it has
lowered prices. I expect the same would happen in the
biotechnology industry if Waxman Hatch is expanded to include
biologics.
Mr. Chairman, I am also concerned about the manner in which
the FDA is implementing the pediatric exclusivity provisions of
FDAMA. The intent of the law was to create an incentive for
companies to discover new uses in pediatrics for their products
in exchange for 6 months of exclusivity for the work done. The
FDA's interpretation of the law, however, has in essence been
granting companies patent extensions without receiving the
pediatric benefits it was intended to generate.
Two areas I am particularly concerned about are the ability
of companies to use old studies to obtain patent extensions and
the granting of exclusivity based on active moiety rather than
on product-by-product basis. The pediatric exclusivity
provision of FDAMA should be prospective, and needs to be
strengthened.
Mr. Chairman, the issue of dietary supplement regulations
is not progressing, in my opinion, in a timely manner. The
industry and the public have been asking for the proposed final
regulations for good manufacturing practices and the
publication is still pending at the FDA. The discussion today
examines modernization of the FDA, yet it takes more than 6
years to get quality standard regulations for dietary
supplements.
In addition, we are awaiting publication of the Department
of Health and Human Services Inspector General's report seeking
tighter regulations on dietary supplements. The final draft of
the report allegedly requires mandatory reporting of
supplements and their ingredients. Not only does the draft
report unfairly paint a biased picture of the industry, it also
understates the benefits of supplements.
Last, Mr. Chairman, the country is facing a crisis in food
safety. The FDA is in need of food safety modernization in
terms of better inspections and better labeling. I am
introducing two bills to address these issues, but I want to
highlight the fact that the Bush Administration's food safety
record in its first 100 days is dismal. I am interested in
hearing from Dr. Applebaum of the National Food Processors
Association on this urgent issue.
Thank you, Mr. Chairman.
Mr. Bilirakis. I thank the gentleman. I will advise the
gentleman that I have talked to the committee staff over the
last few days. We are going to devote an entire hearing to the
generic drug issue.
Mr. Pallone. Thank you, Mr. Chairman.
Mr. Bilirakis. I think in order for all of us to be able to
make this very important vote, I am going to have to break,
unfortunately. So forgive us. I'll run right on back. As soon
as I get back, we'll get started.
[Brief recess.]
Mr. Bilirakis. Mr. Whitfield, for an opening statement?
Mr. Whitfield. Mr. Chairman, thank you very much. I've been
looking forward to this hearing today. I commend you for
initiating the holding of this hearing.
I would initially, Mr. Chairman, with unanimous consent ask
that I submit for the record a copy of a statement of the
Grocery Manufacturers of America. This is an issue of
particular importance to them. Even though they are not
testifying, they would simply like to get their views reflected
in the record.
Mr. Bilirakis. By all means, without objection, that will
be the case.
[The statement follows:]
Prepared Statement of Grocery Manufacturers of America
GMA is the world's largest association of food, beverage, and
consumer brand companies. GMA member companies sell more than $460
billion in consumer food and other products each year and employ more
than 2.5 million workers in all fifty states. GMA speaks for food and
consumer brand manufacturers at the state, federal, and international
levels on legislative and regulatory issues.
GMA and its members were deeply involved in the consideration and
enactment of both the Nutrition Labeling and Education Act (NLEA) of
1990 and the Food and Drug Administration Modernization Act (FDAMA) of
1997. We have appeared at FDA hearings to discuss implementation of
these two statutes and have submitted comments to the agency on
proposed regulations intended to implement them. We welcome this
opportunity to present our views on these important matters to the
Subcommittee at this time.
GMA's comments will cover five different areas: (1) FDA's highly
restrictive regulation of disease/health claims under the NLEA of 1990
and the FDAMA of 1997, (2) the failure of FDA to implement the January
1999 decision of the United States Court of Appeals in the Pearson
case, that applied the free speech provisions of the First Amendment to
food labeling, (3) the expansive regulation by FDA of structure/
function claims as implied drug claims rather than as food claims, (4)
the successful implementation by FDA of the new approach to regulation
of indirect food additives under FDAMA, and (5) the continuing need for
national uniformity in all aspects of food regulation.
1. FDA's Highly Restrictive Regulation of Disease/Health Claims for
Food.
Initially in the NLEA of 1990, and subsequently in the FDAMA of
1997, Congress sought to expand the availability in food labeling of
helpful information for consumers about the relationship between diet
and disease. By its narrow and constricted implementation of these
provisions, however, current FDA policy prevents important health
information from reaching the American public. This is detrimental to
both personal and public health. There are five ways in which FDA has
failed to implement NLEA and FDAMA in the way intended by Congress.
First, NLEA requires FDA to approve any claim relating to the
relationship between a nutrient and disease if it is truthful,
nonmisleading, and is supported by significant scientific agreement. On
its face, this statutory provision authorizes claims about a diet/
disease relationship based upon preliminary research or emerging
science, where the evidence is not yet definitive, as long as the state
of scientific development is accurately described. Nonetheless, FDA has
chosen to interpret and apply this provision only where there is
overwhelming science to support a diet/disease relationship, thus
preventing the public from learning about new scientific developments
until they have matured into hard science. This was not the intent of
Congress and it is not in the public interest.
GMA strongly believes that this provision of the law is being
improperly implemented and that the FDA approach prevents consumers
from obtaining important health information. We urge the new
Administration to reverse the FDA approach and to implement the law as
it was written.
Second, FDA has interpreted the statutory standard of ``significant
scientific agreement'' so narrowly and stringently that very few diet/
disease relationships can stand up to the FDA requirements. As a
result, FDA has approved only a handful of disease/health claims under
the NLEA and the FDAMA, in spite of strong scientific evidence
supporting a number of other diet/disease relationships. As a practical
matter, the FDA interpretation of this provision approximates the
requirement of a full scientific consensus. This was never the intent
of Congress.
GMA urges the new Administration to return the standard of
``significant scientific agreement'' to its original intent. A
reasonable scientific basis, rather than overwhelming scientific proof,
should be sufficient to support claims as long as the basis for those
claims is adequately characterized.
Third, FDA has insisted upon ``model'' disease claims that are
lengthy, detailed, and complex, and thus poorly suited for consumer
understanding and communication. The food industry has decades of
knowledge and experience in consumer communication. FDA has little or
no expertise in this area. FDA should approve the basic diet/disease
relationship and allow the industry to determine how best to
communicate that relationship to the consuming public, as long as the
claims remain truthful, accurate, and nonmisleading.
Fourth, FDA has narrowed the statute to permit only disease
prevention claims and to exclude disease treatment claims. Nothing in
the statute authorizes such a limitation.
It is readily apparent that food can treat as well as prevent
disease. Numerous foods are used as part of a therapeutic regimen.
People with some types of heart disease or hypertension are placed on
strict diets designed to treat their existing condition. There is no
statutory or public health basis for the FDA limitation on disease/
health claims and as a result, people who should be told about the
dietary means of treating disease are denied this important
information.
Fifth, frustrated with FDA's continuing restrictions on disease/
health claims in food labeling, in 1997 Congress included in FDAMA a
specific provision to expand disease/ health claims by authorizing
their use based upon authoritative statements by other federal science
agencies and the National Academy of Sciences. Once again, however, FDA
has severely blunted the intent of Congress by interpreting this
provision to allow FDA to veto any claim authorized by another agency
if FDA disagrees with that other agency. This policy has effectively
eviscerated the FDAMA provision.
GMA urges the new Administration to adhere to the intent of
Congress and to respect the published position of the federal science
agencies as Congress intended.
2. FDA's Failure to Implement the Pearson Decision
In the landmark case of Pearson v. Shalala, 164 F.3d 650 (D.C. Cir
1999), the United States Court of Appeals determined that the
restrictive implementation by FDA of disease/health claims for food
labeling under the NLEA represents an unconstitutional limitation on
free speech. FDA was ordered by the court to approve disease/health
claims in food labeling that, when considered with accompanying
explanatory information or disclaimers, are accurate, truthful, and not
misleading.
This particular court case arose in the context of four claims that
had been petitioned for use in connection with dietary supplement
products. As a result, FDA has limited the Pearson decision to dietary
supplement claims and has refused to apply the same principles to
conventional food claims.
There is no basis either in the NLEA or in the Constitution itself
for distinguishing between disease/health claims in dietary supplements
and in conventional food. If a disease claim is supported for one, it
is supported for the other (absent some clear scientific basis for a
distinction).
GMA initially petitioned FDA to abandon its policy on this matter.
In response, FDA wrote a member of Congress saying that it would not
apply the Pearson decision unless and until ordered by a court. GMA has
therefore petitioned FDA explicitly to adopt the same claims for
conventional food that it has now approved for dietary supplements
under the Pearson decision. If FDA fails to respond, or denies this
petition, GMA is prepared to resort to the courts in order to preserve
the First Amendment rights of those firms that manufacture and market
conventional foods.
We would very much prefer not to have to go to court to settle this
matter. GMA urges the new Administration to reverse the current FDA
policy and to recognize that Pearson applies to conventional food, and
indeed to all products regulated by FDA.
3. FDA's Expansive Regulation of Structure/Function Claims As Implied
Drug Claims.
Since 1938, the Federal Food, Drug, and Cosmetic Act has recognized
that claims relating to the effect of food on the structure or function
of the human body may appropriately be made in food labeling without
the product being classified as a drug. Under the Dietary Supplement
Health and Education Act of 1994, structure/function claims are
explicitly permitted for dietary supplement products as a ``safe
harbor'' from drug regulation. In establishing regulations to
distinguish between structure/function claims that are permitted for
food (including dietary supplements), and disease/health claims that
are only permitted for drugs, FDA has announced a policy that many
structure/function claims would be regarded as implied disease claims
and therefore would not be permitted for food. Once again, this
exceeded the intent of Congress.
It is clear that any claim relating to the effect of a food or
nutrient on the structure or function of the human body will inherently
imply some utility for the prevention or treatment of disease. It would
be virtually impossible to formulate a structure/function claim that
did not have this potential implication, whether directly or
indirectly. Thus, FDA has denied to the food industry, by its new
regulations, numerous important structure/function claims that provide
important health information to consumers.
For example, FDA states that an appropriate structure/function
claim is limited to ``helps maintain healthy cholesterol levels'' and
does not include ``helps reduce cholesterol levels to a healthy
level.'' This policy cannot possibly be defended on public health
grounds.
GMA urges the new Administration to reverse this policy. Structure/
function claims that only indirectly imply utility in preventing or
treating disease should be regarded as appropriate for food products in
order to educate the public about important health aspects of the daily
diet.
FDA's Successful Implementation of the new Indirect Food Additive
Provisions.
Under FDAMA, Congress authorized a new approach of premarket
notification for the regulation of indirect food additives, i.e., food
additives that are used in packaging food or for other food-contact
purposes but that are not directly added to food. This provision has
been implemented by FDA in a direct, efficient, and effective way. FDA
is to be commended on formulating and following a policy that has
replaced an inefficient and ineffective premarket approval approach
with the new streamlined premarket notification system. GMA believes
that this model could appropriately be used in other areas of food
regulation as well, as a substitute for lengthy, costly, and ultimately
unworkable premarket approval.
5. The Continuing Need for National Uniformity in Food Regulation.
The NLEA advanced toward the important goal of national uniformity
in food regulation. NLEA provided national uniformity for most aspects
of food labeling. It failed, however, to include national uniformity
for food warnings or for food safety. GMA believes that, in order to
have a comprehensive and integrated national system of food protection,
enactment of national uniformity legislation is essential.
Our nation-wide economy cannot support fifty differing state laws
and regulations governing the food supply. Interstate commerce
throughout the wide reaches of our country requires a consistent,
uniform, and predictable system of laws and regulations that permit
transport of food under a single set of regulatory standards. GMA has
actively sought both administrative and statutory adoption of national
uniformity in food labeling for the past several years, and will
continue to seek this objective until it is ultimately achieved.
Mr. Whitfield. In addition to that, Mr. Chairman, I would
just simply say that the aspects of this hearing today, we
cover a number of different areas. Labelling is one of those
areas that I was quite involved in when we passed this
legislation back in 1996 or 1997. While generally I have been
pleased with the progress that has been made in that area, I do
think that there has been some real disappointment in the way
that FDA has proceeded on this particular aspect of it.
Rather than getting into it with my statement, I will be
asking some questions as we go through the hearing. With that,
I yield back the balance of my time.
Mr. Bilirakis. I appreciate that. It looks like we may be
going into recess where they are going to try to get things
worked out. So we may have a little bit of relief here.
Without objection too, the opening statements of all
members of the subcommittee will be made a part of the record.
The Chair now recognizes Mr. Brown, the ranking member.
Mr. Brown. Rationality is winning out on the House floor.
Thank you, Mr. Chairman. I would like to thank Dr. Suydam
and other distinguished witnesses for joining us this morning.
The title of this hearing is evaluating the effectiveness of
the Food and Drug Administration Modernization Act.
If you consider the major goals behind the legislation,
that enactment, you have to say that FDAMA has been quite
effective. With the exception of the pediatric provisions, the
overriding purpose of FDAMA was to streamline the approval of
drugs and devices, and relax what the food industry perceived
as overly stringent restrictions on health and nutrient claims.
Are new drugs and devices approved more rapidly now?
Absolutely. Are drug manufacturers conducting more pediatric
clinical trials? Absolutely. Are the health claims and other
food-related provision in FDAMA the right ones to meet the
concerns of the food industry? Based on their written
testimony, the National Food Processors Association still feels
the FDAMA provisions are on target. It's the implementation of
those provisions that needs some fine-tuning.
If effectiveness is your standard, FDAMA is a success. My
concerns regarding FDAMA do not have to do with effectiveness.
They have to do with cost effectiveness.
As we work on reauthorizing the pediatric exclusivity
provisions of FDAMA this year and the PDUFA provisions of FDAMA
next year, we need to look both at the benefits and the costs
of the new FDA. The maintenance of effort provisions in FDAMA
require FDA to spend up to pre-specified levels on new drug
approvals before user fees kick in. The authorized spending
threshold stands regardless of FDA's annual appropriation.
As a result, FDA has been forced to channel very finite
resources from other FDA functions into new drug approvals.
That means several things. There are huge costs associated with
starving other FDA activities, like generic drug approvals,
like market surveillance, like food safety initiatives to
accommodate new drug approvals.
It takes 12 months on average to review a new drug
application or NDA, as we call it. Six months, if it's a so-
called fast-track drug. It takes 18 months on average, however,
to approve a generic drug application, a so-called ANDA.
There are about 300 scientists on staff to review generic
drug applications. There are 2,100 scientists on staff to
review: 300 for generic applications, while 2,100 on staff to
review new drug applications. Delayed access to generic drugs
costs taxpayers literally billions of dollars each year.
To get a sense of these costs, the excess consumer spending
associated with the pediatric exclusivity provisions are
informative. HHS estimated that delayed access to the limited
number of generics held up by the pediatric exclusivity
provisions costs consumers and the Federal Government close to
$700 million each year. Seven hundred million dollars per year
for a 6 month delay in access to a handful of generics.
If you inflate that number to account for the fact that
every generic drug currently faces an average 6 month delay in
approval, it's clear that it's starving, as we really are
doing, the Office of Generic Drugs. It's costing consumers
billions of dollars a year in lost savings.
Let's consider the costs of under-funding food safety
initiatives. Five thousand Americans it's believed die each
year from food-borne illnesses. Hundreds of thousands of
Americans are hospitalized each year from food-borne illnesses.
Millions of Americans otherwise become ill from food.
In addition to the well-known and well-documented cases of
food-borne illness, Americans need to be concerned about the
emergence of antibiotic resistant bacteria in food, genetically
modified organisms of unknown risk, and lethal contaminants
such as mad cow disease and others for which no detection test
is currently available.
Yet we inspect--again, look at how this agency is starved
when we shift resources--we inspect only seven-tenths of 1
percent of food imports. If anything, the enactment of FDAMA
has intensified the need for post-market surveillance. Yet
enactment of that legislation limits the resource available for
that activity. We speed up the approval process. We spend more
money on approval. We spend less money on post-market
surveillance as drugs get in the marketplace more quickly. We
spend more money--drug companies spend more money advertising
those drugs. The use of those drugs begins much more quickly
than it did in the past.
Because of FDAMA, there is immense pressure on FDA to
approve new drugs and devices as quickly as possible. That, as
I said, coupled with aggressive direct to consumer advertising,
means that more people are exposed to new products more
quickly. If something is wrong with one of these products, more
lives are affected. We absolutely need to improve post-market
surveillance of these new drugs and new devices. That requires
resources.
None of these concerns means that we're spending too much
on new drug approval. Not at all. It means we are spending too
much on new drug approval relative to other priorities. We
either need to increase spending on these other priorities or
rethink the maintenance of effort requirements in FDAMA.
As we evaluate the cost-effectiveness of FDAMA, one of the
most difficult calculations relates to the pediatric
exclusivity provisions of the act. Pediatric testing and
labelling are invaluable. The question is not whether the
Federal Government should encourage, some would argue require
drug companies to do this type of testing. The question is are
we paying more than is necessary for pediatric testing.
Let's go back to the HHS estimates. The exclusivity
provisions cost American consumers $65 million per drug. While
the drug industry won't disclose the kind of information we
need to estimate the cost of pediatric clinical trials, drug
makers have to disclose information on the costs of orphan
drugs, clinical trials to receive their tax credit. Based on
that information, it costs about $3 million on average to
conduct a clinical trial.
Still, just for argument's sake, take the industry's
estimates for the cost of pediatric testing. They stated a cost
from $5 to $35 million for a clinical trial. If we split the
difference, we could hand the drug industry a check for twice
their investment and still save money on pediatric testing
relative to the exclusivity provisions. Even if you don't split
the difference and assume that each and every clinical trial
costs $35 million, and that's probably not true, we could
promise the drug industry a 50 to 75 percent return on their
investment and still save money. Even the most profitable
industry in the world, which coincidently is the prescription
drug industry, doesn't enjoy returns like that today.
The drug industry is fiercely protective of the pediatric
exclusivity provisions. Hard to blame them. The Federal
Government should be fiercely protective of the Nation's
children. We should make sure that prescription drugs are
thoroughly tested and correctly labeled for pediatric use. That
doesn't mean we should actively contribute to grossly inflated
drug prices. That is simply not necessary.
I thank the Chairman, and look forward to hearing from the
witnesses.
Mr. Bilirakis. Mr. Greenwood, for an opening statement.
Mr. Greenwood. Thank you, Mr. Chairman. I also thank you
for holding these hearings.
I remember, Mr. Chairman, probably 6 years ago when then
Chairman Bliley called me up and asked if I would chair a task
force to reform FDA. I remember saying at the time that what I
knew about FDA I could squeeze onto a three-by-five card, but I
would be happy to do it. We put together a group. Mr. Burr
headed up the pharmaceutical piece, Mr. Barton the medical
device piece, Mr. Klug, former Member Klug, the food safety
piece, and we engaged in a process that was agonizingly long
and complex, where we interfaced with the industries,
interfaced with the patient groups. We interfaced with the
agencies. Spent days at a time with Dr. Kessler in my office,
worked in I think a bipartisan fashion. It was difficult. It
was controversial, but unlike a lot of effort that occurs
around here, it produced a result of which I think we all can
be proud.
By every measurement that I have been able to take since
then, this is an act that has been successful. The fundamental
problem that we were faced with is that the Food and Drug
Administration understood that its role was to make sure that
we maintained the gold standard in this country, that nothing,
no drug, no device, no food product passed muster unless it was
proved to be safe. The problem was that they didn't seem to
have as a mandate the notion that they needed to nonetheless
get these products to the patients expeditiously, and that
someone was just as harmed and just as dead if they died
waiting for a promising drug as they were if they took a drug
that wasn't safe. I think that has changed. I think it has all
been to the good.
I think the pediatric exclusivity, as I think we'll hear
today in testimony, has been an extraordinary success. It
solved the problem that was unresolved for decades. We have
learned in the interim. We can refine this statute. I think all
of the issues that members on both sides of the aisle have
raised ought to be on the table. But I think we ought to be
prudent because we don't want to go backwards. I think our
first order of business should be to do no harm, and make sure
that nothing that we do in any way undermines any of the
success that we have had.
I think we ought to also make sure that we don't stall out
on this behavior on this process over controversies. There is a
very long list of very controversial areas we can get into that
will probably be unresolvable, and could have the effect of
causing us to fail to get these statutes reauthorized.
I look forward to working with members on both sides of the
aisle, and am pretty confident that we can get that done. I
yield back the balance of my time.
Mr. Bilirakis. I thank the gentleman.
Mr. Deutsch, for an opening statement?
Mr. Deutsch. Thank you, Mr. Chairman. I would like to thank
the chairman and the ranking member for calling this hearing.
Obviously the issues that we will hear about today are of
great importance. All of our constituents rely heavily upon the
drugs and medical devices that the FDA regulates. My district,
as many of you know, is comprised of a large number of senior
citizens. My constituents and actually obviously constituents
throughout the country have been able to live longer and
healthier lives because of the advances in pharmaceutical and
medical devices in the last few years. Seniors can now take
drugs that lower cholesterol and high blood pressure as well as
take advantage of amazing medical devices such as stents to
treat artery blockages.
I am going to mention just a couple of statistics and facts
that I brought out. We just came back from a break period, had
about 25 town meetings during that period, a number of them in
senior communities. One of the things that is just a striking
statistic to talk about what the FDA has been part of in the
last 36 years since Medicare was created.
When Medicare was created in 1965, the average life
expectancy of an American was 65 years old. That's an
incredible statistic because today that life expectancy in the
36 years has increased by more than 10 years.
On the other side of this sort of statistics which I think
sometimes statistics can in fact give us real insights, in 1965
before Medicare was created, the average out-of-pocket expenses
for seniors for health care was 11 percent. Thirty-six years
later, with Medicare paying most hospitalization and most
physician fees as well as other fees, the average percentage of
a senior in America's out-of-pocket costs for health care is
now close to 19 percent of their income with Medicare existing.
I think those two statistics in many ways talk about the
medical science and what has happened in the last 36 years. It
is a different world. That is why so many people on this panel
have been committed to providing prescription drug coverage as
a benefit of Medicare. But it also is literally there are tens
of millions of people who are alive today because of advances
in medical science. So there is probably nothing more
important, if you look at it in this global way, that the
government has done than exactly what the FDA has done within
its jurisdiction.
I think it is imperative that we take a look at
reauthorizing FDAMA and PDUFA and we ensure that there is a
proper balance between safety, economics, and timeliness. The
FDA obviously has an important job in making sure that our
constituents, have access to safe and effective products in a
timely manner. I hope that we can hear from our witnesses today
about how the current process functions and what, if anything,
we can do to improve that.
I yield back the balance of my time.
Mr. Bilirakis. I thank the gentleman.
Mr. Buyer, for an opening statement?
Mr. Buyer. Thank you, Mr. Chairman. I appreciate you
holding the hearing and providing us to focus on the attention
of the progress of the FDA Modernization Act of 1997.
As I understand it, one of the goals of the act was to
shorten the review times of the FDA for new drugs and medical
devices. As we're all aware, patient health is not protected if
they are denied the access to medical treatment due to the
bureaucratic delay.
I am looking forward to hearing the testimony from the FDA
and drug and device industries on the success in meeting the
goals. One out of eight jobs in Indiana is in the health care
industry. Medical technology is a significant and growing part
of Indiana's economy, and it is important that government not
impede the breakthroughs in pharmaceutical and medical
technology that can improve the quality of life, not only of
Hoosiers, but citizens in our country and around the world.
The United States is the global leader in the health care
field. We certainly do not want to see our cutting-edge
forfeited to overseas competition. To maintain the edge,
government must be a partner in the approval process without
sacrificing safety and efficacy. I know this is not an easy
thing to do. I look forward to the hearing.
I yield back the balance of my time.
Mr. Bilirakis. I thank the gentleman.
Ms. Capps?
Ms. Capps. Thank you. Thank you, Mr. Chairman, for holding
this hearing. It is a very important topic for our committee to
entertain and discuss and the Congress as a whole to review its
past actions from time-to-time. This is an appropriate way to
spend our time, to measure our success and determine the need
for future action.
I am particularly pleased that today we are focusing on the
Food and Drug Agency Modernization Act and its implementation.
The FDA is vitally important to the health and safety of the
American people. Its review of new and existing drugs, devices,
and food is an essential protection for our constituents. But
it is also extremely important that efforts to protect people
do not inadvertently cause them harm because they cannot get
access to state-of-the-art care.
The state of medicine is dramatically changing every day.
New technologies are being developed rapidly, and old
technologies are in constant need of upgrades. There are always
new ideas right around the corner, which is wonderful and one
of the best things about our country. It means that many
patients will be able to try out new treatments and improve
their care. Many who have lost hope may have it restored.
Others will see their quality of life improved by these new
treatments.
But it creates a two-sided challenge, I believe, for the
FDA. On the one hand, all the new technologies and ideas need
to be vetted so that doctors, patients, and everyone else can
have confidence that there is no unnecessary risk. New ideas
mean much more work for the FDA. On the other hand, we have to
make sure that we don't discourage innovation and that we make
it easier for patients to get the benefits that have been
discovered in a timely fashion.
If a new technology becomes bogged down in a review and is
slow to help our constituents, then we have not achieved the
potential of these innovations. It's a fine line to walk. We
need to help you, we need to help the Food and Drug
Administration to find the right path.
FDAMA was an excellent start. I want to applaud the FDA for
the tremendous progress that it has made on this issue. But
there are components of FDAMA which we need to review. It has
already been mentioned, but I also believe that the development
of pediatric exclusivity is one such change. Its implementation
has meant that more and more drugs are being evaluated for use
on children. This has meant a higher quality of care for our
Nation's young people. But it has come at such a high cost, I
mean literally. The extension of exclusivity has slowed the
development of generic drugs and meant higher costs for
consumers for a longer period of time. This may be a cost that
we have to bear in order to improve children's health care. But
we need to examine all of our options and really question
whether we in this case do in fact have the right balance.
There may be a way to give companies an incentive to
conduct these studies and still bring down the cost of
prescription drugs. It is our responsibility to find this way
or these ways if they do in fact exist. It means working
together. I look forward to that opportunity to work with you
to build on the changes that you have already introduced in
FDAMA. More will always need to be done. So I conclude by
saying that we can't afford to rest on our laurels. I know you
don't want to either. We must continue to examine ways to
improve the Food and Drug Administration and its processes.
Thank you.
Mr. Bilirakis. I thank the gentlelady.
Mr. Burr, for an opening statement.
Mr. Burr. Thank you, Mr. Chairman, for holding this
hearing. Let me thank all the witnesses who have volunteered to
come.
When we were asked to start on FDAMA in 1995, there were
many people within this institution that said this is a big
thing, don't do it. Washington and Congress don't do things
this big. It's because of the bipartisan approach that was
taken, the partnership that was established not only across the
aisle, but from Washington, from the Capitol and downtown, but
more importantly, from the Capitol and across the country. As I
read some of the testimonies, I am amazed to see the revisions
of history as it relates to the process not including the
American people.
Years were spent with patients groups, making sure that
every anticipated result of FDAMA had a positive impact on
people who were sick and dying. The only way that you could
ever get legislation of this magnitude through this institution
was for members to concentrate on patient health, to
concentrate on a vision of the future, to concentrate on what
it takes to unleash the capital that's needed privately and
publicly for research and development, for better understanding
of drug treatment and drug interactions.
We were able to find that balance. I will agree with some
of my colleagues, it's not perfect. Don't judge Congress on
whether we get it perfect or not. Judge us on whether we fix
it, because we learn as the years go on. We are at a point that
we have learned.
We have learned that through pediatric exclusivity, that
companies are now going through the clinical process of some
very valuable data that pediatricians across this country need
to treat kids. I don't think anybody wants to take that away.
Is the right length of exclusivity 6 months, 4 months or 12
months? We don't know, but hopefully before we take the
legislation up, we'll turn to experts that are in the field,
not just in the pharmaceutical field. We'll turn to generics,
but more importantly, we'll turn to pediatricians, the ones
that actually treat our children, and ask them how does it
work? What do we need to do? How long should the
reauthorization be for?
Let me suggest to you that FDAMA was done for one reason
and one reason only. It was to open the line of communication
between companies and the approving agency. It was to make sure
that there was no lack of communication because there was no
desire to approve.
We spent 2\1/2\ years for one reason, because it was very
difficult to protect the gold standard that was established at
FDA, that we felt that was so important that anything that we
did could not lower that standard. We had our critics, I will
assure you. We met with every one of them. I think in the end,
we got as close to maintaining that gold standard as any
legislative process could do.
I would encourage our witnesses today to be honest. I would
encourage my colleagues to be inquisitive. I would encourage
the chairman to move quickly. Let's make sure that we
reauthorize pediatric exclusivity. If we can this year, and
it's the will of my colleagues, I hope we reauthorize PDUFA
this year, not next year when it's up. Let's do it this year
while there is political will and not an election that's
looming.
To do big things in health care requires one to set aside
politics and concentrate on patients. I am convinced, Mr.
Chairman, that the atmosphere is such on both sides of the
aisle that we're focused on patients. Let's move as quickly and
as inclusively as we can toward the reauthorization.
I thank the chairman. I yield back.
Mr. Bilirakis. I thank the gentleman.
Mr. Stupak?
Mr. Stupak. I'll waive my opening statement, Mr. Chairman.
Mr. Bilirakis. The Chair appreciates that.
Mr. Bryant?
Mr. Bryant. Thank you, Mr. Chairman. I also will waive my
opening statement.
Mr. Bilirakis. I thank you.
Dr. Ganske?
Mr. Ganske. I think it's time to move on, Mr. Chairman.
I'll waive mine.
Mr. Bilirakis. Thank you, Dr. Ganske.
I will note that a gentlelady who is a member of the full
Committee of Energy and Commerce but not a member of the
subcommittee has asked to introduce a panelist from the next
panel.
Please proceed.
Ms. McCarthy. I thank you, Mr. Chairman, for that courtesy.
I thank the first panel for indulging me in this moment. But
because of the importance of what this subcommittee is doing
and the importance of what the full committee will eventually
take up, I wanted the opportunity to introduce Dr. Greg Kearns
to you.
Although the veterans on this committee will recall his
testimony before the full Energy and Commerce Committee when we
were initially approving FDAMA, he has now had the experience
as a champion of pediatric health care in my region at
Children's Mercy Hospital, and certainly in the Nation, to come
before you today and to reflect on how it's working and what
further reforms might be needed, and certainly for the need to
reauthorize pediatric exclusivity in the law.
He is a doctor of pharmacology and a professor of
pediatrics and pharmacology at the University of Missouri,
Kansas City. He is also the chief of the Division of Pediatric
Pharmacology and Medical Toxicology and the program director of
Pediatric Pharmacology Research Unit at Children's Mercy, and
the clinics.
It's to me a very great effort that this subcommittee is
making to take this up ahead of time and to try to reauthorize
it because from everything that I have read in the testimonies
that I have looked at, it is working for the benefit of our
children. Dr. Greg Kearns is here today to reflect with you on
how to it improve for the future.
Thank you very much, Mr. Chairman, for allowing me this
opportunity.
Mr. Bilirakis. By all means, you are welcome.
[Additional statements submitted for the record follow:]
Prepared Statement of Hon. W.J. ``Billy'' Tauzin, Chairman, Committee
on Energy & Commerce
Mr. Chairman, I commend you for holding this timely hearing which
will consider whether the reforms contained within FDAMA have
successfully lessened regulatory burdens at the FDA.
FDAMA represents the first comprehensive re-write of our nation's
food and drug laws in more than thirty years. It contains provisions
intended to speed the approval of safe and effective drugs and devices,
and provisions which help provide consumers with more health
information about the food they eat. Today we are here to determine
whether or not these reforms are working.
While all of the provisions contained within FDAMA are very
important, a good portion of this hearing will focus on the drug title
of the bill. This makes sense, as the pediatric exclusivity provision
within FDAMA is up for reauthorization this year, and the Prescription
Drug User Fee Act must be reauthorized before the end of next year.
Allow me to explain the importance of these provisions.
According to the American Academy of Pediatrics, which will testify
today, most drugs used to treat illnesses in children have never been
formally tested or approved for pediatric use and lack even basic
dosage recommendations for children in their labeling. To encourage the
research-based pharmaceutical industry to develop specific information
about uses and doses of prescription medicines for children, the
pediatric exclusivity provision provides an incentive of six months
marketing exclusivity which attaches to any existing patent protection.
The results of this provision have been extremely positive. And
don't just take my word for it. According to the Clinton FDA ``the
pediatric exclusivity provision has done more to generate clinical
studies and useful prescribing information for the pediatric population
than any other regulatory or legislative process to date.'' Between
1991 and 1996, only 11 pediatric studies were completed by the
pharmaceutical industry at the request of FDA. After passage of the
pediatric exclusivity provision, in three short years the
pharmaceutical industry has agreed to conduct 411 pediatric studies in
the hope of obtaining the additional six months of exclusivity.
Already, there have been 18 label changes for the benefit of children,
all at the cost of only one-half of one percent to the nation's
pharmaceutical bill.
But we can do better. Because the exclusivity only attaches to
drugs with remaining patent protection or exclusivity, many drugs used
in children will not be tested because there's no economic incentive to
do so. We must ensure that when this provision is reauthorized, we
include language which results in these drugs being studied for
pediatric uses.
PDUFA represents another success for the American consumer. PDUFA
authorized the FDA to collect fees from companies that produce drugs
and biologics to hire more reviewers and support staff and upgrade
information technology. In 1992, there were 1,277 drug reviewers within
FDA, and today that figure has nearly doubled. And the result? Approval
times have been cut in half, and the percentage of new drugs introduced
in the United States before being introduced in other countries has
nearly doubled.
But FDAMA is more than pediatric exclusivity and PDUFA. It
represents an effort to have industry and government work more
collaboratively in order to speed the decision-making process, and it
represents an effort to get better information in the hands of
patients, doctors and consumers. I look forward to hearing from the
various stakeholders who will testify today to determine whether these
reforms are working, and I yield back the balance of my time.
______
Prepared Statement of Anna Eshoo, a Representative in Congress from the
State of California
Thank you, Mr. Chairman, for holding this hearing today. It's hard
to believe FDAMA is up for reauthorization already.
I feel like it was just yesterday that we tackled this issue,
working night and day to write legislation that would streamline the
agency and speed live-saving products to our constituents without
sacrificing safety or effectiveness.
As one of the leaders of that effort, I'm proud to see the
successes that have resulted.
Medical device and pharmaceutical companies throughout my
congressional district consistently applaud the dramatic improvements
FDAMA made to the approval process.
Product approval times have been cut in half, bringing cutting-
edge, life-saving therapies to patients sooner than ever.
However, I'm concerned that there still may be a few snags.We'll
hear from industry representatives today that pre-market approval times
are still twice the statutory mandate at 360 days instead of 180.
Agency interpretation of ``least burdensome'' means to proving
safety and effectiveness has been too broadly interpreted and is
delaying approval of important patient products.
The Agency has dragged its feet in implementing third party reviews
and dispute resolutions--two key provisions of FDAMA.
I look forward to hearing from Ms. Suydam on these issues. However,
I must also say that I'm disappointed that President Bush has not yet
appointed a FDA Commissioner.
I find it quite disconcerting that the agency entrusted to protect
the public health from unsafe food, drugs and devices is still
functioning without leadership.
But there's another issue that I'm interested in and look forward
to hearing from the witnesses on--reuse of single-use medical devices.
In 1999, after reading several media reports of delicate single-use
devices, such as balloon catheters and biopsy forceps, being reused on
patients and causing infection and injuries, I contacted the FDA to ask
why they weren't regulating this potentially dangerous practice.
The response was less than satisfactory. I was told that the FDA
just simply didn't have the resources to regulate this practice and,
therefore, was nowhere near developing a policy on reuse.
Faced with an Agency that was failing to act, I introduced
legislation to require reprocessed devices to undergo approval for
safety and effectiveness. Within a week, FDA issued a proposed
regulation, which was finalized last year.
I'm pleased that the Agency finally took action on this important
public health issue. Profits should not be put ahead of patients.
I'll be interested to hear from the witnesses how implementation of
the regulation is progressing.
Thank you, Mr. Chairman.
______
Prepared Statement of Eliot L. Engel, a Representative in Congress from
the State of New York
Mr. Chairman, I want to thank you for calling this hearing today,
and I want to thank all of the witnesses for their time and their
testimony. We will be discussing one of the most important issues we in
Congress face--ensuring the health and welfare of the people of this
country as they eat their meals, take their medicine, and use numerous
products and devices that they think are safe. But it is not only
safety that is at issue today, it is also efficiency and whether or not
the Food and Drug Administration (FDA) is reviewing and approving or
disapproving submissions in a timely manner, thus ensuring that the
best technologies are available to the public.
In 1997 Congress enacted the Food and Drug Administration
Modernization Act (FDAMA) to streamline the administrative process in
order to get new technologies to the public in a safe and timely
fashion. Despite those efforts, we have heard testimony in this
committee time and again stressing the need for further reform because
there are life-saving medications and devices sitting in storage
awaiting FDA action. We are here today to examine the successes and
failures in FDAMA to determine what action, if any, is necessary at
this time. We will hear testimony praising the success of the
Prescription Drug User Fee Act (PDUFA) for cutting review times in
half.
We will also hear criticism that PDUFA may compromise safety
because of what has been dubbed--a ``sweat shop'' mentality at FDA to
get drugs approved quickly and the possible bias PDUFA has created due
to the FDA's reliance on the additional funding it generates. We can
also use the knowledge acquired from PDUFA to implement changes in the
medical device approval process. That is, would user fees, or some
other form of revenue generating provision, enhance the medical device
review process. I will inquire about this later when I have the
opportunity to question members of our panel.
Pediatric exclusivity is also at issue. There is strong criticism
by some suggesting that 6 months of exclusivity is too big a trade-off
for testing drugs and dosing them for children. However, we will also
hear praise by some for the enormous benefits it has created in
pediatric medicine. In fact, we will hear from Dr. Richard Gorman in
his testimony about the tremendous gains in pediatric medicine in only
3 years since the exclusivity provision was enacted. Congress must
examine these issues closely as certain provisions are set to expire in
the coming years. While there may be some fine-tuning needed to some of
the FDAMA provisions, we must not undue the gains we have made.
Mr. Chairman, new and innovative technologies are emerging everyday
that have the potential to save lives or greatly enhance the quality of
life for so many. We in Congress must work with industry and the FDA to
enhance current practices to bring products to the public in a safe and
efficient manner. While safety must not be compromised, if there are
ways to speed-up the administrative process we must consider doing so.
We must not let bureaucracy stifle innovation. I look forward to the
hearing the testimony from our witnesses and hope to work with you Mr.
Chairman and Ranking Member Brown, and the rest of the Members on the
Committee to bolster FDA's efforts to safely and effectively carry out
its mission.
______
Prepared Statement of Hon. Gene Green, a Representative in Congress
from the State of Texas
Thank you Mr. Chairman, and thank for holding a hearing today on
the effectiveness of the Food and Drug Administration Modernization Act
(FDAMA).
Over the past few years, we've heard a lot about the cost of
prescription drugs, but very little about the agency that ensures their
safety and quality.
But just as important to seniors as a Medicare prescription drug
benefit, is ensuring that important, life-saving drugs can are
available when seniors need them.
I supported this legislation when it was first introduced in the
105th Congress because I believed it was necessary to improve the
process by which the FDA approved pharmaceuticals and biologics.
And by many standards, the legislation has been successful.
But as we begin consideration for reauthorization of FDAMA, I think
it is important that we hear from the different parties about what they
perceive are the successes and failures of this bill.
There are a number of concerns about the implementation of FDAMA,
including the impact of the Prescription Drug User Fee Act (PDUFA).
By many standards, PDUFA has been successful in ensuring that life-
saving medications make it to the marketplace as quickly as possible.
The user fees collected through PDUFA have enabled the FDA to speed
up the application review process for pharmaceutical and biological
products.
In the three years since we last authorized PDUFA, the agency has
met almost all of its performance goals. The average approval time for
FY 00 was only 11.9 months, down from almost 21 months just five years
ago.
But there are some concerns about the effect of PDUFA on product
safety
Ensuring that the integrity of FDA's approval process is not
compromised is of paramount importance to all Americans, and I am very
interested to hear from the FDA regarding measures they have in place
to ensure that quality is not compromised in the name of expedience.
I also have some concerns regarding the impact of the performance
goals in PDUFA on the culture at the FDA.
A common complaint from both consumer groups and FDA alike, is that
``sweat shop'' conditions have impacted employees at FDA, prohibiting
them from attending continuing education classes, raising their stress
levels, and resulting in high turnover.
This environment is not only bad for employees, but it's bad for
the process.
Training scientists takes a tremendous amount of time and
resources.
The loss of those human resources impacts the ability of the FDA to
do its job.
There is also a real shortage of financial resources at FDA.
In a recent Congressional briefing on PDUFA, FDA has expressed
concern that PDUFA is crowding out other non-PDUFA programs, such as
post market surveillance, approval for generic pharmaceuticals, and
oversight of direct-to-consumer marketing.
It is important that the activities at FDA be balanced and that
adequate resources are provided to ensure that FDA can meet its
mission.
In addition to PDUFA, I am interested to hear from our witnesses
regarding other elements of FDAMA, such as the issues surrounding
pediatric exclusivity, and the effects it has on the ability of
generics to compete.
Studies by HHS have revealed that, while providing exclusivity has
improved labeling for children in some areas, it has not gone far
enough.
According to HHS, the incentive is not adequate for drugs with low
sales volume, off patent products, and the entirety of biologic
products.
The incentive has also not been effective for neonatal populations.
Now is a good time to exchange ideas on ways to improve this
situation to ensure that all important drugs and biologics are
available to children.
Mr. Chairman, thank you again for holding this hearing.
I look forward to hearing the testimony of our witnesses today, and
yield back the balance of my time.
______
Prepared Statement of Hon. John D. Dingell, a Representative in
Congress from the State of Michigan
Mr. Chairman, thank you for scheduling this hearing to evaluate the
effectiveness of the Food and Drug Modernization Act (FDAMA). As you
know, this law was the bipartisan product of a lot of hard work by our
colleagues, our staff, the Senate, the Food and Drug Administration
(FDA), and stakeholders.
I agree with those who generally consider FDAMA to be a success.
That said, experience shows that every law and program needs periodic
review and revision. Though this is our first hearing to review FDAMA,
I hope it will not be the last. There are many issues under the
auspices of FDA that I would like for us to examine, whether formally
styled as oversight of FDAMA, or not. Let me list a few.
For a number of years I have introduced legislation, and soon I
will again, to enhance the safety of the nation's imported food supply.
We face ever more important challenges in the form of microbial and
other food-borne contaminants that strike hardest at the most
vulnerable among us. FDA estimates that fully one fourth of America's
population is considered to be especially vulnerable to food pathogens
due to age (children and the elderly) or health status (weakened immune
systems from cancer, organ transplant, HIV infection, and the like). I
happen to believe that FDA needs enhanced authority and resources to
deal with these challenges.
Then there is tobacco. The Supreme Court threw out FDA's regulation
aimed at teen smoking. It is our job to provide FDA with the authority
it needs to do its job in this area. Secretary Thompson and even the
largest tobacco company, Philip Morris, agree that FDA should have
jurisdiction to regulate this product. The issue deserves our time and
attention.
Dietary supplements are virtually unregulated, notwithstanding the
fact that many of them contain pharmacologically powerful active
ingredients. This industry has no good manufacturing practices (GMPs),
no mandatory adverse event reporting system, and FDA lacks adequate
authority and resources to protect the public from hazardous, even
lethal, supplements.
Imported drugs are an increasingly important source of concern. The
so-called personal use policy is a sham and millions of Americans are
subjecting themselves to great risk in the form of drugs from unknown
foreign sources. Congress passed a law last year that could have made
things worse. This committee did not report that legislation, nor has
it held a hearing on the subject. I think we could perform a valuable
service for our colleagues holding hearings about the perils of which I
speak.
Also, over the past several years, we have seen several new drugs
withdrawn from the market because of the harm they caused. Was it the
company's fault? Was FDA lax or overburdened? Are these problems the
result of too-quick approval? The Congress would benefit from reviewing
these problem drugs more closely.
I look forward to hearing about how the specific provisions of
FDAMA are working. Because the pediatric exclusivity provision of
section 111 expires at the end of this year, I will be particularly
interested in the testimony regarding that aspect of FDAMA. There is
apparent consensus that testing and labeling of drugs that are used on
children is an important objective. My questions concern the means of
achieving that objective.
In examining the six month period of exclusivity provided by
current law, or any alternatives to it, I have three questions. First,
is the provision effective? Second, is the provision efficient? Third,
is the provision equitable? I have concerns with the six month
exclusivity incentive on all three counts. So did the Secretary of
Health and Human Services in her January 2001 report to Congress, ``The
Pediatric Exclusivity Provision.''
It is clear that exclusivity is not an effective incentive to
promote pediatric testing in important pharmaceutical areas. It is not
effective for off patent products, it is not effective for small market
products, and biologics are not even eligible for the incentive.
The incentive is not efficient in so far as its ``one size fits
all'' aspect conveys a windfall on blockbusters like Claratin that get
the same six months as products with vastly smaller sales volume.
Finally, the incentive is inequitable because it is paid for by
consumers who use the drug being studied by delaying generic
competition for six months. The benefits of pediatric testing are
societal, and society, not a relative handful of consumers, should pay
its costs.
Given these facts, we should be open to discussing and developing
alternatives that meet the agreed upon objective in a better way. I
look forward to working with my colleagues and interested parties on
this matter.
Finally, I want to say just a general word about the FDA. FDA
cannot simply ``do the best it can with what it has'' in the form of
authority and resources. The magnitude and nature of the challenges
facing FDA are different today than they were at any time in our
history. Resistant microbes, undetectable pathogens, and genetic
modifications are but a few of the new challenges to old problems. As
one of today's witnesses aptly put it, FDA modernization is a
continuous process. We need to be sure we provide the oversight and,
where needed, the resources and authority for FDA to be responsive and
responsible to the consuming public now and in the future. So again, I
express my hope that this will be the first of many hearings that focus
on FDA's programs and responsibilities.
Mr. Bilirakis. All right. We'll move onto the first panel
now. We have Linda Suydam, Dr. Suydam, who is a Senior
Associate Commissioner of the Food and Drug Administration. Mr.
Steve Northrup, Executive Director of the Medical Device
Manufacturers Association, and Dr. Rhona Applebaum, Executive
Vice President of Scientific and Regulatory Affairs for the
National Food Processors Association.
Ms. Suydam, since you are the Administration witness, we
will set the clock to 10 minutes. By all means, please proceed.
You all know that your written statement is already a part of
the record. We would hope that you would complement it. You are
recognized.
STATEMENTS OF LINDA A. SUYDAM, SENIOR ASSOCIATE COMMISSIONER,
FOOD AND DRUG ADMINISTRATION; STEPHEN J. NORTHRUP, EXECUTIVE
DIRECTOR, MEDICAL DEVICE MANUFACTURERS ASSOCIATION; AND RHONA
S. APPLEBAUM, EXECUTIVE VICE PRESIDENT, SCIENTIFIC AND
REGULATORY AFFAIRS, NATIONAL FOOD PROCESSORS ASSOCIATION
Ms. Suydam. Thank you. Good morning, Mr. Chairman and
members of the committee. I am Linda Suydam, Senior Associate
Commissioner of the Food and Drug Administration. I am pleased
to be here today to discuss the agency's progress and success
in implementing the Food and Drug Administration Modernization
Act of 1997.
FDA has made a strong commitment and given high priority to
implementing the Modernization Act in a manner that is
consistent with both the letter and the spirit of the law. We
are well aware that FDAMA, as we call it, is landmark
legislation of exceptional significance for the future of the
FDA and for the future of the public health in our country. We
wish to thank the committee for their thorough, comprehensive
work performed in drafting FDAMA. We are particularly
appreciative that you based this historic act on the principle
that underscores its benefits, that FDAMA made improvements
without changing the high public health standards FDA is
charged with upholding.
Over the past 3\1/2\ years, FDA has worked hard to
implement this new law. We have met nearly every statutory
deadline. We have issued dozens of regulations, guidance
documents, Federal Register notices, and reports to carry out
the goal of this wide-reaching law. I ask that my written
testimony and supplementary material that expand on the
agency's activities to implement the act be included in the
record.
Mr. Bilirakis. Without objection.
Ms. Suydam. Overall, FDAMA has been a success. While the
broad statute covers many issues, I would like to focus the
committee's attention on two key provisions of FDAMA that will
sunset next year and require Congressional action: the
reauthorization of the Prescription Drug User Fee Act, PDUFA,
and the pediatric exclusivity provision. The pediatric
exclusivity provision expires on January 1, 2002, and PDUFA on
September 30, 2002.
During the 8\1/2\ years of PDUFA, the Agency's performance
has met the highest expectations. While adhering to rigorous
standards for safety and effectiveness, FDA has met virtually
all of the program's review goals. PDUFA I was directed at
reducing drug review times. During PDUFA I, FDA exceeded all of
its performance goals, and significantly reduced those review
times.
PDUFA II included some performance goals to further reduce
review times, but many of the performance goals were also
directed toward reducing clinical drug development time. These
goals included accelerated consultations on critical drug
development issues, timely resolution of major disputes, and
rapid handling of other clinical drug development issues such
as clinical holds.
PDUFA has created significant benefits for the public,
industry, and for FDA. Not only has FDA significantly reduced
review times and clinical drug development times as a result of
the PDUFA programs, but we have also significantly reduced
approval times, and therefore, the overall time it takes to get
new drugs to the market.
For industry, one measure of PDUFA's advantage is that now
nearly 80 percent of new drugs worldwide are first launched in
the United States due to the favorable regulatory climate that
exists here as opposed to 40 percent prior to the enactment of
PDUFA.
FDAMA's pediatric exclusivity provision is also helping to
ensure access to and safe use of therapies for children whose
treatment has historically been hampered by inadequate
information about the safe and effective use of drugs in the
pediatric population. Providing adequate pediatric use
information for drugs and biologics has long been a high
priority for the Agency. We are pleased to report that the
industry's response to the incentives offered by this provision
have been enthusiastic.
As you know, in June 1998, we issued written guidance to
communicate to the industry our plans for implementation of the
pediatric program, and updated this document in October 1999,
to provide additional information. The results speak for
themselves. Between June 1998, when the guidance document was
published, and April of this year, FDA has received over 218
proposed pediatric study requests. Through our ongoing work
using mechanisms such as our Pediatric Advisory Subcommittee,
we continued to move toward our goal of having adequate
pediatric use labeling information for all drugs used in all
children. Experience with this provision has also revealed
several categories of products and age groups for which this
approach has not worked particularly well.
FDA looks forward to working with the committee to
reauthorize PDUFA and the pediatric exclusivity provision. We
believe that in drafting new authorizing language the following
principles should be taken into account. First, FDA's high
public health standards must be maintained and enhanced.
Second, the integrity of FDA's decisionmaking must be
preserved. Finally, FDA must possess an adequate science base
for the programs it implements.
I am pleased to report that President Bush's fiscal year
2002 budget for FDA provides for the first time in 7 years,
full cost of living increases for FDA employees, and an overall
increase of almost 10 percent for the FDA budget. This will
enable us to continue to positively meet the challenges of
PDUFA.
Thank you for FDAMA. Thank you for the opportunity to be
here today. I will be happy to answer any questions you may
have. I look forward to working with the committee in the
future.
[The prepared statement of Linda A. Suydam follows:]
Prepared Statement of Linda A. Suydam, Senior Associate Commissioner,
Food and Drug Administration
INTRODUCTION
Mr. Chairman, Members of the Committee, I am Linda Suydam, Senior
Associate Commissioner at the Food and Drug Administration (FDA or the
Agency). I am very pleased to be here today to discuss the Agency's
progress and success in implementing the Food and Drug Administration
Modernization Act of 1997 (FDAMA or Modernization Act). FDA has made a
strong commitment and given high priority to implementing the
Modernization Act in a manner consistent with the letter and spirit of
the law.
FDAMA is an important addition to FDA's legislative framework. As
you know, it was passed after a thorough congressional examination of
the Agency's policies and programs; it addressed virtually all of them
comprehensively; and it settled a debate about FDA's role by
reaffirming the Agency's vital importance for public health protection.
This is a law we can all be proud of.
FDA thanks the Committee for the diligent, comprehensive work it
performed in drafting FDAMA, and, in particular, for adhering to the
principle that underscores the benefits of this legislation; that FDAMA
made improvements without changing the high public health standards FDA
is charged with upholding. Only by maintaining these high standards and
ensuring regulatory decision-making based on sound science can future
legislation, such as the reauthorization of the Prescription Drug User
Fee Act and the pediatric exclusivity provision, serve to effectively
promote and protect the public health consistent with FDA's historic
mission.
FDAMA added new mission objectives that call on the Agency to carry
out all of its operations--domestic and foreign--in cooperation with
its stakeholders. This emphasis on FDA's need to extend its regulatory
cooperation is so essential for our operations that these objectives
are included among the five fundamental principles that offer the best
strategy for meeting FDA's formidable challenges in the future. These
principles are:
Base all FDA operations and programs on strong science, as the
principal guarantee of the high quality of FDA's public health
protection.
Make regulatory decisions in the context of each product's
total life cycle, to ensure its safety and effectiveness when
it is in wide use.
Consider our decisions also from a global perspective, to take
into account the numerous international developments and
factors that affect public health in the United States (U.S.).
Use leveraging as the primary means for maximizing the effects
of FDA's actions.
Maintain FDA's traditionally high public health standards,
because they always will be critical for ensuring effective
health care delivery, consumer confidence, and a level playing
field for the competitiveness of U.S. industry.
Over the past three and one-half years, FDA has worked diligently
to implement this new law, which, as we stated, touches nearly every
aspect of the Agency's mission.
We have met nearly every statutory deadline, issued dozens of
regulations, guidance documents, Federal Register notices, and reports
to carry out the goals of this wide-reaching law (see Attachment).
I would like to begin with two key provisions of FDAMA--
reauthorization of the Prescription Drug User Fee Act and the pediatric
exclusivity provision. The pediatric exclusivity provision will expire
on January 1, 2002, and the fee authority of the Prescription Drug User
Fee Act will expire on September 30, 2002. Maintaining these
authorities is important to the Agency, and we look forward to working
with the Committee during the reauthorization process.
PRESCRIPTION DRUG USER FEE ACT
The most concrete expression of the leveraging principle in FDAMA
was the reauthorization for five more years of the Prescription Drug
User Fee Act of 1992 (PDUFA). As you know, PDUFA authorizes FDA to
receive manufacturers' user fees in return for achieving performance
goals agreed to by Congress, the pharmaceutical industry and our
Agency. The result is expedited access to a greater number of important
new therapies. PDUFA is nearing the end of its second five-year term
and, therefore, I will examine in greater depth our experience with
PDUFA I and II.
During the eight-and-a-half years of PDUFA, the Agency's
performance has met the highest expectations. While adhering to
rigorous standards for safety and effectiveness, FDA has met virtually
all of the program's review goals. PDUFA I was directed at reducing
drug review times. During PDUFA I, FDA exceeded all of its performance
goals and significantly reduced review times. PDUFA II included some
performance goals to further reduce review times, but most of the
performance goals were directed towards reducing clinical drug
development time. These goals included accelerated consultations on
critical drug development issues, timely resolution of major disputes,
and rapid handling of other clinical drug development issues such as
clinical holds.
Under PDUFA II, FDA has exceeded almost all of its performance
goals resulting in a continued reduction in review times. In addition,
drug development times also have decreased significantly. According to
the Tufts Center for the Study of Drug Development, the clinical
development time for new molecular entities declined by 22 percent from
the early to the late 1990s.
Not only has FDA significantly reduced review times as a result of
the PDUFA programs, but it has also significantly reduced approval
times, and, therefore, the time it takes to get new drugs to market.
Total approval time is the time from the initial submission of a
marketing application to the issuance of an approval letter for that
application. It includes both FDA's review time and the time the
sponsor spends answering deficiencies noted by FDA and can encompass
several review ``cycles.''
The median total approval time for new drug and biologic
applications submitted in Fiscal Year (FY) 1999 dropped to 11.6 months
from 20.1 months in FY 1994. Given the progression of PDUFA II review
goals, median total approval times could drop to 10 months in FY 2001
or FY 2002 if the current rate of first review cycle approvals is
sustained.
Median total approval time for priority applications submitted in
FY 1999 was six months, less than half the median total approval time
for priority applications submitted in the early PDUFA years. Priority
applications, a subset of all applications, have a PDUFA review
performance goal of six months.
Drugs are now reviewed in the U.S. as fast or faster than anywhere
in the world, without compromising the very stringent standards that
Americans have come to expect. This is remarkable, particularly in
light of the fact that over the past seven years, pharmaceutical firms
have introduced 234 new molecular entities into the market--a sizable
increase over prior decades. Although European pharmaceutical companies
dominated the industry ten years ago, U.S. companies now have an
overwhelming lead in world markets.
Let me take a moment to mention the products themselves. Drug and
biologic approvals in 2000 included a large number of products that
represent significant advances over the products that were previously
available. Important new therapies brought to market in the past year
include: three new drugs to treat cancer; the first protease inhibitor
approved to treat HIV infection in children as young as six months;
four drugs to treat heart disease and circulatory disorders of the
nervous system; a malaria treatment effective in areas where the
disease is resistant to other anti-malarial drugs; the first anti-
inflammatory corticosteroid that can be used in a nebulizer by very
young children; the first in a new class of antibiotics; a treatment of
cancer-in-situ in the absence of associated invasive cancer of the
bladder; the first multivalent conjugate pneumococcal vaccine for
infants and toddlers under the age of two; the first drug to reduce the
severity of neck and shoulder muscle contractions and the resulting
abnormal head position and neck pain associated with cervical dystonia;
the first thyroid replacement drug to undergo a stringent FDA review;
three new drugs and five new uses of existing drugs for ``orphan''
patient populations of 200,000 or fewer; and 13 new pediatric uses for
already approved adult drugs.
In the biotech area, 2000 saw the approval of products that delay
the time to disease progression in malignant osteopetrosis; reduce the
signs and symptoms of rheumatoid arthritis in patients with inadequate
response to methotrexate; and delay structural damage in patients with
moderately to severely active rheumatoid arthritis. These are only a
few exciting examples of products that are being made available to the
patients who need them.
For the industry, PDUFA provides huge benefits:
Drug companies' products are able to take fuller advantage of
granted patent terms, which yields additional revenues, because
they come on the market more quickly due to shorter development
and review times.
The development of guidance documents, earlier meetings and
increased FDA reviewing staff have made the processing of
submissions more understandable and predictable, and therefore
provide a more consistent and dependable basis for companies to
develop plans for production and other activities.
In addition, FDA's guidance and consultation received by drug
sponsors under PDUFA help them improve the quality of their
product applications, which reduces the cost of drug
development.
One measure of these advantages to the industry is that between
1996 and 1998, nearly 80 percent of new drugs world-wide were first
launched in the U.S. due to the favorable regulatory climate.
For FDA, PDUFA has also brought significant benefits:
The performance goals have helped streamline the management of
drug and biological product reviews.
The program's requirement for comprehensive product reviews
and responses has resulted in improved quality of the
application process.
Most important of all, the fees have enabled the Agency to
hire additional medical and other specialists, and to upgrade
the technology that is essential for the success of the
program.
PDUFA has provided the Agency with some challenges. Between 1994
and last year, the number of review goals to be met by FDA has tripled.
The number of PDUFA submissions has grown by 64 percent, from not quite
1,500 in FY 1993 to almost 2,500 in FY 2000. In addition, there are
other industry meeting and procedure goals in PDUFA that add up to more
than 3,500 FDA actions a year, most of which occur before an
application submission (and fee collection). These actions are
connected with the preparation, scheduling, conduct, follow-up and
tracking of formal meetings requested by industry that may involve as
many as 10-20 FDA staff and 15-30 industry representatives. Another
notable trend has been the upsurge in drug advertising directed to
consumers (DTC) and physicians.
PEDIATRIC EXCLUSIVITY
FDAMA's pediatric exclusivity provision in section 111 (section
505A of the Federal Food, Drug, and Cosmetic Act), like PDUFA, is also
scheduled to sunset in 2002. FDAMA's pediatric exclusivity provision is
helping to ensure access to, and safe use of therapies for children
whose treatment has historically been hampered by inadequate
information about the safe and effective use of drugs in the pediatric
population. Providing adequate pediatric use information for drugs and
biologics has long been a high priority for the Agency. We are pleased
to report that the industry's response to the incentives offered by
this provision has been enthusiastic. As you know, in June 1998, we
issued written guidance to communicate to industry our plans for
implementation of the pediatric program, and updated this document in
October 1999, to provide additional information to industry.
The results speak for themselves. Between June 1998, when the
guidance document was published, and April 1, 2001, FDA has received
over 218 proposed pediatric study requests. Through our ongoing work
using mechanisms such as our Pediatric Advisory Subcommittee, we will
continue to move toward our goal of having adequate pediatric use
labeling information for all drugs used in children.
The purpose of encouraging pediatric studies is to provide needed
pediatric efficacy, safety and dosing information to physicians in
product labeling. Of the 28 drugs granted pediatric exclusivity, 18
drugs have newly approved labeling for pediatric use. Labeling changes
are expected approximately 6-12 months after the studies have been
submitted. Of the 18 drugs whose labels have already been changed, four
were new molecular entities for which pediatric labeling was available
at the time of initial approval. The 14 remaining marketed products now
have complete labeling in the relevant pediatric population.
Studies of six of these products resulted in identification of
significant changes in dosing or adverse events either specific to or
newly defined in the pediatric population.
Two examples of these clinical findings are:
Midazolam (Versed)--higher risk of serious life threatening
situations in children with congenital heart disease and
pulmonary hypertension who need lower doses than predicted to
prevent respiratory compromise;
Gabapentin (Neurontin)--need to use higher doses in children
less than five years of age in order to control seizures and
new adverse events such as hostility and aggression identified
in children less than 12 years old.
As required by the pediatric exclusivity provision, the Department
issued a report to Congress in January 2001, on the experiences under
the new law. The Report stated that the pediatric exclusivity provision
has done more to generate clinical studies and useful prescribing
information for the pediatric population than any other regulatory or
legislative process to date. Experience with the provision has also
revealed several categories of products and age groups for which this
approach has not worked. For example, the exclusivity provision does
not address the drugs that have no patent protection and sponsors have
no economic incentive to study these products.
FDA looks forward to working with the Committee to reauthorize
PDUFA and the pediatric exclusivity provision. FDA believes that when
drafting new authorizing language, the following principles should be
taken into account:
FDA's high public health standards must be maintained and
enhanced.
The integrity of FDA's decision-making must be preserved.
FDA must possess an adequate science base for the programs it
implements.
IMPLEMENTATION OF OTHER FDAMA PROVISIONS
With the tools provided by FDAMA, FDA is becoming a stronger,
better Agency, one whose actions remain firmly based in science to
promote and protect the public health.
The value of a strong, science-based FDA cannot be overstated--it
reaps public health benefits for both individual citizens and the
nation as a whole. An FDA that sets and meets high scientific standards
provides a high level of assurance to our citizens; (1) assurance that
product risks are minimized; (2) assurance that consumers receive
reliable information to assess and manage the remaining risks in
concert with a health professional, or on their own; and (3) assurance
that reviews for new products are conducted in a predictable and timely
manner, giving patients early access to new safe and effective
products.
FDA's procedures should provide consumers with confidence in the
decisions it makes about the products that they take and give to their
families, and provide industry with the confidence that the Agency's
decisions are fair and based in science.
From an economic standpoint, a strong, high-performance FDA
stimulates innovation, enhances U.S. competitiveness in global markets,
provides a level playing field for industry, and strengthens the
domestic economy as a whole by inviting increased foreign investment
and contributing to reduced health care costs.
I would like to focus today on how FDA's implementation of the
Modernization Act is helping to enhance the public health by producing
the following outcomes: (1)increase access to new medical products; (2)
provide more effective management of FDA's limited resources; (3) make
our regulatory processes more effective and efficient; and (4) increase
consumer and industry confidence through collaboration.
ACCESS TO MEDICAL PRODUCTS
There are a number of FDAMA provisions, in addition to PDUFA and
pediatric exclusivity, that help ensure greater patient access to
medical products.
Fast Track
The first of these is the fast track provision in section 112. In
the fast track provision, Congress codified FDA's accelerated approval
regulations and thus codified our approach to expedited drug
development. Fast track is meant to facilitate the development, and
expedite the review, of drugs that are intended to treat a serious or
life-threatening condition and that demonstrate the potential to
address a serious unmet medical need.
Since the passage of the Modernization Act, we have granted fast
track designation to a wide range of therapies--not just for AIDS and
cancer drugs, as some believe, but for drugs to treat atherosclerotic
vascular disease, acute stroke, diabetes, adult respiratory distress
syndrome and pancreatitis, and genetic abnormalities of infants. As of
March 2001, FDA's Center for Drug Evaluation and Research (CDER) had
received 108 requests for fast track designation--69 were granted, 25
denied, and 14 are still pending. As of March 31, 2001, FDA's Center
for Biologics Evaluation and Research (CBER) had received 62 requests
for fast track designation--38 were granted, 23 denied, and one is
still pending.
Since we began implementing this provision, CDER and CBER have
approved nine novel products, including Herceptin, a monoclonal
antibody for metastatic breast cancer (in 4.7 months), Enbrel for
rheumatoid arthritis (in 5.8 months), Ziagen for HIV (in 5 months), and
Pneumococcal Conjugate Vaccine for the prevention of streptococcus
pneumoniae in infants and children (in 7.5 months). In addition, three
marketed products were approved for new indications under the fast
track program: Remicade for rheumatoid arthritis, Gamma interferon for
osteopetrosis, and Taxotere for non-small cell lung cancer. As
implemented by FDA, this program is plainly helping to ensure that
important therapies for serious and life-threatening illnesses are
being brought as quickly as possible to the patients who need them.
To provide clear information to industry regarding participation in
the fast track process, last fall we issued a guidance document that
defines the criteria for qualification for the fast track drug product
development program, sets out the process for designation as a fast
track drug product, and describes programs for expediting development
and review of fast track products. The Agency has received feedback
that commends this document as an excellent resource for sponsors who
are interested in receiving fast track designation for their products.
Supplemental Applications
Just as it is important to get the most complete information about
all patient populations on a drug's label, it is also important to get
all of the information about a drug's uses on the label. This is why
Congress directed FDA to take steps to encourage the submission of
supplemental applications for new uses for approved medical products,
and steps to ensure that such applications are acted upon
expeditiously. Since enactment, the Agency has made programmatic
changes in CDER, CBER, the Center for Devices and Radiological Health
(CDRH), and the Center for Veterinary Medicine (CVM) to encourage
supplemental applications for new uses, and ensure that the Agency acts
on the applications that it receives in a timely manner. The Agency has
also issued guidance that clarifies what is needed to demonstrate
effectiveness for a new use.
Expanded Access to Investigational Therapies
Congress and FDA realized that there are times when a patient's
interest is best served by getting an investigational medical product
as quickly as feasible, sometimes before a complete evaluation and
review can be finished. The expanded access provision (section 402) of
the Modernization Act was included in the legislation to facilitate
access by patients with serious or life-threatening illnesses to
promising, yet unapproved new products. By codifying and expanding this
program, the statute ensures that this program will continue to provide
expanded access to patients in the future.
Humanitarian Use
Congress also recognized that there are limited circumstances when
there are too few subjects to justify a full-scale evaluation of a
medical device. The humanitarian use device provision (section 203)
provides an easier path to market for devices used to treat rare
conditions or diseases. Under this provision, a manufacturer is not
required to meet the effectiveness requirements in the statute, but
rather must show that the device does not pose an unreasonable or
significant risk of illness or injury, and that the probable benefit to
health outweighs the risk from its use. Since implementation of the
Modernization Act, CDRH has approved 21 humanitarian use devices,
including: a fetal bladder stent, to treat urinary tract obstruction in
unborn babies; an electrical bladder stimulator for urinary
incontinence for use in children for the treatment of neurogenic
bladder disease secondary to spina bifida; a pulmonary valve for
children under age four with absent or diseased valves; and an
extracorporeal immunoabsorption system for treatment of patients with
hemophilia A and B who have inhibitors to Factor VIII and IX
coagulation factors.
Postmarketing Studies
On April 30, 2001, FDA's regulations implementing section 130 of
FDAMA which requires sponsors of approved drugs and biologics to report
annually on the status of postmarketing commitments became effective.
These regulations modified existing reporting requirements for new drug
application (NDA) drug studies and created a new reporting requirement
for biologic products.
FDA may request postmarketing studies to provide additional
important information on how a drug works in expanded patient
populations or to identify safety issues that occur at very low
frequency or in special patient populations. In the case of drugs and
biologics approved under accelerated approval regulations,
postmarketing studies are performed to confirm a drug or biologic's
long-term clinical benefit when approval was granted based on studies
using surrogate endpoints.
These new regulations were of special interest to patient and
consumer advocates who were concerned about timeliness of applicants in
completing postmarketing commitments and of FDA in reviewing study
results and modifying drug labeling. The regulations will provide FDA
with a mechanism to monitor study progress through the annual
submission of study status reports. FDA will post the status of
postmarketing studies on its public website and publish in the Federal
Register an annual summary of industry progress in fulfilling
postmarketing commitments. FDA has committed to timely review and
evaluation of completed studies and to requiring timely modification of
drug and biologic labeling where appropriate.
EFFECTIVE MANAGEMENT OF FDA RESOURCES
Part of meeting the Agency's mission to protect and promote the
public health involves effective management of FDA's resources. There
are several FDAMA provisions that reduce the Agency's workload in some
areas so that those resources can be provided to areas with the
greatest public health risk.
Third Party Review
One such provision is the device third party review program
(section 210), which provides an alternative review mechanism for low-
to-moderate risk devices, thereby allowing FDA to target its scientific
review resources on higher-risk devices. There are currently more than
670 types of devices eligible for review by third parties, and 12
accredited third party organizations. CDRH recently expanded the
program to include all devices eligible for review by third parties
under the statute and has been working with industry representatives to
encourage greater use of this new approach.
User Reporting
Another provision that allows the Agency to focus its resources is
section 213, device user reporting. Prior to passage of FDAMA, all
device user facilities were required to report serious adverse events
to FDA. Under FDAMA, FDA now has authority to establish a sentinel
system for user reporting, which would have a representative sample of
hospitals and other user facilities reporting serious adverse events to
FDA. The Agency has already conducted a pilot sentinel system, which
was very successful. FDA is working to put an expanded sentinel system
in place. This initiative could ultimately ease the reporting
requirements for user facilities and enhance the value of reports the
Agency receives.
MORE EFFICIENT AND EFFECTIVE REGULATORY PROCESSES
FDAMA includes a number of provisions that streamline and expedite
FDA's product review processes by ensuring that sponsors know what is
required, and by eliminating unnecessary requirements. Clearly, PDUFA
helps the Agency make decisions in a more timely manner. At the same
time, PDUFA and other aspects of the statute ensure that FDA's
decisions are consistent and predictable. FDA's regulatory requirements
are clarified, providing industry with information on how to most
effectively comply with the applicable laws.
Meetings with Sponsors
Both as part of the PDUFA agreement formalized as part of the PDUFA
performance goals and as part of a separate FDAMA requirement (section
119), the Agency is committed to meeting with drug sponsors to discuss
and reach agreement on the design and size of clinical trials. Any
agreements reached can only be changed under limited circumstances.
Similarly, the device provisions provide for early meetings with
potential sponsors to focus on the type of valid scientific evidence
needed for device approval and to reach agreement on a study plan.
These provisions are ensuring that industry knows up front what is
required and does not waste time conducting unnecessary studies.
In addition, many provisions of the Modernization Act are premised
on the principle that regulatory requirements should not exceed what is
required to promote and protect the public health.
Premarket Notification
An example of matching regulatory requirements to meet public
health risk is the premarket notification provision in section 206.
More than 75 Class II types of medical devices have been exempted from
premarket notification requirements, enabling manufacturers to get
their products to market and the patients who need them more rapidly.
The types of devices exempted include: clinical laboratory equipment
and test kits, kidney stone dislodgers, clinical thermometers,
biofeedback devices and physical rehabilitation devices. In addition,
pursuant to this section, all but a limited number of reserved Class I
devices are also exempt from 510(k) premarket notification.
Manufacturing Changes
FDAMA also streamlines the process for drug and device sponsors to
make changes to certain manufacturing processes. For example, the
provision on scope of review in section 205 permits device
manufacturers to notify FDA 30 days before instituting certain types of
manufacturing changes instead of submitting a premarket approval (PMA)
supplement. This means that the device manufacturer can often start
marketing a device made under this new process at least five months
sooner than usually would have occurred before FDAMA. The device
industry has already used this provision 215 times. The drug provision
permits drug manufacturers to make minor and moderate manufacturing
changes without prior approval of a supplemental application. The
biologics industry has submitted 2623 notifications of changes
requiring a supplement submission 30 days prior to distribution of the
product made using the change. In addition, industry has submitted 482
notifications of changes requiring a submission that may be implemented
as soon as the submission is made.
Least Burdensome Means
Section 205 of FDAMA is similarly premised on the principle that
regulatory requirements should not exceed what is required to promote
and protect the public health. This provision requires FDA, in
consultation with the applicant, to consider the ``least burdensome''
appropriate means of evaluating device effectiveness that would have a
reasonable likelihood of resulting in approval. The requirement to
consider the least burdensome means applies to both existing statutory
paths to market: premarket notifications (510(k)s) and premarket
approval applications (PMAs and Product Development Protocols). While
FDAMA does not change the standards for premarket review, it clarifies
that the Agency's review is to support the substantial equivalence or
safety and effectiveness of medical devices.
To foster a collaborative approach to the implementation of section
205 of FDAMA, CDRH hosted a meeting with stakeholders on January 4,
1999, to solicit comments and suggestions regarding the least
burdensome approach to medical device development and evaluation. CDRH
heard formal presentations at that meeting and also received written
comments. As a result of communication with our stakeholders, FDA
determined that the issue of highest concern is when clinical data
would be required for devices.
In January of 2000, CDRH formed a Least Burdensome Steering
Committee consisting of senior managers within the Center. In addition,
representatives of FDA participated in a Least Burdensome Industry Task
Force aimed at addressing the least burdensome provisions. The Agency
has been reporting the results of this collaborative effort on FDA's
website so that interested parties can contribute their ideas and track
FDA's progress in this area. While the main focus of the group has been
in developing and articulating the concept and principles that underlie
the least burdensome requirement, several guidances have been developed
to help reduce unnecessary burdens in bringing new devices to market.
All of these guidances are on our least burdensome website. Most
recently, the Center completed a draft guidance entitled, ``The Least
Burdensome Provisions of FDA Modernization Act of 1997: Concept and
Principles.'' This document, which contains the Agency's interpretation
of the least burdensome provisions, will be posted shortly on FDA's
website.
While developing the guidance, FDA has been working to implement
these provisions. Training sessions for CDRH staff and advisory
committee members have been conducted and will be expanded once the new
guidance is final. Even without a final guidance, however, FDA has many
examples of successful use of the least burdensome approach. For
example, FDA reviewers approved a pediatric indication for a marketed
cardiac ablation catheter without requiring a prospective clinical
study because reviewers determined that existing literature supported
the device's safety and effectiveness in children. Patient registries
and literature were also used to support the approval of a bone cement
for fixation of a hip prosthesis.
Abbreviated Study Reports
Another example of process improvements is the provision on data
requirements in section 118, which directs FDA to issue guidance on
when abbreviated study reports may be submitted in NDAs and biologics
license applications (BLAs), in lieu of full reports. On September 13,
1999, FDA published a final guidance that describes when abbreviated
reports and synopses can be used to submit effectiveness data. This
guidance not only provides clarity, it should also ensure that industry
is not submitting more information than is required by the Agency.
Device Standards
Congress and FDA also recognized that industry's ability to rely on
standards will help to streamline the approval or clearance of medical
devices. Under the provision on device standards in section 204, CDRH
recognized more than 567 consensus standards that manufacturers may use
to satisfy portions of device review requirements, thus simplifying and
expediting product review. Of these 567 recognized standards, over 100
were proposed by industry for recognition as a result of active
solicitation by CDRH. A few examples of consensus standards nominated
by industry and recognized by CDRH include: standards that can be used
to describe and select the necessary biocompatibility testing; most
American Dental Association specifications for dental materials and
devices; and certain standards for safety requirements for
electromedical equipment, covering over 30 individual standards on
mechanical limits electrical safety considerations for electrically
powered devices.
At the same time, CDRH is trying to broaden the impact of the
standards recognition program mandated by FDAMA. CDRH is enlisting its
stakeholders in setting priorities for developing standards that can be
recognized in the future and encouraging manufacturers to incorporate
recognized standards as part of their product specifications, which
allows extremely brief product descriptions, and thus, less lengthy
510(k)s.
Single Biologics License
In addition, FDAMA has helped to streamline the processes for
submissions from industry by codifying the modernization of certain
biologics regulations. In October 1999, FDA issued a final rule to
implement the modernization of regulations provision in section 123,
which requires manufacturers to make a single submission for a
biologics license, instead of separate applications for the
establishment license and the product license. When FDA first proposed
to streamline the biologics application process for specified products,
industry representatives indicated that the change would result in
considerable savings of time and money. Since the implementation of the
single application/single license approach, industry representatives
have confirmed this to be the case.
Dispute Resolution
While many of the provisions in the Modernization Act are designed
to facilitate agreement between FDA and industry on regulatory
requirements, inevitably, there will be disputes that remain. Section
404, the provision on dispute resolution, requires the Agency to
clarify the processes for resolving scientific disagreements, including
requests for advisory panel review. While our existing regulations and
procedures have worked well to resolve many disagreements, the Agency
is taking steps to enhance its dispute resolution processes.
First, the Agency revised Title 21, Code of Federal Regulations
section 10.75 to clarify the availability of review of scientific
disputes by an advisory panel. CDRH created a medical devices dispute
resolution panel, and issued a draft guidance that describes how that
panel will be used to resolve scientific disputes. CDRH also issued a
general guidance document that provides an overview of all of the
Center's dispute resolution processes and has appointed a CDRH
ombudsman. CDER and CBER have developed guidance to explain their
processes as well.
CONSULTATION WITH CONSTITUENCIES
We have worked to ensure that everyone affected by the Agency's
actions has a voice, and that each voice is heard. While all of these
voices may not share the same viewpoint, we have found that this open
discourse can engender confidence.
FDAMA has contributed significantly to the Agency's effort to
collaborate in a credible and reliable way with our constituencies. For
example, section 406(b) of the Modernization Act directs the Agency to
consult with our constituencies to ensure that we fulfill our statutory
mandates and that we communicate clearly with our stakeholders. We have
held a series of meetings, during which we have listened to those
outside the Agency. We hosted a national interactive videoconference
that was simulcast to interested parties in eight different cities.
During our national broadcast, we had senior staff at each of the
locations to hold a more focused communication with members of consumer
groups and the regulated industry in these areas of the country. During
these meetings, we received useful feedback on the Agency's
performance, as well as constructive suggestions as to how the Agency
can continue to improve.
Public Meetings
Finally, FDA has held many public meetings to discuss
implementation of specific provisions. For example, CDER and CBER have
held several public meetings on implementation of certain provisions.
These include four public meetings on the implementation of the
positron emission tomography (PET) provisions, three public meetings on
the radiopharmaceuticals provisions, and advisory committee meetings on
pharmacy compounding.
CONCLUSION
FDA has been fully committed to implementation of FDAMA. However,
while devoting time, energy, and resources to this effort, we also have
worked to meet our other responsibilities. They include: protecting the
safety of the nation's food supply and blood supply, reviewing new food
additives to ensure their safety, speeding our reviews of new generic
drugs and medical devices and developing a comprehensive regulatory
strategy for dietary supplements--which involves the implementation of
another complex statute.
I am proud of the work that the Agency has done in fulfilling our
FDAMA commitment to Congress and to the American people, and I hope
that you share this sentiment. Thank you for the opportunity to be here
today.
Mr. Bilirakis. Thank you very much, Doctor.
Mr. Northrup?
Mr. Northrup. Thank you.
Mr. Bilirakis. Five minutes, sir, or in that category.
STATEMENT OF STEPHEN J. NORTHRUP
Mr. Northrup. Chairman Bilirakis, and members of the
subcommittee, I thank you for the opportunity to speak with you
today. My name is Steven Northrup. I am the Executive Director
of the Medical Device Manufacturers Association based here in
Washington, DC.
MDMA is the national voice for the entrepreneurial sector
of our industry. The association was founded in 1992 by a group
of entrepreneurs who needed a forceful and independent voice in
the Nation's capital. Two-thirds of the 6,000 companies in our
industry employ fewer than 50 people. But these entrepreneurs
are widely acknowledged as the source of most of the
breakthroughs in medical technology. Our role in MDMA is to
work with the Congress and with our regulators to ensure that
medical device entrepreneurs have a commonsense and equitable
regulatory environment in which to innovate.
We are pleased the subcommittee is holding this hearing. I
am sure most of you recall the difficulties our industry was
experiencing with the FDA in the early 1990's. To your credit,
you took decisive action by passing FDAMA, which established or
expanded a number of new initiatives designed to improve the
regulatory climate for medical products. For your efforts, I
extend our members' deepest appreciation.
I am pleased to inform you today that from our perspective,
the FDA generally has done a commendable job of implementing
FDAMA. Average product review times are down significantly
since the mid-1990's, though the FDA still has some work to do
to meet its statutory deadlines. The industry's relationship
with the FDA also has become less contentious. Most
importantly, we have made these improvements without
compromising patient safety. Much of this is due to the
leadership of people like Dr. Suydam and of Dr. Feigal, who
directs the FDA's Device Center.
Despite our general satisfaction, there remain a few areas
where continued effort is needed. In our written statement, I
have described our concerns about the FDA's implementation of
some of these key provisions on third party review of marketing
applications, on the resolution of scientific disputes, and on
determining the least burdensome pathway to market.
Frankly, the Agency's implementation of these provisions
has been slow and remains incomplete. While the specific
circumstances of each of these situations are different, the
instances collectively call into question the Agency's
commitment to implementing all of FDAMA. In our mind, there
were no insignificant aspects of that law.
Now to be fair, the FDA has taken positive steps recently
on each of the issues I raised in our testimony. As an
industry, we are willing to leave the past behind and to move
forward with the Agency on these important initiatives.
Nevertheless, the problems highlight the need for the
subcommittee to continue its careful evaluation of FDAMA, and
to hold the FDA accountable for its proper implementation.
Our experience also has taught us that the modernization of
the Agency cannot be achieved fully through just one piece of
legislation. The modernization of the FDA should be a
continuous process directed toward ensuring that the FDA has
the tools, the structure, the talent, and the culture to deal
with a world in which the pace of innovation is ever
increasing.
For example, there are a number of products on the horizon
that blur the traditional lines between devices,
pharmaceuticals, and biologics. The development of stents
coated with drugs that inhibit the tissue growth that causes
arteries to re-narrow after angioplasty, a condition called
restinosis, suffered recently by Vice President Cheney, is one
rather high profile example of a combination product upon which
scientists, engineers, and physicians are currently working.
We believe combination products like this don't fit neatly
into the FDA's traditional regulatory structure, which reflects
the different laws and standards that govern the review of
drugs, of devices, and of biologics. To avoid regulatory
delays, we need to prevent jurisdictional disputes or
inefficient review processes that result from disagreements on
how to regulate these hybrids.
One way that Congress could address this issue is by
directing the FDA to establish an Office of Combination
Products. Such an office should have the authority to manage
the review of a combination product and to coordinate all
necessary involvement by the various FDA centers. We believe
this would improve the process and reduce the likelihood that
clashing regulatory structures within the FDA will delay the
review of future combination products.
Drug-coated stents are but one example of the wave of
innovation for which the FDA must prepare itself. To help
prepare the Agency for the challenges it will face in this new
century, MDMA and the other national device industry
associations are working together to develop a series of
legislative proposals for your consideration. The ideas we are
developing, such as the one I have outlined, all are aimed at
enabling the FDA to use its resources more efficiently, at
augmenting the expertise of the Agency's staff, and at assuring
the FDA's accountability for its actions.
We look forward to sharing our ideas with you soon, and to
working with you on the continued modernization or more
appropriately futurization of the FDA. Thank you for this
opportunity to speak with you. I look forward to your
questions.
[The prepared statement of Stephen J. Northrup follows:]
Prepared Statement of Stephen J. Northrup, Executive Director, Medical
Device Manufacturers Association
Chairman Bilirakis and members of the subcommittee, I thank you for
the opportunity to speak with you today about the implementation of the
Food and Drug Administration Modernization Act of 1997 (FDAMA), as well
as some issues the subcommittee should consider as it evaluates the
future challenges faced by this agency. My name is Stephen Northrup,
and I am the executive director of the Medical Device Manufacturers
Association (MDMA), based here in Washington, DC.
MDMA is the national voice for the entrepreneurial sector of the
medical device industry. The association was created in 1992 by a group
of business executives who believed that the innovative and
entrepreneurial sector of the industry--an industry in which most
companies employ fewer than 50 people--needed a forceful and
independent voice in the nation's capital.
To support these entrepreneurs, our 150 member companies work
together with us to ensure that the federal government does not burden
innovators with unnecessary or unwise laws or regulations. While we
recognize and support the federal government's role in protecting the
public health, we also believe government regulation should not prevent
or hinder the development of truly beneficial new therapies nor deprive
patients of the latest advances in medical care.
As you know, the medical device industry is an integral component
of the good health of the American public. The technological
innovations and breakthroughs developed by medical device manufacturers
have produced the wonders of modern medicine and surgery. Simply put,
medical technology enables millions of Americans to live longer, more
comfortable, and more productive lives.
Entrepreneurs play an important role in the development of these
medical innovations. As I mentioned earlier, two-thirds of the 6,000
companies in our industry employ fewer than 50 people. Nevertheless,
these enterpreneurial firms are widely acknowledged as the source of
most of the major breakthroughs in medical technology.
The entrepreneurs in our industry have different needs than do the
large companies. Fair, predictable, and consistent regulatory actions
provide the necessary environment in which entrepreneurs can make best
use of the natural advantages they have over their larger competitors--
their focus, creativity, and adaptability. The large companies possess
two things, however, that these entrepreneurs do not have--time and
resources.
Therefore, when the regulatory system is unclear, unpredictable, or
unfair, this negates the natural advantages of entrepreneurs. As in
most industries, when the regulatory process becomes more of a ``game''
than a system, the winners will be those companies that have the time
and resources to ``play the game.'' MDMA's role in all of this is to
work with the Congress and with our regulators to ensure that medical
device entrepreneurs have a common-sense and equitable regulatory
environment in which to bring their innovations to market.
We are pleased that the subcommittee is holding this hearing to
evaluate the effectiveness of FDAMA. The development and passage of
FDAMA is largely responsible for stimulating an era of responsiveness
and cooperation on the part of our industry's main regulator, the Food
and Drug Administration (FDA). For the new members and staff on this
subcommittee, I will walk back in time several years to highlight the
importance of the legislation we are discussing today.
In the early 1990s, the outlook for medical device innovators and
entrepreneurs was grim. New and improved products languished in long
review queues and backlogs at the FDA. The relationship between the
industry and the agency was adversarial, and communications were poor
at every level. Companies were moving their research and development
overseas and conducting their clinical studies in countries where
regulatory approval was more timely. The FDA simply did not seem to
recognize the negative effect that its policies were having on the
health of the American public, who watched as patients in Europe and
elsewhere reaped the benefits of American ingenuity first, if not
exclusively. The hearings this subcommittee held during those dark days
are rife with examples of important medical products developed by
American companies but unavailable then to American patients.
Fortunately, many members of Congress saw the impact of the FDA's
actions (or lack thereof) on the medical technology industry and the
patients we aim to serve. In response, Congress passed FDAMA, which
established or expanded a number of new initiatives designed to improve
the regulatory process for medical products. In addition, Congress
recognized that the FDA should be charged not only with protecting the
public health, but also with promoting it by facilitating access to new
therapies. FDAMA was the vehicle for updating the agency's mission to
reflect the new role Congress expected the agency to take. For your
efforts, I extend our members' deepest appreciation.
MDMA'S GENERAL PERSPECTIVE ON FDAMA IMPLEMENTATION
I am pleased to inform you that, in general, the FDA's Center for
Devices and Radiological Health (CDRH) has done a commendable job of
implementing the medical device provisions of FDAMA. From the most
critical and bottom-line perspective-how long does it take the FDA to
determine a reasonable assurance of the safety and effectiveness of a
new product?--the numbers tell a story of great improvement.
According to CDRH's most recent annual report, the center reviewed
4,397 premarket notifications (also known as 510(k) submissions) in
fiscal year 2000, slightly less than the 4,593 reviews completed during
the previous year. The center's average review time was 77 days, the
shortest average time in more than a decade, and well within the
statutory 90-day requirement.
Average total elapsed time to premarket approval (PMA), which is
required for more complex or higher-risk devices, was 362 days in
fiscal year 2000, a 54 percent reduction from the ``peak'' time of 788
days in fiscal year 1996. While this is an improvement, we are still
far from the statutory requirement of 180 days for PMA applications.
The working relationship between the medical device industry and
the FDA also has improved since the passage of FDAMA. A survey
conducted in 1999 by PricewaterhouseCoopers LLP and CONNECT, the
University of California at San Diego's Technology and Enterpreneurship
Program, found that communications in general between life sciences
companies and the FDA have improved significantly since 1995, when the
organizations first began their bi-annual survey. For instance, the
1999 survey found that the percentage of respondents who believed their
company's communications with the FDA were ``excellent'' increased from
34 percent in 1995 to 47 percent in 1999, and the percentage of
respondents who indicated that contacts with FDA reviewers were
``easy'' or ``very easy'' rose to 64 percent in 1999 from 52 percent in
1995.
At this point, I should note that there is no evidence to suggest
that faster reviews of medical devices and a more collaborative
relationship between industry and the FDA have come at the expense of
patient safety. It's important to remember that increasing regulatory
efficiency, not lowering standards, was the goal of FDAMA.
SPECIFIC PROBLEMS WITH FDAMA IMPLEMENTATION
Despite our general satisfaction with the implementation of FDAMA,
there are still a few areas where continued effort is needed. These
areas include provisions that we consider to be cornerstones of FDAMA,
and for which the FDA has not implemented the letter or the spirit of
the law as fully as we believe the Congress intended. Three of these
are the provisions on third-party review of marketing applications, on
dispute resolution, and on arriving at the ``least burdensome'' pathway
to market.
Third-party review (Section 210)
To begin with, the subcommittee should know that the FDA took more
than three years to implement fully the third-party review provisions
of FDAMA, which directed the FDA to accredit third parties in the
private sector to conduct the initial review of 510(k) submissions for
low-risk (Class I) and moderate-risk (Class II) devices.
You may have heard that manufacturers have been slow to utilize the
third-party review program, and that is true. During the first 17
months of the FDAMA third-party review program, third parties reviewed
only 54 submissions. However, during those first 17 months, the FDA
permitted third parties to review only a fraction of the types of
devices that are eligible under FDAMA.
The FDA's internal policy, as described in October 1998 and
November 1998 guidance documents, permitted third-party review of class
II devices only if device-specific guidance or recognized consensus
standards existed. According to the FDA, this was to ensure
``consistency among different third party reviewers'' and to ``enhance
the timeliness of the agency's review process'' once a third party
submitted a recommendation.
However, we argued to the FDA that products for which no guidance
documents or consensus standards exist--a long list that even includes
such products as electronic stethoscopes, medical support stockings,
and infrared lamps--are exactly the types of products for which third-
party review would be most attractive to manufacturers and most
beneficial to the FDA.
As you may know, the FDA publishes guidance documents for use by
industry and by the agency's own staff. These guidance documents
describe preferred approaches for the processing, content, and
evaluation of regulatory submissions and the design, production,
manufacturing, and testing of regulated products.
Generally, if the FDA has published a guidance document on a
particular product, this means that industry professionals and FDA
reviewers already have a good understanding of what it takes to
determine a reasonable assurance of the safety or effectiveness of that
product. Appropriate premarket submissions for these products
theoretically should be simpler for manufacturers to assemble and for
FDA staff to review.
However, third-party review holds the greatest value for those
products for which the FDA has yet to publish a preferred approach to
determining safety or effectiveness. In these cases, organizations in
the private sector may have particular scientific expertise that does
not reside within the FDA and may be able to make sound recommendations
to the FDA much more quickly. The FDA, in turn, could then make more
timely decisions on whether to clear or approve the products.
After MDMA made these arguments to the agency, the FDA updated the
list of devices eligible for third party review in June of 2000,
immediately adding 57 devices for a total of 211. In January 2001, the
FDA then published a guidance document to initiate a pilot program that
will allow third-party review of any device regulated by CDRH that is
not prohibited from such review under FDAMA. This two-year pilot adds
another 460 devices to the program, which, combined with the June 2000
expansion, represents more than a 300 percent increase in eligible
product types from the program as first ``implemented'' in 1998.
The latest statistics show that manufacturers are already beginning
to take greater advantage of the third-party program. Through the first
five months of fiscal year 2001, third parties have reviewed 41
submissions, compared to 47 submissions reviewed by third parties
during the entire fiscal year 2000. We suspect that this increase in
usage is related to the expansion of the program.
While we appreciate the FDA's eventual expansion of the third-party
review program to the limits set forth under FDAMA, we wonder why it
took so long, particularly since FDA officials constantly lament an
agency-wide lack of resources. From our perspective, if resource
constraints are indeed a problem at the FDA, then the agency should
have fully implemented the third-party program from the beginning and
should be promoting to manufacturers the program's potential for
shortening product review times and for alleviating the agency's
shortage of resources.
Dispute resolution (Section 404)
Another provision of FDAMA for which the actual implementation is
incomplete is Section 404, commonly known as the ``dispute resolution''
provision. Section 404 of FDAMA directed the FDA to establish ``a
procedure under which [a sponsor] may request a review'' of a
``scientific controversy'' between the agency and the sponsor of a
product if no other appropriate legal or regulatory mechanism exists
for resolving the dispute.
The FDA's first response was to publish a direct final rule on June
16, 1998 in response to Section 404 of FDAMA. Under this rule, the FDA
would have permitted drug and device manufacturers to request review of
scientific controversies by an appropriate advisory committee. However,
the FDA ended up withdrawing this rule after our industry and others
complained that the rule was not consistent with the intent of FDAMA.
As the FDA eventually acknowledged, the rule did not contain critical
information, such as the process for selecting members of an advisory
committee convened to resolve a dispute, the timeframes for conducting
the reviews, the standards for granting or denying a review, and the
weight to be given to advisory committee recommendations.
In the end, the FDA chose to allow each of its centers to develop a
center-specific approach to implementing dispute resolution. For its
part, the Center for Devices and Radiological Health has published a
draft guidance document outlining how its dispute resolution process
will work and has hired an ombudsman to oversee the workings of a
Medical Devices Dispute Resolution Panel, which held its first
organizational meeting in October 2000.
We are pleased that CDRH has set up a separate advisory panel and
has hired an ombudsman to deal with dispute resolution, and we hope
that CDRH and FDA officials will give the panel's decisions due
deference. However, the panel has yet to hear its first dispute, though
we are aware of companies that have petitioned for a hearing. As a
result, it is difficult for us to assess this provision of FDAMA. Once
we have had a chance to observe the workings and actions of the Medical
Devices Dispute Resolution Panel, we will report back to the
subcommittee with our impressions.
``Least burdensome'' pathway to market (Section 205)
Implementation of the ``least burdensome'' provisions of FDAMA is
another area of the law for which we would give the FDA an
``incomplete'' mark. As a result of the FDA's initial unwillingness to
work collaboratively with industry on this issue, the agency only two
days ago released in draft form its long-awaited guidance document to
explain its comprehensive approach to implementing the ``least
burdensome'' provisions. This delay of more than three years since the
passage of FDAMA is a critical shortcoming of the agency's
implementation efforts, as these provisions capture best the true
spirit of FDAMA--ensuring that unnecessary regulatory requirements do
not delay patients' access to new technologies.
As you know, FDAMA added the following two provisions, commonly
referred to as the ``least burdensome'' provisions, to the Federal
Food, Drug, and Cosmetic Act:
Section 513(a)(3)(D)(ii)
``Any clinical data, including one or more well-controlled
investigations, specified in writing by the Secretary for
demonstrating a reasonable assurance of device effectiveness
shall be specified as a result of a determination by the
Secretary that such data are necessary to establish device
effectiveness. The Secretary shall consider, in consultation
with the applicant, the least burdensome appropriate means of
evaluating device effectiveness that would have a reasonable
likelihood of resulting in approval.''
Section 513(i)(1)(D)
``Whenever the Secretary requests information to demonstrate
that devices with differing technological characteristics are
substantially equivalent, the Secretary shall only request
information that is necessary to making substantial equivalence
determinations. In making such requests, the Secretary shall
consider the least burdensome means of demonstrating
substantial equivalence and request information accordingly.''
Industry sought these provisions to remedy one of the major
problems we perceive at the FDA: the inconsistent application of law,
regulation, and guidance by FDA officials in the review of marketing
applications. This inconsistency has contributed to excessive review
times that have delayed the introduction of new or improved products.
These delays, in turn, have a disproportionate impact on entrepreneurs
who are trying to bring their first devices to market, not to mention
the patients who are waiting for these innovations.
The FDA held its first public meeting to discuss the ``least
burdensome'' provisions on January 4, 1999, more than a year after
President Clinton signed FDAMA into law. At that meeting, industry
representatives offered to work together with the FDA in a joint
agency-industry-consumer working group to develop guidance on
implementing the ``least burdensome'' provisions. The FDA verbally
rejected our offer during the January 4, 1999 meeting, and the
rejection was reiterated in a February 18, 1999 letter to participants
at that meeting. Despite the willingness often voiced by FDA officials
to work collaboratively with industry on the development of guidance
documents, the letter informed us that the FDA had ``determined that
the time and resource commitment necessary to proceed via that
mechanism at this time will be less efficient than building upon the
extensive information and varied opinions that have already been
expressed on this issue.''
Over the course of the ensuing two years, and thanks to the
interest and involvement of this subcommittee's members and staff, the
FDA relented on its original unwillingness to work with industry on the
implementation of the ``least burdensome'' provisions. To their credit,
CDRH officials did accept another offer extended by industry in
November 1999 to work collaboratively on developing guidance. Over the
next five months, CDRH held a series of meetings with the Least
Burdensome Industry Task Force, a working group comprised of
representatives from the various national and regional industry
associations. The meetings culminated in the agency's March 2000
release of a paper that reflected the spirit of this joint effort,
which was to capture the intent of the ``least burdensome'' provisions
and to aid in their incorporation into the device development process.
On May 1, 2001, the FDA finally released a draft guidance document
based on the agency-industry paper. This draft guidance correctly notes
that FDAMA did not change the standard for premarket clearance or
approval of medical devices, and defines ``least burdensome'' to mean
an approach to addressing a premarket issue ``that involves the most
appropriate investment of time, effort, and resources on the part of
industry and FDA.'' The guidance document also identifies the following
basic principles that flow from the ``least burdensome'' provisions:
the spirit and the letter of the law should be the basis for
all regulatory decisions;
information unrelated to the regulatory decision should not be
part of the decision-making process;
alternative approaches to all regulatory issues should be
considered to optimize the time, effort, and cost of reaching
proper resolution of the issue; and
all reasonable mechanisms to lessen review times and render
regulatory decisions within statutory timeframes should be
used.
The draft guidance document describes how the ``least burdensome''
principles should apply to 510(k) submissions and premarket approval
applications, and outlines some general applications of the principles.
We are pleased that the FDA published this draft guidance on the
``least burdensome'' provisions in time for today's hearing, and we
trust that the agency will continue to train its reviewers and its
advisory panels in the application of these concepts and principles to
their responsibilities. While the wording of the recent guidance on the
``least burdensome'' principles is important, these training activities
are just as crucial to promoting the greater consistency we seek in the
FDA's review process.
In addition, we hope the FDA is developing metrics with which to
gauge whether the ``least burdensome'' principles are being employed
consistently. On this point, we would like to commend CDRH for taking
what looks like a step in this direction.
As part of its February 28 final guidance on the ``early
collaboration meetings'' required under Sections 201 and 205 of FDAMA,
CDRH published a set of checklists that it will collect from meeting
participants. The FDA intends these checklists for use by both the
applicant and the agency's review team leader in assessing the FDA's
incorporation of the ``least burdensome'' approach in determining the
type of valid scientific evidence needed for marketing approval.
We believe that the FDA should use such checklists or other
appropriate tools as part of an ongoing process of measuring the
application of the ``least burdensome'' principles in the day-to-day
work of the agency. Without such evaluation, it will be impossible to
determine whether the ``least burdensome'' provisions of FDAMA are
being implemented successfully or whether controversies that arise
between the agency and manufacturers are isolated difficulties or
represent more systemic problems.
NEED FOR CONTINUED MODERNIZATION OF THE FDA
MDMA commends the subcommittee for holding this hearing to see
whether the law you wrote is being implemented as you intended, and we
encourage you to continue this evaluation. We believe, however, that
the modernization of the FDA cannot be achieved fully through just one
piece of legislation. The ``modernization'' of the FDA should be a
continuous process that ensures that the organization and its culture
keeps up with and adapts to its environment. The milieu in which the
FDA operates is one of constant change and continual advances in
medical technology, and we need to ensure that the FDA has the tools
and the talent to deal with a world in which the pace of innovation
undoubtedly will increase.
I will offer an example to illustrate this point. On the horizon,
we see a number of products in development today that blur the
traditional lines between devices, pharmaceuticals, and biologics.
Stents coated with drugs to fight restenosis and other conditions;
implanted drug-delivery pumps; artificial livers, kidneys, and
pancreases; nerve regenerators; and devices that deliver genetic
therapies are but a few of the ``combination products'' upon which
physicians, engineers, and researchers are working currently. MDMA
believes that the regulation of these drug-device and biologic-device
combinations presents a variety of challenges for the FDA and, by
extension, for the companies that will develop these products.
Congress acknowledged the challenges inherent in regulating
combination products in the Safe Medical Devices Act of 1990 (SMDA).
Section 16 of SMDA emphasized that the FDA must regulate a combination
product based on the product's primary mode of action. In other words,
if the FDA determines that a product's primary mode of action is
pharmaceutical, then the task of regulating that product falls to the
FDA's Center for Drug Evaluation and Research (CDER).
Although a product's primary mode of action determines which FDA
center is responsible for its regulation, the designated center often
needs additional expertise regarding components of the product that are
outside its jurisdiction. In recognition of this, CDRH entered into
intercenter agreements in 1991 with CDER and with the FDA's Center for
Biologics Evaluation and Research (CBER). The agreements outline how
the center with jurisdiction over a combination product may or must
consult with the other centers.
When the primary mode of action of a combination product is
obvious, the FDA can assign jurisdiction quickly and the review process
usually runs smoothly. However, we anticipate that many of the
combination products in development today, such as those I mentioned
earlier, will be more difficult to categorize and will not fit neatly
into the 1991 intercenter agreements. To avoid unnecessary delays in
reviewing these products, we need to prevent jurisdictional disputes or
inefficient review processes that result from disagreements within the
FDA or between the FDA and a manufacturer. The longer the FDA takes
debating jurisdiction and regulation, the higher the costs to
manufacturers and to patients, since the process of clearing or
approving a product for marketing cannot begin until the FDA decides
which of its centers has the power to grant the clearance or approval.
The FDA already has begun to recognize these difficulties. To
promote consistency in the regulation of cellular and tissue-based
products, for example, CBER and CDRH established in 1998 a Tissue
Reference Group (TRG) comprised of three representatives from each
center. The TRG provides manufacturers of these products with a single
reference point for answers to questions regarding jurisdiction,
policy, and regulations. The TRG, which meets twice per month, also
participates in developing guidance documents in the areas of tissues
and cellular therapies.
Congress could build upon such ideas for solving these problems by
directing the FDA to establish an Office of Combination Products. Such
an office should have the authority to determine how a combination
product will be reviewed and to coordinate all involvement by and
interaction between the various FDA centers in the review of specific
marketing applications. We believe such an office could operate with a
very small but multi-disciplinary staff, augmented on an ad hoc
application- or technology-specific basis by experts on detail from the
various FDA centers. Such an office would improve upon the current
process of managing the review of combination products, and would also
reduce the likelihood that disagreements between centers, which
manufacturers cannot control, will delay the review process.
The hybrid products I mentioned earlier are but a few examples of
the wave of innovation for which the FDA must prepare itself. As we
speak, scientists are investigating how to provide physicians and
patients with greater therapeutic feedback by integrating information
technologies and wireless communication capabilities into medical
devices, engineers are exploring how to use nanotechnological concepts
to create tiny medical tools to advance the science of minimally
invasive medicine, and researchers are studying how to develop
customized therapies based on an individual patient's own genetic or
cellular characteristics. These areas of inquiry, as you might imagine,
are just the tip of the proverbial iceberg.
Some of these explorations will prove fruitful, and some will not,
but all of them will present the FDA with complicated regulatory
dilemmas. To help prepare the FDA for the challenges it will face in
the new century, the national device industry associations--MDMA, the
Advanced Medical Technology Association (AdvaMed), and the National
Electrical Manufacturers Association (NEMA)--are working together to
develop a series of legislative proposals for the subcommittee's
consideration. The ideas we are developing, such as the one I have
outlined, are aimed at enabling the FDA to use its resources more
efficiently, augmenting the expertise of the agency's staff, and
assuring the FDA's accountability for its actions. We look forward to
sharing these ideas with the subcommittee in the near future and to the
vigorous debate that we hope to engender about the continued
modernization--or, more appropriately, the ``futurization''--of the
FDA.
Mr. Bilirakis. Thank you very much, Mr. Northrup.
Dr. Applebaum?
STATEMENT OF RHONA S. APPLEBAUM
Ms. Applebaum. Thank you, Mr. Chairman, for the opportunity
to represent the food industry and give you our perspective on
the implementation of FDAMA. The National Food Processors
Association is the Nation's largest food trade association and
the industry's leader on scientific, technical, and regulatory
issues involving food science and food safety. We operate three
laboratory centers, including one here in Washington.
NFPA believes that the passage of FDAMA represented a
significant advance in the statutory environment to provide
responsible information to the public relative to conventional
foods. We appreciate this committee's work to address many of
the problems in the foods area that our member companies
experienced prior to FDAMA, and in particular, we appreciate
the efforts of Congressmen Ed Whitfield and Ed Towns, who
authored the bulk of the FDAMA food provisions.
In the regulation of foods, FDAMA resulted in: one, the
approval of irradiation for use on red meats; two, a
streamlined process for approving food contact substances which
are primarily used in food packaging; and three, a reduction in
label clutter through the elimination of the requirement of a
statement referring consumers to nutrition label on food
products.
Despite these successes, the Agency's implementation of
food labeling reforms for health claims, which provide
consumers with important health information about food products
as well as irradiation labelling, has been a disappointment.
FDA remains reluctant to permit certain types of food labelling
that would give consumers important health and safety-related
information.
The food labelling provisions of FDAMA were reaction to
decades of overly restrictive policies that inhibited truthful
and non-misleading label statements. Unfortunately, FDA has
taken great pains in its implementation of these provisions to
exclude as many claims as possible. FDA turned down the first
nine health claims submitted under new FDAMA provisions. Two
FDAMA claims were authorized for whole grain foods and heart
disease and cancer, and for potassium and reduced risk of
hypertension. But these small achievements are not adequate
proof that FDA has abandoned its restrictive policies on health
claims.
FDA's overly restrictive labeling policies have not
withstood judicial scrutiny since FDAMA was enacted. In the key
case on health claims, Pearson v. Shalala, the court held that
FDA must consider whether appropriate disclosures could render
a health claim on dietary supplements truthful and non-
misleading even if it was based on preliminary scientific
findings. The court also held that FDA's failure to consider
authorizing health claims accompanied by a disclaimer violated
the First Amendment.
The holding in the Pearson decision required that FDA
revisit its decision on the four contested dietary supplement
health claim petitions that were the basis for the complaint.
But the case has implications that reach far beyond its facts.
Indeed, the Pearson decision called into question the overall
regulatory policies used by FDA for authorizing health claims.
On December 1, 1999, FDA announced its plan to implement
the Pearson holding. The implementation plan is referred to by
the Agency as the 10-year plan because of its estimated decade-
long timetable for implementation. With all due respect, NFPA
maintains that it is unacceptable for conventional foods to
wait until 2010 for relief from restrictive health claims
policies.
FDA's labelling policy also discourages important food
safety technologies, such as irradiation, from coming to
market. In report language accompanying FDAMA, Congress called
for amendment of the existing irradiation disclosure
regulation, and instructed FDA to explore alternative labeling
for irradiated food, noting any required disclosure should not
be perceived as a warning or give rise to inappropriate
consumer anxiety. Despite this Congressional directive, FDA has
been slow to act, only publishing an advanced notice of
proposed rulemaking regarding alternative labeling for
irradiated products in 1999, with no further action to date.
Nevertheless, NFPA is encouraged, but we wonder why this
important reform of food safety information is taking so long.
In conclusion, the Pearson decision and FDA's response to
it, as well as its reluctance to review its labeling policy for
irradiated foods, highlights the facts that FDA historically
has approached food labeling restrictively. FDA has been slow
to move away from this approach, and generally has done so at
the direction of Congress or the judiciary.
Again, we appreciate very much the important reforms this
committee made in FDAMA. We stand ready to provide this
committee with whatever assistance it may need as it considers
the successes and disappointments of FDA's implementation of
this important public health law. Thank you very much.
[The prepared statement of Rhona S. Applebaum follows:]
Prepared Statement of Rhona S. Applebaum, Executive Vice President,
Scientific Affairs and Regulatory Affairs, National Food Processors
Association
Mr. Chairman, my name is Rhona Applebaum, Executive Vice President
for Scientific Affairs of the National Food Processors Association
(NFPA). NFPA is the voice of the $460 billion food processing industry
on scientific and public policy issues involving food safety,
nutrition, technical and regulatory matters and consumer affairs.
NFPA's three scientific centers, its scientists and professional staff
represent food industry interests on government and regulatory affairs
and provide research, technical assistance and consultation, education,
communications and crisis management support for the association's U.S.
and international members. NFPA members produce processed and packaged
fruit, vegetable, and grain products, meat, poultry, and seafood
products, snacks, drinks and juices, or provide supplies and services
to food manufacturers.
NFPA believes that the passage of the Food and Drug Modernization
Act of 1997 (FDAMA) represented a significant advance in the statutory
environment to provide responsible information to the public relative
to foods. NFPA and its member companies appreciate this Committee's
work to address many of the problems in the foods area that our member
companies experienced prior to FDAMA. In particular, we appreciate the
efforts of Messrs. Whitfield and Towns, who authored the bulk of the
FDAMA food provisions. In the regulation of foods, FDAMA resulted in:
(1) the approval of irradiation for use on red meats; (2) a streamlined
process for approving food contact substances, which are primarily used
in food packaging; and (3) a reduction in label clutter through the
elimination of the requirement of a statement referring consumers to
the nutrition label on food products (the referral statement).
Despite these successes, the agency's implementation of food
labeling reforms for health claims which provide consumers with
important health information about food products, as well as
irradiation labeling, has been a disappointment. In the hearings that
culminated in FDAMA, many Members of this Committee expressed the hope
that statutory reforms would, among other things, help change the
culture at FDA. Unfortunately, with regard to food labeling, these
culture changes have not been realized--FDA remains reluctant to permit
certain types of food labeling that would give consumers important
health and safety related information. Thus, FDA, though well-
intentioned, prevents consumers from receiving truthful, non-misleading
information about their foods.
HEALTH & NUTRIET CONTENT CLAIMS
The food labeling provisions of FDAMA were a reaction to decades of
overly restrictive policies that were inhibiting truthful and
nonmisleading label statements. Despite Congressional attempts to
create a workable food labeling policy through the Nutrition Labeling
and Education Act of 1990 (NLEA), FDA implemented the NLEA, especially
the health and nutrient content claim provisions, in an overly
restrictive manner. As a result, Congress, through FDAMA, established
alternative pre-market notification procedures for health claims and
nutrient content claims which are based on, and consistent with, the
published statement of an authoritative U.S. scientific body
responsible for public health protection.1 But FDA has taken
great pains in its implementation of these provisions to exclude as
many claims as possible. FDA turned down the first nine health claims
submitted under this provision.2 With regard to eight of the
nine claims, FDA asserted that they were not based on sufficiently
``authoritative'' statements.3 Two FDAMA health claims have
been authorized--for whole grain foods and heat disease and cancer, and
for potassium and reduced risk of hypertension--but these small
achievements do not illustrate that FDA has abandoned its restrictive
policies on health claims.
---------------------------------------------------------------------------
\1\ 21 U.S.C. Sec. 343(r)(3)(C). (This alternative is in addition
to the existing mechanism for approval of such claims, found at 21
U.S.C. Sec. 343 (r)(4), which allows persons to petition FDA to issue
regulations authorizing the use of a health claim. In order for a
health claim to be authorized, FDA must find ``significant scientific
agreement'' that the claim is appropriate).
\2\ See 63 Fed. Reg. 34,084 (June 22, 1998).
\3\ Id.
---------------------------------------------------------------------------
FDA's overly restrictive labeling policies have not withstood
judicial scrutiny since FDAMA was enacted. Specifically, in Pearson v.
Shalala,4 dietary supplement manufacturers, distributors,
and consumer organizations brought suit against FDA, alleging that the
agency's regulation of health claims in supplement labeling was an
unconstitutional restriction of their First Amendment rights. The court
held that FDA's failure to consider authorizing health claims
accompanied by a disclaimer violated the First Amendment.5
The court termed the justification of FDA's restrictions, ``almost
frivolous.''
---------------------------------------------------------------------------
\4\ 164 F.3d 650 (D.C.Cir. 1999).
\5\ Id. at 658.
---------------------------------------------------------------------------
The supplement manufacturers had unsuccessfully petitioned FDA to
approve proposed health claims accompanied by qualifying statements
that would disclose any shortcoming regarding the sufficiency of the
scientific evidence supporting the claims.6 Using the First
Amendment analysis for commercial speech, which was first articulated
in Central Hudson v. Public Service Com'n of N.Y., 7 the
court found that, while the FDA had a substantial governmental interest
and the challenged regulation directly advanced that interest, there
were less restrictive means available to achieve the ends
sought.8 In particular, the court held that--FDA was
required to consider whether inclusion of appropriate disclosures would
negate the otherwise misleading nature of a health claim such that the
claim accompanied by a disclosure could be authorized.9
---------------------------------------------------------------------------
\6\ Id. at 653-54.
\7\ 447 U.S. 557 (1980)
\8\ Pearson, at 657.
\9\ Id. at 658. (``It is clear, then, that when the government
chooses a policy of suppression over disclosure--at least where there
is no showing that disclosure would not suffice to cure
misleadingness--government disregards a `far less restrictive'
means.'').
---------------------------------------------------------------------------
In finding that disclosures are preferable to complete suppression
of commercial speech, the court did not conclude that all health claims
may be made truthful with the use of a disclosure, and deferred to FDA
to determine whether a claim is so misleading that it could not be
rendered nonmisleading by a disclosure.10
---------------------------------------------------------------------------
\10\ Id. at 659.
---------------------------------------------------------------------------
The holding in the Pearson decision required that the FDA revisit
its decision on the four contested dietary supplement health claim
petitions that were the basis for the complaint, but the case has
implications that reach far beyond its facts. Indeed, the Pearson
decision called into question the overall regulatory policies used by
FDA for authorizing health claims.
On December 1, 1999, FDA announced its plan to implement the
Pearson holding. The implementation plan is referred to by the agency
as the ``Ten Year Plan'' because of its estimated decade-long timetable
for implementation.11 The plan is narrowly structured to
address health claims for dietary supplements exclusively, reserving
for later resolution any possible applicability of the Pearson decision
to conventional foods, despite the fact that the regulations at issue
in Pearson apply to both dietary supplements and conventional foods.
With respect, NFPA maintains that it is not acceptable for conventional
foods to wait until 2010 for relief from restrictive health claim
policies.
---------------------------------------------------------------------------
\11\ See Dietary Supplement Strategy (Ten Year Plan) (Jan. 2000).
---------------------------------------------------------------------------
IRRADIATION LABELING
In addition to preventing consumer access to important health
information about their food products, FDA's labeling policy
discourages important food safety technologies from coming to market.
In the Statement of Managers, which accompanied FDAMA, Congress called
for amendment of the existing, highly prescriptive irradiation
disclosure regulation. As previously mentioned, irradiation was finally
approved for use on red meats after the petition was pending for nearly
three and a half years. In addition, irradiation has been approved for
use on poultry, shelled eggs, flour, produce including, potatoes and
other fruits and vegetables. Yet, we rarely see irradiated foods in our
local grocery stores. Why is that? The answer can be found on the food
label.
FDA currently requires irradiated products to state that they are
``Treated with Radiation'' or ``Treated by Irradiation'' and bear the
international symbol for irradiation, known as the radura logo. With
the passage of FDAMA Congress required textual disclosure be no more
prominent than the ingredient statement on the food product. Although
FDA has implemented that FDAMA requirement, it has taken little action
to address Congress' directive that the agency conduct a substantive
review of its irradiation labeling policy.
As part of the Statement of Managers accompanying FDAMA, the
conferees instructed FDA to engage in notice and comment rulemaking to
explore alternative labeling for irradiated food products. In their
instruction to FDA, they noted, ``The conferees intend for any required
disclosure to be of a type and character that it would not be perceived
to be a warning or give rise to inappropriate consumer anxiety.''
Despite this Congressional directive and aggressive follow up by the
Appropriations Committee, FDA only published an advanced notice of
proposed rulemaking regarding alternative labeling for irradiated
products in 1999.
If a consumer sees a product containing labeling that looks like a
warning they won't buy it. In the case of irradiated foods this is a
real problem. Many believe that the radura logo resembles an upside
down mushroom cloud. The words ``irradiation'' and ``radiation'' are
discomforting to consumers--research shows this. By engaging in a
notice and comment rulemaking, FDA can use its expertise to create a
science-based labeling policy for irradiated foods that makes sense.
Although this nation has one of the safest food supplies in the world,
incidents of foodborne illness do occur. An important food safety
technology like irradiation can go a long way in eliminating the
incidence of foodborne illness. FDA's current labeling requirements for
irradiated foods do not address statements on food safety benefits and
discourage marketing of these foods. In the interest of food safety,
FDA must act on irradiation labeling now. NFPA is encouraged that FDA
is seeking to undertake consumer research on irradiation labeling, but
we wonder why this important reform of food safety information is
taking so long.
The Pearson decision, and FDA's response to it, as well as its
reluctance to review its labeling policy for irradiated foods, bring
into sharp focus FDA's disregard of commercial speech protection. FDA
historically has approached food labeling restrictively, chilling
dissemination of truthful and nonmisleading information and
prescriptively compelling label disclosures. FDA has moved away from
this approach only grudgingly, generally at the direction of Congress
or the judiciary. The agency's food labeling regulation today remains
constitutionally infirm and suspect in a number of areas.
CONCLUSION
NFPA appreciates the important food reforms this Committee made in
FDAMA. We stand ready to provide this Committee whatever assistance it
may need as it considers the successes and disappointments of FDA's
implementation of this important public health law.
Thank you.
Mr. Bilirakis. Thank you very much, Doctor.
The Chair will start the inquiries.
Dr. Suydam, nothing in PDUFA requires FDA to approve a drug
application. Correct?
Ms. Suydam. That is correct.
Mr. Bilirakis. Then the performance goals, as I understand
them, merely require the FDA to review and act upon
applications. In the written testimony of witnesses in the
second panel, and from discussions with the staff too, there
have been claims made that PDUFA has lead to the public health
and safety being compromised due to increased drug recalls.
Is there any truth to such an assertion? Does the FDA
sacrifice the safety and effectiveness requirements because of
PDUFA? I assume your answer to that of course would be no, it
does not.
But take the time to explain.
Ms. Suydam. Thank you, Mr. Chairman. The FDA believes that
our standards have been maintained, and that we continue to
review and approve or disapprove pharmaceutical products based
on the quality of the data submitted to us, and the fact that
the data support the product being approved.
I might point out that the rate of withdrawals from the
market, which is in fact one way to measure whether in fact
safety has been in any way inhibited, is the same as it has
been for the last 20 years. The rate is somewhere around 2.9
percent. That has been the case for 20 years. Now the number
might be higher because we are approving more things. More
things are on the market than were on previously. But the rate
of withdrawals has remained steady for approximately the last
20 years.
Mr. Bilirakis. This is a very significant claim on their
part. I think that all parties would agree that the
modernization act has worked well, that PDUFA has done what it
was intended to do in general. But, there are groups that find
fault with it.
Why would they make this claim? There has to be some
substance to it, I would think, rather than just all
supposition or speculation.
Ms. Suydam. There have been some, and my speculation is
that there have been some very high profile drug withdrawals in
the last few years that have received a lot of public scrutiny
and public press. We understand the current concerns of groups
about products coming on the market.
I think one thing I pointed out in my testimony that I'd
like to reiterate is the fact that the United States is now the
country of first introduction for new drugs in 80 percent of
the cases. That's very different than it was in the early
1990's prior to PDUFA. So you are more likely or you may be
more likely to have a withdrawal early in the process because
of the fact that it's been introduced into a larger population
of patients as opposed to the numbers. As a result, you will
see the very rare side effects that you might not see during
the clinical trials.
Mr. Bilirakis. A frequent criticism of PDUFA is that the
appropriations thresholds in the statute effectively force
scarce dollars into drug reviews at the expense of other
important FDA initiatives. Can you respond to that?
Ms. Suydam. The FDA budget is obviously restricted, as all
Federal budgets are to some extent. I believe that the benefits
of PDUFA have really out-weighed the potential costs of moving
money from one program to another.
Mr. Bilirakis. Has PDUFA been an unanticipated burden on
FDA? In other words, from the accountability standpoint?
Ms. Suydam. I believe that in my written testimony you will
see that the performance goals that have been established under
the PDUFA II program, have given us an added burden that I'm
not sure warrant the cost of tracking them. For example, we are
tracking every meeting with industry. We are tracking the time
between when the meeting is set up and when the meeting is
held. There are more than 3,500 different entities that have
been tracked in PDUFA II.
I think since we have virtually met every performance goal,
perhaps now is the time to think about those goals and think
about whether we need to have that level of tracking.
Mr. Bilirakis. All right. When we finish up here, I would
ask you all not only to respond to written questions, but to
submit any suggestions to us. Mr. Burr is still here. It's
important in the process of reauthorizing PDUFA whenever we do
it, that we kind of hear your inputs in terms of suggested
changes, legislative changes that we could make which would not
hurt the effort but basically benefit, and your help. Thank
you.
Mr. Brown?
Mr. Brown. Mr. Chairman.
First, Mr. Northrup, I want to compliment you on your
testimony. I agree with you that obviously FDA modernization is
a continuous process. It seems to me that the variety of
products in the device field surpasses that of any other area
of FDA oversight and regulation. That invites new challenges
for keeping FDA both responsive and responsible. I was
intrigued by your proposal for a new Office of Combination
Products and look forward to learning more about the details as
that unfolds from you.
Dr. Suydam, I was intrigued by your comments on page 10,
that 80 percent of new drugs worldwide first launched in the
U.S. was 40 percent before this legislation. You used the
words, ``due to the favorable regulatory climate.'' I would
like to know on what information you base that. Also, could the
reason be, I mean I understand that the numbers are easily
provable, but whether it's due to the regulatory climate, I
would also think it might be in part due to the fact that when
products are launched in the United States, the economic gain
is potentially greater because this Congress has done little--
some think it shouldn't and some think it should--this Congress
has done little of any kind of changing the price structure. No
other country allows prescription drug prices so freely to
move, if you will, that prices are higher here than in other
countries in the world.
Is that also a major reason that this huge increase in the
number of drugs launched in this country has occurred?
Ms. Suydam. Mr. Brown, it could very well be that that's
part of the reason. But what I was focusing on was the fact
that under FDAMA with the increased resources provided for us
under PDUFA, we have reduced the median review times from 20
months down to 12 months for normal product applications, and
from 12 months to 6 months for priority applications. I think
that in itself speaks to one of the major reasons why we are
the country of first introduction for new pharmaceuticals.
Mr. Brown. You would say that's, in your mind, that's
clearly the primary reason for the increase, not the fact that
prices are significantly higher here and the reward
significantly higher here economically for the launch of those
new products?
Ms. Suydam. I think that's probably one of the other
reasons, but FDA's purview is not necessarily to look at the
economics of the industry in that sense.
Mr. Brown. Except you made a statement here, ``due to the
favorable regulatory climate,'' so I would hope that FDA's
purview is to come here and if you make an assertion to be able
to defend it.
Ms. Suydam. Yes. I do believe that we have improved the
climate. I think I was making the cause and effect between the
times of approval and all of the things that we have done
through the implementation of PDUFA, and the change that we've
seen in the regulatory review time, and in fact, the whole
clinical drug development time in general is down.
Mr. Brown. I applaud what you have done that way. Does that
then beg the issue of responsibility of our government, a
responsibility to our citizens and a responsibility perhaps for
the introduction of these new drugs that make their way around
the rest of the world, that we should put significantly more
resources into post-market surveillance? I mean we have seen,
if in fact twice as many, percentage-wise, I don't know the raw
numbers, but twice as many percentage-wise numbers of drugs
have been approved by FDA, meaning there are many more of them
on the market, more quickly with a shorter period of time of
approval, not less efficient or less safe perhaps, but there
are more on the market, more quickly, coupled with direct to
consumer advertising, which really had not kicked in with any
appreciable degree at the time of FDAMA's enactment, let alone
PDUFA's, but FDAMA's enactment. Does that mean that the drug
industry and this Congress and the FDA have a significantly
greater responsibility in post-market surveillance with the
onslaught of new drugs, with the faster approval process, with
the direct to consumer advertising, with the more and more
people using these drugs much more quickly in much higher
numbers than they were ever used before when there weren't
these TV ads and the accelerated numbers of visits by people to
the doctors, drug reps to the doctors and all that. Doesn't
that give us a greater responsibility on post-market
surveillance?
Ms. Suydam. I believe that it does. In fact, the Agency's
budget last year included some additional money for adverse
event reporting systems and also this year's proposed budget,
the 2002 budget, includes dollars to enhance those efforts
across all of our product areas, because we do believe that we
really need to focus on post-market as well as the pre-approval
side of our whole regulatory responsibility.
Mr. Brown. Have we come close to, not in terms of
equalizing in dollars for sure or even employees, but have we
come close to meeting our responsibilities in the post-market
surveillance in comparison to meeting our responsibilities on
the clearance, on the drug approval?
Ms. Suydam. Well, I think our budget proposals would lead
one to the conclusion that we need additional resources to
enhance our post-market study of products.
Mr. Bilirakis. The gentleman's time has expired.
Mr. Brown. Can I ask for a more specific answer? I'm sorry,
Mr. Chairman.
Mr. Bilirakis. Very brief.
Mr. Brown. Have we done as well with our responsibility in
post-market surveillance as we have in this Congress and the
FDA in carrying out its responsibility to accelerate the
approval process?
Ms. Suydam. I think, Mr. Brown, that the PDUFA program
itself has focused on pre-market, and therefore, the resources
have been added to that program.
Mr. Brown. I'm not talking about that. I am talking about
the responsibility to the public. Have we done as well in post-
market surveillance as we have on speeding the approval of
drugs to the market?
Ms. Suydam. I think it is hard to make the judgment that we
have done as well. I think we have done the very best possible
job we could do with the resources we have available to do it.
Mr. Brown. That really isn't my question, but I am not
going to get the answers.
Mr. Bilirakis. Mr. Greenwood, to inquire?
Mr. Greenwood. Thank you, Mr. Chairman.
I am going to address my questions to you, Dr. Suydam, and
on pediatric exclusivity. As I alluded to in my opening
comments, I don't think there is any question about the fact
that this provision has been an enormous success. Some of the
numbers, 11 pediatric studies done between 1991 and 1996, 411
studies done since 1998. Estimates of lower hospitalization
costs due to better pediatric dosing information can save up to
$228 million per year for five diseases alone.
President Clinton's FDA report said that ``pediatric
exclusivity provision has done more to generate clinical
studies and useful prescribing information for the pediatric
population than any other regulatory or legislative process to
date.'' I could go on with all of this. This estimate that if
we could reduce even one-one-hundredth of the annual economic
impacts from these leading causes of death and disability by
providing more effective treatments to children, making for
healthier adults in the process, the $7 billion saved each year
would be 10 times more than the nearly $700 million that FDA
has estimated is the yearly cost to society from the pediatric
exclusivity awards. That's from the Tufts study. So that it has
been a success is not a question.
What the question obviously is is, is the 6 months the
right number? Does it lead to what some have called windfall
profits and so forth? The only ways I can think of to change
that is to change if people think that some drug companies make
too much money is to reduce the 6 months for everybody or have
some sliding scale negotiated, additional exclusivity that
would be negotiated between the companies and the FDA. I worry
about that because it puts a whole lot of uncertainty into the
process. At least what we have now is certainty.
I am interested in your thoughts about this. Do you have
concerns about the 6 month exclusivity? Do you think we should
tamper with it?
Ms. Suydam. Mr. Greenwood, the Administration really has
not had an opportunity to fully discuss the entire pediatric
exclusivity provisions. We really have not come to any
positions on the 6 month exclusivity at this time. But we will
be happy to work with the committee in the future on both the
pros and cons of the 6 months.
Mr. Greenwood. Let me ask this. The FDA has requested--can
you tell me how many studies have been initiated by the FDA?
Ms. Suydam. We have issued 188 written requests for
pediatric studies.
Mr. Greenwood. Okay. Has it been your experience that
companies have declined studies because of lack of financial
incentive?
Ms. Suydam. I don't believe that that has been the case.
Mr. Greenwood. Did FDA have any expectations prior to the
passage of the pediatric exclusivity provisions about what to
expect, the number of requests that it would generate? If so,
have the number of requests exceeded your expectations?
Ms. Suydam. Obviously the response from the pharmaceutical
industry has been incredibly vigorous. We have wanted to have
this kind of activity for many years, and have not been
successful prior to the passage of this particular provision in
getting the pediatric studies done that we thought were
necessary.
Mr. Greenwood. Let's turn to the issue of whether you need
more resources on the generic side of the house. Are you able
to comment about that?
Ms. Suydam. Our generic program is a program that I think
has a tremendous workload. We have approximately 300 FTEs--
people--in that program in general. We are not meeting the
statutory review times that have been laid out for us in the
law.
Mr. Greenwood. Do you have estimates of what it would take
to get up to the statutory review time?
Ms. Suydam. I do not. But we would be glad to explore that
and get back to you.
Mr. Greenwood. Would it be fair to say it's on the order of
magnitude of something like 10, 15 to 20 pediatricians? I'm
sorry, not pediatricians, excuse me, additional staff members.
Is that the ballpark?
Ms. Suydam. I really have not looked at the issue of how
much it would take to meet the deadline. So I think I would
prefer not to answer in specifics.
Mr. Greenwood. Thank you. My time has expired.
Mr. Bilirakis. Mr. Pallone, to inquire?
Mr. Pallone. Thank you, Mr. Chairman.
I wanted to ask Dr. Suydam, I mentioned in my opening
statement about with regard to pediatric exclusivity, that the
FDA's interpretation of the law has in my opinion in essence
has been granting companies patent extensions without receiving
the pediatric benefits it was intended to generate. That was my
concern.
Two areas I mentioned was the ability of companies to use
old studies to obtain patent extensions, and the granting of
exclusivity based on active--I guess that's moiety--I don't
know if I'm pronouncing it right.
Ms. Suydam. Moiety, yes.
Mr. Pallone. Rather than on a product-by-product basis. So
what I hear is that they are using old studies, and they are
not necessarily relevant product-by-product. What do you think
about that? Should we be prospective in the way we look at
this? Should the law be changed in that respect? I just wanted
your comment on it.
Ms. Suydam. Mr. Pallone, I think the most important thing
about the pediatric exclusivity provision is that studies are
being done. Studies are being done for the first time. We are
getting products labelled, which is the actual outcome you
want, so that physicians everywhere know how to use a product
and how to use a product correctly. So I think in general it
has been a very positive program. I don't think that there has
been a lot of the things that you have mentioned.
Mr. Pallone. You're not concerned that it goes against the
intent or somehow it's not in accordance with the intent?
Ms. Suydam. I believe the intent of the act was to have
products labelled so that physicians everywhere in the United
States can understand the effect of that particular product for
their patients of all ages. I think that intent is being met.
Mr. Pallone. I mentioned also dietary supplements. I wanted
to ask you a question about that. The industry and the public
have been asking for these proposed final regulations for good
manufacturing practices. They haven't been published yet. I was
wondering if you could tell us when they are likely to be
published? It seems like it has taken them more than 6 years to
get these quality standard regulations for dietary supplements.
I would just like to know what we can do in Congress to assist
the Agency to do a better job in this, because I think it is a
major problem that these haven't come out.
Ms. Suydam. We agree with you, Mr. Pallone, that good
manufacturing practice regulations for dietary supplements are
essential. They are a high priority for the Agency. The
regulation is now under review by the Administration. We hope
that it--the proposal, will--it's a very complex regulation--
not something that is easy to review--be available shortly.
Mr. Pallone. You don't have an idea of the date though,
this summer, fall?
Ms. Suydam. No. I'm sorry, I don't think I can.
Mr. Pallone. All right. Let me ask one more thing. That is,
this is with regard to medical devices. I know you have the
510(k) reviews, devices that already exist like a pacemaker,
and you have the PMA reviews for new devices. The 510(k)
reviews are close to meeting the statutory requirements of
FDAMA, but the PMA review has taken a lot longer. Of course the
whole purpose of FDAMA primarily I think was to address these
breakthrough products. These are the ones that can bring
tremendous improvements to the lives of patients.
So I was wondering what combination of resources, whether
it be appropriations, legislation or whatever, would be
necessary to achieve statutory compliance for the PMA reviews
as well as the 510? But there's obviously a big difference now
in terms of the time.
Ms. Suydam. Mr. Pallone, the timeframe for 510(k)s has been
90 days that is the statutory deadline. Surprisingly a large
number of products come through the 510(k) process. Even some
relatively new or what might be considered somewhat novel
products, more than 4,000 were approved last year through the
510(k) process. So it is a significant workload. I think
companies are particularly pleased that our performance there
is good.
I agree that we need to work on enhancing our pre-market
approval in the area of medical devices for those complex
devices. But I would point out that these are far more complex
products. You have far more information to review. We do need
additional time to look at those products. So it could be a
combination of additional resources, and also making
improvements in the process itself. The times have come down
significantly since where they were in 1995.
Mr. Bilirakis. The gentleman's time has expired.
I didn't mean to interrupt your response.
Mr. Whitfield?
Mr. Whitfield. Thank you, Mr. Chairman.
Dr. Suydam, the food labelling provisions that we included
in FDAMA were adopted specifically in reaction to what we
considered decades of overly restrictive policies inhibiting
truthful and non-misleading label statements. As you are aware,
we specifically provided for pre-market notification procedure
for health claims, content claims which were based on,
consistent with, published authoritative, scientific bodies on
that issue.
So after FDAMA was enacted, the first nine claims, health
claims were turned down, denied by FDA. A lawsuit was brought,
in Pearson v. Shalala case. The court ruled that FDA's
restrictions were unconstitutional basically or a violation of
free speech. They specifically said that the restrictions were
almost frivolous, and remanded it back to FDA. It is my
understanding that now FDA has adopted a 10-year plan to review
this as it applies to dietary supplements. Even though the
regulations at issue in Pearson v. Shalala included not only
dietary supplements but also the conventional food plan. You
all even wrote a letter to a Member of Congress saying we're
not going to apply this food plan unless the court specifically
orders it.
Now it appears to me as a member that was involved in that
part, that you all almost defied the intent of Congress in
making it easier to get these claims labels out there on not
only health supplements, dietary supplements, but also food,
conventional food.
Ms. Suydam. Mr. Whitfield, clearly it is not the Agency's
position to willfully ignore the intent of Congress on this
particular provision. I would like to point out that after our
guidance was issued on health claims, the two claims that have
been submitted since then were approved. We think that the
guidance document in itself will provide the kinds of
information that people need to do in order to have a health
claim approved.
We agree with you that valid information needs to be on the
label, and the label is an incredibly important document. We
need to assure that it is accurate and not misleading. I mean
that's clearly important, incredibly important to us.
I want to point out that the 10 year plan is an overall
plan, a strategic plan for dietary supplements in general. I
would not construe it to be that we aren't going to move on
health claims for conventional foods until after we have
finished all of the 10 year activity on dietary supplements. I
think it was designed to look at the entire category of dietary
supplement products and determine all of the activities that
needed to be done, and then to put a framework on it, on how
can we do this work given the resources we have to implement
this program.
Mr. Whitfield. Well, the fact that you all wrote this
letter to a Member of Congress stating that you did not intend
to apply it except if the court specifically ordered it seems a
little bit at variance with what you are saying.
I would simply say to you that I don't know who the new
head of FDA is going to be. I don't know if you are going to be
there or not, but many members of this committee are going to
be writing a letter to whoever the new head is, and telling
that person that we are going to be looking at this issue
closely because as I said in the beginning, I feel like the
intent of Congress has not been complied with, and even the
court said that they thought the restrictions were frivolous.
So I wanted to raise that issue.
Ms. Suydam. Thank you, Mr. Whitfield. We will go back and
look at that issue.
Mr. Bilirakis. I thank the gentleman.
Mr. Deutsch?
Mr. Deutsch. Thank you, Mr. Chairman.
Dr. Suydam, I think that--your staff has hopefully briefed
you of some questions that I am going to ask regarding the
issues regarding Andrex Pharmaceutics and Bioville and the
patent issues related to that. I bring them up in this setting
for a couple of reasons. One of which is I think all of us
understand that the incentives to extend the exclusivity is
incredible. I mean the dollar amounts are not in the millions,
but in the billions. Very creative, very well-paid attorneys,
consultants have come up with just about every possible thing
that we can't possibly think of beforehand to try to extend
these patents in ways that I think is obviously contrary to the
intent of Congress in terms of public policy issues.
As I am sure you are aware at this point, I think this is
an issue of first impression, the case of Andrx and Biovail
with Tiazac, where there was an exclusivity based on a patent
that is almost 17 years old, where a company comes in and
basically puts another patent based on the formulary of that
drug in a non-approved drug. So it's a drug that hasn't gone
through any trials at all. In that case, the FDA listed that
patent, so effectively has now extended the exclusivity for 17
additional years. Really almost gaming, I mean the system has
been gamed to the detriment of Congressional intent, to the
detriment of consumers, to the detriment of basically the
entire system.
I know it's a box that you are in. But I guess my question
to you is can you get out of the box or do you need
Congressional legislation to get out of the box?
Ms. Suydam. Mr. Deutsch, I don't have the specifics of
those two cases that you cite. I would suggest that we discuss
that with you at some other time when we have the specifics.
I would say that I believe the chairman had said he was
interested in having a hearing about generics at sometime in
the future. I am not prepared to talk about the generic program
in that sense today.
Mr. Deutsch. Again, I heard the chairman as well. Again, I
know my staff has spoken to your staff so I just assumed that
you would be prepared maybe more extensively than your last
response. This has been going on now for several months.
What I would hope is that I can get a specific response
within a relatively short timeframe. This has been going on now
literally for several months, so hopefully within a week or so.
And that in the response, I don't get--again, I understand the
FDA is in a difficult situation, but we are where we are. Do we
expect that--I mean what my fear is clearly on the policy side,
you know, is once the system has been gamed this way one time
successfully, what is to stop every one from gaming the system
this way tomorrow, the next day, the next day, the next day? I
mean and again, it has been game. I don't think there's
anything about that.
So I mean what I'm asking for you is again, the chairman, I
am well aware of the hearings that he's talking about. He
doesn't have dates for those hearings at this point in time, so
let me just ask you point blank. Can I expect a response within
a week's period of time?
Ms. Suydam. I understand your concerns about the program in
general. We will attempt to get you the response you ask for as
quickly as possible.
Mr. Deutsch. I mean I'm really asking you to commit
yourself to a time period, not as quickly as possible. What is
the timeframe that you believe you can get back to me on it?
Ms. Suydam. Within the next 2 weeks.
Mr. Deutsch. Okay. I appreciate that.
Let me also, let me just jump because I see my time is
running out. The FDA estimates the 6 month extension for
pediatric exclusivity costs the American taxpayer $695 million
a year. Could FDA or NIH provide grants to pay for additional
pediatric studies? This would seem to be a big savings in
comparison to the current system where the NDA holder requests
to study and reapplies a significant--you know, reaps a
significant reward. The government should focus on the drugs
they find important to study and save the taxpayers a
significant amount of money.
What criteria is the FDA using to determine if a drug is
eligible for pediatric exclusivity at this point?
Ms. Suydam. I believe we are following the intent of the
statute to determine if there is a use of the product in
children, if the product is a legitimate product for use in
children.
Mr. Deutsch. Is that the extent of the criteria that you
are using at this point?
Ms. Suydam. I would like to ask Ms. Axelrod to look it up
for me in the statute.
Mr. Deutsch. I appreciate that.
Mr. Bilirakis. The gentleman's time has expired, but I
think we should allow a response.
Ms. Suydam. We can provide that.
Mr. Bilirakis. Maybe a quick response now, then possibly
maybe follow it up.
Ms. Suydam. Follow it up.
Mr. Bilirakis. With something more detailed in writing to
Mr. Deutsch and to the committee.
Mr. Deutsch. Thank you.
Mr. Bilirakis. Can we get a quick response?
Mr. Deutsch. If she can't do it now, we can get it back in
writing.
Ms. Suydam. Okay. I prefer to do that.
Mr. Bilirakis. All right. Why don't you do that. If you
would please, I would appreciate it.
Let's see, Mr. Upton?
Mr. Upton. I'm actually not quite ready.
Mr. Bilirakis. Not quite ready? That's the first time I
have heard that one.
Mr. Upton. I didn't think I was next in the queue.
Mr. Bilirakis. Mr. Burr?
Mr. Burr. Thank you, Mr. Chairman.
Mr. Bilirakis. I'm trying to go according to the committee
rules, but you guys won't let me.
Mr. Burr. Dr. Suydam, won't you be glad when there is a
permanent commissioner?
Ms. Suydam. Yes, I will.
Mr. Burr. Let me clarify something for Mr. Deutsch. If it's
a drug for breast cancer, are we going to conduct trials on it
for pediatric exclusivity?
Ms. Suydam. No, I don't believe.
Mr. Burr. How about prostate cancer?
Ms. Suydam. I don't believe we would.
Mr. Burr. The majority of the drugs that are coming through
applications today actually are targeted for an elderly
population. Isn't it true that just a small percentage of those
may have some hope to be used in pediatrics? Therefore, a
majority of what applications are in the system today would
never be considered by the FDA, who ultimately decides each
drug that may go through a pediatric exclusivity trial. Right?
Ms. Suydam. Yes, that's correct.
Mr. Burr. So in fact, we can look at the FDA not at the
industry and say the industry is gaming the system. If there is
any mistake that's made, it is where we have evaluated
something that we thought would be beneficial to children, and
then maybe in the end we found out it wasn't.
Ms. Suydam. Right. Or maybe detrimental to children.
Mr. Burr. Yes. We're not going to be perfect, are we?
Ms. Suydam. That's right.
Mr. Burr. Isn't the majority of the emphasis behind
pediatric exclusivity to make sure that drugs that we were
currently giving children that may have potentially done
damage? Because we didn't know as much about dosages. We didn't
know as much about reactions. Isn't it in fact the
pediatricians who have said we have learned some valuable
information in the short time that this exclusivity has been
offered?
Ms. Suydam. Yes. I think you will be hearing later in the
second panel from the pediatricians. They will be saying those
same things.
Mr. Burr. Let me ask you, should we reauthorize PDUFA now,
the user fees?
Ms. Suydam. Yes, I believe PDUFA should be reauthorized.
Mr. Burr. No hesitancy on the part of the FDA to do that?
Ms. Suydam. No. No, there's no hesitancy on my part.
Mr. Burr. Let me ask you, I'm going to try to clear up a
few things that were asked earlier. Is it reasonable for
everybody to expect that when you move from a controlled trial
of 1,000 people and you have a drug that's approved and it goes
to a population of 100,000 people, that we expect we will see
some reactions that we didn't pick up in the thousand person
controlled trial?
Ms. Suydam. Yes. Very reasonable.
Mr. Burr. So what we have gone through since the passage of
FDAMA, where all of a sudden people have highlighted new
reactions to specific drugs, is not significantly different
from what we saw before. Whether the process took 3 years
longer if your trial was 1,000 people and it was controlled and
it took 3 years longer, we would have never seen those
unanticipated reactions until we got to a larger sampling,
which in that case would be the patient population.
Ms. Suydam. That is correct.
Mr. Burr. Is the FDA concerned about post-approval review?
Ms. Suydam. We are concerned about post-approval review,
which is one of the reasons we focused our budget in budget
requests for the last 2 years, additional resources for us to
look at adverse events that are occurring with all products
that we regulate.
Mr. Burr. Can I volunteer this subcommittee or certain
members on both sides of the aisle to work with the FDA to come
up with what all of us can agree is a successful post-approval
process?
I think what we currently have at the FDA is deficient. I
think that opinion is shared by a number of members on this
subcommittee. I believe that with what we have learned and what
we know today, we can come up with a mechanism that has the
highest degree of confidence that not only that we're watching
after we have approved it. In fact we catch things. I don't
think the system in fact is that reliant today.
Let me move to Mr. Northrup. The numbers that I have on the
510(k)s is that the average reviewing time is 77 days. Let me
just ask you for a clarification. If the FDA is reviewing a
510(k) and they ask for additional information once, twice, 15
times, don't they actually stop the clock, wait until the
information is received, and once the information is received,
disseminate it, start the clock back up until the next time
they need information, stop the clock? Is that the correct
procedure?
Mr. Northrup. That I correct, I believe. I welcome a
correction from the FDA if I'm wrong, but I believe that is
correct.
Mr. Burr. A 77 day average is in fact a correct time
relative to the clock running, but it's not necessarily
indicative of the entire length of time that it takes to
review.
Mr. Northrup. No, that's true. That time does not include
the time that the company is taking in between the time the
clock stops and starts to collect the information, submit that
to the FDA.
Mr. Burr. How successful have we been, in your opinion, on
third party review?
Mr. Northrup. I don't think we have been as successful as
we could have been. I think it's true that manufacturers have
not taken advantage of third party review, but a large part of
that is because the third party review program, until very
recently, had not been expanded by the Agency to include all
those products that were eligible under FDAMA.
In January of this year, the FDA did in fact release
guidance that expanded the program to include all those
products that are eligible under FDAMA. So again, I would give
them a grade of incomplete. I think it is too early to tell the
ultimate success of third party, but we're certainly seeing the
numbers start to increase now that more products have been made
eligible for the program. We think it will be a success. We
hope it will be a success.
Mr. Chairman, I thank you for the time. I yield back.
Mr. Bilirakis. Ms. Capps?
Ms. Capps. Thank you. I was not a Member of Congress when
FDAMA was enacted, but I have heard nothing but praise about
the process. I want to commend this committee--because FDAMA
came out of this committee and also the FDA--for the landmark
progress that you have made in this regard.
But, Mr. Chairman, I am struck by the remarkable nature of
this hearing. It may suggest, at least it does enter my mind,
that we have in place a regulating agency which, because of
tremendous advances in different kinds of advances in
technology, the mechanism for regulation is--I guess the word
would be archaic. The principles are there, but the changes
have been perhaps too dramatic that the regulatory mechanisms
don't fit the mold.
I wanted to talk about, I think we had examples from both
Dr. Applebaum and Mr. Northrup, areas that are pushing at the
limits of what the FDA is capable really of doing. Again, I
think it is our responsibility to take this seriously, which is
why I think this is so important.
Mr. Northrup suggested that, and my question is to you, Dr.
Suydam, that the combination, Office of Combination Products
might be established. He listed the example of the stent where
it is a device and also a medication. I wanted to know what
your reaction is to this suggestion. But I also wanted to
explore what the previous questioner sort of just generally
brought up in the area of third party review or basically peer
review, because I think that's what this is leading toward.
Ms. Suydam. Let me answer the last part of the question
first.
Ms. Capps. The last part wasn't a question yet.
Ms. Suydam. Oh okay. All right.
Ms. Capps. I'd like you to answer the first part first.
Ms. Suydam. I don't think we have had time to evaluate the
idea of an Office of Combination Products, although I think it
is a very intriguing suggestion. I do know that we have been
dealing with combination products for quite some time.
Ms. Capps. Yes.
Ms. Suydam. We have a mechanism in place where we work with
the two parts of FDA to assure that there is a lead center, and
that lead center then has responsibility for the overall
application, and then works with the other center to make sure
that the issues related to the particulars of their product
regulations are being met.
I think right now I would not say that that has failed us.
I think it has in fact been fairly successful. I think we will
have to look at it as we deal with more and more of these
products. I, for one, just from a bureaucratic philosophy,
don't like the idea of creating new offices because sometimes I
think we can use the structure we have in a creative way. That
is what I would prefer to do.
Ms. Capps. I guess I would suggest that it is so time
consuming to make old patterns fit new techniques. Perhaps we
could be able to help you. I would like to offer that this is a
topic for this committee to really address, whether there needs
to be a sense of urgency about it. I know some of these devices
are approved for use in other countries. I have a feeling that
there are places in this world where lives are enhanced and
maybe saved. We're really not where we should be.
That leads me to ask you, I understand Mr. Northrup
answered the previous question about third party reviews by
saying there has not been time to evaluate it. Well, they
didn't get put into place very quickly either. Again, this is
kind of breaking the mold of the traditional way of dealing
with it. I want to know what again, we can do to assist?
Certainly if these techniques and technologies are so
innovative, it would be a challenge for FDA to stay in the
position of being able to review them. That, I would imagine,
is why the idea comes up.
What can we do to legitimize that, to help that to work
more efficiently?
Ms. Suydam. FDA is very open to the idea of third party
review. We believe that the provision is working well and is an
idea that is working well.
We were reluctant to start out with a huge number of
products in the process initially. I think that is certainly an
approach where we chose to be a little conservative and to try
to get some experience with the third parties. We did not know
what kind of reviews we would be getting from the third
parties, how much work it would require on our part once they
were finished. Now we have had that experience. We know that
there are third parties that are very reputable, that do a good
job, that we can use. I think therefore our philosophy was to
extend it to the full range of products that were eligible in
January, which we did. We will continue to hope that the
industry uses it at a greater rate than they have in the past.
I do want to point out that our track record in devices for
novel therapies is a good one. Eighty-five percent of the pre-
market approval applications are reviewed in our statutory
time. So the outliers are just in that 15 percent.
Ms. Capps. I guess I would respond and in closing, I know I
have used too much time, by saying that we should get over the
fact these are novel. I think this is the future of medicine.
Somehow FDA--this is a stretch, but we also need to be able to
embrace that this is medical practice today. These areas of
combinations of what----
Ms. Suydam. Absolutely, we agree with you. We are well
aware that that is the case.
Ms. Capps. Thank you.
Mr. Greenwood [presiding]. Is the gentleman, Mr. Upton,
ready?
Mr. Upton. I'm ready.
Mr. Greenwood. The gentleman is recognized for 5 minutes.
Mr. Upton. Although I'm late for the lunch that you are
chairing.
Ms. Suydam, as you know, I introduced legislation that was
incorporated into FDAMA back in 1997. It allowed the food
manufacturers to put health claims on their labels when the
claims are based on authoritative statements by NIH, CDC, and
other Federal scientific organizations provided that you all
are given 120 day notice.
What I'm interested in today is to take a little snapshot
in terms of how that has worked. I think in your testimony, I
regret that I was in an Education markup, I think along the
lines of about nine notifications have come your way, but I
would be interested to know of those, how many have you
received? Of those, how many have you turned down, and the
reasons for such. How long does it take on average for the FDA
to act on those petitions once they are submitted under the
pre-approval process? Perhaps what constructive ideas might you
offer in terms of how we can even better streamline this
process as we look to the days ahead?
Ms. Suydam. The record on our health claim notifications is
one that I spoke to in that we have received 11.
Mr. Upton. Denied two?
Ms. Suydam. We approved two and denied nine. The two
approved had been approved after our guidance was issued, which
we believe has helped the process, and will encourage more
claims to be approved.
We have been on time for the most part. The 120 day
statutory deadline has been exceeded, but I believe we had
authority to negotiate with the submitter on an extension which
was done, and we met those deadlines at that time.
Mr. Upton. Do you have any suggestions in terms of what we
might do in the future? Or do you think the process is working
fairly well?
Ms. Suydam. My suggestion is that the guidance document has
helped the process. I would like to go back and talk with our
people in the Center for Food Safety to ask them to look at the
process and see what kind of suggestions we can make to you.
Mr. Upton. Great. Thank you.
I yield back my time.
Mr. Greenwood. The Chair thanks the gentleman, and
recognizes the gentleman Mr. Stupak for 5 minutes.
Mr. Stupak. Thank you.
Doctor, before PDUFA and before you had the drug user fees,
how long did it take to approve a drug?
Ms. Suydam. For standard applications it took about 30
months.
Mr. Stupak. Thirty months? Okay, and now under FDAMA, in
1994 according to your testimony, it's down to 20 months, in
1999, about 11.6 months, and you anticipate it could be less
than 10 months soon.
Ms. Suydam. Yes.
Mr. Stupak. Okay. So if a drug was approved before FDAMA,
less than a year, that was unusual?
Ms. Suydam. Yes.
Mr. Stupak. In the testimony, you indicate that the drug
review time has decreased significantly by 22 percent, and
under FDAMA II, further review time by the Agency has been
reduced. So in some of the answers to the Chair's questions
about recent recalls, you said that the FDA has not compromised
safety or effectiveness of the drugs, but the percentage of
recall is basically the same prior to FDAMA. That is because we
have more drugs out on the market. More drugs, we have
decreased drug development time, and less review time.
The mistakes and the errors, if you will, or the recalls,
we have had what, 11 in the last 3\1/2\ years, recalled drugs,
that resulted in about 1,000 deaths?
Ms. Suydam. I do not know the number exactly. But I am
assuming you have the correct figures.
Mr. Stupak. Sure. Those recalls of at least 11 over the
last 3\1/2\ years resulting in about 1,000 deaths, and GAO
estimates, because it's a voluntary reporting process, your
errors, the adverse event reporting system, it's probably 1 to
10 percent, somewhere there, of the actual number. Correct?
Ms. Suydam. In overall adverse event reporting, yes. I
think probably if you are talking specifically about deaths, it
is more likely that we would have those reported.
Mr. Stupak. Really? Okay. It's still voluntary, right?
Ms. Suydam. Yes.
Mr. Stupak. And a doctor has to make a connection or the
manufacturer has to make a connection between the drug and the
death before they are required to make the report on the
errors?
Ms. Suydam. Yes. That is correct.
Mr. Stupak. Well, see under FDAMA and all these other, the
Modernization Act, if it's better, why do we have more deaths
than before? I mean take a look at this. Before we went in, in
26 years before FDAMA, you had eight recalls. In 26 years you
had eight recalls. In the last 3\1/2\ years, you have had 11
recalls. If this is supposed to be better, why do we have more
recalls and more deaths than you did in the 26 previous years?
Ms. Suydam. Mr. Stupak, I do not have the numbers in front
of me to debate your numbers. They don't seem right to me. What
I would say is that there have been thousands, in fact probably
hundreds of thousands of patients who have been helped because
they have had greater access to therapies. They have had that
access to therapies much faster. Therefore, perhaps there are
thousands of people who did not die because they had the
therapy that they needed.
Mr. Stupak. That's because we have more drugs out there.
Right?
Ms. Suydam. Because we have products that provide the
benefits that are needed for the patients who have these life-
threatening diseases.
Mr. Stupak. To some of us, that's like saying you know
before FDAMA, we had ten airlines and one out of ten would
crash. Now with FDAMA, we have 100 airlines, and now we have
ten crashes. It's better because we have more legroom, we have
better food, ticket price is lower.
You see, some of us feel that if it's supposed to be an
improvement, but your percentage of error is the same and the
percentage of deaths over people who take prescriptions are
about the same, where is the improvement? Where is the
increased safety and efficiency for the American public?
Ms. Suydam. Any time a drug is approved, it is a benefit-
risk ratio. That benefit-risk ratio has always to be taken into
consideration.
Mr. Stupak. But the benefit-risk ratio, according to your
testimony and some previous answers, is about the same. So
where is the improvement?
Ms. Suydam. The benefit is that the product is available to
patients sooner. That's not being included in your
calculations.
Mr. Stupak. So we die sooner?
Ms. Suydam. No. So that people are treated and live longer.
Mr. Brown. Will the gentleman yield?
Mr. Stupak. Sure.
Mr. Brown. To follow up on that point, Dr. Suydam, you
still would not say that we have fallen short in any way on
post-market surveillance. Sure you want to move things through
the process faster, but we're simply not bulking up, if you
will, or making more efficient or effective post-market
surveillance.
Ms. Suydam. Right.
Mr. Brown. I yield my time back.
Mr. Stupak. The point I would add, you keep saying that
these are life-saving drugs. Of the 11 that have been recalled,
only one has really been sort of considered a life-saving drug.
These were drugs that were approved for other things and people
were dying from them. So they really wouldn't be, all 11 were
not considered life-saving drugs. Correct?
Ms. Suydam. I think each of them had benefits, and some of
them were life saving and some of them were not.
From 1981 to 2000, we had 543 new molecular entities
approved. Fourteen were withdrawn. That is in that time period.
So the numbers that you were citing I think are slightly
different.
I would suggest that perhaps for the record we could submit
a new report that we put out from our Center for Drugs on our
2000----
Mr. Bilirakis. Why don't you identify it, and then we can
accept it.
Ms. Suydam. It's the Center for Drug Evaluation Research
Report to the Nation 2000, Improving Public Health Through
Human Drugs.
Mr. Bilirakis. Okay. Without objection, that will be made a
part of the record.
[The report referred to is available at:]
PDF: http://www.fda.govcder/reports/rtn2000/rtn2000.pdf
HTML: http://www.fda.govcder/reports/rtn2000/rtn2000.htm
Slides: http://www.fda.govcder/reports/rtn2000/rtn2000.ppt
Mr. Bilirakis. Your time has expired, Bart. If you have
another few seconds.
Mr. Stupak. Sure. Let me ask this question. In late 1998, a
consumer group found 27 instances in which a drug was approved
over FDA staff objections, and 14 instances in which staff were
told not to present data at advisory committee meetings which
might adversely affect the chance of a drug being approved.
Would you care to comment on that?
Ms. Suydam. The process of drug review and approval is one
that includes many layers of review. It has the medical
officer, the individual medical officer, the individual
statistician. Then it moves through to the supervisor,
supervisory medical officer, to the division director. Drugs
are often looked at from different perspectives in terms of
each of these specialties. I do not know if those statistics
are correct or not, but I do know that our process is thorough
and that yes, sometimes that scientists come to different
conclusions about products, and that all of our scientists may
not agree on any one product. It is the judgment of the Agency
that has to be made in the end.
Mr. Bilirakis. The gentleman's time has expired.
Mr. Stupak. Mr. Chairman, if I may, the statistics I have
used have come from testimony from some people who will testify
in the second panel. Also, as far as the only eight
prescriptions were pulled for safety reasons in the previous 26
years, I would submit for the record Sunday Gazette Mail.
Mr. Bilirakis. Without objection.
Mr. Stupak. January 7, 2001.
Mr. Bilirakis. Without objection, that will be the case.
[The information referred to follows:]
[Sunday, January 7, 2001--Sunday Gazette-Mail]
Spate of drug recalls raises safety concerns
By Knight-Ridder
In the last four years, 10 prescription drugs and a vaccine have
been taken off the market after killing and injuring thousands of
people.
The drugs had noble purposes, including checking diabetes,
relieving pain, and fighting high blood pressure. The vaccine immunized
babies against a potentially deadly infection.
For the vast majority of the 32 million Americans who took these
medications, they worked--or at least caused no harm.
But for tens of thousands of patients, the withdrawn drugs were a
disaster, causing temporary or permanent heart, liver, bowel or other
injuries. Some injuries were so severe that the patients required organ
transplants or other surgery. Thousands were fatal.
Safety withdrawals of 11 pharmaceuticals in four years appear to be
unprecedented. eight prescription drugs were pulled for safety reasons
in the previous 26 years.
``We are seeing the breakdown of a system that was far from perfect
to begin with,'' said Daniel A. Hussar, professor of pharmacy at the
Philadelphia College of Pharmacy. ``I have a great concern that there
will be even more serious problems before society says, `Enough is
enough, we need the system fixed.' ''
Consumer and patient advocates, academic physicians and
pharmacologists, and health-policy analysts say no step of the
pharmaceutical process, from development lab to patient bloodstream, is
free of blame.
They fault drug companies and the federal Food and Drug
Administration for the approvals of drugs they say are questionable,
and they chastise Congress for underfunding the FDA and pressuring the
agency to play ball with drug companies.
But what the critics find most inexcusable is that the nation has
no reliable way to track and investigate problems with drugs.
The monitoring system for drug safety is so weak and underfunded
that Americans do not know for sure which drugs are causing the most or
most serious problems, why they are causing problems, or what measures
would help reduce the future toll, the critics say.
``When an airplane crashes and kills 200 or 300 people, it's pretty
hard to hide,'' said Larry Sasich, a pharmacist and research analyst at
Public Citizen's Health Research Group, a Ralph Nader-affiliated
organization in Washington, D.C.
``But we could lose 200 or 300 people a month to deaths from
adverse drug reactions in this country and not even notice it, because
we have no system of adequately capturing all the serious drug
reactions.''
In fact, it seems likely that the monthly death toll from drugs is
well above 300. Although there is no accurate count of U.S. drug
fatalities, the most frequently cited estimate pegs them at 100,000 a
year. That is more than twice the number of deaths from traffic
accidents.
The toll is so uncertain because doctors are not required to report
bad drug reactions; if they choose to do so, they inform either the FDA
or the manufacturer. Manufacturers must forward any such reports to the
FDA.
FDA officials, who agree that the system of post-market drug
monitoring is no match for the problems, have begun to plead with
Congress for more funds to beef it up.
The state of the bare-bones U.S. drug-safety monitoring system is
this:
The FDA learns of only I percent to 10 percent of serious
adverse drug reactions those leading to injury, hospitalization
or death--studies have estimated.
Information about drug outcomes that could be gleaned from
insurers' databases is going virtually untapped.
A Drug problems are investigated by the FDA, and potential
conflicts are created because examiners who have recommended
drug approvals are also involved in withdrawal decisions.
The FDA's annual budget for safety reviews of drugs on the
market is $17 million--roughly equal to what Americans spend on
prescription drugs every 90 minutes.
The questions about drug safety arise after a successful decade-
long push by Congress and the pharmaceutical industry to get the FDA to
approve drugs more quickly. With nearly $900 million in drug-industry
funding since 1992, the FDA has increased its staff for drug and
vaccine reviews by about 60 percent and has cut the time for routine
drug approvals from two years to one year.
At the same time, the rise of direct-to-consumer advertising has
helped spur the much more rapid use of new drugs, so that millions of
people may be exposed to a drug before its risks are fully identified.
And the speedier FDA approvals mean that the European market no
longer serves as an early-warning system, as it did in the late 1950s,
when thalidomide use in Europe resulted in devastating birth defects;
the drug was never approved here.
Given all these holes in the system, the worry is not that so many
drugs--but that too few--are withdrawn, said Brian L. Strom, a
physician, pharmacologist and medical-statistics expert at the
University of Pennsylvania School of Medicine.
``The drugs that have been withdrawn from the market are the
successes,'' he says. ``I worry about the others that are out there,
because drugs that are on the market aren't adequately monitored.''
FDA and drug-industry officials dispute such grim assessments. They
say the drug approval and safety monitoring systems work better than
the critics acknowledge.
Janet Woodcock, director of the FDA's Center for Drug Evaluation
and Research, said: ``One reason more drugs are being taken off the
market is that we are being more aggressive in pulling them off.''
Bert Spilker, senior vice president at the Pharmaceutical Research
and Manufacturers of America in Washington, D.C., agrees that the
recent withdrawals are a positive sign. ``They demonstrate that the
system works well to protect the American public,'' he said.
Nevertheless, in briefing material for a hearing in September, the
FDA acknowledged that safety monitoring has suffered.
``Our workforce and real resources for most programs other than
``drug approvals'' have contracted each year since 1992,'' the agency
wrote. ``An area we have not been able to fund adequately is responding
to reports of adverse events related to the use of prescription
drugs.''
In an interview, Woodcock said she would be happy with the $50
million budget for post-market monitoring that has been tentatively
suggested by Sen. Edward F. Kennedy, D., Mass. She disagreed with calls
to channel funds into mandatory reporting by physicians of severe drug
reactions, and said additional money would be better spent in analyzing
drug data available from insurance companies.
Post-market monitoring is a critical function because often it is
not until a drug goes into widespread use that problems emerge. This
fact is not a failure in either drug development or drug approval, said
Alastair J.J. Wood, professor of medicine and pharmacology at
Vanderbilt University.
Rather, it is a consequence of human diversity and the fact that
rare events may not be ,detected in the few hundred or thousand
patients in premarket trials, he says.
In the three phases of premarket testing, conditions are kept
simple: the subjects are commonly people whose only medical problem is
the one addressed by the drug under study, and who aren't taking any
other medications.
In the real world, though, people often have more than one ailment
and take more than one drug.
Because of the tremendous number of possible combinations, it would
be prohibitively expensive and time-consuming to broaden the premarket
tests to mimic the real world, Strom says.
So the first real-life test of a drug comes after it has been
approved, and its first few years on the market are often called a
Phase IV trial.
Also in Phase IV, doctors begin--quite legally--to prescribe the
drugs for longer periods or in larger doses than recommended, or use
them to treat conditions for which they were never tested. These
experiments may reveal new ways to use a drug, but they may also
precipitate new problems.
``When a drug comes on the market, that's really a controlled
experiment,'' Wood says. ``You don't know everything about the drug at
that point, so you should be monitoring it carefully. And we don't have
the proper system for doing that.''
Moreover, the lack of information means it takes longer to discover
the mechanism, such as liver damage or cardiac arrhythmia, by which a
given drug causes harm--information that could help pinpoint other
drugs that might cause the same problem, Wood wrote two years ago in
the New England Journal of Medicine.
The prescription medications pulled from the market for safety
reasons in the last four years were:
--Lotronex, which quelled the pain and diarrhea of irritable bowel
syndrome. It was taken off the market in late November.
--Pondimin and Redux, either of which served as the ``fen'' half of the
``fen-phen'' diet-drug combination. Fen-phen was linked to
pulmonary hypertension and heart-valve problems.
--Seldane, an antihistamine that could cause heart problems when taken
together with certain antibiotic or antifungal medications.
--Posicor, for hypertension and angina, which had harmful interactions
with 25 other drugs.
--Duract, a pain medication, which was implicated in liver failure,
primarily in patients who took it for more than 10 days.
--Hismanal, an antihistamine, whose interactions with some other drugs,
including Prozac, could cause fatal irregular heartbeats.
--Raxar, an antibiotic, which was associated with heart problems.
--Rotashield, an infant vaccine against rotavirus, which was implicated
in bowel obstructions.
--Rezulin, a diabetes drug linked with at least 63 deaths among 400
reported cases of liver failure.
--Propulsid, a treatment for severe nighttime heartburn, which was
associated with heart problems that killed at least 80 people
and injured nearly 350 others.
Even many who are calling for more-stringent safety monitoring
defend the FDA's speeded-up approval process. Strom, for example, says
faster drug reviews are not less thorough but are simply compressed
into fewer months.
The main concern is that safety monitoring has been squeezed by the
congressionally mandated focus on faster drug approvals. Under the
legislation that authorizes industry funding for the approval process,
the FDA is also required to chip in additional money each year. But
Congress has not increased the agency's budget enough for it to keep up
with other needs at the same time, the agency said in its September
briefing paper.
And while the drug industry has been eager to fund a quicker
approval process, it has steadfastly refused to provide any money for
post-market safety monitoring. That refusal was understood when the
1992 law was passed and was written into the 1997 law.
The industry refuses because post-market drug surveillance is a
public service and should be funded by Congress, said Jeff Trewhitt, a
spokesman for the Pharmaceutical Research and Manufacturers of America.
Besides analyzing HMO databases, other suggestions for improving
post-market monitoring include establishing a safety review board
separate from the FDA's drug approval staff, limiting direct-to-
consumer advertising of new drugs, and finding innovative ways to
gather data on drug outcomes.Interestingly, many critics reject the
suggestion that mandatory reporting by physicians is needed. It has
been tried in various states and countries, but has not worked because
doctors do not comply, said Raymond Woosley, dean for clinical research
at Georgetown University Medical Center in Washington.
The FDA and some in the outgoing Congress had begun to suggest that
drug safety monitoring should get a closer look in 2002, when the law
authorizing industry funding of FDA activities will be up for renewal.
This time, the drug industry may be willing to talk about providing
some funding.
``We would be willing to discuss this with the FDA, because we'd
like to see what performance goals they would agree to in exchange for
user fees, and what benefits industry would see,'' Spilker of the
pharmaceutical industry group said. ``We are open to listening to what
they propose.''
Mr. Stupak. That you, Mr. Chairman.
Mr. Bilirakis. Mr. Deal, to inquire?
Mr. Deal. Thank you, Mr. Chairman.
Mr. Northrup, under the section 210, third party review
process that you say has now been expanded by FDA, has it been
expanded to include the 510(k)s?
Mr. Northrup. It has been expanded to include all the
products now that are eligible under FDAMA. That is correct. We
would certainly like to see it expanded further, Mr. Deal. If I
might say, the concept of third party review is not new. It is
new to the FDA, but it is not new. The entire European system
of regulating medical products is based on third parties, not
just for review of the devices initially, but for inspection of
the manufacturing facilities. We haven't seen that that system
has compromised the safety of European patients.
So I think that perhaps some of the FDA's reluctance to
expand the program at first was more related to the FDA's
uncomfortableness with this being new to the FDA, not that this
is a totally new concept that we have not seen anywhere else in
the world.
Mr. Deal. The clinical data that's associated with 510(k)s,
does it allow the third party review of those? Or is it
restricted under the language of FDAMA?
Mr. Northrup. No. Currently FDAMA restricts review of
applications to only those class 2 devices for which clinical
data is not going to be required by the FDA.
Mr. Deal. So it would require statutory change in order to
expand it to the 510(k) reviews?
Mr. Northrup. Yes, sir. You are correct on that.
Mr. Deal. Would you advocate that change?
Mr. Northrup. We would, and we will.
Mr. Deal. Dr. Suydam, what is your position on that?
Ms. Suydam. I think that's something we would like to have
more experience with the current program. We'll take that into
consideration as we are considering changes in the future.
Mr. Deal. Overall, have your third party reviews been
successful and of a calibre that you find acceptable?
Ms. Suydam. Overall, we have found the program to be
successful, and have found the calibre of reviews to be quite
high.
Mr. Deal. Does this third party review process facilitate
and speed up your overall review process?
Ms. Suydam. Well, it certainly does take some of the
workload away from the FDA, which would then leave time for
people to do other things.
Mr. Deal. I don't believe anyone gave you an opportunity to
respond to one of the suggestions of Mr. Northrup, made about
creating a division to deal with the hybrid type devices. Do
you have any thoughts on that?
Ms. Suydam. I think I did mention I think having an Office
of Combination Products is an idea that we will consider. I
think we have a process in place right now that has been
working for some time. We have been dealing with combination
products for a long time. It is not necessarily a new concept
to us.
Mr. Deal. Without understanding all the intricacies of your
agency, when you have a hybrid type device or product, does it
require a separate review by two different groups within your
agency or do they work collaboratively in that process?
Ms. Suydam. There is a lead center designated, and then
there is a collaborative process.
Mr. Deal. Thank you, Mr. Chairman.
Mr. Bilirakis. I thank the gentleman.
Does the gentlelady from California wish to inquire of this
panel?
Ms. Eshoo. I do. Thank you, Mr. Chairman.
First off, I want to apologize for not being here earlier
from the beginning of today's hearing, which is a very
important one. There is a hearing downstairs on energy. Of
course as a Californian, I have a vital interest in that issue.
So I ask both the chairman, the ranking member, people that are
part of the panel, and the audience to accept my apology.
I have both a special interest in the issue that we are
reviewing today and a special sense of pride in terms of the
work that we accomplished, Mr. Chairman, on the medical device
reform bill that was then folded into FDAMA.
I think in terms of the work that we have done and the
effectiveness of it, not only finally partnering with the FDA,
but also with people that manufacture the devices, that we
really did a darn good job. Whatever we do in the
reauthorization bill I think is really going to be more
tweaking of the issue than having to completely reform and
really do a massive reform on this. So I want to thank everyone
involved, and of course, Mr. Chairman, you were a steady and
important leader in this. I am proud to have been the
Democratic sponsor of the bill along with Joe Barton.
The first question that I would like to ask is of Mr.
Northrup. Then I would like to go to another question. I am
going to state them both first, and then give you the time to
answer, okay?
You testified to the importance of fair, predictable, and
consistent regulatory actions during the FDA approval process.
When we wrote FDAMA, we included a provision mandating that the
evidence required for FDA approval to be ``the least
burdensome'' needed to meet safety and effectiveness standards.
In your opinion--and if this question has been asked before,
just say it's been asked and I'll go to the record and read
it--has the FDA implemented this least burdensome requirement
in a timely manner?
Then I have another question and it deals with the area of
reuse. Despite extensive scientific evidence demonstrating
serious risks associated with reprocessing of single use
devices, including several studies conducted by the Agency
itself, FDA in my view has failed to meaningfully enforce key
patient safety provisions of the Food, Drug and Cosmetic Act.
It took substantial Congressional and public pressure to force
FDA to finally publish enforcement guidelines on regulation of
this potentially dangerous practice. I still remain concerned
that this guidance, while a step in the right direction, and
I'm always willing to give credit where credit is due. I think
it's important to. I think this still continues to permit the
use of many unsafe, reprocessed devices on American patients.
I would like to know about what the FDA has been actively
involved in working with to develop a strategy to regulate the
reprocessing of single use medical devices. Would you comment
on the FDA's progress in implementing its strategy relative to
the practice? Can you give me a specific example of a product
where you feel that the FDA has failed to take appropriate
steps to ensure the patient's safety? You may not want to
answer that. You may want to answer it in writing or call me,
but I think it's important for the Agency to recognize this.
What do you think can the FDA do to really address this
head on? I think we are failing people in the country.
Mr. Bilirakis. The gentlelady has less than a minute left.
Ms. Eshoo. So I'll stop.
Mr. Bilirakis. Why don't we have maybe a brief response,
and then follow it up, if it's all right with her, with more
detailed answers in writing.
Ms. Suydam. There are two questions. The first is related
to least burdensome. I would suggest that perhaps we were
slower to act than we should have. We have had the least
burdensome guidance, the most recent version just went up on
our website this week, but we did have a least burdensome
guidance 2 years prior to that, and have been working with
industry task forces to come to some agreement about how the
program should be implemented.
Ms. Eshoo. So what's on your website?
Ms. Suydam. The new least burdensome guidance.
Ms. Eshoo. I see.
Ms. Suydam. We do believe it is one that we all feel
comfortable with. I think it serves the purpose and the intent
of the statute.
The second thing you should know is that despite it just
going up on the Web this week, it has been in effect. We have
used----
Ms. Eshoo. Was that in anticipation of this hearing, do you
think?
Ms. Suydam. No. I think the timing unfortunately or
fortunately happened as it did.
I think we are already using least burdensome principles in
the review of products. I have some examples that I could give
you.
On the re-use, if the chairman would like, I think Dr.
Feigal might be able to answer that question.
Mr. Bilirakis. Well, it's the gentlelady's question, but
can we get it done in writing?
Ms. Suydam. We could do that in writing.
Mr. Bilirakis. In a short period of time so that it's----
Ms. Eshoo. I think it is something that obviously it's not
just my interest, but I think an important interest of the full
subcommittee.
Ms. Suydam. Yes. We understand that.
Ms. Eshoo. So I look forward to hearing from you soon on
it.
Mr. Bilirakis. Thank you. Well, I think that with
gratitude, we can excuse this panel.
Mr. Brown. I have some questions for the record for Mr.
Waxman I would like to ask.
Ms. Eshoo. Could I just yield for a moment and I could make
a request on the following?
Mr. Bilirakis. We are going to submit. That's what I was
just getting to. Questions will be submitted in writing, and
we're requesting that those be responded to in a timely
fashion.
Ms. Eshoo. As well as Mr. Northrup, to give him an
opportunity to respond?
Mr. Bilirakis. Oh all of them, the entire panel, the entire
panel, right.
Ms. Eshoo. Thank you, Mr. Chairman.
Mr. Bilirakis. I know you are always willing to do that.
Additionally, as I invited you all earlier, you know there are
some things can be taken care of by the departments and the
agencies and what not, and some things require legislation. I
was going to say litigation unfortunately, but legislation. By
all means please feel free. We're in the process here of taking
a good look at these things. Feel free to let us know how we
can be of some help.
Thank you very much.
The next panel, if they would come forward, please. Dr.
Gregory L. Kearns has already been introduced by Ms. McCarthy.
He is a Professor and Chief of Division of Clinical
Pharmacology and Medical Toxicology with the Children's Mercy
Hospital in Kansas City, Missouri.
Can we have some order, please?
Ms. Carole Ben-Maimon, have I messed that up? Maimon?
President and CEO of Proprietary Research and Development for
Barr Laboratories. She is here on behalf of the Generic
Pharmaceutical Association. Dr. Richard Gorman, incoming chair
of the American Academy of Pediatrics, Committee on Drugs, with
the American Academy of Pediatrics. Ms. Abbey Meyers, President
of the National Organization for Rare Disorders. Mr. Travis
Plunkett, Legislative Director of Consumer Federation of
America on behalf of Patient and Consumer Coalition. Dr.
Timothy R. Franson, Vice President, Clinical Research for
Regulatory Affairs in the United States, Lilly Research
Laboratories, and Dr. David Flockert was invited but apparently
was not able to make it.
That being the case, again, your written statements are a
part of the record. We would hope that you would complement
them, if you would, supplement them, complement them. The clock
is at 5 minutes for each one of you.
Dr. Kearns?
STATEMENTS OF GREGORY L. KEARNS, PROFESSOR AND CHIEF, DIVISION
OF CLINICAL PHARMACOLOGY AND MEDICAL TOXICOLOGY, CHILDREN'S
MERCY HOSPITAL AND CLINICS; CAROLE BEN-MAIMON, PRESIDENT AND
CEO, PROPRIETARY RESEARCH AND DEVELOPMENT, BARR LABORATORIES;
RICHARD GORMAN, INCOMING CHAIR, AMERICAN ACADEMY OF PEDIATRICS
COMMITTEE ON DRUGS, AMERICAN ACADEMY OF PEDIATRICS; ABBEY S.
MEYERS, PRESIDENT, NATIONAL ORGANIZATION FOR RARE DISORDERS;
TRAVIS B. PLUNKETT, LEGISLATIVE DIRECTOR, CONSUMER FEDERATION
OF AMERICA; TIMOTHY R. FRANSON, VICE PRESIDENT, CLINICAL
RESEARCH AND REGULATORY AFFAIRS, U.S., LILLY RESEARCH
LABORATORIES, ACCOMPANIED BY STEPHEN SPIELBERG, VICE PRESIDENT,
DRUG DEVELOPMENT, JANSSEN RESEARCH FOUNDATION
Mr. Kearns. Thank you, Mr. Chairman, and members of the
committee. I am pleased to be here today to testify on behalf
of the pediatric provisions of FDAMA, and to come to you as a
person in the trench, clinical pharmacologist who is privileged
to care for children, to advocate for them, and to conduct the
clinical trials that we have been talking about this morning.
Before I begin, I would like to thank specifically
Representatives Greenwood and Waxman for being the champions of
this, and Congresswoman Karen McCarthy, a truly great citizen
of my home State.
Without question, the efficacy and safety of any drug is
provided for by its study and effective labeling. This goal is
not age specific. Labelling benefits adults as it does
children. You have heard before that for many, many years about
75 to 80 percent of all drugs marketed in our country have not
been adequately labelled for children, meaning neonates all the
way up through the teenagers. FDAMA was the first thing to come
along in the history of our Nation to change that.
We now have a new horizon to look to with respect to caring
for our children. FDAMA was the catalyst to remove children
from the status of being therapeutic orphans. This is critical
because we know that our kids do not vote. They do not possess
a financial or political portfolio sufficient to have them
heard. This one act, FDAMA and the pediatric provisions, have
made all the difference.
You have heard some about the statistics of this. I'll not
talk about all of them because they are in my statement, but I
want to point out that of the studies conducted to date in
pediatric patients, there are 409 carefully controlled trials,
all of which done with oversight of the FDA involving more than
50,000 children and having them participate in a safe manner.
The information that is gleaned from this has affected every
age group, all the way from children at the time of birth, as
I've said before, through adolescence. The fact that 18 drugs
have been labelled for children, not for trivial things but for
common pediatric diseases such as allergies and fever and
gastrointestinal disease, and then some critically important
things such as AIDS, obsessive compulsive disorder. We're not
talking about the odd things. We're talking about things for
kids that are common.
As you have heard before, the activity with regard to
labelling in the short 4 years of FDAMA has so outstripped
anything in any other period of time, it's purely an amazing
accomplishment.
Now there are folks who have been critical of these efforts
and quick to identify profits. But I would like to point out
some benefits, things that are hard to measure, things that are
difficult to put a dollar amount to. Specific benefits that go
with drugs, just a few examples, Midazolam, a commonly used
sedative drug studied under FDAMA. We found through the course
of those studies that there were specific adverse effects that
occurred in children with certain diseases that weren't seen
before.
Etodolac, an anti-rheumatic drug, used to treat the
inflammation in the joints of children with arthritis. Had
pediatric studies been done, we wouldn't have realized that the
dose required to treat a child is twofold higher than an adult,
which means children would have gotten this drug and it would
have failed.
Gabapentin, a drug used to treat seizures, a very serious
condition, we also found by virtue of doing studies in young
children, that the dose of Gabapentin was much higher for this
drug to work.
Last, Propofol, a drug used to cause anesthesia. We found
serious adverse effects in the course of studying this drug in
children, so much so that these have been incorporated into
labelling and will in an appropriate way restrict the use in
certain children. Now this is going to save tragedy. This is
going to save adversity. I can't put dollar figures to it. But
I can tell you with over 20 years of experience, it will make a
difference.
Now proof of benefit of FDAMA in my mind has been
demonstrated beyond question with respect to its impact to
children. But there are some collateral benefits that we
forget. The growth of infrastructures, to focus on pediatric
science, the utilization of this new knowledge to improve our
trials that we do, the creation of training opportunities for
young people, and yes, even the generic industry is going to
reap some benefits from FDAMA.
Each one of these drugs that are labelled for children at
the expense of the innovator company, that pediatric labelling
will carry through when that drug is a generic. Kids depend on
generic drugs just the same as seniors do. That labelling will
improve their utilization and their safety, and will protect
the generic industry from the harm associated with poorly or
unlabelled drugs.
Now it is one thing to have accolades, but the future is
bright. We have to look to the future. We have to improve what
we do. We have to put more money in the infrastructure. It's
not just about who is getting money, but how do we spend it.
There needs to be an Office of Pediatric Therapeutics within
the FDA. There needs to be more emphasis through NIH, as we've
heard earlier, to study drugs in children, and to create and
capitalize on the advancements.
The provisions of future legislation that are aimed at this
process are critical. It has been said before that children are
the greatest resource, and that he who helps a child helps
humanity. There is no question in my mind and the minds of my
colleagues in clinical pharmacology throughout the country,
that humanity has been helped by this wonderful act. I strongly
urge Congress to reapprove FDAMA and all of its pediatric
provisions in tact. Thank you very much.
[The prepared statement of Gregory L. Kearns follows:]
Prepared Statement of Gregory L. Kearns, Professor of Pharmacology and
Pediatrics, University of Missouri--Kansas City, and Chief, Division of
Pediatric Pharmacology and Medical Toxicology, Children's Mercy
Hospitals and Clinics, Kansas City, Missouri
Mr. Chairman, members of the Committee, I am Dr. Gregory L. Kearns,
a Professor of Pharmacology and Pediatrics at the University of
Missouri--Kansas City and the Chief of the Division of Pediatric
Pharmacology and Medical Toxicology at the Children's Mercy Hospitals
and Clinics in Kansas City, Missouri. As a Pediatric Clinical
Pharmacologist, I have been actively involved in the design, conduct,
interpretation and reporting of over 120 pediatric clinical trials
involving both old (i.e., approved) and new drugs for over two decades.
I am here today not representing a given professional organization or
corporate concern but rather, am honored to represent the small but
extremely active academic community of pediatric clinical
pharmacologists: health care professionals who are privileged to not
only advocate for children by direct involvement in their medical care
but most importantly, as the individuals tasked to create new knowledge
that is required to insure that pediatric patients are accorded the
same benefits of safe and effective drug therapy as are adults. It is
truly a privilege and distinct honor for me to address this Congress by
voicing support for re-authorization of the FDA Modernization and
Accountability Act of 1997 (known by the acronym, FDAMA) and in
particular, Section 111 of this act which provides a successful,
complete mechanism for the responsible and careful evaluation of
therapeutic drugs critical for the treatment and prevention of disease
in infants, children and adolescents.
I. INTRODUCTION
I would like to take this opportunity to express my genuine
appreciation to Congress and especially, to Representatives Henry
Waxman (D-CA) and Jim Greenwood (R-PA) for being the champions of one
of the most significant and beneficial federal initiatives aimed at
improving the health of our nation's children. I also want to sincerely
thank Representative Karen McCarthy (D- MO), a truly great citizen of
my home state of Missouri, for her continuing, ardent support of
children wrought through words and actions.
Without question, the safety and efficacy of any form of drug
therapy intended for a human of any age is enhanced through the process
of careful and critical investigation that results not simply in the
approval of a drug for marketing but rather, through its effective
labeling. Labeling insures that prescribers and other health care
professionals charged with monitoring and/or evaluating the outcome of
drug therapy have complete and accurate information upon which to base
decisions and execute their responsibility to patients. This general
goal is not ``age specific'' and in the case of adult therapeutics, has
been unequivocally proven to create individual (i.e., to a given
patient) and societal benefit. This tangible evidence of good is, to a
great degree, attributable to an evolution of therapeutic and
regulatory science, much of which has been wrought by innovation within
the Food and Drug Administration, the National Institutes of Health and
fueled by prudent and purposeful actions of Government. Despite these
important advancements for adult patients, approximately 75 percent of
all prescription drugs marketed in the United States have not been
adequately labeled for use in infants, children and/or adolescents;
many of which are routinely used by physicians in attempts to improve
the health of their patients. The dearth of pediatric-specific
information contained in approved product labeling is not trivial when
one recognizes that for the majority of these drugs, complete
information to enable the most basic therapeutic requirement, the
provision of age-specific/appropriate dosing guidelines, is not
present. A related problem is that many medications not approved for
use by children are not manufactured in dosage forms that can be
readily and/or safely administered to infants and young children. For
example, many medications are provided in capsule or tablet forms that
cannot be swallowed by small children and/or are not available in small
enough dosage increments to permit accurate, safe drug administration.
These ``deficiencies'' can only serve in a collective manner to
increase the risk of adversity in the course of providing drug therapy
in pediatric patients.
It is important to note that this particular situation has not
changed appreciably in the 30 years preceding enactment of FDAMA. It is
for these reasons that pediatric patients were relegated to the status
of therapeutic orphans, thereby placing the most vulnerable portion of
our population at increased therapeutic risk as compared to adults.
This therapeutic travesty was not perpetuated by scientific ignorance
but rather, through inaction fueled by unfounded fears of harm, risk
and the relative absence of a credible political and financial
portfolio possessed by our Nation's children. Fortunately, FDAMA
conjoined with the 1998 Pediatric Final Rule, provides a most effective
``weapon'' to bring pediatric therapeutic injustice to an end.
II. BENEFITS FOR CHILDREN
On November 21, 1997, former President William Jefferson Clinton
signed FDAMA into law; an action that had tremendous bipartisan support
given its focus on our nation's children. Included in the bill is a
provision (i.e., Section 111) that encourages pharmaceutical companies
to conduct specific pediatric clinical trials of drugs with
demonstrated substantial therapeutic use in pediatric patients and
hence, are deemed important for pediatric therapeutics. These trials
are to be conducted in complete accordance with the highest ethical and
scientific standards guaranteed through FDA oversight of the drug
development process. This particular provision of FDAMA also allows
for, but does not promise, the granting of up to six months of
additional market exclusivity to new and already marketed drugs for
which the Secretary of Health and Human Services (HHS) issues a written
request for pediatric studies. Hence, the process associated with
Section 111 is well organized, orderly and squarely focused on the
responsible pursuit of information requisite for improving pediatric
therapeutics. We must not lose sight that Section 111 of FDAMA was
developed for children to specifically serve them and those in our
society who are charged with their medical care. By doing so, it
provides for the first time in the history of the United States a
mechanism to insure that pediatric patients are accorded the same
``therapeutic rights and privileges'' that we have so carefully
provided for adults.
III. FDAMA ACCOMPLISHMENTS--PROOF OF CONCEPT
The statistics associated with FDAMA are indeed both impressive and
staggering. As of April 1, 2001, pharmaceutical companies have proposed
to FDA the study of a total of 218 drugs which in turn, has resulted in
the issuance of 188 formal written requests for the conduct of
pediatric clinical trials involving a total of 154 active drug
moieties. Collectively, these trials represent 409 carefully controlled
clinical investigations conducted in well over 50,000 pediatric
patients, with approximately 20% involving neonates and young infants
and 30% involving children from adolescence down through 2 years of
age. Hence, the data support involvement of the entire pediatric
spectrum in a large number of clinical trials that address unmet
therapeutics needs in children with markedly diverse medical
conditions.
To date, FDA has granted extended marketing exclusivity to 33 drug
moieties--only 21% of the total amount subject to formal written
requests. Of these 33 drugs, 17 (i.e., 52%) have had major revisions of
the approved product labeling; a process that may take 8-18 months
after extended marking exclusivity has been granted. Of further note is
that 12 of these 17 drugs (i.e. 71%) have extensive, routine
therapeutic use in pediatric patients and are used to treat a wide
variety of conditions that afflict infants and children including
fever, allergies, AIDS, gastrointestinal reflux, obsessive-compulsive
disorder, hypertension and pain. Finally, contrary to the many
assertions that have appeared in the lay press over the recent past
that only ``blockbuster'' drugs (i.e., those with greater than $1
billion in annual sales) are the subject of the pediatric exclusivity
provisions of FDAMA, only 2 of the 17 drugs labeled for children meet
this criteria. Without question, the degree of productivity that has
occurred over 4 short years as a direct result of the provisions
contained in Section 111 is remarkable and unparalleled given that in
the 10 years preceding enactment of this legislation, only 11 drugs
were formally (i.e., under the aegis of the FDA) studied in pediatric
patients out of the 70 ``promised'' by the pharmaceutical industry.
Thus, FDAMA works for children and works extraordinarily well.
Those individuals, groups and corporate concerns who are critical
of the aforementioned success story have been quick to identify the
apparent ``profits'' that accrue to the pharmaceutical industry as a
result of the provisions of Section 111 and to estimate the ``costs''
to the adult segment of our society produced by delayed entry of
generic pharmaceutical products to the market place. Relatively
speaking, these particular ``figures'' are easy to generate despite
their not being totally supported by fact and their dependence upon
assumptions. What is more difficult to quantitate are the potential
beneficial health implications (and their associated financial impact)
to infants, children and their families that result from the new
information obtained from clinical trials conducted under Section 111
and now contained in the approved product labeling for 17 marketed
drugs, all of which have a history of substantial pediatric use.
Several specific examples are as follows:
Midazolam (a sedative agent commonly used in medicine and
dentistry): Determination of age- specific doses of a new oral
liquid formulation in infants and children. Also,
identification of specific adverse events associated with
concomitant medicines given to pediatric patients and in
infants and children with specific disease states (e.g.,
congenital heart disease, pulmonary hypertension).
Etodolac (an anti-inflammatory drug used to treat children
with debilitating rheumatoid arthritis): Demonstration of the
need for a markedly increased dose in young children (i.e.
approximately 2-fold higher than adults on a weight-adjusted
basis) as compared to adults in order to prevent lack of
efficacy from ``under-dosing'' in pediatric patients.
Fluvoxamine (an antidepressant used to treat children and
adolescents): Demonstration of a higher dose requirement only
for female patients 8 to 11 years of age, thereby demonstrating
both age- and sex-specific determinants of drug efficacy.
Gabapentin (an oral medication used to treat a variety of
seizure and other central nervous system disorders in both
adults and children): Demonstration of a requirement for a
marked increase in weight-adjusted dose for children less than
5 years of age as compared to older children in order to
attain/maintain effective blood levels of the drug.
Propofol (an intravenous agent used in adults and children to
induce/produce anesthesia and for protracted sedation in adult
and pediatric patients in the intensive care unit):
Demonstration of potentially serious cardiac dysrhythmias in
patients concomitantly treated with fentanyl (a narcotic
analgesic) and also, production of central nervous system
symptoms (e.g., flushing, agitation, tremulousness and
hyperirritability) seen after abrupt discontinuation of the
drug following prolonged infusion. These adverse events in
association with possible differences in mortality in patients
in the intensive care unit treated with propofol resulted in
recommendation against its use (i.e., not indicated) for
sedation of patients in the pediatric intensive care unit.
Sevoflurane (a widely used inhaled anesthetic agent):
Information added to the label warning of the potential for
drug-associated seizures in children.
These illustrations provide tangible evidence of how the risk
profile for many potentially useful drugs will be improved through the
revelation of new pediatric-specific knowledge translated into approved
product labeling--all of which was enabled by their careful, controlled
study in pediatric patients resulting directly from the pediatric
exclusivity provisions of FDAMA. Thus, the evidence is clear. Children,
the intended ``target'' of Section 111 of FDAMA have been the direct
beneficiaries of this legislation. Proof of concept has been
demonstrated beyond question.
IV. COLLATERAL BENEFITS OF FDAMA
Those who question either the wisdom or importance of renewing
FDAMA and maintaining the integrity of its provisions completely ignore
the indirect benefits that have resulted from this legislation.
Important collateral benefits have accrued to society as a direct
result of the marked expansion in pediatric clinical pharmacology
research wrought by the opportunities and requirements afforded by the
provisions of Section 111 of FDAMA. Examples of several of these are
briefly summarized as follows:
The growth and creation of federally funded infrastructures
(e.g., the National Institute of Child Health and Human
Development network of Pediatric Pharmacology Research Units,
the AHRQ-funded Centers for Education and Research in
Therapeutics) dedicated to the conduct of not only pivotal
clinical research in pediatric pharmacology (which includes
phase I and II clinical trials) but also, basic and
translational research in the area of developmental
pharmacology and therapeutics.
Creation of a pediatric infrastructure within the Food and
Drug Administration (e.g., the ``Pediatric Team'') and many
major pharmaceutical companies to not only implement the
provisions of FDAMA but most importantly, to provide an
experienced ``platform'' capable of working cooperatively to
develop pediatric clinical investigations of sufficient rigor
to answer critical questions pertaining to pediatric labeling
and to augment the activities of the Review Divisions within
FDA to insure that the welfare of children is served throughout
the entire drug development process.
Scientific enrichment of pediatric clinical drug trials by the
inclusion of new technology and utilization of the ``new
biology'' (e.g., molecular biology, pharmacogenetics,
pharmacogenomics) in an attempt to glean the most information
possible from a given pediatric investigation and to create new
knowledge regarding the impact of development on drug
disposition and action.
Direct and dynamic utilization of new knowledge in
developmental pharmacology (e.g., the impact of age on the
activity of drug metabolizing enzymes and renal function, the
impact of growth and development on drug action--both intended
and adverse) to continually improve the design and scientific
rigor of clinical trials conducted in infants and children
without increasing the risk to subjects participating in these
critically important studies.
Development of a new ``model system/approach'' for the design
and conduct of pediatric clinical trials that is setting the
standard for this activity throughout the world (e.g., the ICH
E-11 guidance, new initiatives being undertaken by Health
Canada and the Canadian Paediatric Society and the European
Society of Developmental Pharmacology).
Creation of both a need and opportunity to attract young
Pediatricians and other biomedical scientists to the discipline
of Pediatric Clinical Pharmacology to receive the education and
training necessary to fill the profound ``gaps'' that currently
exist for properly trained individuals within academic
programs, the pharmaceutical industry and government (e.g., FDA
and NIH). This is critical to insure that the progress made on
behalf of children during the last four years will continue and
most importantly, continue to evolve during the years to come.
Expansion of pediatric labeling to generic drug products
afforded by FDAMA. It is critical for all to understand that
both adult and pediatric patients benefit from the availability
of high quality generic drug products. As is the case for
``branded'' (i.e. non-generic) drug products, a critical
safeguard to insure the safety and efficacy of generic drugs in
pediatric patients is the inclusion of age-specific labeling
information to guide prescribers in their use. The provisions
of Section 111 provide the avenue for the inclusion of
pediatric information in product labeling that will be
maintained when a product makes the ``switch'' from proprietary
to generic status; the direct costs for which are 100% borne by
the innovator company. Hence, the generic drug industry stands
to receive considerable direct (e.g., evidence-based
advertising/promotion) and indirect (e.g., reduction of risk
from litigation regarding adverse drug effects in pediatric
patients through inclusion of accurate pediatric data in the
approved product labeling) benefits from FDAMA.
V. RECOMMENDATIONS TO INSURE CONTINUED BENEFIT FOR CHILDREN
My comments regarding the importance of FDAMA and its provisions
pertaining to the health and welfare of children echo those made by
several individuals on the panel with me this day and many thousands of
other pediatric health care professionals who, on a daily basis, serve
as advocates for children. The success of FDAMA and our collective
efforts to improve the lives of children demand not only the
administration of accolades but most importantly, that we all
critically examine the future of this legislation so as to guarantee
the successes brought about by its provisions. For FDAMA to evolve in a
manner characterized by continuous quality improvement, our government
will need to nurture this program to insure its effective growth and
development. To accomplish this goal, I offer the following
recommendations for consideration by Congress:
Creation of a mechanism whereby drugs that are off-patent and
are commonly used in pediatric patients (e.g., the list of the
top 100 drugs used in pediatric practice) can be studied in
children with appropriate FDA oversight so as to enable
critical information pertaining to pediatric use to be included
in the approved product labeling.
The development of provisions to both shorten the time between
approval of a Supplemental New Drug Application and when new
pediatric information is inserted into the approved product
labeling to six months. Coupled with this provision should be a
mechanism to rapidly disseminate pediatric use information to
both the professional and lay public.
While FDA has implemented FDAMA to certain measures of
success, it has done so without sufficient financial or
personnel resources to completely accomplish these important
objectives in a truly exemplary manner. As a result, challenges
currently exist that range from inordinate delays in the timely
review of study proposals involving pediatric clinical trials
to recommendations for protocol design and conduct that may not
best serve the true clinical objectives of product labeling for
pediatric patients. A solution to these challenges would be the
establishment of a new Office of Pediatric Therapeutics within
FDA. This new Office should be staffed with pediatricians and
other biomedical scientists skilled in pediatric/developmental
pharmacology and accordingly, who would be fully capable of
insuring that a critical and age-appropriate approach is taken
to the design of pediatric clinical trials and the
interpretation of the data from them. The Office of Pediatric
Therapeutics would drive the process of pediatric drug
development across the FDA and through a collaborative working
relationship with pharmaceutical companies, would be in a
position to markedly improve the quality and quantity of all
pediatric efforts within the Agency.
Establish a provision whereby pharmaceutical companies who are
conducting pediatric clinical trials pursuant to a formal
written request issued by FDA would pay a ``user fee''
designated to specifically support the Office of Pediatric
Therapeutics. The consequences of these directed user fees
would provide support for the establishment of the
aforementioned Office within FDA and also, would increase the
number of pediatric studies requested, insure more timely
review of these studies and as a result, achieve the expansion
of pediatric labeling in a more expeditious fashion.
Provision of substantial and sustaining line item support
within the general NIH and FDA budget for efforts that are
squarely targeted at research and education in pediatric
clinical pharmacology and therapeutics. Such efforts should
include marked expansion of the core funding for the NICHD
Pediatric Pharmacology Research Unit Network, the provision of
additional funds to NICHD to support up to 15 postdoctoral
fellowship positions in pediatric clinical pharmacology on an
annual basis, the creation of a standing Scientific Review
Group (i.e. study section) within NIH dedicated to pediatric/
developmental pharmacology and therapeutics and the allocation
of additional funding within NIH (e.g., to AHRQ) to support the
creation of up to seven pediatric Centers for Education and
Research in Therapeutics (i.e., CERTs) within the U.S.
Collectively, these actions would insure continued evolution of
the scientific infrastructure necessary to insure that the
science of pediatric pharmacology and therapeutics will be
sufficient to service the remarkable opportunity created for
our nation's children provided through the pediatric provisions
of FDAMA.
Based upon all the objective evidence, it is clear that the
provisions of any future legislation aimed at the drug development
process must contain provisions sufficient to insure and sustain
benefit for infants, children and adolescents. In four short years,
Section 111 of FDAMA has done more to improve the health and welfare of
children in the U.S. and abroad than any other pediatric therapeutic
initiative in the history of our country. To terminate the provisions
of this initiative or substantially alter them in any way would once
again relegate infants and children to the status of therapeutic
orphans and thereby, disadvantage them to the point of harm. It has
been said, ``he who helps a child, helps humanity'' and ``how a society
is viewed is in large sense determined by how a society cares for its
children''. Thus, I emphatically urge this Congress to act prudently
and decisively in support of our country's most valuable asset, our
children, by renewing FDAMA and also, further increasing the level of
support provided to the scientific initiatives in pediatric clinical
pharmacology and therapeutics fueled by this landmark legislation.
I would like to thank the committee for affording me the
opportunity to share with you my comments and recommendations. It would
be my pleasure to respond to any questions that you may have.
Mr. Bilirakis. Thank you very much, Dr. Kearns.
Ms. Ben-Maimon?
STATEMENT OF CAROLE BEN-MAIMON
Ms. Ben-Maimon. Good afternoon, and thank you for inviting
me to testify on behalf of the Generic Pharmaceutical
Association.
GPHA represents manufacturers, suppliers, distributors, and
marketers of generic drugs. My prepared testimony this morning
will focus on the pediatric provisions of FDAMA, provisions
that I would like to comment on not only as a physician and
chair of GPHA, but also as the mother of three children.
Let me begin by making it clear that GPHA supports the goal
of encouraging meaningful clinical research aimed at expanding
the safe and effective use of drugs in children. We all want
the best for our kids, and we all need to make sacrifices in
order to ensure that their health is improved.
However, while GPHA supports the goal of encouraging
clinical research to benefit the pediatric population, we
believe the incentive must be balanced with competing health
concerns, and must be designed to ensure that real medical
advances are achieved. This type of program must ensure that
children are exposed to clinical research only when the
research is designed to provide meaningful results, that
outcomes are proportional to the sacrifices being made by lower
income, elderly patients when entry of quality, affordable,
generic drugs are delayed, and that appropriate tools are used
to evaluate the quality of information being obtained and the
true cost and benefits.
GPHA recognizes that Congress did not pass the pediatric
exclusivity law with the intention of increasing the already
robust profits of major drug companies by involving children in
frivolous medical experimentation. Congress' intention was
clearly to provide 6 months of additional exclusivity for brand
companies in exchange for serious, rigorous, original clinical
studies that have the clear potential to provide needed
therapeutic information. Unfortunately, we are concerned that
this has not always been the outcome.
In many cases, the investment in pediatric testing and the
information obtained from such testing pale in comparison to
the financial windfall given to brand pharmaceutical companies
and to the enormous financial burden inflicted on the consumer.
We are concerned that pediatric exclusivity provisions have
been in place for 4 years, and there is still no well-defined
system for measuring its success, its benefits to our pediatric
population, and its costs to those who need more affordable
pharmaceuticals.
According to the Wall Street Journal, and I'm quoting,
``The studies required to gain 6 more months of marketing
exclusivity are relatively small and inexpensive, costing
anywhere from $200,000 to $3 million. But the extended
exclusivity that results can be very valuable. It will boost
drug company sales by more than $4 billion. That $4 billion is
only for the first 26 drugs tested under the program.''
According to the Journal, another 200 proposals to test drugs
on children, worth $6 billion, are pending at FDA. Over the
next 20 years, estimates are that brand name drug companies
will benefit from an additional $30 billion if the exclusivity
provision is reauthorized in its current form.
Congress would be well-advised to ascertain the true costs
of pediatric studies conducted by brand companies so that it
can make objective evaluation of the cost to society of the
additional 6 months of monopoly time brand industry
pharmaceuticals are awarded in exchange for these studies.
You know, Mr. Chairman, it just may be that Congress could
do this for much less cost doing it through research grants to
the NIH. Likewise, we need to consider the detrimental impact
on the consumer when pediatric exclusivity undermines
predictability in the marketplace. The generic industry has for
some time been begging for predictability. Under the current
law, generic companies cannot predict the time of launch for
their products because pediatric exclusivity can be awarded for
up to 60 days after patent expiration.
As Congress considers ways to reauthorize an incentive
system for pediatric research, we ask that you be extremely
careful to reauthorize a system in a way that does not
perpetuate the ability of the brand industry to use it as one
more tool to delay generic competition. One particular area
where Congress must be particularly cautious during the
reauthorization process is in the area of creating incentives
for the pharmaceutical industry to conduct research on off-
patent products. The goal is a worthy one. But if the system to
conduct such research is going to be implemented, Congress must
be sure the system does not allow the brand industry and its
surrogates to delay generic competition through manipulations
of labelling requirements and campaigns that question the
therapeutic equivalency of generic medicines. In addition,
generic companies should also be eligible for the same rewards
as their brand counterparts if they should elect to perform the
necessary research.
Mr. Chairman, as important as these issues are for
consumers, Congress, and the pharmaceutical industry, I want to
emphasize again that above all else in this debate, we support
children. As a mother, I can think of nothing more important
than providing incentives for meaningful clinical research that
will benefit my children and the children of others. Congress
should ensure that children enrolled in such studies are
protected and benefit from the risks they are taking, and that
corporate incentives, money and gifts given to children and
their parents, do not create perverse incentives in the
process.
Congress should look objectively and critically at the true
value of the data being generated, and also consider the impact
of sponsor grants and financial rewards to those experts
endorsing and conducting such studies.
Finally, Congress should try to ensure predictability in
the marketplace so that the price of pharmaceuticals can come
down for consumers, and explore incentives for needed research
that do not threaten market competition.
The GPHA supports your objective.
Mr. Bilirakis. Please summarize.
Ms. Ben-Maimon. One more sentence. Our primary objective is
to provide quality and affordable medicine to patients,
including children. We truly believe there are ways to improve
the system and we would like to work with you to determine
that.
[The prepared statement of Carole Ben-Maimon follows:]
Prepared Statement of Carole Ben-Maimon, Chair, Generic Pharmaceutical
Association
Good morning, and thank you for inviting me to testify on behalf of
the Generic Pharmaceutical Association. GPhA represents the
manufacturers, suppliers, distributors, and marketers of generic drugs
throughout America. My prepared testimony this morning will focus on
the pediatric exclusivity provisions of the FDA Modernization Act of
1997, provisions that I would like to comment on not only as a
physician and chair of GPhA, but also as the mother of three children.
Let me begin by making it clear that GPhA supports the goal of
encouraging meaningful clinical research aimed at expanding the safe
and effective use of drugs in children. We all want what is best for
our kids and are willing to make the sacrifices necessary to improve
their health.
However, while GPhA supports the goal of encouraging clinical
research to benefit the pediatric population, we believe the incentive
must be balanced with competing health concerns and must be designed to
ensure that real medical advances are achieved. This type of program
must ensure that children are exposed to clinical research only when
the research is designed to provide meaningful results, that outcomes
are proportional to the sacrifices being made by lower-income elderly
patients when entry of quality and affordable generic drugs is delayed,
and that appropriate tools are used to evaluate the quality of
information being obtained to determine the true costs and benefits.
GPhA recognizes that Congress did not pass the pediatric
exclusivity law with the intention of increasing the already robust
profits of major drug companies by involving children in frivolous
medical experimentation. Congress' intention, rather, was to provide
six months of additional exclusivity for brand companies in exchange
for serious, rigorous, original clinical studies that have the clear
potential to provide needed therapeutic information.
Unfortunately, we are concerned that this has not always been the
outcome. We are concerned that in many cases the investment in
pediatric testing--and the information obtained from such testing--pale
in comparison to the financial windfall given to brand pharmaceutical
companies and to the enormous financial burden inflicted on the
consumer. For instance, pediatric clinical testing that does nothing
more than assess children's reactions to the fifth or sixth ``me-too''
drug in a particular therapeutic class makes no meaningful contribution
to doctors' ability to treat the relevant disease. We are concerned
that pediatric exclusivity provisions have been in place for four years
and there is still no well-defined system for measuring its success--
its benefits to our pediatric population and its costs to those who
need more affordable pharmaceuticals.
According to the Wall Street Journal, ``The studies required to
gain six more months of marketing exclusivity are relatively small and
inexpensive, costing anywhere from $200,000 to $3 million. But the
extended exclusivity that results can be very valuable. It will boost
drug-company sales by more than $4 billion.'' And that $4 billion is
only for the first 26 drugs tested under the program. According to the
Journal, another 200 proposals to test drugs on children, worth $6
billion, are pending at FDA. Over the next 20 years, estimates are that
brand-name drug companies will benefit from an additional $30 billion
if the exclusivity provision is reauthorized in its current form.
We know that the impact on the American public is significant. The
FDA has estimated that a six month exclusivity reward for pediatric
research raises the costs of prescription drugs $695 million a year.
These are considerations that need to be heard. Congress would be well-
advised to ascertain the true costs of pediatric studies conducted by
brand companies so it can make an objective evaluation of the cost to
society of the additional six months of monopoly time brand industry
pharmaceuticals are awarded in exchange for these studies. You know,
Mr. Chairman, it just may be that Congress could achieve the results it
desires in a far less costly way--doing the research on its own through
organizations like NIH.
Likewise, we need to consider the detrimental impact on the
consumer when pediatric exclusivity undermines predictability in the
marketplace. The generic industry has--for some time--been begging for
predictability. Under the current law, generic companies cannot predict
the time of launch for their products because pediatric exclusivity can
be awarded up to 60 days after a patent expires.
As Congress considers ways to reauthorize an incentive system for
pediatric research, we ask that you be extremely careful to reauthorize
the system in a way that does not perpetuate the ability of the brand
industry to use it as one more tool to delay generic competition.
History has taught us that if there are flaws in the law that allow for
exploitation, this exploitation will occur.
One particular area where Congress must be particularly cautious
during the reauthorization process is in the area of creating
incentives for the pharmaceutical industry to conduct research on off-
patent products. The goal is a worthy one. But if a system to conduct
such research is going to be implemented, Congress must be sure the
system does not allow the brand industry and its surrogates to delay
generic competition through manipulations of labeling requirements and
campaigns that question the therapeutic equivalency of generic
medicines. In addition, generic companies should also be eligible for
the same rewards as their brand counterparts, if they should elect to
perform the necessary studies.
Mr. Chairman, as important as these issues are for consumers,
Congress, and the generic pharmaceutical industry, I want to emphasize
again that above all else in this debate, we support children. As a
mother, I can think of nothing more important than providing incentives
for meaningful clinical research that will benefit my children and the
children of others. Congress should ensure that children enrolled in
such studies are protected and benefit from the risks they are taking,
and that corporate incentives, money, and gifts given to children and
their parents do not create perverse incentives in the process.
Congress should look objectively and critically at the true value of
the data being generated and also consider the impact of sponsor grants
and financial rewards to those experts endorsing and conducting such
studies. And finally, Congress should try to ensure predictability in
the marketplace so that the price of pharmaceuticals can come down for
consumers and explore incentives for needed research that do not
threaten market competition at a time when the public is clamoring for
relief from the high price of prescription drugs.
The Generic Pharmaceutical Association supports your objective. Our
primary objective is to provide quality and affordable medicine to
patients--patients that include the pediatric population. We truly
believe there are ways to improve the current system. And we would
welcome the opportunity to work with you on a matter that is so
important to all of us.
Thank you.
Mr. Bilirakis. Thank you very much.
Dr. Gorman?
STATEMENT OF RICHARD GORMAN
Mr. Gorman. Mr. Chairman, and members of the committee, as
a practicing pediatrician for 23 years, I am beginning to see
first hand in my office on a daily basis the benefits of this
FDAMA and the PDUFA provisions. I am pleased to be here today
to represent the 55,000 pediatricians of the American Academy
of Pediatrics. The pediatric academic research community that
includes the Ambulatory Pediatric Association, the American
Pediatric Society, and the Society for Pediatric Research, also
support and endorse the Academy's testimony.
The Academy of Pediatrics is here today to extend our
sincerest thanks to Congress, and especially to Representatives
Jim Greenwood and Henry Waxman, for championing one of the most
extraordinarily successful Federal initiatives that have ever
been accomplished for children.
As a pediatrician and health professionals, we cannot
overstate how critical the passage of the pediatrics studies
market exclusivity provision within the FDAMA has been toward
achieving medical therapeutic advances for children. For the
sake of children and infants both in the United States and
internationally, we strongly believe that this legislation must
be reauthorized before it expires on January 1, 2002.
To fully understand the positive impact this law has had
for children, I think you are pretty well aware of what has
happened for the 40 years before FDAMA was approved. Despite
several aggressive efforts by the Food and Drug Administration
over the past 40 years to secure more studies to support more
complete usage for children, there continue to be a continuing
and alarming lack of pediatric drug labelling and information.
For the decades prior to FDAMA, children were the canaries
in the mine shafts that acted as the catalyst for change to
improve the safety and effectiveness of medications for all the
people in the United States. It would have been reasonable to
assume that since children's suffering enabled these safety and
efficacy changes to be made, that children would have benefited
from these changes. But remarkably, that was not the case.
Children suffer from the vast majority of diseases and
conditions that occur in adults. Just like for adults,
medications help heal conditions or ease childs' discomforts.
In a little more than 3 years, the pediatric information
available through FDAMA has been dramatic. Over 188 written
requests have been made for 400 pediatric studies. Passage of
the pediatric studies provision has begun a tidal wave of
momentum in building the structures that will be needed to
continue to get more pediatric studies and more pediatric
information available and in the hands of the health care
providers.
The Food and Drug Administration must be commended for the
extraordinary work they have done we think in fairly and safely
implementing the pediatric studies law. The benefit of these
pediatric study provisions for children have been considerable.
Child-friendly formulations will soon be available. It's
wonderful to have a wonder drug, but if your child won't take
it, it is not of much use. The pediatric formulations will be
coming down through FDAMA.
Better labeling will reduce medical errors and adverse
effects. Pediatric labelling can achieve considerable cost
saving to the healthcare system. The FDA has calculated that if
better labeling eliminated just 25 percent of the
hospitalization differential to the five most common diseases
that children come into the hospital for, this effect would
lead to the direct medical cost savings of $228 million
annually.
The success of the pediatrics studies provision must be
preserved and enhanced. The AAP believes there are several
proposals that will further improve therapeutics for children.
We support the inclusion of off-patent drugs. The AAP strong
urges Congress to include a provision for off-patent drug
studies in the reauthorization legislation.
Label changes. The AAP urges Congress to explore ways to
expedite the translation of the new information onto the label.
We also urge the dissemination of pediatric use information.
The AAP urges Congress to explore ways to disseminate
information generated from the pediatric studies.
For neonates, the AAP would urge Congress to acknowledge
the need to study this pediatric population if appropriate, and
at the appropriate point in pediatric studies.
We support the establishment of an Office of Pediatric
Therapeutics within the FDA. The AAP urges Congress to provide
appropriate funding and other needed resources for a newly
created Office of Pediatric Therapeutics within the FDA.
We wish to support the application of prescription drug
user fees to pediatric studies. AAP urges Congress to instate
prescription drug user fees for companies seeking pediatric
exclusivity.
I would like to thank the committee for allowing me the
opportunity to share with you the thoughts of the American
Academy. Once again, I restate our strong support for the
reauthorization of the pediatric studies provision within
FDAMA. Thank you.
[The prepared statement of Richard Gorman follows:]
Prepared Statement of Richard Gorman, on Behalf of the Ambulatory
Pediatric Association, American Pediatric Society, Association of
Medical School Pediatric Department Chairs, and the Society for
Pediatric Research
Mr. Chairman, members of the Committee, I am Richard Gorman, MD,
FAAP, a practicing pediatrician who has taken care of infants, children
and adolescents for over 23 years. Though I am a Clinical Associate
Professor of Pediatric at the University of Maryland School of
Medicine, it is through my practice Pediatric Partners in Ellicott
City, Maryland where I see first-hand the pediatric therapeutic
benefits of which we talk today. With over 80,000 pediatric visits
annually in the five clinical sites in four counties in Maryland, I and
my partners can attest to the importance of this pediatric provision.
The pediatric academic research community that includes the
Ambulatory Pediatric Association, American Pediatric Society,
Association of Medical School Pediatric Department Chairs and the
Society for Pediatric Research also supports and endorses the Academy's
testimony. These societies comprise academic generalist pediatricians,
pediatric researchers, and full time academic and clinical faculty
responsible for the delivery of health care services to children, the
education and training of pediatricians, and the leadership of medical
school pediatric departments.
I. INTRODUCTION
The American Academy of Pediatrics is here today to extend our
sincerest thanks to Congress, and especially to Representative Jim
Greenwood (R-PA) and Henry Waxman (D-CA), for championing one of the
most extraordinarily successful federal initiatives that has ever been
accomplished for children. As pediatricians and health professionals we
can not overstate how critical the passage of the pediatric studies
market exclusivity provision within the within the Food and Drug
Administration Modernization Act (FDAMA--P.L. 105-115) has been toward
advancing medical therapies for infants, children and adolescents. For
the sake of infants and children throughout the United States and
internationally, we strongly believe that this legislation must be
reauthorized before it expires on January 1, 2002.
The American Academy of Pediatrics (AAP) believes that the
pediatric studies provision in FDAMA has advanced therapeutics for
infants, children and adolescents in a way that has not been possible
in several decades prior to passage of this law. Despite several
efforts by the Food and Drug Administration (FDA) over the past 30
years to secure more studies to support more complete usage information
for children, the alarming lack of pediatric drug labeling and
information available to pediatricians and other health professionals
continued. Statistics as recent as 1998 highlight the need for
pediatric drug studies. As recently as 1998 only 20 percent of the new
drugs approved by the JFDA had been studied and labeled for pediatric
use.
For decades prior to FDAMA children were the catalysts for changes
to improve the safety and effectiveness of medications in the United
States but rarely reaped the benefits of those therapeutic advances.
Children acted as the canaries in the mineshafts, dying more quickly
and in greater numbers from therapeutic mishaps. The Food and Drug
Cosmetic Act came into being in 1938 as a result of the death of 107
children from sulfanilamide elixir. Then in 1962 another pediatric
tragedy--fetal malformation from maternal ingestion of thalidomide--led
to an amendment to the FDCA that stated that drugs not only had to be
safe but also effective in the population for which they were marketed.
It would be reasonable to assume that since children's suffering
enabled these safety and efficacy changes to the law to occur, that
children would have benefited from those changes. But remarkably, that
was not the case.
Despite repeated efforts by the Food and Drug Administration to
include the pediatric population in therapeutic advances, it was not
until passage of the pediatric studies provision within FDAMA that we
have begun to realize that goal.
Now, in just a little over 3 years, the pediatric information
available through FDAMA is dramatic. We have over 188 written requests
issued for companies to study drugs in children, representing over 400
pediatric studies. By comparison, in the seven years prior to FDAMA
eleven studies of marketed drugs were completed, though 70 studies were
promised. To complete the picture: FDA has granted 28 products
exclusivity and 18 products include new labeling that provides dosage,
safety and adverse event information that assist pediatricians in
treating children with the correct dose and in avoiding potential
toxicities when medicating children. (NOTE: The process of labeling
begins after the exclusivity has been granted. The labeling process can
take between 8-18 months)
II. BENEFITS FOR CHILDREN
To fully understand the positive impact that this law has had for
children's therapeutics, you must first understand the pediatric
situation prior to FDAMA.
Children suffer from the vast majority of diseases and conditions
that occur in adults. Whether it is hypertension, diabetes, heart
arrythmia, kidney infections, HIV/AIDS, pneumonia, gastrointestinal
disorders, asthma or cancer--children develop these very same diseases.
And so, just like for adults, medications to heal a condition or ease
the child's discomfort from those disorders are needed.
But for pediatricians, there is a feeling of ``Water water
everywhere, but little to drink''. Of all the thousands of medications
found to be safe and effective for adult disorders, only 25 percent are
labeled for pediatric use. That leaves pediatricians with two difficult
choices: 1) not use a medication that could provide relief and help to
the child because it is not labeled for use in pediatrics or 2) use the
medication off-label based on limited studies and/or the personal
experiences of health professionals.
This is an untenable position which pediatricians and other health
professionals are placed in: to either prescribe a drug without
sufficient information or withhold treatment that may provide the best
treatment for a child who is more vulnerable than adult. While off-
label use of medications is a legal and acceptable part of medical
practice by physicians, it should not be the standard. Unfortunately
for children, off-label use is the rule, not the exception, because of
the paucity of prescribing information for this population.
Passage of the pediatric studies provision has begun a tidal wave
of momentum toward getting more and better therapeutic information for
the pediatric population.
The Food and Drug Administration (FDA) must be commended for the
extraordinary work they have done in fairly and swiftly implementing
the pediatric studies law. They are working with limited staff and
financial resources to carry out this unfunded mandate in which they
have to accomplish an unprecedented number of pediatric research
protocols, new formulations, data review, and label changes.
The benefits of this pediatric studies provision for children are
considerable:
Better labeling will reduce medical errors and adverse effects.
Lack of proper information for pediatric patients related to dosing,
toxicity, adverse effects, drug interactions, etc. can lead to medical
errors and potential injury. Medication errors produce a variety of
problems, ranging from minor discomfort to substantial morbidity that
may prolong hospitalization or lead to death.
Pediatric labeling can achieve considerable cost savings to the
health care system. The FDA's January 2001 Report to Congress assessed,
in very broad terms, potential cost savings to the health care industry
that could follow the availability of expanded pediatric clinical
information. The FDA examined the hospitalization rates for five
serious illnesses (asthma, HIV/AIDS, cancer, pneumonia, and kidney
infections) and found significantly higher rates for children than for
middle-aged adults. FDA hypothesized that a substantial fraction of the
difference between these pediatric and adult hospitalization rates for
like disease conditions may be attributable to the greater range of
informed drug therapies and better data on drug dosage for adults. The
FDA calculated that eliminating just 25 percent of the differentials
for these five illnesses would lead to direct medical cost savings of
$228 million annually.
Pediatric labeling can achieve considerable savings for federal and
state public and private programs. Dollars and cents arguments can not
adequately provide the evidence of the effectiveness and importance of
this program for children. Data are difficult, if not impossible, to
find that provides evidence of the cost to a state or the federal
government if a child is temporarily or permanently injured because of
an adverse effect of a medication used without benefit of proper study
and labeling for their age. Equally as impossible to determine is the
cost society has already assumed for less than optimal care for
children because medicines were not available for them. In addition,
the expense of lawsuits related to such occurrences are a financial
consideration.
Child-friendly formulations will be available. Even the most
effective ``wonder-drug'' can not improve a child's health if the drug
is unavailable in a formulation that a child can take (e.g., pills vs.
liquid) or if the taste is unpalatable to an infant or child.
Compliance with a prescription relies on the formulation. If a parent
has to struggle with the child every time a dose is needed, the
likelihood of completing the full prescription to obtain maximum
benefit is greatly reduced.
In addition, it should be noted that new pediatric formulations can
benefit the geriatric population who may also need liquid or
dissolvable formulations for medications.
III. SUCCESS BEGETS CRITICISM
It is disappointing to the AAP that something that is as
extraordinarily success for children has been met with unreasonable,
and in some cases unfounded, criticism that is risking the
reauthorization of this important program. This issue has become the
``darling of the press'' but the stories published do little-to-nothing
to acknowledge the public health benefits that have been and will
continue to be the result of the pediatric studies provision.
Criticism focuses on two main issues: 1) what is perceived as a
windfall profit to the pharmaceutical industry on drugs receiving
market exclusivity under the pediatric studies provision and 2) the
perceived increased risk of including children in pediatric trials
underway through FDAMA.
``Windfall Profits'' to Industry--When talking about ``windfalls''
from this legislation, it is essential to note that the greatest
windfall has been in the area of pediatric research and information now
available for pediatricians. And while it is necessary to assess the
economic impact of this pediatric exclusivity program on the taxpayer,
without a doubt, the greatest impact of this program will be on non-
taxpayers--the infants and children of this nation.
Dollars and cents arguments can not adequately provide the evidence
of the effectiveness and importance of this program for children. When
considering the cost to the public for keeping higher-cost drugs on the
market longer, it is reasonable to also consider the four decades when
children where therapeutic orphans--with very few drugs available for
their proper use. It is appropriate for the public to participate in a
program that affords our nation's children with the long-overdue
therapeutic information that has been granted to the adult population.
The AAP does not take lightly adding costs to the health care of
individuals, but we strongly believe that a parent or grandparent would
be agreeable to spending a few dollars more for 6 months in order to
ensure that the drug their child or grandchild was taking had the
appropriate dosing, safety and effectiveness information and that
adverse events were know at the time the drug was being prescribed.
AAP acknowledges that the 6-month period of exclusivity can provide
a limited number of drugs with a windfall profit from this incentive.
There may be ways to explore a better balance that gets both pediatric
studies done and limits the amount of profits that some of the
blockbuster drugs are receiving. In seeking that possible solution, one
tenet must apply--we must not lose the momentum and number of pediatric
studies that are currently underway. AAP urges caution in crafting a
solution that may satisfy the desire to limit industry profits but may
also limit the number of pediatric studies achieved under the pediatric
studies provision.
Children in clinical trials--As pediatricians our key focus is on
protecting children from harm. That is why we are pushing so hard for
reauthorization of the pediatric studies provision. And that is why we
work to ensure that pediatric clinical trials adhere to the highest
standards of scientific and ethical review. The AAP's Guidelines for
the Ethical Conduct of Pediatric Studies is used as a foundation for
conducting pediatric clinical trials.
AAP is very please with the increased number children in clinical
trials and the prospect of more children participating in trials. It is
a testimony to the success of this legislation. Through these important
clinical trials, information is generated and then disseminated for use
by pediatricians and other health professionals. What is the
alternative to including children in these well-controlled,
scientifically-valid pediatric studies? Having hundreds of thousands of
children taking medications in office settings or at home that have not
been properly studied. Subjecting children to daily uncontrolled,
unregulated, and unreported studies versus including a significantly
smaller number of children (thousands vs. hundreds of thousands) in
controlled clinical trials is a much-preferred alternative.
In addition, there are multiple levels of scientific and ethical
protections in place throughout the process of developing, conducting
and reviewing pediatric studies. Through the Children's Health Act
(P.L. 106-310) all research involving children that is conducted,
supported, or regulated by the Department of Health and Human Services
must be in compliance with subpart D of part 45 of title 46, Code of
Federal Regulations. That means that all the studies conducted as part
of the pediatric studies provision of FDAMA must adhere to those same
rigorous standards. In addition, each study site has an Institutional
Review Board (IRB) that oversees the quality and conduct of the
studies. And lastly, there is a review of the subpart D regulations
underway to ensure the adequate and appropriate protection of children
participating in research.
AAP believes we must be ever diligent to ensure that children are
protected in clinical trials. There is certainly room to improve the
protections that exist but as we move to strengthen protections, we can
be confident that children in clinical trials are being cared for in
optimal clinical settings.
III. NEED TO ENHANCE THE THERAPEUTIC BENEFITS
The success of the pediatric studies provision must be preserved
and enhanced. The AAP believes there are several proposals that will
further improve therapeutics for children.
INCLUSION OF OFF-PATENT DRUGS: In order to continue this successful
therapeutic march forward for children, Congress must consider
including a mechanism to study OFF-patent drugs--those drugs for which
the market incentives of the pediatric studies provision do not apply.
It was the intent of Congress in 1997 to address pediatric studies
for on-patent drugs--those drugs for which market exclusivity was still
running. As I have stated in my testimony, the AAP believes that the
progress made in studies of on-paten drugs has been successful and must
continue. But we still have a significant population of OFF-patent
drugs that are regularly used in children but do not fall within the
parameters of the pediatric studies provision of FDAMA.
The AAP strongly urges Congress to include a provision for OFF-
patent drug studies in the reauthorization legislation. AAP has been in
discussion with staff of several members of Congress to help develop a
reasonable and appropriate way of achieving the goal of getting
priority OFF-patent drugs studied in pediatric populations. We offer
our expertise and assistance as Congress moves forward on this issue.
LABEL CHANGES: The timeliness and thoroughness of label changes are
essential components to the success of helping children get the best
medications for their disease or condition. Getting more and faster
pediatric use information to the pediatricians and other physicians and
health professionals that prescribe medications to children is a
critical goal of the pediatric studies legislation. The AAP urges
Congress to explore ways to expedite label changes.
DISSEMINATION OF PEDIATRIC USE INFORMATION: Dissemination of
information is a critical component to the success of the pediatric
studies provision. While label information provides a critical piece of
information to pediatricians, due to space limitations on package
inserts often prevent important information from being published. There
are significant clinical findings that are necessary for pediatricians
and physicians to review (e.g., a dose change many not be statistically
significant to make it into the label but would be clinically important
information for a physician to review).
AAP urges Congress to explore ways to disseminate information
generated by pediatric studies.
NEONATES--The neonate population (0-1 month olds) is an extremely
important and difficult pediatric group to capture in pediatric
studies. While this population has not benefited significantly from the
pediatric studies provision, there is no easy fix. Prior to conducting
studies in 0-1 month olds, it is usually necessary to establish study
information in older pediatric populations. Given the vulnerability of
neonates, it is critical, both from a scientific and an ethical
standpoint, to be extremely cautious in designing neonates studies.
However, caution should not lead to lack of studies. Neonates also
develop hypertension, lung disease, infections, and congestive heart
failure. They deserve informed drug therapy for their disorders, also.
AAP would urge Congress to acknowledge the need to study this
pediatric population if appropriate and at the appropriate point in
pediatric studies.
ESTABLISH AN OFFICE OF PEDIATRIC THERAPEUTICS WITHIN FDA--In
assessing the effectiveness of the pediatric studies provision, it is
important to note that designing study protocols, overseeing studies,
reviewing scientific data, negotiating labels, staffing pediatric
advisory committees, and other related activities requires significant
FDA staff resources. To date, FDA personnel assigned to these tasks
have been detailed from other divisions and offices around FDA. The
Food and Drug Administration has made tremendous strides, with limited
resources, to implement this provision fairly and in a timely manner.
AAP is eager to increase the momentum that has been built over the
last three years, and believes that in order to do that, Congress must
establish an Office of Pediatric Therapeutics and provide the office
with sufficient resources in order to continue and expand pediatric
efforts. The Office should be charged with coordinating activities
among and between review divisions and provide oversight for all
pediatric activities undertaken by the FDA and coordinated with other
federal agencies.
The AAP urges Congress to provide appropriate funding and other
needed resources for a newly created Office of Pediatric Therapeutics
within the FDA.
APPLY PRESCRIPTION DRUG USER FEES TO PEDIATRIC STUDIES--Applying
prescription drug user fees to pediatric studies will assist FDA with
the resources to increase the number of pediatric studies requested,
conduct more timely reviews of pediatric studies and achieving labeling
faster.
AAP urges Congress to instate prescription drug user fees for
companies seeking pediatric exclusivity.
I would like to thank the committee for allowing me the opportunity
to share with you the strong support of the American Academy of
Pediatrics for reauthorization of the pediatric studies provision
within FDAMA.
I would be happy to take any questions you may have.
Mr. Bilirakis. Thank you, Dr. Gorman. I was busy here
listening to staff, but honestly it had directly to do with
your testimony. So I know it seemed a little rude. I apologize
for that.
Ms. Meyers?
STATEMENT OF ABBEY S. MEYERS
Ms. Meyers. Yes, sir. Thank you, Mr. Chairman.
I would like to focus on pediatric exclusivity and user
fees, but I want to mention two things that weren't in our
written testimony. That is, there were two important provisions
of FDAMA that have been very successful. First, the notice of
discontinuance, which requires companies to tell the FDA 6
months before they intend to discontinue manufacture of a drug.
Originally we had asked for 1 year for this notice, but the
industry negotiated it back to 6 months.
In the last year, you have probably been reading a lot
about old drugs that companies are dropping and patients are
actually desperate when they go to the pharmacy to pick up
their next prescription, and find out nobody is making the drug
any more. So this is a very important provision. FDA is putting
these drugs on the Internet. Pharmacists and doctors and
patients can look at that area on the Internet and find out
which drugs are going to be in short supply and which have been
discontinued.
In FDAMA reauthorization, we would like to see that
expanded to 1 year. This will give other companies a chance to
perhaps license the drug so it won't just stop being available.
Also, the clinical trials data base was in FDAMA. That is
another very successful program. FDA put it on the Internet
about a year ago. People from all over the world are using it
to find out if there are any clinical trials on their disease.
The problem there is that it only requires government-funded
clinical trials. The industry doesn't put studies on unless
they agree to. We really would like to see privately funded
clinical trials on that data base too.
Now as for the pediatric exclusivity, it is critically
important for children. Physicians need to know how to
prescribe these drugs. It has been successful in enticing
companies to study the drugs, but at a very high price to
society.
You have to make it better. You have to fix the problems.
Out of the hundreds of studies that have been done, I think
somebody mentioned over 400 studies, only 18 drugs have been
relabeled for pediatricians. What use are those studies if the
pediatricians can't learn from them?
One of the problems is that the companies negotiate
labeling with the FDA. The FDA can't tell them to change their
label. Those negotiations are dragged out, 1 year, 1\1/2\
years, 2 years. Meanwhile, the pediatricians don't know how to
prescribe the drug. A lot of the problem is sometimes the
relabeling is bad news. It says that the drug shouldn't be used
on children. The companies are generally afraid that that bad
news on the label might scare doctors off. But for the sake of
safety in children, Congress must mandate the relabeling. There
should not be any negotiations.
The research also is being focused primarily not on the
drugs that children need the most, but on the most profitable
drugs. This is a real problem. Of course drugs for asthma, for
example, are not being studied. Yet millions of children are
taking them, along with antibiotics and other types of drugs.
Six months of exclusivity for an antihistamine or an
antidepressant can mean $1 billion in sales. That is a lot of
money for a drug company to make from a study that cost very,
very little money. They don't have to really prove the basis of
the drug. We already know it's effective. They are just looking
for dosage.
Drugs with small annual sales are not being studied.
Generic drugs are not being studied. So the law is costing
American consumers and particularly elderly Medicare patients
billions of dollars.
FDA awards exclusivity on all forms of the drug. If they
study an intervenous form the drug, why should the tablets and
the capsules get the exclusivity? Why should the over-the-
counter drug get the exclusivity? They should only really get
the exclusivity on the drug that was studied, the form of the
drug.
Most important, the exclusivity should not be awarded until
the label is changed. The law also has to contain human subject
protections. FDA doesn't have one bioethicist on staff. It is
critically important that you give enough money to the FDA to
hire bioethicists. It has taken 22 years for the FDA to issue
human protection rules for pediatrics. They first proposed it
in 1979. It was just published, 22 years.
In a way, the drug is taxing the elderly for the sake of
the young. I think that that is something that has to be looked
at. We have given you some suggestions in our written
testimony, to look at the possibility of tax credits to cover
the cost of pediatric trials, maybe 125 or 150 percent of the
cost of the pediatric trials so the companies can make some
money on it, and also to award the length of exclusivity
according to the annual sales of the drugs. Antihistamines
should get a smaller amount than an orphan drug for a rare
disease, for example.
Thank you, Mr. Chairman.
[The prepared statement of Abbey S. Meyers follows:]
Prepared Statement of Abbey S. Meyers, President, The National
Organization for Rare Disorders
Mr. Chairman and members of the Committee, thank you for this
opportunity to speak with you today about the reauthorization of the
FDA Modernization Act (FDAMA). I am Abbey Meyers, President of the
National Organization for Rare Disorders (NORD). NORD is a non-profit
voluntary health agency dedicated to the identification, treatment and
cure of rare ``orphan diseases.'' NORD is the primary patient
organization that advocated for the Orphan Drug Act of 1983, which is
one of the most successful and important health statutes that Congress
ever passed.
One of NORD's primary goals is to promote the development of new
treatments and cures for rare diseases and to make these therapies
accessible to patients. Under the Orphan Drug Act, a rare disease is
defined as a health condition that affects fewer than 200,000
Americans. Keep in mind that there are more than 6,000 of these
disorders, cumulatively affecting an estimated 25 million Americans.
NORD's mission, therefore, is enormous and very much reliant on the
successes achieved by academic scientists, pharmaceutical and
biotechnology companies, medical device manufacturers, and most of all,
the Food & Drug Administration (FDA), which regulates these entities.
The FDA's mission is to ``protect the public health by ensuring
that human drugs are safe and effective.'' 1 But since 1992,
when ``user fees'' were first implemented, the public's trust in the
agency has eroded. FDAMA reauthorized user fees and authorized
``pediatric exclusivity,'' but its primary purpose was to speed the
approval of more new drugs and devices, even if those drugs and devices
were relatively unimportant to the public health. Just look at the
seven drugs that were approved after 1993 and then removed from the
market due to severe adverse reactions and deaths. Not one of these
pharmaceuticals was a life-saving drug. They were drugs for heartburn,
diabetes, and irritable bowel syndrome (chronic diarrhea), a
painkiller, a blood pressure medicine, an antibiotic, and a diet pill.
There was absolutely no reason to rush them to market. Given enough
time to study the data, the FDA might have more adequately identified
their risks and kept them off the market.
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\1\ Report to the Nation, Improving Public Health Through Human
Drugs, US HHS/FDA/CDER, 2000.
---------------------------------------------------------------------------
Consumers nationwide have begun to question FDA's true mission. Is
the FDA a government agency established to protect the American public,
or is it merely an extension of the pharmaceutical industry? Can we, as
``stakeholders,'' trust the scientific judgment of the regulators when
the FDA refers to the pharmaceutical industry as the agency's
``customers''? I would also remind the Committee that the public is not
merely a ``stakeholder.'' We are the ones who may live or die based on
the FDA's decisions.
The Prescription Drug User Fee Act, or PDUFA, was enacted to
provide sufficient funding for the agency to hire the additional staff
needed to review new drug applications at a quicker pace. In exchange
for user fees, the FDA was given the responsibility ( of meeting very
specific ``performance goals.'' These performance goals, often referred
to as ``deadlines,'' have resulted in what some FDA officials refer to
as a ``sweat shop atmosphere.'' For example, for each new drug
application submitted to the FDA, reviewers must master volumes of data
in less than six months or a year, while juggling many other
tasks.2 They quickly burn out from the intense pressure to
perform, and often leave the agency in less than two years and go to
industry to earn higher salaries.3 Performance goals create
another unintended consequence--companies have an incentive to delay
submission of voluminous data, putting the agency under tremendous
pressure to meet user fee deadlines without adequately analyzing the
data. It appears the industry has the best of both worlds--they get
their quick approvals AND they hire the scientists trained by the FDA.
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\2\ How a New Policy Led to Seven Deadly Drugs, Los Angeles Times,
April 17, 2001, by David Willman.
\3\ FDA/Industry Face-Off in Preliminary PDUFA III Discussions, FDA
Week, April 20, 2001, p. 13.
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Given the fact that pharmaceutical firms considers PDUFA ``their''
program (and I quote, ``The time to approval in the review process has
been coming down markedly since WE instituted the program in 1992''),
it is probably a political reality that PDUFA will, in fact, be
reauthorized because it is seen as a way to get products to market
quicker with minimal erosion of patents.4
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\4\ User Fees for Faster Drug Reviews--Are They Helping or Hurting
the Public Health, FDA Consumer, September-October 2000, p. 26.
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But before PDUFA is reauthorized, we feel that consumers and
patients must have assurances that the primary mission of the FDA is to
protect and serve the American public--not to improve the financial
picture of the pharmaceutical industry. As you consider reauthorization
of FDAMA, therefore, we ask that you consider the following
suggestions:
THE POLITICS OF FDAMA
FDAMA was enacted during the Clinton administration, and some
suspect it fell victim to the ``reinventing government'' initiative.
Congress wanted to cut back federal spending, so ``user fees'' were
implemented under PDUFA in 1993. FDAMA incorporated and reauthorized
user fees in 1997 and, at the same time, was supposed to make the
FDA more ``user friendly'' to the drug and device industries.
Government regulatory agencies were told to be more cooperative with
the industries that they regulate, and President Clinton specifically
asked FDA administrators to trust industry as ``partners, not
adversaries.''
Many consumer groups opposed FDAMA because they felt it would lower
the safety and efficacy standards for new drugs, inflate FDA's
resources for new drug reviews, and in turn deflate resources in other
areas of the agency that are critical to the public's health. FDA would
no longer be the ``gold standard'' for the world's health authorities,
and nothing in FDAMA indicated that American consumers would be the
agency's real ``customers.'' Thus, the agency would not become more
``user friendly'' to the public. In fact, Congress, FDA and the
regulated industries negotiated the law, and consumers were
specifically omitted from the debate.
The changes that FDAMA brought about were NOT intended to enhance
or protect the public's health. In fact, the agency had implemented
critically important rules in the 1980s under Commissioner Frank Young
during the Reagan administration for giving ``priority reviews'' to
breakthrough drugs for serious and life-threatening diseases. But the
pharmaceutical industry lobbied Congress for FDAMA on the basis that
the FDA was taking too long to get ``life-saving'' medicines to the
public. The truth was that life-saving medicines were already being
speeded through the process, but the standard ``me-too'' drugs were
taking more time than the industry wanted. Undoubtedly, FDAMA would not
have been enacted if the arguments had been framed in terms of
``speeding new diet pills to the market.''
In 1988, only four percent of new drugs were approved first in the
United States. By 1998, 66 percent of all new drugs were approved first
in the USA.5 But, being first out of the gate does not
necessarily mean you will win the race. When faulty drugs are rushed to
approval, the ``prize'' for being first may be unnecessary exposure to
negative side effects or death.
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\5\ Quickened pace of drug approvals by FDA taking toll, by David
Willman, Los Angeles Times, December 28, 2000.
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REVIEW TIME VS. SAFETY
The approval time for New Drug Applications (NDA) has decreased
dramatically since PDUFA was first enacted. Back in 1993, the medial
approval time was 24.1 months. In 2000, that figure plummeted to 11.2
months, or about 54 percent.6 If you look just at those
statistics, I suppose you could say that PDUFA has been a resounding
success.
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\6\ Approval Times (in months) for NDAs and NMEs Approved, Calendar
Years 1986-2000, FDA, CDER/ORM.
---------------------------------------------------------------------------
However, there have been far too many withdrawals of marketed drugs
after they have killed and disabled people, casting a serious shadow
over the agency's credibility and competency. The publicity fueled by
these withdrawals has further cast doubt on whether the user fee
program is in the public's best interest. Based on those withdrawals,
it is quite apparent to many that the FDA should not be subjected to
the pressure cooker atmosphere created by PDUFA. Products are being
rushed through the review process and, as a result, consumers are being
exposed unnecessarily to sometimes dangerous and life-threatening
drugs. Human beings are not guinea pigs, gentlemen. When FDA determines
that a drug is both safe and effective, we take them at their word.
NORD believes the agency's success must NOT be measured by the
speed of its work, but rather the completeness and scientific soundness
of its work. In fact, some of the drugs that have been removed from the
market in recent years might have been approved with more adequate
labeling if FDA had enough time initially to recognize adverse effects,
and to require appropriate labeling when the drugs were first approved.
FDA reviewers must be given the latitude to review new drug
applications at a decelerated rate if it is deemed scientifically and/
or ethically necessary, especially when a drug is not a life-saving
therapy. Let the reviewers do what they have trained years to do. Of
course, everyone wants to see life-saving drugs come to market quickly,
but only if they have been determined to be safe and effective.
Remember the first law of medicine--First do no harm.
The agency should not be forced to take a ``one size fits all''
approach to drug approval; it is wrong to require FDA to spend the same
amount of time to review all standard or priority drugs and biologics.
Some will need more time. Some will need less. Safety and efficacy
should be the only true measure of whether a drug is approved or not.
DRUG LABELING
It is my understanding that eleven or more drugs have been removed
from the market since 1993, but seven of them were first approved for
marketing after 1993. In many of these cases, FDA ``negotiated''
labeling changes with the manufacturer, and left the drug on the
market, hoping that doctors would notice the new warnings and prescribe
the drug properly. Of course, health care providers usually don't
reread labeling once a drug has been on the market, so after more
deaths and serious adverse events, the FDA finally banned the drugs.
The fact is the FDA seldom orders a company to change its label.
Rather, they ``negotiate'' with companies over wording, and these
negotiations can last for many months while manufacturers try to get
wording that will have the most positive spin to enhance their
marketing plan. We believe that FDA should be given the authority to
order immediate labeling changes without negotiations. FDA's role is to
protect the public's health. Manufacturers should not be telling the
regulators how to regulate the regulators!
ADVERSE EVENT REPORTING
The United States has a voluntary system of adverse event reporting
(AER). It relies on doctors, hospitals, consumers and manufacturers to
report adverse events, but the FDA doesn't have sufficient resources to
analyze the data and try to identify red flags that may point to public
health disasters (e.g., heart problems caused by diet pills). Even with
the incompetencies of the current AER system, voluntary reports of
adverse events from pharmaceuticals rose 89 percent between 1993 and
2000.7 This alone should signal that too many new drugs are
reaching the market before they are adequately studied. The rush to
market is NOT for the sake of the public; it is solely for the sake of
the industry.
---------------------------------------------------------------------------
\7\ Los Angeles Times, April 27, 2001.
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Reauthorization of PDUFA must change this mindset and focus the law
on public health protection and enhancement, including stronger FDA
authority to analyze adverse events and to protect human subjects in
research. To date, the FDA has no bioethicists on staff, no authority
to stop a clinical trial if an informed consent document is inaccurate
or misleading, or even if the study is unethical. Most clinical
research today is funded by the industry, not by the government, and
privately funded research does not have to obey the Common Rule. FDA
should have the authority to enforce patient protections for privately
funded research, and it must be given the funds to do this. Moreover,
Congress should mandate adverse event reporting so that severe
reactions to drugs can be tracked.
POST-MARKETING SURVEILLANCE
Under FDAMA the FDA can ask manufacturers to perform post-marketing
studies, but such studies are not mandatory. Even if the manufacturer
agrees to such studies, the FDA does not have the authority to penalize
the company if the studies are not conducted, and the FDA is the first
to admit they don't even know if companies are doing them. FDA usually
asks for post-marketing studies when they have rushed a priority drug
through the approval process, but there are still unanswered questions.
Often, once these drugs are used in the real world where people take
other medicines, or have other illnesses, adverse events will occur.
At a recent Food and Drug Law Institute educational conference,
industry argued that the FDA ``has no jurisdiction in the area of risk
management''. We happen to agree with the FDA that the industry's
position is ``disingenuous.'' At the same conference, Jane Axelrad,
Associate Policy Director for the FDA, said, ``Drug companies have task
forces out there bombarding doctors with details about drugs and this--
along with direct-to-consumer advertising--is clearly influencing
prescriber practice.'' 8
---------------------------------------------------------------------------
\8\ ibid.
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We ask that you make these post-marketing studies mandatory, and
give the FDA the authority to assess penalties when companies do not do
what they have promised to do. Post-marketing surveillance does not
``step on the toes of the practice of medicine.'' Rather, it goes to
the very heart of the mission of the FDA--to protect American
consumers.
USER FEES
As prescribed by law, user fees can be employed for very specific
purposes ONLY. They cannot be used for critically important public
health functions such as adverse event monitoring or advertising and
marketing enforcement. Nor are they assessed for generic drugs, medical
devices, food importation or cosmetics. So, for almost a decade, the
FDA has been forced to beg, borrow and steal staff and resources,
robbing Peter to pay Paul, to the detriment of other vital agency
operations. With the dangers of Mad Cow disease, bioterrorism, and
bioengineered foods looming in our future, the agency cannot possibly
meet its mandate with insufficient resources! Our nation is poised for
a public health disaster because the FDA simply cannot do its job.
Congress must adequately fund the FDA or institute user fees for all
other areas of FDA's public health responsibilities.
User fees have enabled the FDA to cut new drug approval times in
half, but they have also created a financial dependence by the agency
on the industry it regulates. Understandably, the pharmaceutical
industry wants to continue the user fee program. Every day that the
industry can save on the new drug approval process is one more day they
can sell their drug before their patents expire. However, the FDA's
dependence on the user fees that companies pay creates a perceived
conflict of interest that may compromise the health of the American
public.
The integrity of the US drug approval process is at risk, and the
implications of the loss of public trust here and around the world are
immense. The FDA should not have a direct fiscal interest in optimizing
user fees, because this practice has led to public distrust. Speaking
for myself, I would think twice before being one of the first patients
to take a newly marketed drug. I cannot trust that FDA reviewers in a
``sweat shop atmosphere'' adequately reviewed the product.
The only drugs given priority review at the agency should be
treatments for life-threatening and untreatable diseases, drugs for
patients who are not helped by existing treatments, or drugs for
serious diseases that are safer or more effective than current
therapies. In fact, we would recommend that you examine the FDA's
definition of ``clinical superiority'' in the Orphan Drug Act
regulations. Priority reviews should be given only to drugs that are
substantially ``different'' from the drugs currently on the market and
ones that have been clearly shown to be safer, or more effective, or to
offer a significant contribution to patient care (e.g., an oral version
of an injectable drug).
FDA's annual measure of success or failure should NOT be the number
of drugs it approves during a given year, but rather the medical and
public health advancements that each drug represents. The speedy
approval of drugs for diagnoses that don't exist in medical texts, more
cosmetic, ``me-too,'' or lifestyle drugs, does not represent a major
improvement in public health.
Some drugs should take more time, and some should take less,
depending on the quality of scientific data. Since the Reagan
administration in the 1980s, the agency has had adequate tools to make
investigational drugs available to patients who need them (e.g.,
compassionate use, treatment IND's, early access programs, etc.).
In summary, FDA needs more flexibility on spending user fees (they
should not be confined to new drug reviews), and the onus is on
Congress to either institute user fees for other industries, or
appropriate sufficient funds for all of the other critically important
public health responsibilities of the agency.
PEDIATRIC EXCLUSIVITY
For rare diseases, the pediatric use of drugs that were developed
for adult health conditions is an absolute necessity. Most children are
healthy and may require the normal cough and cold remedies,
antibiotics, and perhaps asthma drugs. Serious health conditions in
children are rare, and medicines to treat their ailments are very
rarely labeled with information about pediatric dosage.
NORD agrees that the pediatric exclusivity provision ``has been
highly effective in generating pediatric studies on many drugs and in
providing useful new information in product labeling.'' 9 We
also agree with the proponents of the provision that it should be
reauthorized by Congress in order to ensure that all children have
access to medications needed to protect and preserve their health. But
we feel that other types of incentives should be examined in the
congressional debate, and careful fine-tuning of the law is needed.
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\9\ The Pediatric Exclusivity Provision, January 2001, Status
Report to Congress, Department of Health and Human Services, U.S. Food
and Drug Administration.
---------------------------------------------------------------------------
We are delighted that the FDA has ``drawn a line in the sand''
against the industry's practice of enrolling healthy children in
clinical trials, and it will no longer grant pediatric exclusivity if
there is no potential benefit for children who participate in such
studies.10 We say bravo to the FDA! The prohibition against
including healthy children in clinical trials has been in effect since
the 1970s (The Belmont Report), and it is part of the Common Rule and
the Declaration of Helsinki. However, privately funded medical research
does not have to obey the Common Rule, so for the past decade American
children have been exposed to risks that are unacceptable in other
industrialized nations of the world.
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\10\ FDA Week, April 25, 2001, p.3.
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We believe there have been other unintended negative aspects of the
pediatric exclusivity provision that should be addressed by this
Congress.
The Wall St. Journal reported that six months of pediatric
exclusivity for the antihistamine Claritin amounts to $975
million dollars in sales to the manufacturer, six months of the
antidepressant Prozac sales amounts to $831 million, while
highly used generic drugs like the asthma compound Albuterol,
and antibiotics like ampicillin, are not being studied in
children at all.
It is estimated that over 20 years of pediatric exclusivity
will cost Americans $13.9 billion, while brand name drug makers
will earn $29.6 billion, and generics will lose $10.7 billion.
Distributors and pharmacies will lose $4.9 billion.
When FDA awards pediatric exclusivity, the exclusivity is
awarded for the active moiety rather than just the pediatric
indication. In one case a company studied an intravenous form
of an indigestion drug on children, but the exclusivity applied
to all liquid and pill forms, and even the over-the-counter
version. Thus, the pediatric exclusivity provision is like a
tax that Medicare-dependant grandparents have to pay for the
sake of their grandchildren, by paying inflated prices for a
longer period of time.
Of the studies that have been done, and the exclusivity
awarded, only a tiny proportion of those drugs have been re-
labeled for pediatric usage. What use is a study when
information about dosage adjustments and side effects is not
available to pediatricians? We believe that exclusivity should
NOT be awarded unless and until the label is actually changed.
The law is inequitable because it leaves out huge categories
of drugs (including biologics) that children need, that will
never be studied. This includes generics and even patented
drugs with small annual sales. The problem is that pediatric
exclusivity encourages companies to study their most profitable
drugs, but not the drugs that have the most intense medical
need for children.
Although we applaud the FDA's recent issuance of an interim
rule providing additional safeguards for children in clinical
trials, the pediatric exclusivity provision, as currently
written, contains no human subject protections. Questions
continue to be raised about clinical research in the pediatric
population, as reports of large cash payments to parents and
other questionably ethical inducements are reported in the
press.
The pediatric exclusivity provision actually bribes companies
to do what they ought to be doing as decent corporate citizens.
Until 1997, companies refused to conduct the studies until they
saw a way to increase profits well in excess of what these
studies cost. The FDA now says it will require all new drugs to
be tested in children and can demand that trials be conducted
when the agency feels a treatment will be applicable to
children's diseases. However, drug companies are suing the FDA
to stop this! The industry says the FDA has no authority to
require companies to study their new drugs on children. We ask
Congress to give the FDA this authority so the agency can
protect the health and welfare of our children. It is
regrettable that the government must force the industry to be
good corporate citizens--a very sad state of affairs indeed.
We also suggest that in the congressional debate about
reauthorization of the pediatric exclusivity rule, you look at
other options that will not tax the elderly with high drug
prices, for the sake of the young. For example, instead of
preventing lower cost generic drugs from reaching the market
when brand name patents expire, why not award a large tax
credit to companies that perform the clinical trials necessary
for pediatric labeling? Perhaps a tax credit of 125 percent of
the costs of the studies would entice companies into supporting
the trials, and even reward generic companies who do pediatric
investigations on older drugs. In fact, Congress' highest
priority should be the development of incentives, or
appropriation of funds, to encourage pediatric research on the
generic drugs most needed by children.
SUMMARY
In summary, Mr. Chairman, the FDA is losing the public's trust
because it does not have the resources to do its job. The strict
deadlines for new drug reviews are forcing drugs out on the market
before FDA scientists adequately review them. Companies that do not
feel their drugs are reviewed properly resort to lobbying Congress.
There ought to be a firewall between industry and the FDA so that
scientists can make their decisions based solely on scientific grounds.
Yes, the FDA should be accountable, but so should the pharmaceutical
industry. Drastically limiting review times while expecting more drugs
to get approved is not the right way to measure success: It is a
prescription for disaster.
We ask Congress to take a very careful look at the law and
recognize that FDA's primary role is to protect and enhance the
public's health. A more careful new drug review process will do much to
avoid public health disasters in the future. FDA has had adequate
mechanisms to allow very promising new drugs to reach the public before
they are approved for marketing, but this should only be for life-
threatening and serious diseases with no other treatment alternatives.
We should not be rushing baldness remedies and indigestion drugs to
market.
We also ask Congress to appropriate sufficient funds for other FDA
initiatives. It has been reported that funding for non-PDUFA programs
is down 20 percent, while PDUFA-related programs have seen increases of
27 percent. The exaggerated emphasis on new drug approvals saps
resources from the agency's other public health functions.
Mr. Chairman, people with rare diseases desperately need new drugs
to save their lives and prevent disability, but not at the expense of
safety and efficacy. When we spend our hard earned money on a
treatment, we want to know first if it is safe, and second if it is
effective. Nothing else matters. Those with very serious and deadly
illnesses are often willing to take higher risks (e.g., cancer
chemotherapy drugs), but only if our doctors know what the side effects
are and how to manage them. Our lives depend on the FDA, and if the
agency cannot do its job, it puts our lives in jeopardy. We trust that
Congress will use its wisdom to bring credibility back to FDA and
bolster its public health mandate.
I thank the committee for its invitation to express the interests
of people with rare diseases in the debate about reauthorization of
FDAMA, including PDUFA and pediatric exclusivity.
Mr. Bilirakis. Thank you, Ms. Meyers. You gave us an awful
lot of suggestions. I jotted down some of them. The rest of
them are all in the record. In fact, I have been talking to the
staff about one of them right now.
Mr. Plunkett?
STATEMENT OF TRAVIS B. PLUNKETT
Mr. Plunkett. Good afternoon. Mr. Chairman, Mr. Brown, my
name is Travis Plunkett. I am the Legislative Director of the
Consumer Federation of America. I am here today on behalf of
the Patient and Consumer Coalition, an ad hoc coalition
representing a diverse array of consumer and patient
organizations. I would like to thank you both for conducting
this much-needed hearing on the Food and Drug Administration
Modernization Act and its impact on Americans nationwide.
I will focus my comments on PDUFA, the Prescription Drug
User Fee Act. Has PDUFA II, as reauthorized in 1997, been a
success? Well, if success is only measured by the speed of drug
approval and the number of drugs getting onto the market, the
answer is a resounding yes. But the FDA's responsibility under
the law is to ensure that new drugs and devices are safe and
effective. By this measure, PDUFA II has some serious problems.
Now clearly there are very important public health benefits
to be gained from faster approval of certain new drugs. This
includes drugs that treat serious and life-threatening
conditions, drugs that provide relief for patients with
illnesses or disabilities, that are resistant to existing
therapies, or drugs that are less toxic than currently
available therapies.
Most Americans, however, would agree that a lifestyle drug
like Viagra or a me-too drug that is just a mere copy of a
bestseller does not need to be rushed to market as quickly as
say an important new anti-cancer agent or an enzyme replacement
therapy for genetic disease. The fact is that as the FDA's
dependency on fees paid by the regulated industry has grown, so
have the number of recalls and warnings.
Mr. Chairman, I don't raise this issue lightly. We can talk
about in questions why it is much more important to look at the
number of recalls and warnings, the number of Americans who
have been affected, as opposed to the rate of withdrawal. That
is, the percentage of drugs withdrawn compared to the number of
new drugs on the market. It is a much more effective way of
evaluating whether PDUFA has increased safety and health.
Eleven prescription drugs have been pulled from the U.S.
market in the last 3\1/2\ years for safety reasons. This is by
far the most such actions taken in any comparable period. Only
one of these drugs, an antibiotic, had lifesaving potential.
But it was later deemed to be unnecessary because other safer
antibiotics were available. More than 22 million Americans took
these drugs. Just last week an anaesthetic was removed from the
market after five people were reported to have died.
Now if we look at these withdrawals a little more closely,
we find that of those 11 drugs, eight were approved after PDUFA
took effect, first took effect in 1993. According to the
Pulitzer prize wining investigation by David Willman at the Los
Angeles Times, seven of these drugs are suspected in just over
1,000 deaths. In overall, these adverse events, as they are
called, have increased in reporting--these are voluntary
reports, as you heard, to the FDA--by 89 percent from 1993 to
2000.
One of the major reasons why these drugs were improperly
allowed onto the market is because PDUFA has very stringent
decisionmaking deadlines that we view as inappropriate,
potentially dangerous, and open to manipulation by the drug
industry. Now the FDA takes pains to explain that these are
performance goals, that they are focused on decisionmaking and
not approving drugs. But there is evidence to suggest that in
the real world, FDA employees have been under tremendous
pressure to meet not just decision deadlines, but also to
approve drugs.
I will just cite the LA Times story to you again. You may
want to look at this. It includes quote after quote from
retired and former FDA employees, that they were under
tremendous pressure from FDA officials and because of the
deadlines under the law to approve drugs, not just make
decisions about them.
These deadlines forced the agency to take a cookie cutter
approach to drug approvals. It is just not in the public
interest to require the FDA to act at the same speed for all
standard or priority drugs and biologics. Some should get more
time. Some should receive less.
Moreover, it's just inappropriate to give a regulated
industry this kind of dominant voice in determining what will
be the process for oversight of that industry, as was done in
crafting PDUFA in 1997. I would like to commend both of you for
doing it differently this time, for having a spectrum, a
diverse array of folks offering a variety of opinions on PDUFA.
The end result is that the regulated industry controls not
only the funding and the timing for new drug approval, but the
measurement tools that are used to determine the FDA's success
or failure in this matter.
I will close with my remarks there, and answer any
questions you have later. Thank you once again for having this
hearing.
[The prepared statement of Travis B. Plunkett follows:]
Prepared Statement of Travis B. Plunkett, Legislative Director,
Consumer Federation of America, on Behalf of the Patient and Consumer
Coalition
Good morning. I am Travis Plunkett and I serve as the Legislative
Director of the Consumer Federation of America. I am here today on
behalf the Patient and Consumer Coalition, an ad hoc coalition of
patient and consumer advocacy organizations working to insure greater
access to safe, effective affordable drugs and medical devices. The
coalition also focuses on enhancing the ability of the Food and Drug
Administration to protect public health through effective enforcement
of the law. (Please see the attached for the coalition's mission
statement and founding members.) This testimony is endorsed by the
following members of the coalition: Center for Medical Consumers,
Consumer Federation of America, Gay Men's Health Crisis, National
Consumers League, National Organization for Rare Disorders, National
Women's Health Network, Public Citizen, UAW and the U.S. Public
Interest Research Group.
I would like to thank Chairman Bilirakis and Ranking Member Brown
for the opportunity to offer comments on the impact of the Food and
Drug Administration Modernization Act (FDAMA) on consumers and patients
nationwide. We urge the subcommittee and the full committee to have
several hearings to evaluate both the impact of FDAMA on public health
and safety, as well as the range of possible changes that could improve
it. I will focus my comments on a key component of the Act: the
expansion of the Prescription Drug User Fee Act (PDUFA.) I will also
comment briefly on the ``pediatric exclusivity'' provision that grants
additional patent life to drug manufacturers that conduct clinical
tests on the effect of their drugs on children.
THE PRESCRIPTION DRUG USER FEE ACT
As you know, PDUFA was first enacted in 1992 to address concerns
about the length of time it took for new drugs to treat life
threatening and disabling conditions to be reviewed and approved by the
FDA. While the issue of new drug approval time had been a contentious
one for several decades, the experience with HIV/AIDS convinced many
that there was room for improvement. PDUFA recognized the reality that
the resources of the agency were constrained and that a shorter
approval process would require considerably more staff devoted to the
drug review process. User fees were imposed upon industry that would
fund the additional agency resources needed to speed up the review and
approval process.
PDUFA was reauthorized in 1997 as part of the FDAMA. However, this
iteration introduced increasingly stringent ``performance goals''
requiring that the FDA meet tight review deadlines. It even includes
stipulated time frames for scheduling of meetings and response to
industry requests. For example, the 1997 PDUFA establishes a
performance target that requires FDA to review 90 percent of priority
new drug applications within 180 days and non-priority new drug
applications with 10 months. These mandates were insisted upon by the
industry that argued that these ``measurables'' were necessary to
ensure that the user fees they paid were not dispersed to fund other
agency activities.
As a result of the 1992 and 1997 legislation, the FDA has
dramatically increased the amount of resources it devotes to new drug
and biologics review and approval from $120 million in 1992 to a
projected $325 million in FY 2002. In FY 2002, it is estimated that a
record half of the resources required for new drug approvals will come
from user fees paid by the regulated industry.\1\
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\1\ Food and Drug Administration, ``PDUFA Background Information,''
August 2000.
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Has PDUFA been a success? Well, if success is only measured by the
goals mandated in 1997, the answer is a resounding ``yes.'' The time
for approval has decreased from a median of slightly less than two
years in 1992 to less than one year at present. A higher percentage of
applications are now approved; 80 percent compared with only 60 percent
in 1992.\2\
---------------------------------------------------------------------------
\2\ Ibid.
---------------------------------------------------------------------------
But the success of a drug review and approval process should not be
measured by speed and approval rates alone. The FDA's responsibility
under law is to ensure that new drugs and devices are safe and
effective. That is the true public health responsibility of the agency
by which its success or failure must ultimately be measured. We believe
that the effect of PDUFA II on public health and safety is a matter for
grave concern.
1. PDUFA creates a financial dependence by the FDA on an industry
it regulates. This is a conflict-of-interest that could compromise drug
safety. Our organizations recognize that PDUFA has provided the agency
with the resources to speed up new drug approvals since 1993. Clearly
there are public health benefits to be gained from faster approval of
certain new drugs. These include medications that treat serious and
life-threatening conditions, drugs that provide relief for patients
with illness or disability refractory to existing therapies, or drugs
that are less toxic than currently available therapies.
However, the FDA's direct fiscal interest in optimizing user fee
income to achieve speedier approval times and get more drugs through
the approval process in each budget year creates an obvious tension
with its responsibility to assure the highest degree of safety and
efficacy of new products. As mentioned above, the FDA's dependency on
fees paid by the regulated industry has grown dramatically since fees
were first initiated in 1993. The integrity of the drug approval
process is what is potentially at risk and, as a result, the safety of
the millions of Americans who use prescription drugs could be
compromised.
The growing number of recalls and warnings related to newly
approved drugs has reinforced our concerns. The agency has attempted to
demonstrate that there is no relationship between faster approval times
and more frequent recalls or additional safety warnings. However, there
have been too many recent withdrawals of marketed drugs that have
killed and injured people that have cast a serious shadow over the
integrity of the approval process. Eleven prescription drugs have been
pulled from the U.S. market in the last three and one-half years for
safety reasons, by far the most such actions taken in any comparable
period. More than 22 million Americans took those drugs. Just last
week, the anesthetic Raplon was removed from the market, after five
people were reported to have died from bronchospasm.
These eleven drugs include three that were approved before PDUFA
took effect in 1993, but the withdrawn drugs Lotronex, Propulsid,
Rezulin, Raxar, Posicor, Duract and Redux have all been approved since
1993. According to the Pulitzer Prize-winning investigation by David
Willman of the Los Angeles Times, these seven drugs are suspected in
1,002 deaths.\3\ This is based on the FDA's reporting of ``adverse
events,'' which doesn't prove that a particular drug caused a death; it
is merely a ``primary suspect.'' However, adverse events reports are
also voluntary, so the true number of fatalities caused by these drugs
could be much higher. Adverse events reported to the FDA increased by
89 percent from 1993 to 2000.\4\
---------------------------------------------------------------------------
\3\ David Willman, ``How a New Policy Let to Seven Deadly Drugs,''
Los Angeles Times, December 20, 2000.
\4\ Ibid. Adverse events increased from 136,836 in 1993 to 258,125
in 1999.
---------------------------------------------------------------------------
Moreover, we are particularly concerned that, to date, the risks
posed by these drugs have fallen disproportionately on women. In
January, the U.S. General Accounting Office (GAO) reported to Congress
on the subject of drug safety with the significant finding that most
drugs withdrawn in recent years had greater health risks for women.
Specifically, the GAO investigation found that, ``Eight of the ten
prescription drugs [withdrawn from the U.S. market since January 1,
1997] posed greater health risks for women than for men'' and that four
of the drugs withdrawn ``had more adverse events in women even though
they were widely prescribed to both women and men.''
Only one of the drugs withdrawn from the market since 1993, the
antibiotic Raxar, had lifesaving potential. It was ultimately
determined to be unnecessary because other, safer antibiotics were
available. Willman's investigation also included reports from a number
of former FDA employees that the need to act quickly--as required by
PDUFA--and the demands of FDA officials, put them under enormous
pressure to approve new drug applications, whether they felt the drugs
were safe or not.
As if to confirm our fears, the term ``customer'' has crept into
the FDA's characterization of the prescription drug industry. We are
very concerned that an agency chartered to safeguard the public's
health would characterize the industry it regulates as its primary
customer, and itself as a ``supplier'' of services (namely new drug
review and approval.) It is the public, not the drug industry, that
should be the FDA's ``customer.'' The medical and public health
consequences of faster drug approval are the appropriate measure of
PDUFA's successes and failures, not the tabulation of the average
number of months a drug requires for approval.
2. PDUFA's performance goals are inappropriate, potentially
dangerous and open to manipulation by the drug industry. Although the
FDA takes pains to explain that the performance goals mandated under
PDUFA are for decision-making, not approval, these goals put the FDA
under tremendous financial pressure to move very quickly on the overall
approval process. Here's what William B. Schultz, a former deputy
commissioner at the FDA told the Los Angeles Times about PDUFA
deadlines: ``You can meet the goal by either approving the drug or
denying the approval. But there are some who argue that what Congress
really wanted was not just decisions, but approvals. That is what gets
dangerous.'' Dr. Solomon Sobel, the former director of the FDA's
metabolic and endocrine drugs division told the Los Angeles Times that
deadline pressure under PDUFA was not just to make decisions: ``The
pressure to meet deadlines is enormous. The basic message is to
approve.'' \5\
---------------------------------------------------------------------------
\5\ Ibid.
---------------------------------------------------------------------------
These goals force the agency to take an unvarying, ``cookie
cutter'' approach to drug approvals. It is not in the public interest
to require the FDA to act at the same speed for all standard or
priority drugs and biologics. Some should get more time, some should
receive less; time should not be the measurement of the agency's
success. The agency has adequate tools to enable patients to obtain
drugs before they are approved for marketing (as with the Treatment
IND), so that desperately ill patients can have early access to
potentially important medicines.
Moreover, it is completely inappropriate to give a regulated
industry a dominant voice in determining what will be the process
(``performance goals'') for oversight of that industry. Congress
established these goals in consultation with the prescription drug
industry and received absolutely no input from consumers. The end
result is that the regulated industry controls not only the funding and
timeline for new drug approval, but the measurement tools that are used
to determine the FDA's success or failure in this matter.
PDUFA allows companies to manipulate the FDA into quickly approving
drugs that the agency has not had adequate time to review. Companies
can do this simply by dragging their feet in submitting required data
and test results until the FDA's ``performance'' deadline draws closer.
If this practice is used on a regular basis, it puts the FDA under
tremendous time pressure to meet its performance goals without
adequately reviewing the submitted data. In other words, the FDA's
performance goals, which are based on the agency's ability to meet many
decision-making deadlines over the course of time, may actually provide
companies with an incentive to delay transmitting some data to the FDA
quickly. If they give the FDA the information ``too early,'' the agency
might actually have more time to find flaws in the information.
3. PDUFA is draining resources from other critically important FDA
public health functions, such as monitoring the safety of drugs once
they are on the market and approving generic drugs for entry into the
market. This distorts the overall priorities of the agency. The
pharmaceutical industry insisted that a large, inflation-adjusted
portion of drug review costs be funded through appropriations.
Congressional budget increases to the FDA have not kept up with the
mandated spending increases in PDUFA. According to the FDA, it has had
to absorb $284 million in unfunded pay raises and other inflationary
costs in the last eight years.\6\ To his credit, the President has
proposed funding in his budget to catch-up on these expenses.
---------------------------------------------------------------------------
\6\ FDA Talk Paper, April 9, 2001
---------------------------------------------------------------------------
Here's what the FDA has to say about the impact of PDUFA on the
rest of their mission: ``We are increasingly concerned that spending
enough appropriations on the drug review process to meet the statutory
conditions makes the FDA less able to manage the resources available in
a way that best protects the public health and merits public
confidence.'' \7\ Former Commissioner Jane Henney went a step further,
``. . . the truth is, the program is barely surviving because of the
way it was designed. We don't have the resources to do the things we
believe are essential, such as adverse event reporting, because they
are not supported by PDUFA funds.'' \8\
---------------------------------------------------------------------------
\7\ Food and Drug Administration, ``PDUFA Background Information,''
FDA, August 2000.
\8\ FDA Consumer Magazine, ``User Fees for Faster Drug Review: Are
They Helping or Hurting the Public Health?,'' September-October 2000.
---------------------------------------------------------------------------
Moreover, the director of FDA's Center for Drug Evaluation and
Research, Janet Woodcock, has expressed a great deal of concern about
FDA staff turnover, and ultimately, their experience and competency.
She has said that the intense timelines under PDUFA have created a
``sweatshop environment that's causing high staffing turnover.'' \9\
Many of the FDA's most highly trained scientists and experts are
leaving within three years, preventing the agency from building an
institutional memory of previous reviews.
---------------------------------------------------------------------------
\9\ Ibid.
---------------------------------------------------------------------------
One of the areas of FDA's work that is suffering from a dramatic
lack of resources in the post-FDAMA and -PDUFA era is oversight of
prescription drug advertising to consumers. As the number of drugs
approved has increased, so has industry spending to promote these
drugs. Since 1997, pharmaceutical industry spending on direct-to-
consumer advertising has skyrocketed: increasing by 42 percent between
1996 and 1997, by 23 percent between 1997 and 1998, and by 40 percent
between 1998 and 1999. In 1999, drug companies spent more than $1.8
billion on direct-to-consumer advertising.
The FDA staff responsible for reviewing these promotional materials
has not increased proportionately. FDA has only 13 people responsible
for primary review of the 32,000 pieces of promotional material that
the agency receives in a year. This level of resource commitment is
clearly insufficient to enable FDA to act promptly on violations of the
requirement that ads be accurate and include a fair balance of
information about risks as well as benefits. Slow action on inaccurate
and incomplete advertisements is a serious problem for consumers. Until
the agency informs a company that it must withdraw or change an ad, the
public will continue to be exposed to false information and to ads that
fail to include important risk information. Delays in this area pose an
unacceptable threat to the public health.
4. PDUFA does not prioritize between speedy approval of drugs that
are truly important and those that represent no therapeutic
advancement. Unfortunately, the FDA's regulatory process as defined by
statute and regulation does not provide it the latitude to prioritize
the new drug approval process based on a ranking of medical and public
health needs. The FDA has four categories for approval of new drugs:
(1) Those for serious or life-threatening conditions for which there is
no adequate treatment; (2) drugs for rare disorders; (3) the majority
of new drugs that are approved, which are redundant chemical
modification of drugs already marketed; and (4) drugs that are granted
priority review because they work in some new way.
We suggest that drugs that fall into the third category above, such
as a drug for erectile dysfunction, or the third or fourth cox-2
inhibitor, do not need to be rushed to market as quickly as an
important new anti-cancer agent or an enzyme replacement therapy for a
genetic disease. Many new drugs that have appeared on the market as a
result of the agency's PDUFA enhanced approval resources, may actually
turn out to provide little, if any, benefit to patients when compared
to older, better-understood and often less expensive predecessor drugs.
5. The best way to insure the timely approval of safe drugs is to
adequately fund the FDA from general revenues. Adherence to this
principle would be the surest way to remove the worrisome potential for
conflict-of-interest that arises when dedicated income streams flow to
the regulator from the regulated industry. If Congress continues to
underfund the FDA, it will be essential for Congress and the agency to
establish better procedures and guidelines to prevent the serious
conflict-of-interest concerns that our organizations have raised in
this testimony.
PEDIATRIC EXCLUSIVITY
FDAMA granted drug companies a six-month patent extension if they
conduct pediatric testing on a particular drug. This provision expires
in January of next year. The Patient and Consumer Coalition agrees with
the FDA that the pediatric exclusivity provision ``has been highly
effective in generating pediatric studies on many drugs and in
providing useful new information in product labeling.'' \10\ As a
result, we support renewing this provision.
---------------------------------------------------------------------------
\10\ Department of Health and Human Services, U.S. Food and Drug
Administration, ``The Pediatric Exclusivity Provision, January 2001,
Status Report to Congress.''
---------------------------------------------------------------------------
However, Congress should enact measures to make pediatric
exclusivity more targeted and effective. Pediatric exclusivity has
delayed the introduction of more affordable generic alternatives on
some very important and widely used drugs and has proven to be very
lucrative for brand drug companies. But it has not yet resulted in the
testing and labeling of some of the most widely used pediatric drugs.
Six of the ten drugs without adequate labeling for children are not
eligible for pediatric exclusivity because they are off-patent. For
example, dopamine hydrochloride, which is used to stabilize the blood
pressure of sick babies, has never been formally tested in children.
Moreover, the exclusivity applies to every formulation of a drug, even
if only one formulation is tested.
We recommend that Congress consider a number of possible measures
that could make pediatric exclusivity more effective and less costly,
while still providing an incentive for brand companies to test. Our
coalition has not formally endorsed any of these proposals yet, but we
urge Congress, as we are, to seriously consider each of them. These
measures could include: tax credits to encourage companies to conduct
studies on drugs that are off-patent; making funds available to the
Centers for Education and Research on Therapeutics (CERT) sites and the
Pediatric Pharmacology Research Units to do testing of drugs that are
off-patent; allowing exclusivity only on the particular formulation of
a drug that is tested, and not on others in that line that will not be
offered to children; scaling the length of exclusivity to the sales of
a drug, so that Americans would not have to pay higher prices on
blockbuster drugs that recoup the cost of pediatric testing in far less
than six months; directly linking the granting of exclusivity to a
company making labeling changes, and codifying the FDA's authority to
require companies to test new drugs on children. Congress should also
insist that the FDA retain bioethicists to review all proposed
pediatric clinical trials in order to ensure that the agency gives
appropriate consideration to the ethical concerns that come up around
the possibility of exposing children to unnecessary and sometimes
dangerous risks in clinical trials.
In conclusion, let me say that Congress will consider no
legislation this year that is more important to this nation's safety
and health. As a result of the serious problems that I have noted with
the Prescription Drug User Fee Act, what is at stake is nothing less
than public trust in the nation's drug safety system. Right now,
Americans have every reason to wonder if the FDA can really protect
them. We urge this committee to act quickly to eliminate conflicts-of-
interest in PDUFA, prevent the drug industry from dictating the
timeline and standards for drug approval and properly fund all FDA drug
monitoring and approval functions--not just new drug approval. It is
time to refocus the FDA's attention on its real customers: the American
people.
Thank you again for the opportunity to offer our comments.
Mr. Bilirakis. Thank you, Mr. Plunket.
Dr. Franson?
STATEMENT OF TIMOTHY R. FRANSON
Mr. Franson. Thank you very much. Good day, Mr. Chair and
members. I am Tim Franson. I am a physician, a pharmacist, and
Vice President of Clinical Research and Regulatory Affairs at
Lilly. On behalf of PhRMA I want to thank you in particular,
Mr. Chair, for the vital role you and this subcommittee played
in helping to enact the 1997 Food and Drug Modernization Act.
The bottom line of my testimony today is this. FDAMA is
working. It is working just as Congress intended, and it is for
the benefit of patients.
My written testimony, which I wish to submit for the
record, sets forth the FDAMA provisions that directly affect
our industry, and outlines our views on some of these
provisions. Clearly many parts of FDAMA were expected to be,
and are, implemented over a period of years. We continue to
work with FDA to ensure that the full potential of these
provisions is realized.
I would like to turn to one of the most significant
programs established by the 1997 law, the Better
Pharmaceuticals for Children Act, legislation sponsored by
Representatives Greenwood, Waxman, and Burr. This act has
dramatically improved all aspects of pediatric drug
development. It changed the way FDA manages pediatric drugs,
prompting the agency to establish a dedicated group of
individuals who focus on drugs for children. It also changed
the way our industry approaches pediatric drug development and
pediatric studies. That law sent a loud and clear message from
Congress. We want our commitment to children to be reflected in
the development of more drugs for children.
The pediatric research incentive has meant that pediatric
patients are now standing on equal terms with adults in the
stiff competition for research dollars at our companies. Our
industry shares the view FDA expressed in its report to
Congress about the pediatric program. The program, the agency
said, ``has been highly effective for many drugs.'' The
response of the pharmaceutical industry ``has been vigorous.''
Our response has been motivated by commitment to improving
children's health, not only by focus on products with high
commercial yield. In fact, when one looks at the list of most
frequently prescribed drugs, as published by Pharmacy Times,
over half of the medications being studied for pediatric
information are outside the top 100 drugs used. The results of
the program speak for themselves. As you have already heard to
date, FDA has issued 188 written requests, inclusive of over
400 pediatric studies, many of which are ongoing.
We also recognize, as FDA and others have suggested, that
some changes might make the program even better. In particular,
we agree with FDA and the American Academy of Pediatrics that a
different approach is needed to produce pediatric studies and
revise labeling for older drugs whose patents have expired, and
for which the pediatric research incentive does not work.
We also agree with FDA that it is not necessary to continue
to exempt pediatric supplemental applications from the
requirement to pay user fees under the prescription drug user
fee program. Such pediatric supplemental user fees we know will
help FDA to expand its efforts in this important area. Most
importantly, will help to ensure that pediatricians and
children realize the benefits of this important initiative as
quickly and as efficiently as possible.
We strongly urge you, Mr. Chairman, to reauthorize the
Better Pharmaceuticals for Children Act. We also strongly urge
that you determine about any proposal to change the program
whether it will help children. We urge you to reject any change
that will not promote the goal of providing better
pharmaceuticals for our children.
Accompanying me today to answer any questions you may have
on the pediatric research incentive program is Dr. Stephen
Spielberg, a pediatrician, a pediatric clinical pharmacologist,
and Vice President of the Drug Development at Janssen Research
Foundation.
Finally, Mr. Chairman, I want to talk briefly about the
other FDAMA program that will expire, the Prescription Drug
User Fee Act, PDUFA. Let me simply say that PDUFA has provided
FDA with necessary funds to hire additional reviewers, update
the agency's information technology infrastructure, and act in
a more timely and predictable manner on drug applications. It
has been highly successful for FDA, for our research-based
industry, and especially for patients.
PDUFA must be renewed in 2002 to provide continuity for
FDA, and ensure that patients continue to receive safe and
effective new medicines as expeditiously as possible.
Thank you very much for the opportunity to testify. I will
be pleased to answer any questions you have.
[The prepared statement of Timothy R. Franson follows:]
Prepared Statement of Timothy R. Franson, Vice President, Clinical
Research & Regulatory Affairs, Lilly Research Laboratories, Eli Lilly
and Company on Behalf of the Pharmaceutical Research and Manufacturers
of America
Mr. Chairman and Members of the Subcommittee: I am Dr. Timothy R.
Franson, Vice President of Clinical Research & Regulatory Affairs at
Eli Lilly and Company, and I am here today on behalf of the
Pharmaceutical Research and Manufacturers of America (PhRMA) to present
the industry's views on the implementation of the Food and Drug
Administration Modernization Act (FDAMA) of 1997, a landmark law that
marked significant progress for public health and patients. PhRMA
represents the nation's leading research-based pharmaceutical and
biotechnology companies that are devoted to inventing new life-saving,
cost-effective medicines.
As the Chairman and other Members of the Subcommittee well know,
FDAMA was the first substantive modification to the pharmaceutical
provisions of the Federal Food, Drug and Cosmetic Act in more than 30
years. It reauthorized the successful provisions of the Prescription
Drug User Fee Act (PDUFA) of 1992, which provided, through the
collection of industry user fees, necessary additional resources for
FDA to use in reviewing new drugs. Next year, this Subcommittee will
need to look into reauthorizing PDUFA. The user-fee law has produced
many critical improvements at FDA since it was first enacted in 1992
and, in particular, has enabled the agency to develop a more efficient
review process that has given patients more timely access to new
medicines. PhRMA looks forward to working with the Subcommittee in this
endeavor.
Another important provision of FDAMA was the Better Pharmaceuticals
for Children Act (Section 111), legislation sponsored by
Representatives Greenwood and Waxman, which provides an incentive to
industry to develop specific information about pediatric uses of
prescription drugs. This latter provision should be reauthorized before
it sunsets at the end of this year--for the health of our children.
Collectively, the reauthorization of PDUFA and other important
structural changes made by FDAMA in FDA procedures have shortened the
FDA review process for New Drug Applications (NDAs) and thus made safe
and effective new drugs available sooner to patients. FDA review is the
final and critical step in a drug-development program that begins many
years before the submission of an NDA or, for a biological product, a
Biologics License Application (BLA), and includes the human clinical
trials for which a company has filed an earlier application with FDA.
The bottom line of my testimony today is this: FDAMA is working
just as Congress intended for the benefit of patients. The 1997 law has
promoted increasingly efficient and effective working relationships
between FDA and patients, doctors, and regulated industries;
increasingly productive communications between FDA and its many
constituencies, including our research-based pharmaceutical industry;
sorely-needed improvements in FDA's information technology; and--most
significantly and importantly--speedier access for patients both to
safe and more effective new products and to experimental medicines
still in clinical testing.
Clearly, many parts of FDAMA were expected to be--and are being--
implemented over a period of years. We continue to work with FDA to
ensure that the full potential of these provisions is realized. We also
recognize that, because the number of applications for new products is
increasing, FDA's workload is growing, and the agency's priorities must
be focused on these applications.
With that as an overview of our overall evaluation of FDAMA
implementation, I would like to turn to one of the most significant
programs established by the 1997 law--the Better Pharmaceuticals for
Children Act.
For a number of years prior to enactment of FDAMA, FDA and
pediatricians had attempted several times to spur the development of
drugs for pediatric patients and to increase the labeling on products
used for children by encouraging more pediatric studies to be
conducted. Notwithstanding these efforts, many medicines continued to
be used for children without adequate labeling information for
pediatricians and parents. The pediatric provisions of FDAMA have
dramatically improved that situation. They changed the way FDA manages
pediatric drugs, prompting the agency to establish a dedicated group of
individuals who focus on drugs for children. They also changed the way
our industry approaches pediatric drug development and pediatric
studies.
Before enactment of the Better Pharmaceuticals for Children Act,
pediatric drug development was often slighted in competition with other
company R&D projects for necessarily limited resources. Because of the
difficulty of conducting clinical studies with children and the
substantial additional risks of such clinical programs, R&D directors
often preferred to focus their limited resources on drug-development
programs for adults.
Thanks to you and FDAMA, a company R&D director today can weigh the
substantial cost of pediatric drug development against the incentive
you provided in FDAMA. That law sent a loud and clear message from
Congress--we want our commitment to children to be reflected in the
development of more drugs for children.
The FDAMA incentive has meant that kids are now standing on equal
terms with adults in the stiff competition for research dollars at our
companies. FDAMA is changing the world for pediatricians who prescribe
drugs for children, for parents who administer these drugs, and, most
of all, for the children themselves.
The statistics speak for themselves. As of April 2001 companies
have proposed to study 218 medicines. This represents a remarkable
increase in interest in conducting pediatric studies. With suggestions
from professional organizations, such as the American Academy of
Pediatrics, industry, and the public, FDA has issued 188 written
requests for pediatric studies and 411 such studies have actually been
initiated. Twenty-eight drugs have received six months of exclusivity
under the 1997 law, and new pediatric labeling has been provided for 18
of these products. Additional label changes will be made as FDA
completes its review of the data from all of the studies.
So far, the completed and ongoing studies have resulted in the
development of new formulations to cover additional and younger
patients and the development of novel clinical trial designs and tools
to evaluate safety and effectiveness. Requests for studies have been
made for drugs in a wide range of therapeutic areas, from common
problems such as treatment of fever, skin infections, and pain to
cardiac disease, endocrine problems, gastrointestinal disorders,
serious infections including HIV, seizure, and other neurologic
disorders. Studies have involved pediatric patients of all ages.
The range of conditions addressed, the variety of drugs being
studied, and the nature of the scientific data requested all show that
FDAMA is successfully addressing unmet therapeutic needs in children.
No other approach, legislative or regulatory, has ever had such a
profound impact on the development and evaluation of medicines for
children.
Why has this legislation worked so well when other approaches for
more than 20 years have invariably failed?
The legislation has been such a success because it addresses the
fundamental impediments that have hampered the conduct of pediatric
studies of drugs in the past--principally the small number of pediatric
patients. Fortunately, most children are healthy. In the adult
population, there are large numbers of patients with diseases such as
heart disease and cancer who are available for clinical trials and who
constitute a large market for medicines to treat those diseases. By
contrast, with pediatric patients, serious and chronic illness is
caused by a wide range of diseases, but relatively few children are
affected by any particular disease. For example, fewer than 0.5 percent
of patients with arthritis are children, and juvenile rheumatoid
arthritis is a different disease than adult rheumatoid arthritis or
osteoarthritis.
The limited patient population has several consequences. First,
clinical trials are inherently more difficult to conduct with children
than with adults. The trials are much smaller because relatively few
children have a given condition. The children are of different ages. As
a result, they may need different, age-appropriate formulations of
medicines for accurate and compliant administration. For example, an
oral liquid may be needed for young children (sometimes different
concentrations for newborns), while chewable tablets may be required
for somewhat older children still unable to swallow pills or capsules.
Further, the pharmacokinetics of drugs (i.e., the rate at which
they are absorbed) varies widely with age. In addition, age-specific
study designs to assess effectiveness and safety may be needed. Studies
are particularly complex in tiny premature infants who may weigh less
than a pound. These babies are among the sickest groups of children.
Added to these complicated technical, scientific, ethical, and
medical issues are unique regulatory requirements. Sometimes, a
development program for pediatric drugs must include the duplication of
an entire clinical program for each of the pediatric age categories for
which an indication is sought. For example, if the clinical development
program included adults 16 years of age and older and the sponsor
wishes to investigate safety and efficacy in children 12 to 16,
tolerance studies may be required.
These tests can be followed by bioavailability and finally safety
and efficacy studies in children with the disease. If the sponsor then
chooses to seek the indication in children ages 6 to 12, the initial
studies would again be tolerance studies followed by bioavailabilty
tests before the safety and efficacy studies could begin. This process
would continue for the age groups below 6 years of age--i.e., 3 to 6, 1
to 3, 6 months to 1 year, and less than 6 months.
It is evident, therefore, that a clinical development program
necessary to address all age groups for children can be much more
extensive than a development program needed to address the age group 16
to 65. And, once formulations are produced and validated, studies are
performed, regulatory hurdles are met, and labeling ultimately is
changed, the market for most medications for children is very limited.
In general, the research-based pharmaceutical industry shares the
view FDA itself expressed in its January 2001 report to Congress about
this program. The program, FDA said, ``has been highly effective for
many drugs'' and the response of the pharmaceutical industry ``has been
vigorous.'' Our response has been motivated by a commitment to
improving children's health, not by a focus on products with high
commercial yield. In fact, when one looks at the list of most
frequently prescribed drugs published by Pharmacy Times, over half of
medications being studied for pediatric information are outside the top
100 drugs used.
We also recognize, as FDA and others have suggested, that some
changes might make the program even better. In particular, we agree
with FDA and the American Academy of Pediatrics that a different
approach is needed to address the issue of how to achieve pediatric
studies and revised labeling for older drugs without remaining patent
life, for which the exclusivity incentive does not apply. We have been
discussing this matter extensively with the AAP and look forward to
working with you to ensure that this issue is addressed appropriately.
We also agree with FDA that in general it is not necessary to
continue to exempt pediatric supplemental applications from paying user
fees under the Prescription Drug User Fee program. Such pediatric
supplement user fees, we know, will help FDA expand its focus on this
important area and--most importantly--will help ensure that
pediatricians and FDA resources for children realize the benefits of
this important initiative as quickly and efficiently as possible.
Several points should be emphasized in considering the vital need
to reauthorize the Better Pharmaceuticals for Children Act this year:
(1) Regardless of other aspects of health economics and health-care
financing, the small number of pediatric patients with a
specific disease available for study, the complexity of the
studies, and the ultimate limited market for pediatric drugs
will remain. If resources are constrained at any time for any
reason, research on the therapeutic needs of children is at
risk. It is crucial to keep the medical needs of children
competitive with the medical needs of adults in the scramble to
obtain company research funds. Section 111 makes that possible.
(2) The Better Pharmaceuticals for Children Act remains a critical
stimulus to study unique pediatric diseases and indications.
Many pediatric diseases differ significantly from those in
adults and FDA's Pediatric Rule thus does not apply. This is
particularly the case for diseases in premature neonates. The
pediatric program is the best mechanism to ensure that the
unique therapeutic needs of children are met.
(3) Section 111 encourages companies to initiate studies in a timely
manner. With the incentive in effect, companies are more likely
to initiate studies earlier in the drug development process
rather than seek to defer the tests. Pediatric studies should
not delay the development of important new therapies for
adults. As more advanced and novel therapies are developed, the
pediatric program can ensure that children fully benefit from
these developments.
(4) Because of technical oversights in the drafting of FDAMA,
antibiotics are ineligible for the exclusivity provisions of
Section 111. Since many of these drugs are likely to have
significant clinical benefits for children, Congress should
ensure they are covered when the pediatric provisions are
reauthorized.
(5) There has been significant variation in interpreting the
legislation and implementing written requests among FDA review
divisions. Much of this is understandable with a major new
initiative. Often, disease definitions, extrapolation of
disease similarity, and thus the nature of the requests have
been inconsistent. Sometimes, this has been caused by a lack of
understanding of pediatric diseases, sometimes by a lack of
pediatric expertise in FDA review divisions.
(6) Where inconsistencies have arisen, consensus approaches have been
developed through the Pediatric Advisory Subcommittee, together
with the American Academy of Pediatrics, the National Institute
for Child Health and Human Development (NICHD, and its
Pediatric Pharmacology Research Units, the PPRUs), other
National Institute of Health (NIH) institutes including the
National Cancer Institute (NCI), and parent/patient groups. All
parties have learned to focus on the therapeutic needs of
children and work to achieve consensus. This has been a major
unanticipated benefit of the legislation. The cooperative
process also has helped to address several issues in the area
of pediatric cancer.
FDA has formed a new Pediatric Oncology Advisory Subcommittee,
and prepared guidelines in the area of pediatric oncology.
PhRMA has created a Pediatric Oncology Task Force. These groups
are working together with the Children's Oncology Group and
NCI. Recognizing that many areas of medical and scientific
complexity now being addressed need to be resolved, FDA should
act to achieve consistency among review divisions, based on the
best pediatric and pharmaceutical science.
Further, FDA needs increased pediatric resources to deal with
these issues. Such resources must include more personnel with
detailed knowledge and expertise in pediatric investigation. To
the extent that some of these matters can be addressed by
increased FDA resources, user fees could be a mechanism. PhRMA
supports the elimination of the current pediatric supplement
exemption under PDUFA, to help achieve the goals of the
pediatric provisions.
(7) While Section 111 is working to meet the needs of children, the
incentives may not be able to overcome the barriers to very
early initiation of pediatric studies for truly life-
threatening but very rare conditions, such as certain pediatric
cancers. There is substantial risk and difficulty in conducting
pediatric studies for new chemical entities under development
for large adult populations, given the rarity of some of these
conditions in children. As we approach the renewal date for the
Better Pharmaceuticals for Children Act, we urge this
Subcommittee and Congress to consider how to improve the
climate for early initiation of pediatric studies. We would, of
course, be pleased to work with you and others who share these
concerns.
Another area that is important, though not directly related to this
program under FDAMA, is the obvious limitation in clinical
investigative resources for pediatrics. This deficiency has become
increasingly apparent. The creation of the NICHD-sponsored PPRUs has
been a major advance. It is critical that pediatric studies be carried
out at centers with extensive pediatric expertise. The safety and
welfare of research participants and the validity of the data generated
are dependent on the expertise of the centers at which studies are
conducted.
PhRMA strongly supports additional new legislation to encourage the
training of the next generation of pediatric clinical pharmacologists,
by providing training funds to the PPRUs and debt forgiveness for
trainees who enter careers in pediatric drug development. Such a
program would develop a pool of talent available to academic medical
centers, industry, and FDA to ensure that advances in therapeutics can
be translated into medicines for children. As the Subcommittee
considers additional ways to advance the health and well being of
children, we would be pleased to discuss further how to increase the
cadre of skilled, trained, and committed pediatric researchers.
In sum, the success of the Section 111 suggests that the current
incentive is reasonable. But the value of the program in adding
clinically meaningful pediatric information to package inserts is still
in its infancy. Because of the brief amount of time during which
applications could be submitted to date (the five-year program could
not really begin until FDA developed a list of relevant drugs (which
took more than a year), many drug sponsors focused only on the products
that could be studied during this relatively short implementation
period. Much more needs to be done.
PhRMA strongly urges Congress to reauthorize the Better
Pharmaceuticals for Children Act. The task has just begun of studying
and labeling currently marketed medications for children. The
increasing rate of industry study proposals and written requests for
studies by FDA shows continuing progress, which would be slowed and
then stopped if Section 111 were allowed to expire.
I would like to address our second major point--implementation of
other FDAMA pharmaceutical provisions. As has been stated, the
overriding goal of Congress, FDA, patients, and industry in working
cooperatively to enact FDAMA, was to ensure that safe and effective new
medicines would be made available to patients as quickly as reasonably
possible. This is occurring without any compromise in FDA's high safety
standards.
In fact, nothing in either FDAMA or the original 1992 user-fee law
lowered the agency's high standards. FDA has long been the worldwide
gold standard of drug review and approval. That standard is being
preserved and, indeed, enhanced. But now, thanks to FDAMA and PDUFA,
many critically important new drugs are being approved in the U.S.
earlier than in foreign countries--a real reversal from a decade ago.
To those who argue that FDA is moving too fast in approving new
drugs, PhRMA suggests that they examine the record. Nothing is more
valuable to our industry and our companies than the safety of their
products--primarily for their patients, but also for their long-term
reputations for trust, integrity, and reliability. Some argue that the
withdrawal of six drugs from the market over the past five years should
trigger a sharp change in policy. But consider that a record number of
184 new molecular entities were approved during this period. As a
result, the percentage of drug withdrawals compared to new-drug
approvals is consistent with historical averages. Moreover, the
reduction in the net drug-approval time by half since the first user-
fee law was enacted means that patients have earlier access to the new
and better treatments they need.
There were a number of FDAMA provisions aimed at improving the drug
review and approval process. Most of the provisions were designed to
improve FDA processes, but some also were directed at industry. All of
the provisions were the result of extensive dialogue between the
Congress, FDA, industry, and the public.
The progress made by FDA to date in implementing FDAMA has been
steady. Most of the guidances required by FDAMA have been completed. We
have provided a list attached to this testimony that notes each FDAMA
initiative that addresses drug regulation or FDA management that
relates to our products. It appears that most of the initiates are
being implemented effectively and efficiently. In some cases, it is
either too early to make an assessment or sufficient data have not been
collected to evaluate the situation.
Mr. Chairman, that concludes my written testimony.
Mr. Bilirakis. Thank you very much, Dr. Franson. The Chair
now yields to Mr. Burr to inquire. You can take your full 5
minutes if you like.
Mr. Burr. Mr. Chairman, it will not take me 5 minutes. I
really just have a statement and a question. I appreciate the
Chair's indulgence, to try to meet a school group.
I see Mr. Shuren here from the FDA. Let me ask, are you the
only representative from the FDA still in the audience?
Mr. Shuren. I believe I am.
Mr. Burr. And your role at the FDA is what?
Mr. Shuren. I am a medical officer.
Mr. Burr. Let me suggest to you, and I will request of the
Chair and the ranking member, that we send a letter to the FDA
once again stating that they have missed a great opportunity
for their policy folks who were here to testify to stay and
listen to the experts. I think that it is a missed opportunity
once again. I hope this is an agency that will learn if we push
it a little bit harder. I hope you will personally carry the
message back. I know that everybody has a hectic schedule, but
there is no greater opportunity than to listen to the same
people that we feel are the experts on these issues who are
willing to come and testify. It certainly saves you time in the
long run. I hope you'll carry it back.
Mr. Bilirakis. Your point is well taken.
Mr. Burr. My question is to Ms. Ben-Maimon, is that
correct? Let me ask you. You said that you had three children.
Ms. Ben-Maimon. I do.
Mr. Burr. If one of your children were seriously ill, and
the doctor said to you ``I can provide an ability for your
child to live for an additional 70 years, but it will cost your
life,'' what would you do?
Ms. Ben-Maimon. Obviously I would give my life for my
child's, without any question.
Mr. Burr. If the promise were only for 20 years, what would
you do?
Ms. Ben-Maimon. Again, there is not any question.
Mr. Burr. If the promise were for 1 day, what would you do?
Ms. Ben-Maimon. I would probably make the same decision.
Mr. Burr. I thank you for answering that question.
Mr. Chairman, I yield back.
Ms. Ben-Maimon. Can I respond though as a physician?
Clearly those are not the kinds of decisions that we need to
make. We need to make decisions where we measure benefits and
risks. I have been in the drug industry both in the proprietary
side and on the generic side for almost 10 years, I guess, and
I have treated patients.
Mr. Burr. Ms. Ben-Maimon, let me say this. There are
doctors to your right. There are doctors to your left. The one
thing I have learned about doctors is that each one has a
response. It may be a little bit different. There is not going
to be consensus. There is a parent in every row. Parents will
answer that question exactly like you did. If our concentration
is on children, then let's stay focused on children. If there
is a remote chance at whatever cost that we can save the lives
of children, then do we not have a responsibility to do it?
Ms. Ben-Maimon. Not if that is not our only choice, because
I think we can save the lives of children while still improving
the lives of others. We should try and do that before we make a
sacrifice we may not necessarily need to make.
Mr. Burr. I'll let the pediatricians battle that one with
you.
Thank you, Mr. Chairman.
Mr. Bilirakis. The Chair yields to Mr. Brown to inquire.
Mr. Brown. Thanks, Chairman.
I'm glad to hear that my friend, Mr. Burr, with whom we've
worked together on a variety of issues, is now going to vote
against the President's tax cut and put more money into child
prevention and other programs that will help America's
children.
Mr. Burr. The gentleman has to realize that the choice is
to leave that money here and let us spend it. I would much
rather get it out of town.
Mr. Brown. That estate tax break is going to save a lot of
children's lives.
Prozac about 6 months ago or some time ago got a 6-month
exclusivity estimated to be worth around $2 billion to the
manufacturer. Prilosec, a very important drug, largest selling
drug in America, estimated sales of $4 billion in the year
2000. It's an important drug for children. Astra
Pharmaceuticals recently did pediatric studies on the drug.
This week they got 6 months of exclusivity for doing so.
This question will be to all six of you. The 6 months of
exclusivity without generic competition for Prilosec for Astra
Pharmaceuticals is estimated to be worth about $1.2 billion in
additional profit. The President's budget, squeezed by the tax
cut, I might add, for the entire National Institute of Child
Health and Human Development for the coming year is $1.1
billion. So Astra for the 6 month extension will get $1.2
billion in additional profit. The President's entire budget for
the NIH Child Health and Human Development is $1.1 billion
total. To be sure, Prilosec is a good effective important drug.
Can each of you honestly, or any of you honestly tell me that
the one pediatric trial that Astra is doing is worth more than
all the NICHD budget together, combined?
Mr. Kearns. The simple answer is no. I don't think it is
worth more than the budget.
There is an incredibly difficult conundrum for those of us
who do pediatric research and care for children. That is, we
have been for so many years without an avenue to include kids,
that most of the work that was done was done out of people's
pockets, meaning academics, schools, medical schools, pharmacy
schools and the like. So now with FDAMA and the pediatric
provision, the avenue to include kids is there.
I must say and confess that when it comes to the issue of
profitability, I really put my head in the sand many times
because of the zeal to do what's right by kids. I am an NIH-
funded investigator. I would love for part of that money to go
to NICHD. It could further improve what we do. Unfortunately, I
don't have a simple solution. The Astra drug is an important
drug for children. It improves the lives of many kids and many
families, but is it worth the NICHD budget? In my personal
estimation, no.
Mr. Brown. Dr. Ben-Maimon?
Ms. Ben-Maimon. I would like to keep my remarks brief
because again, I want to reiterate that we actually do support
the concept. The concern I have again as a physician,
primarily, is that sums that large can actually make the
incentive, turn the incentive into a mechanism to exploit. We
want to encourage children and the study in children, but we
want to be sure that we do it and protect them, and make sure
that we do it when we really need to be doing the research. So
again, I would challenge Congress and ask them as they
reauthorize the pediatric exclusivity provision, that they
consider what is the appropriate incentive to ensure these
studies continue, yet that we do it in a way that we don't
encourage companies to exploit our kids.
Mr. Brown. Dr. Gorman?
Mr. Gorman. The 6 month's exclusivity is a broad brush
painted across many drugs. While in the case that you present
it has become extraordinarily profitable for a single company,
it has also prompted the development of knowledge in other
drugs that are not nearly so profitable.
My favorite example on the list of labelling changes
already is Lacthydrine, which is not on anybody's top 200 list,
and is a cream use for ichthyosis, which is a disease I hope no
one in this room has heard of. It was also incentivized under
this program.
The simple answer to your question again is no. I don't
think that one drug company needs to profit to the extent of
the increased NICHD budget. On the other hand, the information
made available to children today from that study will be
available for the next 100 years. The profitability will be
gone for 99.5 years after that.
Mr. Brown. As I might add would direct government--if the
government did the study directly the same information would be
there, I would add.
Ms. Meyers?
Ms. Meyers. Mr. Brown, I have three children who have a
rare disease. They are adults now. I have been saved by drugs.
But all three have participated in clinical trials. Now I have
six grandchildren. I want pediatric studies to be done for the
sake of my grandchildren. I am very proud to say that my adult
children all did participate when they were children. But when
my 85-year-old mother can't pay for her drugs when she goes to
the drugstore to pick them up, she calls me and asks me to pay
for them. So I feel particularly torn by this problem, asking
my 85-year-old mother who can't afford her drugs, to pay for
her great-grandchildren. I don't think that it is fair. I think
it is Congress' responsibility to make it fair.
Mr. Brown. Mr. Plunket?
Mr. Plunkett. I will just add that our coalition does
support the exclusivity, but we think it has to be more
targeted, more effective and less costly. We shouldn't have to
make this tradeoff, cost versus testing for kids. In our
testimony, we have a range of possibilities we would urge the
committee to explore to make it more targeted and more
effective because the way that it is written now, it does
increase costs for consumers. That's not acceptable, especially
on important drugs like the ones you have mentioned. It
shouldn't happen.
I think that this committee has a range of options it can
consider, from tax cuts to scaling the exclusivity based on the
sales of the drug, to a number of other ideas that can make
this provision more targeted and more effective.
Mr. Franson. In response to your question you had mentioned
several compounds. I think it is important to note that any
time we look at drug studies in pediatrics, they have both
short-term impact and long-term.
In the case of these for exclusivity, you mentioned both
Prilosec and I believe Prozac, both of those are used for a
broad range of problems significant in pediatrics. Both
required at least some, if not a broad range of studies. In the
near term, met important clinical needs.
In the longer term, I think one of the tremendous benefits
of FDAMA and the pediatric incentives has been that it has
created or reignited the excitement for an infrastructure for
doing pediatric clinical studies and research. That was not
present previously broadly in the United States. This has been
a wonderful benefit that will serve the public health long-
term.
Second, it has allowed companies such as ours to reinvest
some of that that has been gained through exclusivity to
actually begin new programs and lines of drug research devoted
exclusively to pediatrics. I think the benefit of that balanced
against the cost long-term would be difficult to project, but
it is not inconsequential. I would suggest that those kind of
benefits need to be weighed in that are very significant.
Mr. Brown. I would add one sentence if I could, Mr.
Chairman. The high end estimate of how much it costs a company
to do pediatric studies is $4 million a day. That is the
extravagantly high end estimate.
Mr. Franson. A day?
Mr. Brown. For the price of Prilosec's exclusivity, we
could fund NIH to do 300 of the most expensive trials or some
larger number obviously of less expensive.
Mr. Bilirakis. The gentleman's time has expired.
Ms. Meyers, I think you said it all when you made the
statement, ``I am torn.'' That is really what it comes down to
here. Everybody has sort of agreed that FDAMA is working. Some
people have indicated there are weaknesses and there should be
changes made, but in general it's working. That is where we're
torn too, because we don't want to take a chance on doing harm,
as Mr. Greenwood indicated earlier in his opening statement. So
that's really what we are faced with here. Obviously your
testimony tears us even that much more.
I wanted to ask, Dr. Franson, a question on another
subject, although it's pertinent to prescription drugs. Who
determines the expiration dates on drugs?
Mr. Franson. The expiration dates on prescription drugs are
determined by testing done by the company and then reviewed and
validated with FDA.
Mr. Bilirakis. So both FDA and the companies determine the
expiration dates?
Mr. Franson. We could not, for example, as an industry
suggest a date that was not scientifically defensible and
validated by a regulatory body.
Mr. Bilirakis. What about input from medical doctors
regarding the expiration dates on the drugs and their efficacy?
Mr. Kearns. It is really very difficult to answer that
question, Mr. Chairman, because the data that was just spoken
about is not generally available to the practitioner. For
instance, if we knew that at the end of a 2-year period of
expiration, for instance, that there was at least 90 percent
potency there, I think few practitioners would have little
heartache in using that drug. But if it was far less than that,
especially for a drug with a narrow margin of safety, are you
being used to treat a very difficult disease, it could be a
real clinical issue. But again, it's the information is not
available.
What drives the practice of medicine is a risk-benefit
paradigm. Made in the absence of validated information, that
becomes so difficult for physicians to do on a day-to-day
basis.
Mr. Bilirakis. I appreciate that. If there's an expiration
date, you as a physician are not going to prescribe that drug
exceeding that expiration date.
Dr. Gorman?
Ms. Ben-Maimon, you are more than welcome to respond to it
if you'd like.
Ms. Ben-Maimon. I'll let Dr. Gorman comment first.
Mr. Gorman. I think to echo that comment, there is very
limited information on drugs being used past their expiration
date. The only one that I'm presently aware of is tetracycline
is really not good to use past its expiration date. Epicac, an
over-the-counter drug that makes people vomit, works for 18
years after it is manufactured. After that, I am not aware of
any information, would be hesitant to prescribe or recommend
that patients use these drugs after their expiration date.
Ms. Ben-Maimon. From the standpoint of industry, data is
generated at room temperature for years out. The requirement is
90 percent. But of course it's sampled. You know, you are not
testing every drug that's on the market. It assumes certain
storage conditions. So drugs clearly are not intended to be
prescribed after their expiration date. I think the cutoff is
for most drugs, from a regulatory perspective, 90 percent. The
problem is what happens in the marketplace and what happens if
the temperature goes up over what the intended storage
conditions are. Clearly the pharmacist is the one responsible,
who should not be dispensing a product that is after its
expiration date. Those products should be returned. So I don't
think the pharmaceutical community would endorse administering
these products at the end of their expiration.
Mr. Bilirakis. I appreciate that. I have visited a health
clinic in Clearwater, Florida, that I have tried to help over
the years, and seen half a dozen volunteers doing nothing but
pulling drugs off of the shelves that have been donated to them
by physicians and throwing them into a container. There's all
sorts of regulations in terms of how they have to dispose of
these drugs. I see all that valuable time that these people
volunteer spent pulling these drugs off these shelves. That's
common place.
I have a problem with that. I realize of course that many
of those drugs have exceeded their efficacious date. But I also
suspect, and I'm not a physician, that in some cases these
dates could be extended out. What about cases where people need
drugs and it's either no drugs at all or else a drug which is
at 90 percent efficacacy and can be available to help? That is
the big question I have in my mind. I have talked to staff
about it over the years. We can't seem to get much help or much
of an answer.
Ms. Ben-Maimon. I think the only way is to retest. I mean
what happens is the data really is generated in real time.
There are products that are retested. You know, if it's past
its expiration date, drug companies do pull product or use
other data to support it. So the only way that I think you
could comfortably prescribe those products and tell patients to
take it is if you retested them.
Mr. Bilirakis. My time has expired. But if any of you have
any comments or thoughts on that subject, I would welcome
receiving those.
Mr. Pallone?
Mr. Pallone. Thank you, Mr. Chairman. During the testimony
a number of suggestions were made. I guess most notably by Mr.
Plunket, about possible measures that either as alternatives or
that would make pediatric exclusivity more effective and less
costly. I just wanted to look into some of those.
My question is to Dr. Franson. It occurs to me that a tax
credit or a direct reimbursement program would be possibly more
effective, efficient, and an equitable incentive than market
exclusivity. If you think about direct reimbursements or
credits, they would cover all products. They would be efficient
since they would more closely reflect the cost of the test.
They would be more equitable since the economic costs of the
testing would be spread across a broader base rather than only
on consumers of the product being tested.
I wanted to ask you whether PhRMA would support, for
example, a three-for-one incentive in lieu of exclusivity.
Would you be supportive of any of these measures?
Mr. Franson. I think we would be happy to assess and
discuss and respond to the committee in whatever fashion to
explicit proposals so we could understand that. I think the one
thing that we remain committed to is that prior to FDAMA and
the pediatric incentive, pediatric research was not being done.
With the incentive, it is. We would want to carefully assess
anything that was proposed to assure that we did not fall back
to the prior state. So I could not commit or refute without
more specifics, but would commit to you to provide a response.
Mr. Pallone. Okay. But what about this idea of the three-
for-one incentive? In other words, for every dollar you spend
on a pediatric test requested by FDA, you would get either $3
cash or a triple tax credit? That's specific.
Mr. Franson. I think speaking as a physician and regulator,
it is something I would be happy to refer back to my colleagues
more sage in those kind of things and could provide a response.
Mr. Pallone. That's fair.
Mr. Spielberg. If I might, I'm Stephen Spielberg. I am
really speaking here as an advocate for pediatrics within
industry. I am a pediatric pharmacologist who daily has to
compete for resources for doing pediatric research.
The issue of the 6 month exclusivity is not on individual
compounds. It's on our portfolio of compounds. When we look at
the number of R&D dollars that I can attribute to pediatrics,
it comes from exclusivity granted to very small drugs with very
modest incomes, and to some very large drugs with very large
incomes.
My ability to be able to compete for those funds and to
assign those research dollars to children is dependent on
indeed having those funds available as a result of the
legislation.
Proof of the pudding is that it works. If you look at the
first 28 drugs that have gone through the process, yes, two are
in the top 10. Nine are not in the top 200. So that the larger
items indeed support the lower items.
Mr. Pallone. I appreciate that. I like the fact that Dr.
Franson is willing to get back to me and maybe answer some of
this.
I want to go one step further, if that's all right. If I
could just ask one more thing, and then anybody who wants to.
Let me just ask him one more thing and then if any of you want
to comment, please.
This idea of--well, in her testimony, Dr. Ben-Maimon
mentioned this Wall Street Journal article that estimated the
cost of pediatric studies for pharmaceutical manufacturers to
be between $200,000 and $3 million, which in turn the Journal
says will increase drug sales by an additional $4 billion for
the first 26 drugs tested. It says over 30 years, if the Wall
Street Journal is accurate, pharmaceutical companies will make
an additional $30 billion.
Now I just wanted to ask Dr. Franson again first, what is
his view of this Journal estimate about how much pediatric
studies cost the members of his association, and how much
additional revenue they have earned. Second, because the
companies themselves are the best source for providing the
committee, since you are so willing to provide stuff, it would
be helpful if you could forward information to us about the
cost. In other words, the Wall Street Journal is saying
something. I don't know if you agree with that, but you are
obviously the best source for providing the committee with
information as to how much the studies that have been completed
already cost. If you could give us that kind of information, it
certainly would be helpful as a follow-up.
Mr. Franson. Thank you. I would be happy to respond to that
now. Regarding those figures, I believe those are quoted with
the assumption that a single pediatric blood level, that is
dosing study, could provide the basis for pediatric
exclusivity.
Our understanding in discussions with FDA is that of all
the drugs that have been provided a written request, none has
only that as a facet. Therefore, that is a vast underestimate.
In many of the studies that have had pediatric requests
filed, multiple studies of different diseases have been
required for clinical trials. Therefore, in addition to a
pharmacokinetic or blood level study, there may be two studies
required for a single indication or type of disease affliction,
additional studies for more for that same drug. Therefore, the
time and expense and skill necessary to complete those studies
is significant. In the example of some we have had experience
with, eventuated in over 22,000 pages of documentation
submitted to FDA for pediatric exclusivity.
Mr. Pallone. If you could just get back to us with regard
to the three-for-one possibility or the tax credits, or maybe a
critique of the Wall Street Journal, I would appreciate that.
Any information you could provide us about whether it's
accurate or what the real facts are.
Mr. Franson. It would be our pleasure. Thank you.
Mr. Pallone. Thank you.
Ms. Meyers?
Ms. Meyers. I would just say that a few months ago, FDA
issued a statement saying that in the future all new drugs will
have to be studied for children, so when they reach the market
they will already be labeled for pediatrics. A number of PhRMA
companies are suing the FDA to stop that. I would like to know
why.
Mr. Buyer [presiding]. If you can answer the question, it's
an open question. Questions come from the panel, not among the
members who are sitting at the table.
The Chair now recognizes himself. To Dr. Tim Franson I will
ask this question, Ms. Meyers, based on something I have read.
In testimony you claim that performance goals contained within
PDUFA created an incentive for drug companies to delay
submission of data to the last moment, thus putting the FDA
under tremendous pressure to meet the user fee deadlines. Do
you see any evidence of this in your industry?
Mr. Franson. Regarding delays? If a company were to do
something of that nature, to submit part of an application late
after an initial application, there is actually a penalty
imposed. That is called under FDA regulations at the Center for
Drugs a major amendment. That would require the sponsor, the
pharmaceutical company, to have a 90-day period of additional
review granted to the FDA. So there would be no advantage for a
sponsor to do something of that nature. It would be very
important to the sponsor and to FDA to have sufficient time to
review the substance of the information. So no, that is not our
experience.
Mr. Buyer. Thank you. Has PDUFA led to higher percentage of
drug recalls?
Mr. Franson. In the PDUFA period, I believe that the issues
cited by FDA are correct. The withdrawal rate of 2 to 3 percent
is accurate. In fact, I am personally surprised that it is not
higher, given the vast number of drugs now introduced first in
the United States as opposed to overseas. Of those 11 drugs
that were cited, I believe four of those withdrawn drugs were
actually approved before PDUFA. Therefore, it would be very
difficult to ascribe a gap in the PDUFA review process when
those drugs had already been on the market before that act.
Mr. Buyer. In January, the Clinton FDA report to the
Congress stated that ``PDUFA has been very successful.'' Do you
see any reason to dispute that comment?
Mr. Franson. I would not dispute that.
Mr. Buyer. Thank you.
Doctor, how many of the 188 drugs examined under the
pediatric exclusivity, how many of them were blockbuster drugs,
are you aware of?
Mr. Franson. Regarding blockbuster, I'm not sure how
everyone would define that. By the rankings----
Mr. Buyer. Over a billion dollars.
Mr. Franson. I believe I will ask my colleagues. Two of
them may have been in that category. Is that correct?
Mr. Spielberg. Of the first group through, yes, that's
right.
Mr. Franson. So two.
Mr. Buyer. Both the FDA pediatric exclusivity and Tufts
University reports examined tremendous cost savings associated
with pediatric exclusivity provisions. Do you believe that the
pediatric exclusivity provisions may in fact save money in the
long run? Do you believe that?
Mr. Franson. I would like to ask Dr. Spielberg to answer
that.
Mr. Spielberg. Yes. I think in fact if you look at the
FDA's report, when they deal with five conditions and only five
conditions, they estimate savings by 25 percent decrease in the
hospitalization of about $228 million a year. But that is only
for five conditions. That is a modest estimate of the savings.
If I may point out two compounds that have been approved,
Midazolam and Propofol. Both used for sedation in children in
hospitals with new labellings and precaution. The most
hazardous thing in pediatric hospitals is anesthesia and
sedation for procedures, for example, a kidney biopsy or a
liver biopsy. Getting proper information on dosing and
precautions for those two medicines not only will decrease
morbidity to those individual children, it will decrease
hospital stays because the children will be properly sedated so
the procedure can be done so you don't have to delay it until
further medicines are administered. But it is going to decease
the adverse effects of those medicines dramatically.
Mr. Buyer. Thank you.
The FDA tried more than 20 years to get the pharmaceutical
industry to conduct pediatric testing, but none of their
efforts succeeded until the pediatric exclusivity was passed.
FDA reported in January that the pediatric exclusivity
provision has done more to generate clinical studies and useful
prescribing information for the pediatric population than any
other regulatory or legislative process to date. Why has the
pediatric exclusivity proved so successful when other
initiatives have failed?
Mr. Franson. I think Steve is an expert, would be best to--
--
Mr. Spielberg. I think again from my experience trying to
encourage pediatric drug development, both on the academic side
and now in industry, what it does is it fundamentally raises
the priority of pediatric studies' allocation of R&D dollars,
knowing that we have a reliable return on a compound, when that
return can't be justified by pediatric sales and when we have
very high risk in doing those pediatric studies, we don't know
if we are going to get exclusivity. We don't know if we are
going to get negative labelling, which should be in there for
children if there is a negative effect. That covers those
issues, and therefore raises the priority of doing pediatric
studies.
It is even more important for the new drugs coming down the
pike because if we are going to invest early on, the needs of
the pediatricians are early studies of those new drugs that are
going to cure kids. We have got to get an incentive for those
studies to be done early. That is why it works.
Mr. Buyer. Help me here. A drug manufacturer can only get
the 6 month exclusivity if FDA gives it to you. What about can
you ask for it? Can manufacturers ask for it?
Mr. Spielberg. We can propose studies, but one of the key
issues in this whole issue in the accountability issue is that
the FDA determines the precise nature of the written request.
We can propose studies and then they can add on several
additional studies, or change those studies. The FDA written
request is the absolute sine qua non for us getting the
exclusivity, but it also holds them accountable for the public
health need and it holds us accountable for doing the right
studies. That is why more than a third of the studies of those
411 are full efficacy studies. These are not simple PK.
Mr. Buyer. All right. Thank you.
In my questions, I refer to the pediatric exclusivity
provisions of the report, January 2001 staff's report to
Congress. I ask unanimous consent it be placed in the record.
Hearing no objections, so ordered.
[The report is available at:]
http:///.fda.gov/cder/pediatric/reportcong01.pdf]
Mr. Buyer. I also refer to the Pediatric Studies Incentive:
Equal Medicines for All, the white paper. This is what we're
referring to as the Tufts report. I ask unanimous consent that
it also be placed in the record.
Hearing no objection, so ordered.
[The report follows:]
The Pediatric Studies Incentive: Equal Medicines For All
White Paper by Christopher-Paul Milne, Assistant Director, Tufts Center
for the Study of Drug Development
INTRODUCTION
In November of 1997, the FDA Modernization Act (FDAMA) was signed
into law, amending the Food, Drug and Cosmetic Act and the Public
Health Service Act. The pediatric studies provision (Section 111) of
FDAMA grants drug companies an additional 6month period of market
exclusivity for new or marketed drugs in exchange for conducting
pediatric studies requested by the FDA. FDAMA requires FDA to submit a
report to Congress examining all issues relevant to the experience
under the pediatric studies incentive program (hereinafter, the
``incentive program''). In particular, the FDA is to focus on the
effectiveness of the program in improving information, the adequacy of
the incentive, the economic impacts on taxpayers and consumers, and
suggestions for modifications. This white paper by the Tufts Center for
the Study of Drug Development (Tufts CSDD) will provide an additional
viewpoint on these and other relevant issues. This report is based on
our own research as well as publicly available information, and focuses
primarily on the present and future impact of the legislation as it
relates to four areas of concern: effect on public health; building a
pediatric research infrastructure; unforeseen impact; and, the cost-
benefit ratio.
BACKGROUND
The 1962 amendments to the Food, Drug & Cosmetic Act made children
therapeutic orphans because it required manufacturers either to test
drugs in children or discourage their use in children with label
disclaimer statements. Now, 40 years later, some 75% of marketed drugs
are not labeled for use in children, despite the fact that many of them
are therapeutically indicated for children and are used routinely off-
label in the practice of pediatric medicine. This has resulted in a
kind of ongoing natural experiment. Information on dosing, drug
interaction, safety, and efficacy is developed, not in controlled
trials that are carefully observed in a few hundred children, but
instead in thousands of doctors' offices, homes, and hospitals, where
hundreds of thousands of children may be exposed unnecessarily to
adverse consequences before a drug is withdrawn or otherwise limited in
its use.
The reason that these circumstances have persisted is that there
are significant disincentives to studying drugs in children. These were
noted in the Senate Committee testimony on the pediatric studies
provision of FDAMA. They include a limited return on investment,
liability concerns, and the difficulties of enrolling and studying
pediatric patients (1). Although there were past efforts by FDA to
encourage industry to study the pediatric uses of drugs developed for
adults, these had been of a voluntary nature, either by design or
default. The results were generally considered, even by FDA itself, to
be ``disappointing.'' In 1997, FDA proposed to make the study of
pediatric indications mandatory. This crystallized a complementary
effort by pediatric research advocates to get a pediatric studies
incentive provision included in the FDA Modernization Act of 1997. The
exodus of children from forty years in the desert of therapeutic exile
was now to be driven by the carrot-and-the-stick.
EFFECTS ON PUBLIC HEALTH
The public health consequences of the existing situation are that,
due to the lack of proper information, especially on correct dosing,
and the lack of age-appropriate formulations, children are at an
increased risk for under and overdosing, improper administration of the
drug, and failure to follow the prescribed dosing regimen (i.e.,
noncompliance). In addition, children may be denied access to
therapeutic advances because some practitioners might delay using a new
drug on children off-label until there has been some experience with
them in adults, or, they may never use what could be the best available
treatment because it has not been properly formulated for children and
may lack accurate pediatric use information. This problem of suboptimal
utilization may be especially widespread in pediatric practice, because
close to 40% of prescriptions for children are not written by
pediatricians (2). Practitioners who are not routinely engaged in the
care of children may be more wary of using medicines off-label in
children.
Public Health Benefits of Improved Information
As a result of the incentive program, a great deal of information
is being generated on pediatric indications for both new and already-
marketed medicines. Of the 12 medicines labeled so far for pediatric
use through the incentive program, one-third were medicines new to the
market and two-thirds were already on the market (3). While just these
few drugs have already made a significant contribution to improving
therapeutic options and practice for hundreds of thousands of children
(3), an additional 200 drugs could be labeled over the next few years.
As of January 1, 2001, FDA reported that they had issued 39 written
requests soliciting pediatric studies on their own initiative as well
as 134 written requests in response to 210 proposed pediatric study
requests (PPSRs) from industry (4).
There are indications that as many as three times the number of
pediatric clinical trials may be ongoing now as were being performed in
1997, before the initiation of the incentive program under FDAMA (5).
From September 2000 to January 2001, Tufts CSDD conducted a survey of
drug companies that were the sponsors of the first 40 products
receiving written requests.\1\ Of the 25 survey responses, 16
enumerated the number of clinical studies conducted per request. There
were 44 studies being conducted for 16 written requests. Assuming an
average of close to three clinical studies per request, one can
estimate that for the total number of written requests being undertaken
under the incentive program, over 500 clinical trials in children are
currently being planned, conducted, or already completed, in comparison
to less than 150 clinical trials in 1997 (6).
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\1\ Sponsors for 25 of the 40 products responded to the survey
(62.5% response rate). Of these 25 responses, 20 stated that pediatric
study report submissions were planned or had already been sent to FDA.
A review by Tufts CSDD indicated that 14 of these 20 products have, in
fact, received pediatric exclusivity as of February 15, 2001.
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Dosing and use information, as well as the availability of
appropriate formulations for pediatric indications of adult medicines
will help make these medicines safer and more effective for children.
At the same time, the upsurge in public attention and interest from the
general medical community may also help alleviate the problem of
suboptimal utilization in children of drugs developed for adults.
Public Health Benefits of Increased Pediatric Drug Research
The public health benefits that will accrue from increased
pediatric research have already been recognized. In the few therapeutic
areas in which there was considerable pediatric research already, such
as AIDS and cancer, there has been a concomitant decrease in the
adverse impacts of those diseases. For example, reported pediatric AIDS
cases have declined 70% since 1992 due to the development of drug
regimens to prevent perinatal transmission (7). Similarly, during the
last few decades, well over 50% of pediatric cancer patients (the NIH
reports it may be as high as 70% now) have been enrolled in clinical
research, and today 75% of pediatric cancers are curable (8, 9).
Now under the incentive program, intensive research is being
conducted not just in a few disease areas but on over 70 diseases and
conditions of children (3). The majority of these diseases and
conditions are in therapeutic areas in which scant research in children
had occurred prior to the incentive program. However, these same
therapeutic areas are the ones in which research is most urgently
needed.
Tufts CSDD reviewed nine studies and reports published in
professional journals or available from FDA, which discussed a variety
of adverse outcomes in children resulting from interactions with
therapeutic drugs. This review indicated that therapeutic areas
historically involving high risk to children are prominently
represented among the active moieties \2\ (i.e., active ingredient)
appearing on the original ``FDAMA List'' of active moieties for which
additional information may produce potential health benefits in the
pediatric population (10). An updated review by Tufts CSDD of those
problematic therapeutic areas indicates that the top three (central
nervous system, cardiovascular, and hormonal) correlate with the
therapeutic areas covered by the three FDA reviewing divisions
(neuropharmacological, cardio-renal, and metabolic & endocrine)
receiving the most PPSRs as of January 2001--83 PPSRs or 40% of the
total, for which FDA has already issued 59 written requests (4).
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\2\ Active moieties are defined by FDA as the molecule or ion
responsible for the physiological or pharmacological action of the
drug.
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In addition to the number, breadth and public health significance
of the diseases and conditions being addressed, dosing and use
information is also being developed for the whole expanse of pediatric
age groups. Of the responses to the Tufts CSDD drug company survey, 18
stated the age range for which pediatric studies were being done or had
been completed. Tufts CSDD categorized the results using FDA age
classifications.\3\ The indication count by age-group was as follows: 4
for neonates; 8 for infants; 16 for children; and, 9 for adolescents.
It is noteworthy that 32% of these studies included neonates and
infants--age-groups for which little information was previously
available.
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\3\ Neonates--age 0 to 1 month; infants--age 1 month to 2 years;
child--age 2 years to 12 years; and, adolescent--age 12 years to 16
years.
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More Child-Friendly Formulations Become Available
Besides age-appropriate use information, another key factor in
making medicines safe and effective for pediatric patients is the
availability of child-friendly formulations. Children are notoriously
problematic when it comes to taking medications as prescribed by their
healthcare practitioners. Children have documented non-compliance rates
ranging from 50-75%, rates that worsen with chronic diseases such as
asthma and diabetes (11). Disagreeable taste and difficulty in
swallowing tablets or capsules, especially for children under six, are
among the reasons for such high non-compliance in children (12).
Besides decreasing the effectiveness of medicines, the lack of child-
specific formulations increases the risks of adverse reactions for
children, since they are exposed to doses and inert ingredients
intended for use only in adults (13). Similarly, the use of
extemporaneous formulations, which are pediatric preparations made by
doctors and pharmacists from medicines only commercially available in
adult product forms, increases the difficulty of accurate dosing and
wastes staff time and money. One pediatric researcher noted that his
children's hospital spent over 11 hours a day compounding
extemporaneous products, and that as many as 20% of medication errors
in children may be attributable to such products (14).
The incentive program is improving this situation for children. The
Tufts CSDD survey of drug companies shows that out of 20 active
moieties for which pediatric studies were being done or already
completed, 4 included the development of new pediatric formulations.
Again, extending this experience to the rest of the 200 or so studies
that are under way could mean that dozens of new child-friendly product
forms could reach the market over the next few years.
Improving Global Public Health
As important as label information is for pediatric practitioners in
the U.S., it is even more important to the practice of pediatric
medicine in other countries. This is especially true in the developing
world, where other forms of information, such as reference texts, may
not be readily available and where care may have to be provided by
individuals who are not professionally trained medical practitioners
(e.g., government public health workers, humanitarian emergency
personnel, missionaries, etc.). While the public health of children in
the U.S. is the main focus of the incentive program, U.S. children will
not be its only beneficiaries. A review by Tufts CSDD showed that
approximately 70 active moieties that appeared on the 1998 FDAMA list
also comprise nearly one-third of the World Health Organization (WHO)
Essential Drugs List, a list of drugs determined to be critical to
meeting the health needs of the world's nations (15). Despite the fact
that many of the medicines on the Essential Drugs List are older, off-
patent drugs used for treating acute conditions or tropical diseases,
18 active moieties of these drugs have been the subject of written
requests already issued by the FDA. When these drugs are labeled for
use in children and become available for distribution worldwide, the
benefits of the U.S. incentive program will extend to all the world's
children.
This, in turn, will help indirectly to further safeguard public
health and safety here in the U.S. For example, AIDS has been declared
a national security threat because of the destabilizing influence the
epidemic is having on areas vital to U.S. interests. Along with AIDS,
other diseases addressed by medicines eligible for the incentive
program are transmissible and can cause transnational epidemics (e.g.,
tuberculosis, hepatitis C, and influenza). There are several million
children residing in the U.S. that are recent immigrants for whom the
public health toll can be ameliorated if labeled medicines for treating
and preventing tropical diseases are available for use here as well as
in their countries of origin (15, 16). Lastly, there is increasing
recognition that the U.S. has a responsibility to help improve the
public health of our international trading partners and geopolitical
neighbors as part and parcel of the reality of globalization.
BUILDING A PEDIATRIC RESEARCH INFRASTRUCTURE
As Dr. Ralph Kauffman, a leading pediatric researcher and advocate,
pointed out in a recent newspaper article: While an infrastructure for
clinical testing of drugs for adults has evolved over the last few
decades, that infrastructure never developed for children (17). There
are very good indications that the infrastructure is now under
construction as a result of the pediatric studies incentive program.
Effect on the Outsourcing Industry
Because of the rapidity with which the industry has had to respond
to the pediatric studies incentive due to the deadlines inherent in the
process of applying for the exclusivity, the major drug companies have
had to marshal their resources very rapidly. The Tufts CSDD survey of
drug companies shows that the initial sponsors responding to the
incentive program accomplished this by diverting in-house resources and
relying on outsourcing service providers. In fact, 8 out of 15
respondents to the question on the use of outsourcing said that
outsourcing firms were employed to conduct all or part of the studies.
The outsourcing industry consists of a number of service providers for
a variety of clinical trial related tasks, ranging from data management
to actually conducting clinical trials. Thus, the first building blocks
of the nascent pediatric research infrastructure would appear to be
found among the contract research organizations (CROs), site management
organizations (SMOs), and independent clinical investigative sites that
comprise the outsourcing industry.
A survey of 120 CROs by CenterWatch, an industry watchgroup
focusing on the business of clinical trials, indicates that the number
of CROs with pediatric trial expertise grew from 32% to 45% during 1997
to 1999 (18). At the same time, among 436 investigative sites, the
number with pediatric expertise increased from 13% to 22% (18).
Similarly, a group of non-profit academic SMOs, called the Pediatric
Pharmacology Research Units (PPRUs), which is a network of academic
medical centers specializing in pediatric research and organized under
the aegis of the NIH, doubled its number of participating institutions
in 1999 from 7 to 13 in reaction to the increased workload from the
pediatric research initiative (13). The PPRUs themselves may be working
on as many as 70 industry-sponsored studies (19).
A Tufts CSDD survey of 35 CROs revealed that of the 21 respondents,
13 are working on pediatric studies.\4\ These 13 CROs are collectively
conducting 113 studies involving 7,000 patients. Just this sample of
CROs and SMOs (representing roughly about 5% of their respective
outsourcing service sectors) are working on nearly 200 pediatric
studies themselves, compared to less than 150 pediatric studies
involving drugs being done by the drug companies and outsourcing
industry as a whole in 1997 (6). Half of the CRO respondents to the
Tufts CSDD survey, who noted that pediatric research was responsible
for most or some of the additional workload they had experienced in the
last 2 years, said that this was due, in particular, to FDAMA's
pediatric provision.
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\4\ In the fall of 1999 and winter of 2000, Tufts CSDD conducted a
follow-up survey of 35 CROs who had responded to an earlier survey
distributed to all CROs with exhibition booths at the 1998 Annual Drug
Information Association meeting. The response rate was 60% (21/35).
---------------------------------------------------------------------------
At the same time, the supply of researchers available to conduct
pediatric drug trials appears to be increasing. There were fewer than
2,500 investigators with some degree of specialization or certification
in pediatrics and current experience in pediatric drug research in 1997
(13). Soon after the incentive program was in full sway, stories in the
media and trade press reported the creation of specialized pediatric
research groups within two of the largest CROs--Quintiles and Parexel.
In addition, two large SMOs have launched pediatric-specific ventures--
Pediatric Clinical Trials International and Kelson Pediatric Partners,
which collectively can call on the services of 500 doctors with
pediatric training and nearly 2,000 investigators. This increase in
personnel dedicated to conducting pediatric clinical trials was also
evident from our survey of CROs. Of the 13 CROs currently conducting
pediatric studies, 4 had added staff explicitly for pediatric studies--
on average about 3 staffpersons per CRO. Also, 3 of those 4 CROs had
created new units within their organizations dedicated specifically to
pediatric drug clinical trials.
FDA Acknowledges Increase in Pediatric Studies of Drugs
FDA recognizes the extraordinary growth that has occurred in the
field. When CDER announced the creation of a new position--science
director for pediatrics--it stated that the responsibility of the new
position was to focus on the rapidly expanding field of pediatric
clinical trials (20). In a recent quote from USA Today, FDA's Associate
Director for Pediatrics, Diane Murphy, predicted that the number of
unlabeled medicines on the market for children will decrease from 75%
to 50% over the next 5 years (21). According to an unpublished Tufts
CSDD review of efficacy supplements approved from 1995-2000, this
change may already be taking place. Before FDAMA, from 1995 to 1997,
there were only 39 efficacy supplement approvals on the basis of new
research for pediatric indications. Since FDAMA, from 1998 to 2000,
that number has nearly doubled to 71.
Science of Conducting Pediatric Trials Has Been Advanced
The science of doing research in children is also evolving as the
architects of trial protocols must design new approaches for studying
pediatric patients in clinical trials. The Tufts CSDD survey of drug
companies indicates that population pharmacokinetic studies have been
done for 13 of 20 active moieties. Population pharmacokinetic studies
are a nontraditional approach to studying the effects of the drug on
the body that requires fewer invasive procedures to be performed on
each patient. For 2 active moieties, long-term follow-up studies were
being conducted. This is a time-consuming type of clinical
investigation recommended by FDA for chronic-use and preventative
drugs, but which in the past has been done infrequently. In addition,
sponsors developed 3 new biological sampling techniques and 4 new
clinical or surrogate endpoints (i.e., measures of benefits derived
from the treatment). An example of one newly created measure of
clinical benefit was the development by one sponsor of a novel rating
scale for anxiety in pediatric patients. The lack of measures for
clinical benefit from therapeutic agents for pediatric anxiety
disorders had previously hampered proof of efficacy for such drugs. If
the advances resulting from just these few pediatric studies are
representative of the several hundred studies now under way, the
science of pediatric clinical trials has come a long way in one-tenth
the time it took to develop the research infrastructure for adult
medicines.
UNFORESEEN IMPACT
Although there were some predictable outcomes from the pediatric
studies incentive program such as the vigorous response by the drug
companies, a host of unforeseen effects have occurred as well--by-and-
large these have all been beneficial.
Other Countries Emulate U.S. Incentive Program
Due to the example of the U.S. program, which has been applauded in
the United Kingdom, Canada, and Europe, there has been a dramatic
upsurge in international activity related to pediatric research.
Numerous studies and reports have been published over the last several
years documenting the use of off-label drugs for children in various
countries throughout the world, such as Australia, Japan, Britain,
Canada, and the Netherlands. Two international groups that provide
recommendations on the evaluation of therapeutic drugs, the European
Medicines Evaluation Agency (EMEA) and the International Conference on
Harmonization (ICH), have published guidelines on the conduct of
clinical trials in children, and noted the need for more pediatric
research as well. The European Union's Council of Health Ministers
recently adopted a resolution that also recognized this need and
invited the European Commission to make appropriate proposals for
incentives, regulatory mandates, and other supporting actions to
address this urgent problem (22).
Pediatric Provision Complements FDA Modernization Act and Orphan Drug
Act
The pediatric provision has had a synergistic effect with regard to
other provisions of FDAMA and the Orphan Drug Act (an R&D incentive
program for medicines addressing rare disorders). A survey by Tufts
CSDD of companies engaged in the development of fast track products for
serious and life-threatening illnesses (FDAMA Section 112) demonstrated
that close to half of them (11/23) were being studied for pediatric
indications as well as for adult indications (23). Similarly, a Tufts
CSDD survey of biotechnology and pharmaceutical companies on the use of
the single controlled trial for proof of efficacy (FDAMA Section 115)
showed that half of the respondents were doing so for pediatric or
orphan indications (24).
Orphan drugs often include indications for pediatric use because
many rare diseases are genetic or metabolic in origin. In fact, the
FDA's Office of Orphan Drugs has provided support for some early
development work on pediatric indications of drugs by non-industry
sponsors. These sponsors then interest the drug companies in pursuing
these indications for pediatric exclusivity, as occurred recently with
the drug propofol (25).
Pediatric Research Benefits Adult R&D
Another unanticipated outcome from the incentive program is that
researchers are now looking both ways--up and down the age scale. Not
only are drugs for adults now being developed with a view towards their
pediatric uses, but the reverse is happening as well; drugs and drug
formulations developed for children are being extended to adults. For
example, TPIO is an investigational drug being studied as a potential
treatment to improve post-operative outcomes in infants undergoing
cardiac bypass surgery. The sponsoring company has been buoyed by its
success with trial results in the targeted population of infants and
has decided to extend its investigation to adults (26). Similarly,
results of studies to support the pediatric exclusivity application for
the AIDS drug abacavir were later extrapolated to adults to support
approval of the drug for that population (27).
Pediatric formulations of drugs designed to ease administration of
medicines in children, and thus increase compliance, can be utilized in
other difficult-to-treat populations, such as the elderly or adults who
have difficulty swallowing pills. For example, Ascent Pediatrics'
Primsol was developed for children as the first liquid formulation with
trimethoprim (an antibiotic) as the sole active ingredient, for the
treatment of otitis media in children. However, in addition it has
recently received approval for a second indication--the treatment of
urinary infection in adults (28).
Development of Rigorous Ethical Standards for Pediatric Research Gets
Increased Attention
The pediatric studies incentive has focused media, government, and
industry attention on pediatric research. The Boston Globe recently
published an article detailing a number of pediatric clinical trials
investigating drugs and other therapies in which there were ethical
issues and safety concerns (5). Although few of these trials were
conducted for the purpose of pursuing pediatric exclusivity, and the
trials were conducted at various research facilities including state
and federal government institutions as well as academic medical
centers, the incentive program was the impetus for bringing them to
public attention.
There is now a growing awareness that pediatric clinical trials
require special considerations in their design, additional safeguards
in their implementation, as well as specially equipped facilities and
appropriately trained personnel. There is a consensus now among
international bodies, which provide guidance on clinical research
(e.g., the EMEA and the ICH), that it is necessary to address the
ethical issues inherent in pediatric research, along with the
scientific, technical, and practical ones. In the U.S., the incentive
program has been the impetus for FDA's convening a Pediatric Ethics
Working Group within its Pediatric Advisory Subcommittee to assist FDA
in addressing ethical issues in pediatric research. The NIH instituted
a policy coincident with the advent of the pediatric studies program
stating that children must be included in all human subjects research
funded by the NIH unless there are scientific or ethical reasons to
exclude them. The NIH policy also requires research plans to detail the
capacity of the researchers to provide appropriate pediatric expertise
and facilities (29). The 106th Congress, as well, just recently enacted
the Children's Research Protection Act to increase safeguards for
children involved in research and to provide funding for the study of
pediatric pharmacology (30).
Public Health Risks of Off-Label Use Viewed as Outweighing Risks of
Research
Without the impetus of the pediatric studies incentive program, it
is possible that pediatric clinical trials would have remained in the
backwater of the research mainstream and ethical problems may have
continued to come in under the radar screen of public scrutiny.
Moreover, 40 years worth of natural experiments--using drugs in
children that had been studied only in adults--would have been ignored.
There is an uneasy balance that must be negotiated when weighing the
risks from increasing research on children and using drugs off-label.
This tension was highlighted recently by a prominent pediatric
practitioner and professor of child health from the United Kingdom,
Professor Choonara, who was applauding the American pediatric studies
initiative in an article published in the British Medical Journal (31).
Choonara pointed out that the alternative to not doing pediatric trials
is the continuance of using medicines in children without any evidence
base. Such a situation, Choonara believes, recently lead to the deaths
of 15 children from the use of a sedative in critically ill children.
Choonara asserts that if this medicine had been studied as part of a
clinical trial, one death would have led to an urgent reappraisal of
the trial and the treatment (31). That child's death would have been a
tragedy, but one that might have prevented 15 other tragedies.
COST-BENEFIT RATIO
As noted previously, children have been effectively denied access
to safe and effective medicines, since 75% of marketed drugs are not
labeled for pediatric use. This leads to underutilization of what may
be, not only the best treatments available, but the most cost-effective
ones as well. Studies by managed care organizations have found that
treatment with medicines may often provide the most cost-effective
therapeutic option (i.e., as opposed to surgery, lifestyle management,
no treatment, etc.) and that they can also lower complications from
disease as well as decrease rehospitalization rates (32). As
importantly, healthy children become healthy adults; much adult illness
and distress has its origin in childhood (33). Any investment that we
make in the short-term now to improve children's health could result in
tremendous health care cost savings in the long-term. The economic
value of reducing mortality from just cardiovascular disease alone is a
staggering $1.5 trillion annually (34). An estimated 13% reduction in
mortality from such cardiovascular-related events as heart attacks and
strokes is attributable to new drug therapies that reduce blood
pressure and cholesterol (34).
Economic Impacts of Leading Causes of Death in Childhood from Disease
Among the leading causes of death for children in 1997 are a number
of illnesses that can be mitigated, cured, or prevented by drug and
biological products currently on the market or in development, and
whose annual economic impacts for 1998 have been quantified (see Table
1).
Table 1. Annual Economic Impact and Rank as Leading Cause of Death (1997) for Diseases Treatable with
Pharmaceuticals in U.S.\5\
Rank of Disease Among Top 10 Causes of Death by Age Group
----------------------------------------------------------------------------------------------------------------
Economic
Infants Children Youth (15- Impact (per
Disease (>1) (1-14) 24) Adult (25+) year, in
billions)
----------------------------------------------------------------------------------------------------------------
Heart Disease............................. 5 5 5 1 $286.5
Pneumonia/Resp. Infection................. 6 7 8 4 $12.0
Stroke (Cerebrovascular).................. 8 10 9 3 $45.3
Infectious & Parasitic Disease............ 9 ............ ............ ............ $12.0
Cancer.................................... ............ 2 4 2 $149.1
HIV....................................... ............ 8 7 ............ $64.1
Bronchitis/Asthma/Emphysema............... ............ 9 10 5 $46.5
Diabetes.................................. ............ ............ ............ 6 $98.0
Total..................................... 4 of top 10 6 of top 10 6 of top 10 6 of top 10 $713.5
----------------------------------------------------------------------------------------------------------------
Adapted from ``Kids at Risk,'' Harvard Center for Risk Analysis, April 2000; and, ``Top Ten Disease Categories
by Cost,'' Pharmaceutical Research and Manufacturers of America, December 1999 (35, 36).
\5\ Other conditions or events not listed in Table 1 which are among the ten leading causes of death for the
various pediatric age-groups shown are: certain conditions originating in the perinatal period; birth defects;
ill-defined conditions; unintentional injuries; homicide; certain intestinal infections; and, suicide (35).
If even one-hundredth of the annual economic impact from these
leading causes of death and disability (see Table 1) was reduced by
providing more effective treatments to children, making for healthier
adults in the process, the $7 billion saved each year would be 10 times
more than the nearly $700 million that FDA has estimated as the yearly
cost to society from the pediatric exclusivity awards (3). Currently,
$45 billion a year, just 56 cents per person/per day, is spent on
medical and health research by all sources of funding (34). The $700
million annual costs of the incentive program would add an extra penny
per person/per day, and be well worth the bargain.
Treatment for Childhood Mental Illness Needs More Therapeutic Options
Even analyses of diseases that are leading causes of death do not
begin to tell the story of potential healthcare cost savings from the
pediatric studies program. One in ten children in the U.S. suffer from
mental illness severe enough to cause impairment, yet fewer than 1 in 5
receive treatment (37). Again, these childhood disorders make for
unhealthy adulthood; 74% of 21-year-olds with mental disorders have a
history of prior problems (38). Yet, there are few psychotropic drugs
approved specifically for the treatment of pediatric psychiatric
disorders (38). The economic consequences of mental illness are
staggering--$42 billion a year just from anxiety-related disorders such
as panic attacks and obsessive-compulsive disorder, with 40% of the
population affected being children (39), and an additional $44 billion
for serious depression (40). For the nearly 4 million children affected
with ADD/ADHD (41), median per capita annual health costs are more than
double that of an unaffected child (42). No wonder that for the year
2000, the legislative agendas of 19 states included bills related to
children's behavioral health (43).
The incentive program is helping to address the need for more
therapeutic options to treat mental illness in children. The
therapeutic area for which drug companies have submitted the greatest
number of study proposals (29 PPSRs as of January 1, 2001) under the
incentive program is neuropharmacological drugs. Pediatric studies have
already been completed for 4 of these drugs, and 3 have been labeled
for pediatric use.
Health and Economic Needs Addressed by the Incentive Proizram Are
Unappreciated
A concern expressed by some critics of the incentive program is
that awards have been granted for medicines treating diseases and
conditions with little impact on the pediatric population, but which
are very lucrative for the sponsors of the drug (44). One such
condition is high blood cholesterol levels, considered a risk factor
for heart diseases and stroke. It is worth noting that 36.5% of
children in the U.S. have high cholesterol levels, according to one
report (45). Arthritis and hypertension are other illnesses that some
assert are not pediatric problems, yet the prevalence of rheumatoid
arthritis in U.S. children is between 71,000 (46) and just under a
100,000 (17), while that of hypertension is estimated to be 1% of the
pediatric population, or some 750,000 children (47).
Other conditions are criticized as being of minor clinical
significance for children, but of major importance for drug company
profits (44). One such condition is seasonal allergic rhinitis (SAR).
Yet at a time when the academic performance of America's children is of
paramount concern, the impact of this condition is anything but minor.
SAR affects 10% of school-age children, causing missed school days,
poor school performance, and impaired function on standardized tests
(48).
An unappreciated healthcare cost efficiency potentially realized
through the auspices of the incentive program is Medicaid cost savings.
As of 1995, some 17 million children were covered by Medicaid (49). An
additional 7 million of the nation's 11 million uninsured children are
now eligible for coverage under state Child Health Insurance Programs
(CHIPS) or Medicaid expansions (50), so that potentially 25 million
children will be covered by federal and state programs within a few
years. In fact, a spokesperson for one children's hospital in Florida
noted that 60% of their pediatric patients are Medicaid-dependent (14).
The potential healthcare cost savings that could be realized
through improvements for therapeutic options in children are difficult
to overstate. For example, the annual costs for treating Medicaid-
dependent children for just three diseases listed in Table I--AIDS,
asthma, and diabetes--could be nearly double (~$1.2 billion) FDA's
estimate of the yearly costs to society from the incentive program (36,
51-56).\6\
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\6\ For AIDS, Medicaid paid out an estimated $3.9 billion in 2000.
The percentage of all AIDS victims that are children and teenagers is
about 5-6%, but Medicaid pays for about 90% of those costs as opposed
to 50% of adult costs. So, the toll for pediatric AIDS comes to about
$190 million (36, 51, 52). For asthma, the cost to Medicaid and
Medicare exceeds $1 billion. Given the high mortality rate of asthma in
the elderly, the eligibility of poor or disabled, elderly asthmatics
for Medicaid, limited drug benefits in Medicare, and the fact that only
13% of the population are elderly, it is likely that only about 10% of
these costs are Medicare. Of the remaining $900 million, pediatric
asthmatics could account for as much as one-third of those costs (~$300
million) since they comprise one-third of the asthmatic population
overall and have higher hospitalization rates (53, 54). For diabetes,
the CDC estimates that 5-10% of diabetes is type 1, typically diagnosed
in childhood. The American Diabetes Association reports that diabetes
cost Medicaid $10 billion in 1997. A conservative estimate (since it
does not take into account the small but growing population of
pediatric type 11 diabetics) of pediatric costs for diabetes would be
$750 million (55, 56). Adding these costs together amounts to ~$1.2
billion annually.
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Costs to the Poor and Elderly Are Not Unreasonable
One concern about the cost-benefit ratio of the pediatric
exclusivity program that has been voiced is the impact of the
additional period of market protection on the prices of drugs for the
poor and elderly. Ironically, sacrificing the affordability of
medicines to the poor for the sake of availability to children is not
really an issue. Children are the poor! Close to half of the Medicaid
population (42%) are children (57). Another large percent of the poor
are the families of those children. Denying children access to labeled
drugs, denies poor children access to the best available treatment. It
also makes poor parents pay more out-of-pocket. Medicaid usually
provides a drug benefit, but often it may not cover off-label drugs,
except for cancer and AIDS medicine (13).
The real question then, is what is the trade-off as far as the
elderly are concerned. At first glance, this appears to be a genuine
point of contention, especially as Congress contemplates extending
Medicare benefits to include prescription drugs. A comparison of the
top 50 drugs used by the elderly (58) with the February 2001 list of
drugs issued written requests, reveals that 4 of the top 10 and 22 of
the top 50 drugs for elder care are the subject of written requests,
and thus potentially extended market protection. This theoretically
could delay access to less expensive generic versions of certain
commonly used drugs in elder care. However, a closer look at the list
reveals that there would be somewhat of a lesser impact than it would
first appear. Four of the 22 drugs are different strengths of the same
drugs, reducing the number on the list to 18. An additional 7 are
therapeutically similar to other drugs on the list and are in
therapeutic categories for which there are a number of available
alternatives on the market besides the ones on the list (i.e., GERD,
antihypertensives, and lipid-lowering drugs). This reduces the number
of drugs commonly used by seniors that could be impacted by the
incentive program to 11. For those 11 drugs, it is unlikely that any
senior would be using more than two of these drugs at exactly the same
six-month period that they may be protected from generic competition.
In addition, many of the elderly, if they are poor or low-to-middle
income, have some form of prescription coverage through Medicaid and
state drug assistance programs for seniors (59). So, while a
statistical analysis could generate high dollar numbers indicating an
impressive detriment to the public coffers in theory, the actual out-
of-pocket expense for any senior citizen is likely to be minimal and
temporary.
Costs to Taxpayers and Consumers Are a Matter of Social Equity
As for the putative cost to taxpayers and consumers in general,
again at first glance, this could seem like an unfair bargain. Data for
1999 show that 5 of the top 10 and 22 of the top 50 prescription drugs
by sales (60) have active moieties, which are the subject of written
requests, again indicating potential increased costs due to delayed
availability of lowerpriced generic alternatives. However, another way
of ranking the top prescription drugs reveals that there is a social
equity factor to be calculated in the cost-benefit equation. Eight of
the top 10 and 28 of the top 50 prescription drugs by number of
prescriptions written (61) also contain active moieties for which FDA
has issued written requests soliciting needed pediatric studies. Thus,
many of the most commonly prescribed medicines currently available for
the general population are not adequately labeled for use in children.
Yet, making these commonly used drugs available to children is not
likely to significantly increase costs for the government or other
third-party payers. Children are something of a bargain when it comes
to prescription drug costs. The average toll for a month's worth of
prescription medicines for children and college students is only $10;
adult prescription needs are 3 times more expensive and seniors are
over 10 times as costly (62).
Concern that increased availability of medicines for children will
lead to overuse is probably not warranted either. In fact, there is
some evidence to suggest that pediatric practitioners are becoming more
judicious in their use of medicines in an area formerly thought to be
rife with overuse. The National Center for Health Statistics has
determined that the number of antibiotic prescriptions written per
1,000 children declined by 34% from 1990 to 1998 (63).
The social equity factor becomes increasingly weighty when one
considers that society in general has historically overlooked the
health needs of children. A 1997 survey found that only 4% of the
public felt strongly enough about issues of children's health to have
written or spoken to public officials about them within the last year,
whereas 4 times as many had contacted public officials about Medicare
and Social Security issues (64). Yet, children are less likely to have
a regular source of medical care. For example, among the elderly, only
4.1% did not have regular access to medical care (65), while among
children, 6.5% do not have regular medical care (66). An estimated 13%
of U.S. children also lack health insurance, leaving them 3.5 times as
likely to go without needed medications and mental health care compared
to insured children (66). Although children comprise 27% of the general
population in the U.S., they comprise 42% of the poor in this country
(57), circumstances which, by themselves, contribute to poor health
outcomes for children later in life, such as stroke and certain cancers
(67). The incentive program represents one of a series of steps
necessary to address the fact that children have been overlooked by the
present-day healthcare system.
Liability Costs Affect Everyone
A review by Tufts CSDD of tort litigation cases from the late 1960s
to the mid1990s, which were compiled in a 1998 legal compendium (68),
indicates that of 147 active moieties listed by FDA as having received
written requests by February 15, 2001 (4), 19 had been the subject of
litigation. One active moiety, which as of 1997 was the subject of some
270 cases, was excluded from the review because settlement or award
amounts of the few cases resolved in favor of the plaintiffs were not
known. The other 18 active moieties were the subject of 76 cases: 60
alleging injury to adults and 16 injury to children. Of these 76 cases,
settlement or award amounts were reported for 22. The total amount
awarded to plaintiffs was over $82 million exclusive of court costs,
legal fees, expert witness fees, and other charges. The average amount
awarded in adult cases was $671,813, while in cases involving children
the average award was $898,100 (excluding one case with a 20-year-old
college student as the plaintiff that resulted in a $67 million award).
Because of the lag time involved in cases reaching the courts,\7\ it is
likely that few drugs approved in the 1990s are represented here, and
some of the cases are 20-30 years old, when awards were generally for
lower amounts. For example, some of the award amounts sought by
plaintiffs in more recent cases that are still pending before the
courts were in the neighborhood of $100 to $155 million. Moreover, 90%
of actions never reach court, some state cases are unreported, and
settlement amounts are often undisclosed as part of the settlement
agreement. Thus, the actual litigation costs from cases involving these
active moieties could be many fold higher.
---------------------------------------------------------------------------
\7\ Typical malpractice awards in 1996 were from incidents that
occurred in 1988 (69), and a similar lag effect is likely in product
liability cases as well.
Table II. Average Payouts by Type of Defendant from 22* Litigation Cases
Involving Drugs Receiving Written Requests (*3 cases had multiple
defendants; for 2 of these, total liability amounts were attributed to
both defendants)
------------------------------------------------------------------------
Type of Defendant, Number in
Average Award or Settlement Amount Parentheses ()
------------------------------------------------------------------------
$33,632,500.............................. Manufacturers (2)
$1,324,000............................... Hospitals (5)
$784,500................................. Medical Doctors, Dentists
(15)
$1,020,000............................... Government (2)
$67,000.................................. Medical School (1)
------------------------------------------------------------------------
As seen in Table II, the defendants were not manufacturers by-and-
large, but doctors and hospitals. So, while manufacturers are
justifiably leery of litigation because of the size of the awards
against them, liability fears affect all levels of health care, from
medical students to liability insurers. It is also worth noting that
prospective litigation costs may be passed along to consumers and
taxpayers in the form of higher drug prices. A study published in 1997
found that liability risk is responsible for one-third to one-half of
the price differential between the United States and Canada where drugs
are substantially lowerpriced (70). Thus, any liability avoided by
better labeling for drugs used in children, especially since they
typically involved more costly awards in this sample of cases, will be
beneficial across all segments of society.
Costs to Industry
The FDA report to Congress detailed the ``costs'' to the generic
and retail pharmacy industry (3). However, these are not really costs
but ``unrealized profits'' from the lengthening of the period of market
protection for some brand-name drug products. Yet, generic
manufacturers are not forced to enter the market for any particular
drug product, and they are already selective as to where they choose to
compete. For example, there already exists a portion of the
pharmaceutical market comprised of drugs unprotected by patents and
without generic competition that is nearly equal in dollar volume to
the current portion of the market held by generics (71). So, the
incentive program is not actually costing the generic industry anything
in terms of losses of current market share or actual expenditures for
increased staff, equipment and facilities, but from a delay of future
profits. Since the ``costs'' to the retail industry are based on the
higher mark-ups they can command for generic drugs over brand-name
drugs, their costs also are not actual losses or expenditures, but
unrealized profits.
In contrast, the costs to the brand-name drug companies can be
stated in terms of time, staff, and actual dollars spent. The Tufts
CSDD survey of drug companies indicates that the costs of the trials
have not been particularly high, averaging $3.87 million per written
request, although ranging as high as $20 million. The per-patient costs
have been somewhat higher than expected, averaging $20,405 per patient
compared to FDA's estimate range of $5,000 to $9,000 (72). The average
number of patients, based on 15 responses to the Tufts CSDD survey, was
203 patients per written request. If these figures are representative
of all pediatric studies that are under way for the 173 written
requests issued as of January 1, 2001, then drug sponsors will spend
approximately $717 million on pediatric studies under the program.
Taking into account the reported average costs from our survey for
formulation development of $750,000 per formulation and that one-fifth
of the written requests in our survey required a formulation to be
developed, that amounts to an additional $26 million. The total then
would be close to $750 million.
However, clinical investigations of as many as 250 active moieties
(i.e., from 210 industry PPSRs and 39 FDA-initiated written requests)
may be in process already. Considerable expenditure will accrue to any
sponsor conducting pediatric clinical trials even if the studies are
not ultimately completed. In the Tufts CSDD survey of drug companies,
only I out of 25 respondents did not submit a PPSR and had no plans to
submit pediatric study reports. This suggests that only 4% of sponsors
will not undertake at least some work on any active moiety that is the
subject of either an industry study proposal or FDA-initiated written
request. It would not be unreasonable then, to estimate that industry
costs could climb upwards of a $1 billion for the 250 active moieties
being studied under the current incentive program. This may be a
conservative figure, as a year still remained in the statutory period
when this estimate was calculated.
In actuality, the drug companies never really balked at the actual
cost in dollars for doing the studies (13), but more so the limited
return on investment, and hence the opportunity costs of investing
resources needed elsewhere. The studies do take time, on average almost
2 years (22.75 months) according to the Tufts CSDD drug company survey,
and some companies have been at it for as long as 48 months without
nearing completion. Also, the studies take considerable numbers of
personnel. From the number and types of studies reported in the Tufts
CSDD survey and published numbers of staff typically utilized for each
type of study (13), we estimated that each written request required 21
full-time staff-persons. For 173 written requests that would entail the
services of close to 4,000 research personnel (and over 5,000 staff for
the 250 active moieties that are likely to be studied).
The reason that opportunity costs and hence dedication of resources
are so critical is that pharmaceutical companies compete not only among
themselves, but also with other industries for investment dollars. In
order to maintain a growth rate of 10% and continue to attract
investors, pharmaceutical firms must produce 3-5 new chemical entities
(NCEs) per year, with sales potential of over $350 million per year--
so-called blockbuster drugs (73). These competitive pressures have
reputedly been one impetus for all the merger activity that has taken
place over the last few years. The response by the firms to the
pediatric studies incentive has been robust, but only because it was
attractive enough to lure some of their attention away from other
mainstream R&D activities. The pediatric sales market itself is
insufficient to render the commitment of resources profitable. In fact,
when the European Union's Council of Health Ministers recently
discussed possible approaches to encouraging more pediatric research,
it noted that R&D costs are not amortized because of the small number
of children affected by each disorder in an age bracket (22).
Reauthorization of the Incentive Program with Modifications Is
Necessary to Ensure that Benefits Accrue to All
As costs of the incentive program do not accrue equally across all
economic sectors neither have the benefits been spread equally among
all putative beneficiaries. Neonates, in particular, have been a
problematic age-group within an already problematic sub-population.
While the lack of information is an especially critical concern in this
age-group, the barriers to conducting such studies are especially
onerous, not the least of which are the difficult risk-benefit
decisions facing the IRBs that must approve such studies. However, more
headway has been made with neonatal studies through the incentive
program than with regulatory approaches.\8\ But much remains to be
done. The 1998 FDAMA list noted that approximately two-thirds of the
active moieties listed needed information for the neonatal age-group,
but the Tufts CSDD survey indicates that only one-quarter of active
moieties are currently being studied for use in neonates under the
incentive program.
---------------------------------------------------------------------------
\8\ For example, 11% of studies done in response to written
requests included neonates according to the Tufts CSDD survey of drug
companies, while only 5% of pediatric studies done to comply with the
1998 pediatric rule were for neonates according to Tufts CSDD annual
surveys of marketing applications for NCEs from 1997-1999.
---------------------------------------------------------------------------
Similarly, active moieties for cancer drugs appear to be a
disincentivized therapeutic area. Although 12 written requests had been
issued as of January 1, 2000 by FDA's Review Division for oncology
drugs, 9 of those were issued just since October 1, 2000, and no
pediatric exclusivities have been granted yet. Also, for most active
therapeutic areas under the incentive program, there are more PPSRs
than written requests. For oncology drugs there were only 8 industry
proposals. This could reflect reputed difficulties in this therapeutic
area such as demanding clinical trial requirements and scant
availability of patients. In fact, it is likely to remain problematic
to sufficiently incentivize the study of older oncology drugs. Efforts
may be more fruitfully devoted to establishing special incentives for
oncology drugs in development so that children have access to
therapeutic advances as soon as possible, if there are no better
treatment options available.
As for other therapeutic categories that have not resulted in any
pediatric exclusivity awards (i.e., medical imaging, reproductive, and
anti-infective drugs), medical imaging products are used for diagnostic
purposes and study participants may be difficult to recruit, especially
as a protocol involving the use of healthy children or patients with an
illness unbenefited by medical imaging may not pass the risk-benefit
threshold of IRB review. Reproductive drug needs are limited for this
age-group. Anti-infectives are problematic because antibiotics approved
before the passage of FDAMA are not eligible for the incentive. While a
number of antibiotics are labeled for children, some needed ones are
not. Again the solution may be to incentivize the development of
pediatric indications for new antibiotics so that they can replace
older marketed ones that are unlikely to be studied under the incentive
program in any case.
Congressional intent was not to limit the benefits of improved
information on the pediatric uses of drugs to some children, but rather
to extend them to all children. The following recommendations for
modifications to the incentive program should help to address this
goal:
Pediatric Studies Provision--first and foremost, the pediatric
incentive program under FDAMA should be extended for another
five years for all eligible active moieties in order for the
pediatric research infrastructure to become selfsustaining and
for the other benefits discussed in this white paper to be
realized for the long-term.
Pediatric User Fees--the report by FDA to Congress (3) and the
fact that over 65 FDA personnel are currently listed as
participating in 12 pediatric oversight activities (12)
demonstrate that FDA needs dedicated resources for the
incentive program to fulfill its goals. These should be
generated by pediatric exclusivity application fees.
Treatment INDs--drugs in development which are made available
to children with serious or life-threatening illness, such as
cancer, under an expanded access protocol for a sponsor-
submitted treatment investigational new drug application should
be granted a 6-month transferable exclusivity award upon
acceptance of the pediatric study reports for the active moiety
by FDA.
Neonatal Studies--sponsors that develop neonatal indications
for already-marketed drugs should be granted a 6-month
transferable pediatric exclusivity period.
Unmet Medical Needs--sponsors that develop pediatric
indications for already-marketed drugs that address serious or
life-threatening illnesses or diseases/conditions for which
insufficient treatment, prevention, or diagnostic options
currently exist should be granted a 6-month transferable
pediatric exclusivity period.
Antibiotics--sponsors that develop pediatric indications
different from the adult indications for new antibiotic drug
applications should be granted a 3-month transferable pediatric
exclusivity period.
CONCLUSIONS
The pediatric studies incentive program was added to FDAMA in
recognition of the special needs and concerns attendant with developing
medicines in children. It took 40 years for the research based
pharmaceutical industry to build the current R&D infrastructure. It was
built for adults. Accommodating it to provide for the needs of children
will take more than 4 years. It will require significant investment of
time, money and personnel. Some business sectors will gain, while
others will not. Yet, the ones gaining are also the ones taking the
risks and doing the work. In the short-term it will require some trade-
offs, by Americans as taxpayers and consumers for the sake of Americans
as children, parents, and grandparents. In the long-term, we all stand
to share in the benefits of equal medicines for all.
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Mr. Buyer. I now yield 5 minutes to Mr. Stupak.
Mr. Stupak. Thank you, Mr. Chairman.
Mr. Franson, the FDA briefed this committee that the
highest end of what a single ped trial costs is $4 million. Do
you agree with that figure?
Mr. Franson. I would not agree that a large scale clinical
trial involving hundreds of thousands of patients would be that
economical.
Mr. Stupak. So you are saying it would be more?
Mr. Franson. I'm saying that depending on the number of
patients and the complexity of it, the cost would be
proportionate. I am not sure what assumptions were factored
into the FDA estimate.
Mr. Stupak. What would a $4 million study get us? Can you
give us the size and the type of complexity we are dealing with
here?
Mr. Franson. Well there's a lot of factors one would have
to sort out. In other words, is it a long-term or a short-term
therapy. Does it require single or multiple comparisons to
established drugs? Based on all of that, one would have to then
frame how much.
Mr. Spielberg. To give you some additional insight, even a
simple pharmacokinetic study which will be done on adults at a
single center with 20 normal volunteers, when we do one of
those pharmacokinetic studies, we usually do it at half a
dozen, maybe even 10 centers, such as the pediatric
pharmacology research units. That means two or three patients
per center. That means vastly increased internal costs as well
because we have to send out monitors to each of those sites. We
have to provide drugs to each of those sites. Vastly more
complicated.
The pediatric efficacy studies that we do are again, much
more complicated. We agree completely that the ethics and the
way in which these studies are done are critically important.
So we have to monitor more closely. We have much more
complexity in doing the studies. So that if you look at your
average adult study and your average pediatric study for a
comparable number of patients, in fact the costs are greater
for the pediatrics.
Mr. Stupak. Dr. Franson, in some testimony back and forth
there, I just want to make this point. No one is suggesting
that the PDUFA and its user fees increase withdrawals or
recalls of drugs. But I think what people are asking is whether
the tight timeframes that's under FDAMA have increased
withdrawals by rushing review. That is our concern, is is the
tight timeframe rushing review. I noticed in your testimony you
indicated there's been six drugs recalled in 5 years, but
everything we have seen and heard today, it's really 11 drugs
in about 4 years. So there is quite a disagreement there.
I made the analogy earlier of an airplane accident, so you
have 10 airlines, you have one accident, and now you get to 100
airlines with 10 accidents. To a lot of us, that's not
acceptable. Our concern is are we rushing things here with this
review?
Mr. Franson. I appreciate that question. My response to the
pre-PDUFA drugs was of that complement of 11, four of those
were in the pre-PDUFA era. So there would have been no
possibility for a compression of review.
I would also look at the quality of review during the time
of PDUFA and say in general, exceptionally high. Also, that
none of these reviews to my knowledge have eventuated in an
abbreviated review of safety.
I would almost look at the PDUFA phase and say it actually
is evidence that new attention to direct review is actually
helping the overall surveillance process. I would also point to
the fact that in the last 3 to 4 years, FDA has constituted a
new Office of Post-marketing Drug Risk Assessment, that they
have the new Med Watch programs, and in essence, they have
capacity and also systems to do a better job.
Mr. Stupak. But even on the Med Watch program, that's
really directed only to the health care professionals. It is
not given to the general public. If you are relying on the
public to tell you an adverse event reaction on a drug by only
giving notice under Med Watch to the physicians, how is the
general public going to help you monitor these drugs and do the
volunteer reporting that you rely upon for the accuracy of the
drug and make sure you're not having an adverse effect, when
Med Watch is only within.
I have read and seen enough articles that say once a drug
is labelled and out there, doctors don't go back and review the
labelling. They just don't do that. They rely upon the initial
labeling of that drug, and that's what they use it for, unless
someone, with all due respect, hits him or her with a hammer,
then he'll start to realize that hey, there's been some
changes. Med Watches don't work. That Med Watch and ``dear
doctor'' letter goes to the doctors, not to the consuming
public.
One more, they have asked me to ask you. What do you
believe is the mean, median, and mode of the trials done for
pediatric exclusivity, cost? They forgot cost in there. For
cost. If you want to just submit that later.
Mr. Franson. We would be happy to assess that and provide
written comment. We would ask that we do that with some
assumptions included so that we're accurate.
Mr. Stupak. Let me follow up with one more, if I may. We
were talking about Med Watches and all that. In the PDUFA and
all that, we tried to do mandatory post-marketing survey while
having the drug companies pay for it. That has always been
resisted by the drug companies. Why is that? I mean if you pay
to have an expedited review to get the drug on the market
quicker, then why wouldn't the drug companies, pharmaceutical
companies, be willing then to pay for post-marketing review?
That's when we really see how a drug works in the real world,
not under the Phase I, II, or III, which are really sort of set
clinical trials. So why wouldn't the pharmaceutical companies
be receptive to it?
Mr. Franson. I'm not sure I could respond for every
company. I would say in certain drugs at the present time there
are actually Phase IV agreements for monitoring, for patient
registries. I think that depends on the particular compound. So
there are at least, I'm sorry I can't quote you the number, but
we would be happy to provide that, where agreements have been
reached.
Most companies provide study follow-up in certain settings,
be they large HMOs which have data bases for follow-up. I am
sure that given the stipulations of those kinds of studies, we
would be happy to investigate and assess further.
Mr. Stupak. Well, when you take a look at it, in 1992, when
the first PDUFA came out, we couldn't get it in there. In 1997,
it was actually written in the law that we wouldn't be
charging, pharmaceutical companies would not have to be charged
for post-marketing surveys. That really was at the request of
the pharmaceutical companies.
I am just trying to figure out why is the strong objection?
If you are paying for a quick review, why not pay for post-
marketing review?
Mr. Franson. Well, I think to go back to the understanding
of PDUFA, it was specifically constituted in order to provide
FDA additional resources they did not have in order to
accomplish the review process. If that scope is going to be
expanded, I am sure we would be more than happy to participate
in the discussion and construct of that.
Mr. Stupak. So if we try to change that law in PDUFA III I
guess we would be going to now, you would be wiling to at least
entertain that idea?
Mr. Franson. I think we would be willing to discuss
whatever all parties would see as being within the interests of
public health.
Mr. Stupak. Would you be also interested, would the
pharmaceutical companies be interested and lend their support
in forcing of Phase IV agreements?
Mr. Franson. I believe the enforcement of Phase IV
agreements is already part of the prior FDAMA, or at least has
been introduced as tracking.
Mr. Stupak. Okay. Well, not quite. Okay. Do I still have
time?
Mr. Whitfield [presiding]. You are 2 minutes over.
Mr. Stupak. I have got a lot of questions. I didn't even
get to labeling yet.
Mr. Whitfield. Mr. Stupak, you are a couple minutes over.
Mr. Stupak. I understand. I understand.
Mr. Whitfield. So it's my turn now.
Dr. Kearns, FDA claims that proper pediatric labelling can
save hundreds of millions of dollars a year. Do you agree or
disagree with that assessment?
Mr. Kearns. I would basically agree. I am not a
mathematician in the sense of economics, but if we look at the
labeling that's happened in the last 4 or 5 years, of those
drugs that have been studied in kids, and if we look at the
kinds of the things that are in labelling, imagine that a drug
company having adverse event information to the tune of saying
that more patients, pediatric patients in a trial on this drug
died, now the implications for the medical care provider of
that information are incredible. Could that save hundreds of
millions of dollars in health care costs? Could it save
hundreds of millions of dollars in litigation? I think so. I
think it really could.
So the impact of labelling, as I stressed in my comments
and in my written testimony, it is hard to attach dollar
figures to, but for those who care for children, I think it is
a critical issue. We won't see the impact of it early. It is
going to take 10, 15 years of continued use with new
information before we really know what happened.
Mr. Whitfield. Yes, ma'am?
Ms. Ben-Maimon. I just want to make a few comments, one for
the record. I think PhRMA actually made a citizens petition
submission about a year, just over a year ago, requesting that
the FDA decrease the number of trials being required for
pediatric exclusivity, and claiming that the requirements were
too rigorous. I think it is probably worthwhile for the
committee to take a look at that petition.
In addition, with regard to labeling issues, which was just
coming up, that is an issue that has to be dealt with very
carefully, especially from the standpoint of generic drugs,
because as the labels are changed, if there are exclusivities
associated with those labels that even go further than the 6
months, or if there are patents associated with those labels,
the generic industry is unable to use the label. Since we are
required or would like to use, especially when it comes to
safety data and especially safety data in children, we would
not want to put out products that had a different label or
didn't include that data.
So I think the committee needs to look cautiously when it
deals with these labeling changes to ensure that it doesn't
actually extend the exclusivity even further than the 6 months
that was contemplated by Congress.
Mr. Whitfield. Thank you for that comment. I appreciate it.
Would anyone else like to comment on that at all? Thank you
very much.
Dr. Kearns, have the 18 pediatric labelling changes
approved by FDA so far provided a meaningful benefit for the
pediatric population, in your view?
Mr. Kearns. I think without question if we just use one
compound that I mentioned, that Dr. Spielberg mentioned,
Midazolam, before the innovator company made an oral
formulation, before that was tested in children, that drug was
given to kids because it's a very good sedative agent. The way
it was given, there were all kind of ways that people would go
and take the injectable drug and mix it in Kool-aid with no
stability testing, no understanding of the dose. Many times it
wasn't stable. But with a properly made formulation, testing in
hundreds of children, defining the dose, as we said before
defining a safety profile, that drug is probably used 100 times
every minute in the United States in pediatric practices. Not
just hospitals, dental offices, in any kind of doctor that you
can imagine that needs to do a procedure on a child. That is
just one example. So without question.
Mr. Whitfield. Well that is a good example too. Thank you.
The Tufts Center for the Study of Pediatric Development
found that without this exclusivity provision, that pediatric
sales market itself was insufficient to render the resources
needed to study drugs in children. Now could you compare and
contrast for the committee the interests in pediatric studies
prior to and after the passage of the exclusivity provision?
Mr. Kearns. I think in terms of the academic community in
pediatrics, and in particular pediatric clinical pharmacology,
the interest has always been there. In fact, the work has been
there.
If you look at the published literature, there is
information. We sometimes forget that pediatricians like Dr.
Gorman or Dr. Spielberg didn't use these medicines, you know,
on a whim. There are published information about them. That has
profiled the use. But it is not generally available. Many times
that information comes from uncontrolled settings. So making it
formal, putting it under the aegis of the FDA, giving a
construct that we know and have known for decades works for
adults, makes children their therapeutic equals.
There was a comment or two earlier, and I forget who made
it, about the issues of money and somehow it all gets down to
money it seems like, about would it be better if the money was
given to NIH and NIH studied those drugs or this side or the
other. Let me tell you as somebody who has been working for a
couple decades doing this and an NIH-funded investigator, the
National Institutes of Health is not equipped to do these
studies of children. They are not equipped. The Food and Drug
Administration has been very helpful and very innovative. But
when we look at some of the negotiation and what goes on, there
is not the kind of talent at the agency that there needs to be
at the agency, in part, limited by funding.
So if we want to do some funding things, let's make user
fees available to support the Office of Pediatric Therapeutics
at the agency. Let's put some money into the infrastructure to
create the kind of expertise across all of government that will
not just make this process work, but make it work better.
Mr. Whitfield. Yes, sir.
Mr. Spielberg. I would echo Dr. Kearns comments. Indeed,
the real necessity for having pediatric expertise on all sides
within industry, certainly within the FDA, to be able to
produce the kinds of written requests that act in the public
health interest.
I think one of the interesting contrasts before and after,
you know before the legislation, several of the drugs that were
labelled now, if you look back at old pediatric handbooks and
textbooks, the doses were wrong. The new information that we
now have has provided correct doses, both to produce efficacy
as well as to decrease side effects. That is exactly the kinds
of information that we wanted from this act, and it has
produced it.
Mr. Whitfield. Good. Good. Thank you very much.
I recognize Mr. Wynn for 5 minutes.
Mr. Wynn. Thank you, Mr. Chairman. Unfortunately, the
Energy Subcommittee was meeting at the same time dealing with
the California crisis, and I didn't get a chance to hear the
panel's testimony, so I have got some reviewing to do in the
meantime. I would like to yield to my colleague, Mr. Stupak,
the balance of my time.
Mr. Stupak. Okay. Thanks to the gentleman for yielding
because I do want to ask some questions on labelling. You both
made some good points on labelling, especially in pediatrics on
how, you know, you've got the doses that were wrong. We learned
from it. There have to be changes. But whether it's adult or
children, why then does it take so long to get a labelling
change? I mean if you look at it and you talk to the FDA, they
say they have to negotiate all these changes. If it is so
critical that the changes be made, why do they have to
negotiate with the companies? Why wouldn't we get it out there
immediately?
Mr. Franson. If I may respond. Usually labeling is the
final step in a review process of an application. Therefore,
the industry and the FDA discuss the scientific attributes of a
product. Then there is labelling.
In my experience, the discussion takes days, not months,
and that it represents the caboose on the train. The delay that
may be perceived here is that pediatric exclusivity is granted
at a period as defined by the act much sooner than the end
point for the review time. So what people see as a lag is
merely the execution of exclusivity which occurs by legislation
before the end action letter and labeling. It is not our
experience that labeling is dragged out.
Mr. Stupak. Really? I'll be happy to share with you
examples, some of them even 2\1/2\ years before the label is
changed. Two-and-a-half years. These are drugs where deaths
were resulting, and 2\1/2\ years. That is insane.
Now after you make your label change, okay, let's say you
make a label change. What responsibility then is it on the
pharmaceutical company, if there is a label change, to recall
the drugs that are out there, prescriptions that are out there
sitting on the shelves? Is there any requirement to withdrawal?
What is the usual course of business then? Let's say you make
that label change and the other drugs are out there,
distributed all over the United States. What requirement or
responsibility legally, ethically, or morally does a
pharmaceutical company then have to get the new package out
there with new labelling or to doctors, to consumers, and
everyone to see?
Mr. Franson. That would depend entirely on what the
contents of the label change are. There are some label changes
that are a formulation.
Mr. Stupak. How about one that says that due to experience
with this drug that death may be associated with it. Now that's
a pretty serious consequence. So what requirement then is there
on the pharmaceutical company to recall or reclaim those
packages that are out in the United States?
Mr. Franson. I think the responsibility is on the entire
healthcare system, inclusive of the sponsor, to immediately get
information on new safety changes to practitioners,
practitioners being both pharmacists and physicians. In those
cases where some of us have had experience with making such
informational blasts, they may take the form of broad
electronic plus written, and in some cases even direct contact,
hospital formulary groups, and those which keep compendia of
medical information are also contacted.
Mr. Stupak. Does the pharmaceutical company ask for the
pharmacists or the doctor's office to return and they will
replace their samples, not samples but their supply?
Mr. Franson. It would be important to separate the fact
that if a new adverse event, for example, is observed, that
does not mean the drug product is in any way flawed. It means
there is new information associated with it.
Mr. Stupak. Well significantly enough to negotiate a label
change and eventually to put all the dear doctor letter and a
Med Watch and everything else. So I mean I can't say that the
drug itself is the sole cause, but certainly it is a
significant contributing factor to the death of this individual
or whatever it might be, the adverse reaction.
Mr. Franson. We think it is very important to provide the
information to those who need to have it, who are doing the
prescribing. As to your analogy, would we ask everybody to
drive their car back to the factory to replace an important
part, I think that would depend on the situation.
Mr. Stupak. Yes. We usually get recall notices, right? So
at least then the consumer knows that that product at least is
being recalled and takes that precaution. Some recall notices
say you have to get it in right away. Others say come in, we'll
order the part and we'll take a look at it. At least there is
some notice given to the consumer, and at least there is a
chance to rectify the situation. So I was wondering if the same
analogy would apply to labelling.
Mr. Franson. I misunderstood earlier. In response to your
question, actually when situations of this sort occurs, FDA has
a scaled, if you will, escalation process based on the level of
severity of a finding. A company would discuss with the FDA
whether something necessary needed to be done, anywhere from
correspondence to a recall. So again, depending on the
situation, that could be one of the possible outcomes, a
recall.
Mr. Whitfield. Mr. Stupak, your time is up. We are going to
be submitting additional written questions, and we would be
happy to include any that you might have as well.
Mr. Stupak. Sure. I thank the gentleman for yielding.
Mr. Wynn. Mr. Chairman, could I just inquire? How many days
will we have to submit written, because I think I would like to
submit written questions. About how much time?
Mr. Whitfield. A couple weeks.
Mr. Wynn. A couple weeks? Thank you very much.
Mr. Whitfield. Ms. Ben-Maimon, you were going to make a
comment but you were not able to. Do you want to?
Ms. Ben-Maimon. Very quickly. I think from the standpoint
of labeling, I would like to bring it to the attention of the
committee that labeling negotiations actually begin during the
development process. Much of the time spent during development
is not only to prove safety and efficacy, but to negotiate or
to ensure that the outcome, the kind of label that will appear
on the bottle, is what you desire.
I think that is important when you look at R&D dollars,
that you realize that much of the money being spent is to be in
a position to be able to negotiate your labelling, such that
you have the outcome that you desire.
Mr. Whitfield. I might make a comment that when I said 2
weeks, we want the replies back then. We want the questions
going out by next Wednesday.
Mr. Wynn. Thank you.
Mr. Whitfield. Mr. Deal, do you have any questions?
Mr. Deal. More of an observation. I understand the
difficulty with which everyone has to deal with this entire
subject matter. Certainly the questions and comments that we
have heard indicate some of those concerns. I have had an
experience recently with a very good friend of mine, a
constituent, who is on the other side of the issue. That is,
wanting to know why all of a sudden a drug that she considered
to be a lifesaving drug was withdrawn from the market, a
situation in which maybe a discussion between whether it was
voluntarily withdrawn by the company or perhaps done so at the
insistence of the FDA.
But be that as it may, and it's in a negotiation process on
that particular drug. It appears from all of the information
that I have been able to gather with regard to this particular
drug, it involves the bad effects, the results that were not
favorable--I think maybe a death occurred--were probably
prescribing the drug for patients who did not really meet the
criteria for which the drug was intended.
I know that is a very touchy and sensitive area as to what
pharmaceutical companies can do to fully educate the medical
community as to what is an appropriate condition for which the
drug is to be prescribed to avoid those kind of situations. But
it is unfortunate on two counts. It is certainly unfortunate on
the bad experiences that result from the medication having a
contrary result. But it is likewise disastrous for those who
have had very good results from it and have no other
alternative drug on the market, to have that drug suddenly
withdrawn from them. The most pathetic situation that I have
seen in a very long time, of a woman who is now down to 71
pounds, feels that her life is ruined, and the drug is gone.
So as someone who has seen the other side of the
constituent concerns about drugs that are perceived to be very
beneficial, but are suddenly withdrawn, I would just simply add
my concern and my encouragement that when these kinds of cases
arise, to try to resolve those as quickly as possible, because
there are those who are depending on those drugs and have a
very difficult time understanding why once a salvation had been
provided, it is now taken away from them. That is the most
recent constituent concern that I have encountered.
So there are certainly very many facets to all of the
things that all of you deal with. I think we all appreciate
that fact.
Mr. Bilirakis. Would the gentleman yield?
Mr. Deal. Yes, I would.
Mr. Bilirakis. Is there any adequate remedy available for
that woman? No exceptions? Any comments on that? Should there
be? Should there be something in the law that would afford that
person, that type of individual the opportunity to continue to
use this withdrawn drug?
Mr. Franson. I would comment that there are very special
circumstances that go through FDA approval processes that allow
compassionate use access to drugs, and that there are other
agreements that may be reached. They are on a case-by-case
basis.
Ms. Meyers. Often when that happens, FDA will tell the
company to put the drug back on an IND, which is an
investigational new drug. It becomes experimental again. These
patients, we have known patients for example with epilepsy
drugs that were withdrawn from the market that have taken them
for the following 10 years, as long as the company agrees.
Now barring that, let's say the company does not agree, if
the drug is approved in Europe the FDA has a regulation for
individual importation of drugs. If you have a prescription,
you can get up to 90-day supply and order it from a European
pharmacy. So if it's in another country, American consumers can
get it.
Mr. Bilirakis. Is it conceivable that that drug may be
available?
Mr. Deal. Well, I don't mention the names, et cetera, and
the reason being that I think the negotiations are in the very
final stages of working out an agreement to get the drug back
on the market with maybe more restricted labelling. I certainly
don't want to do anything to jeopardize that or to prejudice
anyone's opinion in that regard. But I did ask those very same
questions.
Those options did not appear to be available simply because
they thought a broader option was available once the
negotiations were concluded. Now if the negotiations are not
successful in a relatively short timeframe, I am going to have
a constituent who is going to be asking for those kind of
optional remedies, at least--because I asked the same thing. I
said well why can't somebody who has had a very good result and
who wants to proceed with the use of the drug not have the
ability to do that. So some of you may hear from me again if
negotiations don't go very satisfactorily.
Mr. Bilirakis. Yes, Dr. Kearns?
Mr. Kearns. Thank you. If I could just make a quick
comment. This has to do with post-marketing data and decisions.
If during the course of a clinical trial a serious adverse
event becomes apparent, it is fairly easy to make decisions
about whether a drug needs to go on or not. But in the post-
marketing period, it is very, very difficult, especially when
we are left with a reporting system that's voluntary.
At a recent NIH conference about 3 weeks ago, a
presentation was given that said physicians report on average
about one adverse event every 350 years. This was data given by
a person who is a pharmaco-economics person. I can't verify the
source of it. But in a spontaneous reporting system, all we
have many times are numerator data. We don't have the
denominators. Looking at the descriptions of those adverse
events sometimes are laughable, but yet they register on the
radar screen of the agency who with its charge to protect the
public will often times start the initiative for
decisionmaking.
I believe as a professional, that part of our system really
does need some fixing. We really have to have good data. We
need good drugs on the market that help people. We don't need
to throw the baby out with the bath water. But at the same
time, we need to know when we've got a drug that maybe made it
to market, and because of an effect that we couldn't see in the
clinical trials of a couple hundred patients, that we can
prudently act to protect society.
Mr. Deal. Thank you, Mr. Chair.
Mr. Whitfield. I want to thank the panel very much for your
patience and your time. We all enjoyed your testimony very
much, and we look forward to working with you as we continue to
deal with this issue.
Remember, next Wednesday, questions must be in. We hope in
2 weeks they will be----
Mr. Bilirakis. Not only questions in, but just the point
raised by Mr. Deal. If there are any areas where you feel, you
know, if you were king, you would change or at least suggest
changed, you have got the opportunity to do that. Submit all
that information to us.
Thank you very much.
[Whereupon, at 1:59 p.m., the subcommittee was adjourned,
subject to the call of the Chair.]
[Additional material submitted for the record follows:]
Prepared Statement of Advanced Medical Technology Association
I. INTRODUCTION AND SUMMARY
The Advanced Medical Technology Association (AdvaMed) is pleased to
submit the following testimony on the implementation of the Food and
Drug Administration Modernization Act of 1997. AdvaMed is the largest
association of medical technology innovators in the world, representing
more than 800 manufacturers of medical devices, diagnostic products,
and medical information systems. Two thirds of AdvaMed's members are
small businesses, and the vast majority of those firms have 50 or fewer
employees. Our members manufacture nearly 90 percent of the $62 billion
in health care technology products purchased annually in the U.S. and
more than 50 percent of the $147 billion in health care technology
products purchased worldwide.
AdvaMed would like to express to the members of this Committee our
thanks and appreciation for making your vision of modernizing FDA laws
a reality, and passing the ``Food and Drug Administration Modernization
Act of 1997'' (FDAMA). Further, AdvaMed is pleased to have the
opportunity to discuss some important aspects of that legislation for
the medical device industry, and the triumphs and difficulties in its
implementation. Also, we would like to share AdvaMed's views on ways to
develop the central goals of FDAMA including FDA's mission to not only
protect but to promote the public health, in the way Congress intended.
This hearing occurs at a critical juncture for FDA. America stands
on the cusp of a revolution in medical technology. As was highlighted
by members of FDA's Science Board at a meeting April 13, many emerging
breakthroughs--such as tissue-engineered technologies and drug/device
combinations--will not fit easily into FDA's existing regulatory
framework. The agency faces a significant challenge in effectively
overseeing development and approval of novel medical technologies in
the coming years.
AdvaMed believes it is critically important for FDA, Congress, and
medical technology companies to work together to prepare the agency for
the coming revolution in medical technology and promote timely patient
access to lifesaving and life-improving medical technologies.
Today's hearing is an important first step towards that goal. To
prepare FDA for the future, we must first look back to ensure that
FDAMA's legislative changes have been fully implemented and are
achieving their goals.
For example, FDAMA helped to streamline the premarket review
process by permitting FDA to ``recognize'' national and
international consensus standards through publication in the
Federal Register. Because FDA has recognized a large number of
such standards, persons who submit 510(k)s and PMAs often can
submit declarations of conformity to applicable standards
instead of reams of data demonstrating conformance to a
standard. This process shortens the time it takes to
effectively review a premarket submission, results in prompter
review decisions, and holds persons accountable for their
declarations by requiring them to maintain for FDA the data
upon which a declaration is made.
FDAMA embodied the important goal of increased collaboration
between industry and the FDA. The law created several meetings
to address premarket submission issues and required FDA to
include stakeholders in the process of assessing and
recommending regulatory improvements. Although the
effectiveness of meetings in reaching agreements on data
necessary to achieve market approvals needs work, the agency
has been willing to listen to our concerns. Additionally, there
have been stakeholder meetings, and a continuation of that
process to capture the thoughts from scientists, physicians,
consumers and industry will surely benefit FDA as it attempts
to modernize its regulatory process.
These provisions are but a few that show how FDAMA changed the law
to achieve the goals of public health protection, greater
collaboration, and more efficient regulation. Although significant
progress has been made, there remain areas for improvement. For
example, for the last 3 years, the average total elapsed review times
for PMA submissions remain at about 12 months--nearly twice the
statutory review time of 6 months--even though many of the FDAMA
provisions were intended to streamline PMA reviews. AdvaMed recommends
a few fixes to FDAMA that may be helpful, as well as suggest changes in
the law to help prepare and support FDA for the continuing challenges
presented by rapidly developing health care technology.
II. FDAMA HIGHLIGHTS.
Expanded Access to Investigational Therapies & Diagnostics
FDA has implemented a number of FDAMA provisions effectively and
the public has benefited as a result. Through reliance on FDAMA, the
agency has achieved benefits for individuals with significant need for
expanded access to unapproved and life saving technologies.
Specifically, FDAMA provided persons who need new technologies for
treatment access to investigational devices when various statutory
conditions are met. Additionally, FDAMA facilitated the effectiveness
of the law's humanitarian device provisions to ensure that patients in
need of these orphan devices have the earliest access to them possible,
and the agency has done well in implementing this provision. Further,
FDA has effectively implemented FDAMA's requirement for 30-day notices
instead of 180-day premarket reviews for certain manufacturing changes.
Each of these agency efforts has resulted in benefits to the public.
The expanded access provisions include emergency, compassionate and
treatment use of devices. This authority complemented authority in
FDA's regulation to allow deviations from an IDE when necessary to
treat patients in substantial need. While emergency use does not
require prior FDA approval, compassionate and treatment use do.
Compassionate use can accommodate small groups of persons who need
investigational devices. Treatment use permits the more widespread
availability of investigational devices. Both of these latter means of
expanded patient access to investigational products require approved
IDEs. FDAMA and FDA's regulations describe criteria for such expanded
access, including that there are no available and satisfactory
alternative treatments. FDA has been reasonable in administering these
provisions; indeed, the agency demonstrated enthusiasm in ``getting out
the message'' about these new means for patients to gain access to new
and advanced therapies. Within sixty days of FDAMA's passage, FDA
published a document entitled ``Guidance on IDE Policies and
Procedures'' that explained the agency's implementation of its
investigational device authority, including discussions of how the new
provisions added by FDAMA complemented existing IDE procedures.
Expanding Humanitarian Use of Devices
Consistent with its endorsement and support of expanded access, FDA
has been responsive to FDAMA's amendment of the Act's humanitarian
device provision. Since 1990, FDA has had authority to approve devices
for uses in treating conditions that affect fewer than 4,000
individuals, on the basis of safety information alone. In a sense
Congress created an orphan device provision and modified the
effectiveness requirement for humanitarian devices. This change reduced
the substantial cost of developing a device, thus providing an
incentive for manufacturers to develop devices that otherwise might
never be brought to market because of small demand. To further ensure
that humanitarian devices are developed for persons who desperately
need them, FDAMA reduced the review period from 180 to 75 days.
Although FDA's annual device reports show that final humanitarian
device decisions are taking longer than 75 days, clearly the agency is
being responsive to the FDAMA requirement and has reduced the overall
time for HDE reviews.
Manufacturing Changes
FDA's success in the humanitarian device area is also seen in the
agency's implementation of FDAMA's manufacturing notice provision. This
provision greatly reduces the regulatory delay that accompanied FDA's
review of manufacturing change supplements. Now instead of submitting
such supplements for potential 180-day reviews before a change could be
implemented, manufacturers can submit 30-day notices for a broad array
of manufacturing changes. Once thirty days have passed, these proposed
changes can be put into effect, unless FDA notifies a manufacturer that
there is a need for a PMA supplement. After FDAMA's enactment, FDA
promptly issued its guidance document describing how this notice
provision would work. A large number of notices have been received and
reviewed by the agency without delays, clearly demonstrating the
clarity and industry's understanding of FDA's manufacturing notice
program.
AdvaMed's members and the public have benefited greatly from the
agency's successful implementation of the notice provision. FDA is not
tied up with unnecessary resource intensive reviews that require
approvals, and manufacturers can keep their manufacturing processes as
efficient as possible without waiting for lengthy periods of time while
their manufacturing supplements work their way to the head of a review
queue.
The implementation of every provision of FDAMA hasn't been as
smooth. A number of key FDAMA provisions, which have substantial
potential to modernize device regulation, have had an uneven
implementation experience.
Least Burdensome
Two critical provisions in FDAMA require the agency to only require
that information necessary to approving a PMA device or clearing a
510(k) device, and to consider the ``least burdensome'' information in
determining premarket approval or clearance requirements. Essentially
what this means is that FDA should not require a randomized, double
blind prospective clinical study if a partially controlled clinical
trial would provide the statutorily required reasonable assurance of
safety or effectiveness.
The agency hasn't always agreed with this view. Initially after the
enactment of FDAMA, it was very difficult to engage the agency in a
discussion of the least burdensome concept. Typically, AdvaMed members
were confronted with randomized clinical trials as the agency's
expression of the least burdensome showing to establish device
effectiveness. Seldom was there even conversation about least
burdensome in the context of substantial equivalence. This concerned me
because it suggested a regulatory ``cultural'' bias within the agency
that was resistant to Congress's direction of avoiding over-regulation.
In response, AdvaMed and others developed a document to define ``least
burdensome'' in order to place the issue before FDA to encourage a
collaborative exchange with an eye toward a regulatory guidance
document. This document, after some resistance from the agency,
achieved its purpose. FDA and industry started to talk and made headway
in describing and defining the least burdensome concept. This effort
has resulted in some least burdensome principles as a starting point
for thought and discussion:
The spirit and the letter of the law should be the basis for
all regulatory decisions;
Information unrelated to the regulatory decision should not be
part of the decision-making process;
Alternative approaches to all regulatory issues should be
considered to optimize the time, effort, and cost of reaching
proper resolution of the issue; and
All reasonable mechanisms to lessen review times and render
regulatory decisions within statutory timeframes should be
used.
We were very encouraged when, two days ago, the agency issued its
guidance document on the least burdensome concept and principles and
that the agency clarified that the least burdensome concept applies to
all devices including in vitro diagnostics (IVDs). AdvaMed also
believes that the above collaboratively derived principles already have
had a positive effect on the agency.
However, our experience with FDA in trying to implement the least
burdensome provisions underlines an important fact. To modernize device
reviewers' approaches to premarket submissions requires a cultural
change at the agency.
We have no doubt that Americans will look back on Congress'
decisions to double the research budget at the National Institutes of
Health and unravel the human genome as two of the smartest investments
yet made in this new millennium. We must be equally sure that the FDA
and other regulatory bodies are prepared to handle the increasing
number and complexity of resultant innovations--like combination
products' with an efficient, clear and predictable pathway to approval.
To accomplish this goal, device reviewers need more opportunities to
discuss submission issues with industry and to interact with outside
scientific and medical experts to bring fresh perspectives into the
device review arena. Consistent with the agency's mission of promoting
patient access to new technology, requesting the most demanding
clinical information is not always the best way to demonstrate safety
and effectiveness of new and complex technologies. This has too often
been the FDA approach.
Early Collaboration Meetings
Congress was acutely aware that collaboration between potential
premarket submitters and FDA would add efficiency to the premarket
review process. To ensure collaboration, two FDAMA provisions were
included in the law, both resulting in binding requirements on FDA.
Effectively, a first meeting (``determination meeting'') required FDA
to determine the least burdensome type of information--ranging from
bench testing to clinical studies--necessary to demonstrate device
effectiveness. The second meeting (``agreement meeting'') permits the
potential applicant to submit device investigation plans, including
clinical protocols for FDA's review and possible agreement. Any
agreement reached at the meeting would be binding.
Congress summarized the importance of these two types of meetings,
stating the provisions were intended
to provide for a predictable structure through which the FDA
and sponsors of applications for marketing of new products can
communicate effectively regarding requirements that must be met
to secure marketing clearance or approval. The Committee
believes that meetings between the appropriate FDA experts and
their industry counterparts may provide one avenue to
successful communication that may result in agreements that can
expedite a manufacturer's understanding of what information,
data, or investigations may be needed for a particular product.
(H.R. 307, 105th Congress, First Session, 1997, at 26)
The effect of a successful implementation of these meetings should be
substantial resource savings for companies and the FDA and the prompter
delivery of new, safe and effective devices to consumers. Without
question, a mutual understanding of devices and device requirements
will ensure the most efficient and effective reviews.
So far, this goal has not been realized. FDA's actions have shown a
continued preference for informal meetings that do not result in
binding outcomes. Although the agency is trying to improve its approach
to these pre-IDE meetings, the number of binding outcomes still pales
by comparison to the number of IDE submissions that pass through the
agency. Active discouragement of these meetings by FDA reviewers has
affected the willingness of companies to request them. Both industry
and FDA must constructively address this situation.
Third Party Review
Another FDAMA provision that's very important to our members calls
for review of 510(k)s by expert third parties outside the agency. Under
this provision, accredited third parties review 510(k)s and make
recommendations to FDA about device clearances. FDA has 30 days to
consider such recommendations and to issue a 510(k) decision.
Originally, FDA limited the program to product types having a specific
guidance document. Typically, these products were the simplest devices
and were associated with rapid reviews. We are encouraged that FDA has
recently expanded the list of devices eligible for third party review,
and believe that this expansion that now includes more complex devices
was necessary to encourage greater utilization of the program.
Dispute Resolution
Implementation of FDAMA's scientific dispute resolution provision
initially began slowly. This part of the law required FDA to promulgate
a regulation establishing a procedure for requesting review of
scientific disputes between sponsors, applicants, or manufacturers and
FDA by a scientific advisory panel. At first, the agency issued a
complicated guidance document, detailing a dispute resolution procedure
and explaining all the review mechanisms that already exist in the
statute and regulations. Since then, however, the Device Center has
appointed an ombudsman, and the ombudsman has been actively soliciting
persons to use his office if disputes or other matters surface that
require an intervenor. This effort to provide industry and others a
voice within the Center is promising and we appreciate the effort being
made to create a reasonable dispute resolution process. Nevertheless, a
cultural change is needed at the agency to ensure that the dispute
resolution process is fully implemented as Congress intended.
III. THE FUTURE
We have seen significant accomplishments by the agency in its
efforts to modernize, both by successfully implementing several FDAMA
provisions, and reengineering a number of its programs. But we know
that the agency must do more to meet the challenges of unprecedented
growth and rapid evolution in medical research and technology. In a
report on the ``Outlook for Medical Technology Innovation'' issued by
the Lewin Group, medical device manufacturers have doubled their R & D
spending to bring these innovative technologies to fruition. As this
trend continues, the agency must be made ready to meet the challenges
associated with the unprecedented growth in the industry.
Many provisions of FDAMA equip the agency with the flexibility to
conserve its valuable resources such as the third party review program.
Industry's use of this program has been limited because more complex
devices whose review would benefit most from a third party are
currently ineligible for the program because of statutory restrictions.
AdvaMed supports the third party review program and would like to see
it used by industry to the fullest extent possible. However, with the
current eligibility criteria, we are concerned that Congress's belief
that third party review will assist FDA's premarket review program will
go unfulfilled.
The intent of FDAMA's expedited review provision was to ensure that
breakthrough devices reach the market as soon as possible. The public
health demands this result and we support any effort that would enable
the agency to ensure that breakthrough devices receive review queue and
review resources priority.
Combination products continue to present challenges to the agency's
standard review mechanisms, resulting in inefficiency and delay.
Although FDAMA streamlined many of the agency's review processes, the
legislation did not address the difficult issues that arise when
devices incorporate drugs or biologics and the efficient review of
these combination products. Because of the unsatisfactory experience
many AdvaMed members have had when devices are reviewed by other
Centers or combination products are assigned to the Device Center with
consultative reviews from CDER or CBER, we recommend creating an Office
of Combination Products and Product Jurisdiction. The Office would
identify a Center with regulatory responsibility for a product based on
the product's ``primary mode of action.'' Additionally, the Office
would ensure the product reviews are timely and, if more than one
Center is involved in a product review, that reviewers assigned to
conduct the review would be under the authority of the Office Director.
Only through increased oversight by an independent authority within FDA
do we believe that combination products, containing devices, will
receive efficient and timely reviews
IV. CONCLUSION
AdvaMed appreciates the opportunity to provide comments on the
implementation of FDAMA. FDAMA created the framework to reform and
modernize FDA's practices and procedures. The record of its
implementation is somewhat inconsistent, with examples of aggressive
efforts by the agency to realize most goals of the legislation, and a
few implementation shortfalls that need attention. On the whole,
AdvaMed is heartened by FDA's positive approach to discussing issues,
and we believe that with increased collaboration between the agency and
industry significant progress is still in the offing.
At the same time, AdvaMed believes that to avoid increasing delays
in the FDA review process, it is critically important to consider what
steps must be taken beyond the FDA Modernization Act to prepare FDA for
the technologies of the future. AdvaMed looks forward to working
constructively with FDA and Congress to achieve this goal and ensure
timely patient access to the emerging breakthroughs in medical
technology.
______
Prepared Statement of Frank Clemente, Director, Public Citizen's
Congress Watch
Chairman Bilirakis and Ranking Member Brown, my name is Frank
Clemente and I am Director of Public Citizen's Congress Watch. Public
Citizen is a 150,000 member national consumer group, which is active on
a wide range of issues including health care. For 30 years we have been
a leading watchdog of the Food and Drug Administration (FDA) and the
pharmaceutical industry on issues such as drug safety and drug pricing.
I want to thank you for the opportunity to comment on
reauthorization of the pediatric exclusivity provision originally
enacted in 1997 as part of the Food and Drug Administration
Modernization Act (FDAMA). In order to provide a context for our views
on reauthorization of pediatric exclusivity, let me first present to
you the prehistory of this provision as discussed in a recent report by
the FDA.\1\
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\1\ Department of Health and Human Services, Food and Drug
Administration, The Pediatric Exclusivity Provision: January 2001
Status Report to Congress.
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In these comments I will be using the term ``labeling'' in its
technical regulatory sense, which refers to the information about the
uses of a drug that appear on the packaging of a drug. Labeling of
prescription drugs is strictly controlled by the FDA. Manufacturers may
only make a claim that a drug can be used for a particular ailment if
the manufacturer has shown, based on sound science and to the
satisfaction of the FDA, that a drug is safe and effective for the
indication in question.
The problem of a lack of labeling for children has been recognized
for over two decades. According to the FDA, in 1973, 78% of the drugs
listed in the PDR lacked sufficient pediatric labeling. In 1991, 81% of
the drugs in the PDR lacked adequate labeling. As recently as the early
1990s, drug companies were doing little to assure that drugs are
adequately labeled for use in children. From 1991-1994, 71% of the new
molecular entities coming onto the market lacked pediatric labeling.
According to the FDA, the lack of pediatric labeling information
``poses significant risks for children.'' In its proposed rule on
pediatric studies issued in 1997, the FDA cited reports of injuries and
deaths in children resulting from the use of drugs that had not been
adequately tested in the pediatric population.
In 1994, the FDA issued a rule requiring drug companies to do a
review of the scholarly literature and to submit a supplemental new
drug application if studies were available to support labeling a drug
for use in children. In 1994, the FDA also started a voluntary plan
designed to encourage drug companies to gather data on pediatric use
both during drug development and after marketing. According to the FDA,
both these efforts met with only limited success.
Between 1991 and 1996, drug companies did little to deal with the
problem of drugs already on the market that lacked adequate labeling
about use in children. They promised to conduct 71 post-marketing
pediatric studies, but only 11 (15%) were completed in that period,
according to the FDA.
In 1997, the FDA began the process of enacting regulations to
require drug companies to test drugs in children for the labeled adult
indication as a condition of a drug's approval by the agency. In 1998
the pediatric rule was finalized. Under the rule, drug companies are
allowed to seek a waiver of the requirement to test a new drug in
children if they believe that it will not be used in children.
Currently, the rule is tied up in court by legal claims that the FDA
does not have authority to issue it.
In 1997, before the pediatric rule was finalized, Congress
responded to the poor results of previous efforts, by passing the
pediatric exclusivity provision as part of FDAMA. Pediatric exclusivity
grants drug companies 6 months of additional patent exclusivity if they
conduct studies of drugs in children that the FDA determines will
provide physicians with useful new prescribing information. The result
was a dramatic increase in the number of pediatric studies being done
by the brand name drug companies. From the time the FDA issued a
guidance in 1998 to September, 2000, over 191 proposed study requests
were submitted to the agency, 58 had been completed, 25 drugs had
received grants of exclusivity, and the drug companies had made
labeling changes on 12 drugs, less than half of those that have
received pediatric exclusivity.
PROBLEMS WITH THE PEDIATRIC EXCLUSIVITY PROVISION
Mistargeted
While the incentive offered to drug companies by the pediatric
exclusivity provision of FDAMA has been successful in increasing the
number of studies done and has provided valuable information to
pediatricians about how to use drugs in children, the law as it
currently stands is poorly targeted. It offers drug companies:
Substantial incentives to test drugs that have high sales,
particularly among adults, not those about which pediatricians
most need more information. Currently brand name drug companies
are receiving 6 months of exclusivity (effectively a patent
extension) for testing a drug on children, even when that
testing is of minimal value, because it is for an indication
that rarely occurs in children, such as ulcers, hypertension,
or type II (adult-onset) diabetes.
Little incentive to test drugs that are still under patent but
not big sellers. Pediatric exclusivity leaves many drugs
unstudied in children, because the drug companies believe they
will not make enough from 6 months of additional patent
protection.
No incentive to test drugs that are currently off-patent. Six
out of ten of the drugs most widely used in children without
adequate labeling are not eligible for pediatric exclusivity,
because they are off patent. One example of such a drug is
ampicillin, which is used to combat infection in children.
Substantial cost to consumers
As a consequence of the pediatric exclusivity provision, consumers
are denied access to lower-priced generic drugs for an additional 6
months. The cost this imposes on consumers is substantial, as is the
corresponding windfall for brand name drug companies. Over the course
of the program's first 20 years, the FDA estimates that the cost to
consumers will be $13.9 billion. The Wall Street Journal recently
estimated that pediatric exclusivity will add $4 billion to brand name
drug company revenues, and this is just for the first 26 drugs tested
under the program.\2\ Who bears the burden of pediatric exclusivity?
Overwhelmingly it is the elderly, who use more prescription medications
than the young, and only about half of whom have reliable year-round
prescription drug insurance. It is the uninsured who pay the highest
prices for prescription drugs, the full retail price, because they do
not have access to the lower prices negotiated by large purchasers such
as HMOs and hospitals.
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\2\ Rachel Zimmerman, ``Pharmaceutical Firms Win Big on Plan to
Test Adult Drugs on Kids'' The Wall Street Journal, February 5, 2001.
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Windfall to drug companies far exceeds the costs of conducting studies
The windfall to the drug companies in the form of higher revenues
as a result of the longer monopoly period provided by pediatric
exclusivity is almost always significantly greater than the cost of the
studies that the drug companies must do in order to be eligible for
exclusivity. The Wall Street Journal estimates that pediatric studies
cost anywhere from $200,000 to $3 million each. This is much less than
additional revenues drug companies will earn as a result of
exclusivity, particularly for blockbuster drugs. If you assume, as The
Wall Street Journal does, that a brand name drug's sales decline by 75%
after the introduction of a generic, and you look at the two most
outrageous examples this is what you find: For testing Prozac in
children, Eli Lilly received 6 months of additional exclusivity, worth
$964 million, more than 300 times the cost of doing a study (assuming
$3 million per pediatric study). Schering Plough received exclusivity
worth $575 million, more than 150 times the cost of doing a study for
testing its blockbuster drug Claritin in children.
While the drug industry is entitled to make a good profit, such
windfalls from pediatric exclusivity are clearly excessive and
unnecessary. As a whole the drug industry, consistently the most
profitable for the past 10 years, can well afford to bear the cost of
doing pediatric studies without any additional incentives. It had $192
billion in sales last year; the top 12 companies had combined profits
of $28 billion--an incredible 19% return on revenue. Merck, the
industry's highest seller, recorded sales of $40.4 billion and profits
of $6.8 billion in 2000. Clearly, this is not an industry that needs
additional corporate welfare to compensate it for the cost of doing a
few million dollars of testing in children.
SOLUTIONS
Given the problems with the current law, Public Citizen urges the
Committee to enact the following legislative changes:
For new drugs used for an on-label indication in children: Codify the
FDA's pediatric rule to require testing of these drugs and end
pediatric exclusivity for this testing.
By codifying the rule, FDA's authority would be clarified and
testing of new drugs that will be used by children for a labeled adult
indication would be assured.
Once FDA has this authority, there no longer would be a need to
give drug companies 6 additional months on their patent and force
consumers to pay higher prices for their drugs as a way of enticing the
companies to test drugs on children.
For drugs still on patent but used for an off-label indication in
children: Pediatric exclusivity should be used as an incentive
to encourage the testing of these drugs in children.
The FDA does not have authority to require companies to test for
uses in children or adults that companies have not sought FDA approval
for at the time a drug was originally approved (off-label uses).
Therefore, it will be necessary to provide incentives to encourage drug
companies to do such testing. For drugs used off-label we recommend the
following more targeted and greatly reduced incentives:
Scale the length of exclusivity to the sales of a drug. As it
is currently structured, pediatric exclusivity offers a
windfall to drug companies when it is granted to a blockbuster
drug with high sales income. Drug companies should receive the
same incentive for testing all drugs that qualify for
exclusivity. This can be done by granting fewer days of
exclusivity to drugs with high sales income and more days of
exclusivity to drugs that have lower sales income. Congress
should set the value of exclusivity that all qualifying drugs
would receive in legislation.\3\ This value should be set at
such a level that it is a sufficient but not excessive
incentive to the drug companies.
---------------------------------------------------------------------------
\3\ While there is an incentive in existing law (other than
pediatric exclusivity) designed to encourage drug companies to do the
testing required to label drugs for off-label uses, the incentive is
weak. Under current law, when drug companies do tests on a drug and
submit a labeling change to the FDA to reflect a new use for a drug,
they receive three years of exclusivity on the new indication. Assuming
that a company sought this labeling change at the end of the patent
life of a drug, this would mean that the company would have the
exclusive right to promote the drug for the particular indication in
question for three years after the patent expired on the active
ingredient in a drug. This grant of exclusivity is not very valuable to
the drug companies, because during those three years if the patent on
the underlying active ingredient had expired, generic drug companies
would be able to produce and sell a competing drug with that active
ingredient, so long as they did not label it for the protected
indication. In contrast, under pediatric exclusivity, generic drug
companies are barred from selling a drug with an active ingredient that
has been granted pediatric exclusivity--a much more valuable prize. It
is for these reasons that pediatric exclusivity is needed to give drug
companies the incentive to do the testing necessary to label drugs for
off-label uses in children.
---------------------------------------------------------------------------
Tie the granting of exclusivity to a company making labeling
changes. It is critical to pediatricians that new information
gathered from drug company testing be reflected in labeling
changes so that they can make the best prescribing decisions.
Unfortunately, under current law companies are awarded
exclusivity simply upon completing tests in children. Some
companies do not pursue the necessary labeling changes in good
faith with the FDA, because there may not be a marketing
advantage to them. Without a requirement that drug companies
make labeling changes in order to receive the grant of
exclusivity, there is no way to assure that labeling changes
will be made in a timely manner.
For older, off patent drugs: Fund independent centers to do testing in
children.
Many drugs that are used in children are older drugs that are off
patent. The pediatric rule does not extend to these drugs. And since
these older, off patent drugs are often made by many different generic
companies, it is not possible to give one company exclusivity in
exchange for testing and a labeling change. Also, in the case of many
low-selling drugs still on patent, the pediatric exclusivity provision
is not an adequate incentive to encourage companies to do studies in
children. For these older drugs and low-selling drugs still on patent
we urge that funds be made available to the Pediatric Pharmacology
Research Units (PPRU) and the Centers for Education and Research on
Therapeutics (CERT) to test the effectiveness of these drugs in
children. (The CERT centers were created by a provision in FDAMA.)
Also, the FDA should require the relevant results of this research to
be reflected in labeling changes.
Again, I thank the Committee for the opportunity to testify. Public
Citizen urges you to end the substantial giveaway to the drug industry
that occurs under pediatric exclusivity. The same goals of the original
law--understanding how prescription drugs approved for adults will
affect children--can be much better achieved by requiring drug
companies to do such testing as a condition of their original new drug
application. We can achieve a much better balance between the needs of
our children and consumers and those of the drug companies than
currently exists under pediatric exclusivity--at a cost to the drug
industry that is small in comparison with their overall revenues.
______
Prepared Statement of Arthur Collins, Chief Executive Officer,
Medtronic
I. INTRODUCTION--MEDTRONIC'S INTEREST IN BREAKTHROUGH THERAPIES
My name is Art Collins. I appreciate the opportunity to provide
testimony to the Subcommittee on Health as you assess the effectiveness
of the Food and Drug Administration Modernization Act (FDAMA).
I am the Chief Executive Officer of Medtronic. Medtronic is the
world's leading medical technology company, providing lifelong
solutions for people with chronic disease. With deep roots in the
treatment of heart disease, Medtronic now provides a wide range of
therapies that help physicians solve the most challenging, life-
limiting medical problems and restore health, extend life, and
alleviate pain. Therapies are organized in four primary groups--Cardiac
Rhythm Management, Vascular, Cardiac Surgery, and Neurological, Spinal
and ENT.
Medtronic's 25,000 employees serve patients in 120 countries.
Medtronic has scientific, manufacturing, education and sales facilities
worldwide. Revenues for the year ending April 30, 2000 were $5.01
billion. Approximately a third of the company's revenue turnover is
contributed by its business overseas and about 25 percent of its
employees are outside the U.S.
As you may know, Medtronic strongly supported the Committee's
important role in developing this legislation. Further, Medtronic is a
world leader in developing breakthrough therapies for chronically ill
patients. Indeed, our Mission Statement directs us to participate in
areas where we can make a unique contribution to human welfare by
developing therapies that alleviate pain, restore health, and extend
life. As a consequence, we are uniquely situated to comment on FDAMA's
support for breakthrough therapies--and further initiatives that might
improve this country's ability to bring breakthrough, life-saving
technologies to critically ill patients.
As its name states, Congress intended that FDAMA would modernize
the FDA's regulatory process. Specifically, the goal was to create an
efficient and effective regulatory process that would bring medical
products to the patients who need them. FDA has done a good job in
making FDAMA work and in ensuring that Americans have access to safe
and effective medical devices and drugs.
Today we can build upon the momentum of FDAMA and work to guarantee
patient access to breakthrough technologies. These are the novel
devices that treat life-threatening diseases or conditions and take
longer and are more expensive to develop than other devices. If we keep
the central tenets of FDAMA in mind, namely:
enhanced collaboration between FDA and industry,
increased certainty in the review process, and
avoidance of over-regulation
we can forge a path for breakthrough technologies to move them from a
biomedical engineer's creative thought to a patient's bedside as
efficiently and effectively as possible. I highlight breakthrough
technologies because we all can agree on their importance, but we also
must recognize the disincentives to their development that currently
exist. By modernizing the regulatory process for breakthrough devices
we can continue the success of FDAMA, dampen some of the disincentives
facing the development of breakthrough technologies, and, most
importantly, help Americans in getting the medical care they need.
II. OBSTACLES TO INNOVATION AND BREAKTHROUGH TECHNOLOGIES
We can define a breakthrough device as one that is novel in design,
operation, or function, and is intended to treat life-threatening
diseases or conditions. I contrast breakthrough devices with ``new''
devices that are modifications of, or incremental changes to, devices
with well-established track records. Because breakthrough devices take
longer and are considerably more expensive to develop than those
incrementally improved devices, sponsors of breakthrough devices must
make a large commitment to the long haul.1
I will provide just one example of such a breakthrough therapy
recently developed by Medtronic and in various stages of consideration
by the FDA and global regulatory bodies. Activa' Therapy is
the umbrella term describing the medical treatment developed by
Medtronic, in collaboration with physician researchers, that uses brain
stimulation to suppress the symptoms of movement disorders. The therapy
uses an implantable medical device to deliver mild electrical
stimulation to brain structures involved in motor control. It includes
in particular Activa Parkinson's Control Therapy, which is the most
significant advance in the treatment of the disease in more than 30
years. Developed by Medtronic in collaboration with pioneering
physicians, the therapy can control the primary motor symptoms of
patients with advanced, levodopa-responsive Parkinson's disease that is
no longer adequately controlled with medication. It is an adjustable
and reversible therapy that uses an implanted medical device to deliver
mild electrical stimulation to either the subthalamic nucleus (STN) or
the globus pallidus interna (GPi) to counter the brain signals that
cause the symptoms of Parkinson's disease. There is currently no cure
for Parkinson's disease and indeed current treatment options have
disabling and unpredictable side effects.
Overall, the medical device industry has demonstrated its
commitment to the research needed to support such innovation. In fact,
the device industry invests a higher percentage of annual income in
research and development than other industries.2 This
investment in R&D has only increased in the last decade. Medical
technology firms invested 5.4% of revenues in R&D in 1990. By 1998 that
figure doubled to 12.9%.3 The United States is the largest
producer of the R&D that leads to new health care technologies and also
is the largest market for these technologies.4
Despite this commitment to technology and innovation, companies
face many barriers in their pursuit of breakthrough devices. Take, for
example, the FDA regulatory process, which can create uncertainty and
high costs, often from time delays, for manufacturers. FDA's inability
today to review efficiently new technologies is understandable;
reviewing these technologies requires considerable resources and
expertise, two things that the agency today struggles to maintain. For
companies with few products, the uncertainty and delays associated with
the FDA's role in the product development and approval process can be
especially challenging as these companies cannot absorb the extra costs
associated with lengthy development processes and untimely reviews.
Indeed, the pressures on small companies created by the FDA regulatory
process have long been recognized by both industry and
government.5
Payment obstacles also discourage innovation and force companies to
scale back their research and development or market their products
abroad first.6 Health insurers, including Medicare, often
have requirements that are higher than the requirements necessary to
gain FDA approval.7 Added uncertainty in the reimbursement
process arises for innovative devices. It is more difficult to secure
payment for these new (FDA approved) devices, which do not have
precedents upon which to rely; compared to incrementally changed
devices, which follow more predictable routes to coverage and
payment.8 Innovative devices also have greater financial
pressure from Medicare's coverage of devices studied under an
investigational device exemption. Medicare may pay for devices that are
newer generations of proven technologies for which initial questions of
safety and effectiveness have been resolved, but will not cover novel,
first-of-a-kind technologies.9 By raising these points, I do
not argue that the reimbursement system is flawed or debate the
policies behind the system; instead, my point is specific: obstacles to
innovation exist and have significant consequences.
I know that you are aware that small companies suffer the
consequences of a delayed regulatory review process and payment
hurdles. Currently, the device industry is primarily comprised of small
companies, which are often the source of novel devices. Indeed, one
study found that start-up firms were disproportionately responsible for
the innovation and early development of novel devices.10 But
funding for small companies is hard to come by and venture capitalists,
particularly when money is tight, do not want to invest in small
companies whose products take a long time to develop, such as medical
devices, and who are part of a highly regulated industry, such as the
device industry.11 Indeed, medical devices are not developed
cheaply; taking a new device from concept to market can cost $20
million or more.12
What may surprise you is that small firms are not alone in feeling
the pressures that deter innovation and development of breakthrough
technologies. Large firms must respond to their investors who prefer
products that have a quicker turn-around time. Incrementally changed
devices fit this bill. As I stated before, there is more certainty in
their review process, which makes that process shorter. Additionally,
with incrementally changed devices the marketing commitment is smaller.
For example, a company does not have to sell a doctor on the benefits
of a newly modified pacemaker; the doctor is familiar with the
technology and will understand the new features. Selling a breakthrough
device to a doctor for a disease that the doctor historically has
treated with a drug requires much more time and
commitment.13
To encourage innovation some firms have undertaken creative
endeavors, but these endeavors can be risky undertakings and, by far,
are the exception and not the rule. I offer as an example, Itasca
Ventures, a ``venture incubator'' formed and operated a few years ago
by my company, Medtronic, Crescendo Ventures, and Vanguard Venture
Partners. Itasca focused on early-stage medical technologies that had
not passed the proof-of-concept and prototype stages and aimed to
nurture device companies to viability. This incubator allowed us to
invest in technology while still meeting Wall Street's financial
expectations that often conflict with a focus on long-term development.
III. BUILD ON FDAMA TO BRING MORE BREAKTHROUGH THERAPIES TO PATIENTS
Today we face a golden opportunity to build on FDAMA's success and
renew our commitment to the innovation and development of breakthrough
technologies. And by ``we'' I specifically mean FDA and industry
because through increased collaboration between the agency and
companies, more breakthrough technologies will be developed and more
patients will be helped. FDAMA created tools to foster collaboration,
for example meetings between the agency and industry early in a
device's development, which can be used to fine-tune the regulatory
process for breakthrough technologies.
Indeed, FDAMA aimed to get devices, including breakthrough devices,
to the public as soon as possible. FDAMA's expedited review provision
identified four situations that triggered review priority including
when devices represented breakthrough technologies. Key to FDAMA was
increasing patient access to new technologies. The goal was to make
review process more efficient and effective through streamlining and
through meetings between the agency and premarket submitters that
emphasized that only the least burdensome data to support an approval
was required. These changes, although they put into law programs, had a
smaller impact in providing patients with early access to breakthrough
technologies.
Although these collaboration tools have been used to some benefit,
I believe there are more tools that FDA and industry can use to further
promote the development of safe and effective breakthrough therapies
for critically ill patients. Specifically, a breakthrough device
mechanism could be put into place, which--
Requires FDA to designate breakthrough device status at an
appropriate stage in the product's development--within 30 days
of a submission requesting such a designation.
Supports the development of protocols that include an ``early
look'' at data to determine whether information exists to
permit a safety and effectiveness determination and, thus, the
earlier availability of a breakthrough device.
Requires FDA to assign a team of reviewers with appropriate
expertise to review a designated breakthrough device.
Grants the device a preferred queue position both before and
after submission of a PMA.
Permits early and ongoing collaboration with the agency by
providing for modular review, and requiring the applicant and
FDA to communicate regularly after the premarket submission, to
ensure the most detailed and efficient review.
Requires that prior to a 90-day meeting, FDA provide a
detailed, written review of any remaining deficiencies.
States that the time to approval after the filing date is 120
days.
In essence, we would create a breakthrough device review process
that offers early collaboration, access to expertise, and
predictability. The process would be implemented by an FDA team that
brings expertise to the review and has ``ownership'' of the
breakthrough project. And through the collaboration encouraged by
FDAMA, the breakthrough device process would result in high quality
inputs in study design, data management, and review.
IV. CONCLUSION
I am confident that if we structure the review of breakthrough
technologies, we will improve both the quality and timeliness of these
premarket reviews and create incentives for breakthrough development.
However, I remain concerned about the premarket review burdens that the
FDA faces today. A breakthrough device mechanism can only function
effectively if we supplement the number of reviewers and the expertise
available to the agency. Indeed, the adequacy and stability of funding
are critical. The task for the government and industry is to ensure
that FDA is appropriately funded to face the challenges of the future.
We have seen in the CDER experience that user fees have worked well.
These fees assist the agency in providing the adequate number of
reviewers with expertise to keep reviews timely. More importantly, they
ensure the timely development and review of new products that provide a
disproportionately positive impact on the public health.
Medtronic continues to fully support FDA's mission to improve the
development of medical devices and help to ensure that safe and
effective products are available to the American public. May we all
continue to support this goal, especially in the area of breakthrough
technologies.
Footnotes
1 Linda Rochford and William Rudelius, New Product
Development Process; Stages and Successes in the Medical Products
Industry, Industrial Marketing Management, Jan. 1997.
2 David B. Fleming and Thomas J. Sommer, Opinion,
Medical Devices Can't Keep Waiting, The Boston Globe, Sept. 16, 1997,
at D4.
3 The Lewin Group, Inc., Executive Summary, Report One:
The State of the Industry, March 24, 2000, at 3.
4 Burton A. Weisbrod and Craig L. LaMay, Mixed Signals:
Public Policy and the Future of Health Care R&D, Health Affairs, March/
April 1999, at 112.
5 Todd Nissen, The Future of the Medical Device
Industry, Business Dateline; Corporate Report Minnesota, Dec. 1993, at
54 (citing a May 1993 report from the House Subcommittee on Oversight
and Investigations which ``noted that both industry representatives and
FDA personnel discussed the possible threat to small medical device
firms that couldn't afford to wait out the lengthy review process'').
6 See, e.g., Manuel Schiffres and Jack A. Seamonds, Is
Red Tape Tying Up High Tech? Keeping the Genie in the Bottle, U.S. News
& World Report, April 21, 1986, at 50 (citing as an example ``Pfizer's
medical-devices group [which] screens research projects and focuses on
new products that generally get hefty medicare reimbursements--the
company may not develop some promising products `simply because [Pfizer
is] concerned that [it] won't be able to sell them in a market
dominated by short-term cost-containment pressures' ''); The Lewin
Group, Inc., Report One: Payment Issues for Medical Technology.
7 See Phil Galewitz, Patients' Access to New Technology
Is Being Increasingly Restricted by Insurers, The Buffalo News, Nov. 2,
1998, at 3A (``Before providing coverage of new technology, health
plans want proof that the products are cost-effective, work better than
other technology, and improve or extend a patient's life.'').
8 The Lewin Group, Inc., Executive Summary, Report One:
The State of the Industry, at 4; The Lewin Group, Inc., Medicare
Patient Access to Technology.
9 Chester A. Robinson, et al., Encouraging Medical
Device Innovation: Reimbursement Problems and New Policies, Public
Health Reports, Sept. 1, 1996, at 468 (noting that at that time
approximately 94% of the 1200 devices being studied in FDA-approved
clinical trials fell into the category of newer generations of proven
technologies).
10 The Lewin Group, Inc., Executive Summary, Report One:
The State of the Industry, at 2.
11 The Lewin Group, Inc., Executive Summary, Report One:
The State of the Industry, at 4-5.
12 Tom Abate, Healing That Hurts; New Medical Devices
Are Saving Lives But Killing Health Care Finances, The San Francisco
Chronicle, June 11, 1999, at B1.
13 See Rochford and Rudelius, New Product Development
Process (explaining that manufacturers of new products are more likely
to use all the stages in the product development process, including a
market study and test marketing, than manufacturers of devices which
are product modifications).
______
National Food Processors Association
June 12, 2001
The Honorable Michael Bilirakis
Chairman
Subcommittee on Health
House of Representatives
Committee on Energy and Commerce
Washington, DC 20515
Dear Chairman Bilirakis: The following are responses to follow-up
questions with respect to the testimony I presented on behalf of the
National Food Processors Association (NFPA) on implementation of the
Food and Drug Administration Modernization Act (FDAMA) before the
Subcommittee on Health on May 3, 2001.
NFPA is the voice of the $460 billion food processing industry on
scientific and public policy issues involving food safety, nutrition,
technical and regulatory matters and consumer affairs. NFPA's three
scientific centers, its scientists and professional staff represent
food industry interests on government and regulatory affairs and
provide research, technical services, education, communications and
crisis management support for the association's U.S. and international
members. NFPA's members produce processed and packaged fruits and
vegetables, meat and poultry, seafoods, drinks, and juices or provide
supplies and services to food manufacturers.
Question 1. In FDAMA, the Congress created an alternative claim
procedure wherein health and nutrient content claims could be based
upon ``authoritative statements'' of the government. This is a
different standard than ``significant scientific agreement,'' which is
required under the Nutrition Labeling and Education Act. Is it your
view that the FDA has interpreted ``authoritative statement'' standard
in such a way that it resembles the ``significant scientific
agreement'' standard?
Response. It is NFPA's view that FDA clearly has tried to interpret
the FDAMA provision in a manner that limits its application to those
consensus-type statements that would survive the most restrictive
reading of ``significant scientific agreement.'' NFPA is on record
challenging FDA's position.
FDA issued guidance in June 1998 (63 FR 32101, June 11, 1998), and
interim final regulations banning nine specific FDAMA health claims,
later that month (63 FR 34084, June 22, 1998), which documented the
Agency's narrow reading of the ``authoritative statement'' provision of
FDAMA, putting entirely in jeopardy the FDAMA premarket notification
procedure. For example, FDA guidance takes the position that a
statement of a federal agency does not qualify as ``authoritative''
unless it constitutes ``the official policy'' of the scientific body.
Under FDA's interpretation, ``subdivisions'' of federal agencies
apparently cannot issue ``authoritative'' statements, regardless of the
scope of responsibility they have been delegated for public health
matters (63 FR 34084 at 34085). Moreover, FDA makes clear that it does
not intend to rely on the scope of authority delegated to a scientific
body to determine whether its statements are authoritative, but rather
to evaluate on a case-by-case basis the proceedings of scientific
bodies to determine whether they are sufficiently deliberative to
measure up to FDA's standards for approval of a health claim petition.
According to FDA, no statement will qualify as ``authoritative'' if
it indicates ``a relationship between a nutrient level and a disease or
health-related condition is preliminary or inconclusive . . . (63 FR
34084 at 34086).'' The Agency interprets FDAMA ``to prohibit a health
claim based on an authoritative statement when there is not significant
scientific agreement that there is a relationship between the nutrient
and the disease or health-related condition . . . (Id.).'' This
reflects FDA's basic view that FDAMA is a ``surrogate'' for, rather
than an alternative to, the health claim petition process authorized by
the Nutrition Labeling and Education Act of 1990. FDA's confined
reading of FDAMA not only leaves little room for FDAMA health claims,
but raises serious First Amendment concerns.
Question 2. FDAMA gave the FDA 540 days to review filed health
claim petitions. Are you aware of any petitions which have exceeded
this 540 day time limit?
Response. Since the enactment of FDAMA, we are not aware of any
health claim petitions which have exceeded the 540-day time limit.
Throughout the history of the health claim petition process, however,
there are several petitions that have been withdrawn rather than pass
through the gauntlet of FDA's health claim review time limitations.
Typically, FDA scrutinizes health claim petitions at the beginning of
the review process. The few health claim petitions that are filed, and
survive the initial screening, allow for relatively easy docket
management in FDA, enabling the Agency to reach closure by 540 days.
In addition, FDA has promulgated a rule (21 CFR Sec. 101. 700)(4))
that requires the Agency to justify any delay in issuing a health claim
final rule for a health claim petition if that final rule is not
published within 540 days from the date of receipt of the petition.
This date is earlier than the statutory deadline. On June 6, 2001 (66
FR 30311), FDA noted that the issuance of a final rule on the health
claims, resulting from petitions, on plant stanol and sterol esters and
coronary heart disease will be delayed until July 25, 2001. In this
Federal Register document, FDA notes that the final rule will be issued
within the statutory time frame.
Question 3. Has the FDA given any indication as to when it will
revisit its advance notice of proposed rulemaking on irradiated
products in order to finalize a rule which will provide consumers with
better information about irradiated foods?
Response. On February 17, 1999, FDA published an advanced notice of
proposed rulemaking (ANPR) calling for comments on labeling revisions
for foods treated with ionizing radiation and suggestions on whether
labeling requirements should expire. The ANPR highlighted the extensive
public record FDA has already gathered on the subject and called for
more information about consumer understanding of the irradiation
process.
FDA's preliminary analysis of the comments it received suggests
there is no consensus on what alternative language would be truthful
and not misleading for disclosure of irradiation processing. The Agency
believes that since these comments provide no clear direction for
rulemaking, it has fulfilled its obligations under FDAMA's conference
report that it provide an open public comment irradiation labeling
issues.
In its recent response to the congressional request on irradiated
labeling concerns raised in FDA's FY 2001 appropriation legislation FDA
stated that it expected to receive a contractor's analysis of the
comments on its ANPR by December 31, 2000. The Agency intends to: 1)
obtain more information on consumer understanding of the existing
label; and 2) attempt to develop a properly informative label that
would not be perceived by consumers as a warning. If these projects are
successful, FDA plans to develop a proposed rule during FY 2001 and
publish a final rule by March 1, 2002.
On March 29, 2001, FDA indicated in a Federal Register notice that
it plans to conduct six consumer focus groups on food irradiation
labeling subjects in April and May 2001, and sought comments on its
request for approval by the Office of Management and Budget (OMB) for
such research. NFPA understands that OMB has approved the research, and
FDA now plans to conduct the series of focus groups on June 18, July 9,
and July 11, 2001.
NFPA applauds the leadership this Committee has shown in oversight
of the implementation of FDAMA and we appreciate this opportunity to
provide the Committee with further information and comments. Please
contact me if you need any additional information on the responses
herein.
Sincerely yours,
Rhona S. Applebaum, Ph.D.
Executive Vice President, Scientific and Regulatory Affairs
______
Generic Pharmaceutical Association
June 13, 2001
The Honorable Michael Bilirakis
Chairman, Subcommittee on Health
Committee on Energy and Commerce
2125 Rayburn House Office Building
Washington, DC 20515
Dear Chairman Bilirakis: Attached please find responses to the June
1, 2001 list of follow-up questions from the May 3, 2001 hearing on
pediatric exclusivity you submitted to Dr. Carole Ben-Maimon, Chair of
the Generic Pharmaceutical Association's Board of Directors. Please do
not hesitate to contact me if you have any additional questions.
Thank you for your continued interest in this important matter.
Sincerely,
Steve Giuli
Director of Government Affairs
Question 1: The FDA Report on Pediatric Exclusivity says that for
children ``the public health benefits have been extensive.'' Do you
deny that this is the case?
Response 1. In order to evaluate the public health benefits of
pediatric exclusivity there must be a clear understanding of what
exactly the standard of measurement is. If the standard being employed
is the number of studies that have been conducted prior to the
pediatric exclusivity provision, compared to the number of studies that
have been conducted after the provision became law, then there is no
question that the pediatric exclusivity provision has achieved the
desired objective. However, I do not believe that Congress intended
merely to create an incentive for the performance of clinical studies.
The intent, as I understand it, was to obtain valuable information and
data that would have an impact on the treatment of childhood illnesses.
Thus, the number of studies being performed is an inappropriate
standard for measuring the provision's success. A more appropriate
gauge would be to measure the quality of the data being generated and
its value and application to those treating patients in the pediatric
community. The Food and Drug Administration (FDA) is the only body
possessing this information and is therefore uniquely suited to render
a judgment on this basis. However, I have yet to see reports
quantifying the impact and value of the data being obtained under the
pediatric exclusivity provision. Only the FDA has access to this data.
Clearly, without the necessary data it is inappropriate for me to offer
an opinion on whether or not the public health benefits of the
pediatric exclusivity provision, have ``been extensive''.
Question 2: The Tufts Center for the Study of Drug Development has
found that without the pediatric exclusivity provision, the pediatric
sales market itself would be insufficient to render the commitment of
resources necessary to study drugs for use in children. Do you deny
this?
Response 2. The short answer is, ``No.'' In my May 3, 2001
testimony before the Health Subcommittee, I unequivocally expressed
support on behalf of GPhA for the continued need for some kind of an
incentive system to spur pharmaceutical research in the pediatric
population. That view has not changed. GPhA fully supports research on
therapies that are important for children. The concern I raised at the
May 3 hearing, and one strongly held by GPhA, is that the magnitude and
type of the current pediatric incentive cryout for careful
Congressional review and continued scrutiny. The Generic Pharmaceutical
Association strongly encourages the Commerce Committee to consider
alternative incentives and programs that would achieve the desired
result of pediatric research without harming other vulnerable sectors
of the population by keeping drug prices high. And GPhA would welcome
the opportunity to work with the Committee to develop such workable
alternatives.
Question 3: The FDA has found that the pediatric exclusivity
provision has increased the nation's pharmaceutical bill by one-half of
one percent, while the Tufts Study found that the actual out-of-pocket
expense for any senior citizen due to pediatric exclusivity is likely
to be ``minimal and temporary''. Do you believe that a one-half of one
percent increase is too much to pay for accurate dosing in children?
Response 3. The answer to this question requires a cost-benefit
assessment. The answer clearly depends on the value of the information
and the advances offered by the research. One area of concern about the
cost of the existing system is that it places the entire burden of
paying for that one half of one percent increase on the narrow section
of patients who have to wait an additional six-months before the low-
cost generic alternative for that particular brand drug to become
available. The average retail price of a brand prescription costs 238%
more than the average retail price of a generic prescription. For the
senior citizen on a fixed income without prescription drug insurance,
the added burden may well be ``temporary'' but it is hardly
``minimal.'' The one half of one percent increase would, to that senior
citizen, be a lot more affordable if it was being paid for by all of
society instead of just a narrow and often vulnerable segment. We
encourage Congress to look at alternate incentives that have less
impact on people who are already struggling to pay for the high costs
of their medications. We believe such alternatives exist, and we would
welcome the opportunity to share our observations.
Question 4: In your testimony you note the fact that ``pediatric
clinical testing that does nothing more than assess children's
reactions to the fifth or sixth generation `me-too' drug makes no
meaningful contribution to doctors' ability to treat the relevant
disease''. The decision about what does and does not make a meaningful
contribution to pediatric health is up to FDA, not the drug
manufacturer, however. If the FDA doesn't issue a Written Request, then
there's no way that a drug can obtain pediatric exclusivity, correct?
Response 4. My understanding is that the FDA issues the written
request, but in addition to that manufacturers can request a written
request from FDA. Regardless of the process, FDA cannot differentiate
between products within a therapeutic class. What benefit is there to
society of rewarding, say, a fourth drug from a given therapeutic class
when three drugs that are equally as effective have already received
the pediatric exclusivity reward? This is a problem since FDA cannot
reliably predict which companies marketing a specific drug within a
class of drugs will perform pediatric studies. In addition, I am not
aware that FDA has ever removed a product from its list. Thus, if three
products with the same mechanism of action and for the same disease are
studied the fourth product in the same category remains eligible for
exclusivity even though the need may have drastically diminished.
As the process moves forward, Congress should also pay equal
attention to the brand industry's campaign to minimize its obligations
under the pediatric incentive program and convince FDA to narrow the
scope of the Agency's study requests. Consider just these two examples.
In a letter to FDA dated April 3, 1998 Steven Spielberg, MD, John
Siegfried, MD, and Marjorie Powell of PhRMA wrote ``Studies can qualify
for exclusivity even if they are unsuccessful and do not lead to new
pediatric indications, dosing information, or formulations . . . [T]he
study or studies need not lead to the filing of a supplemental drug
approval application related to pediatric use to allow the applicable
drug to qualify for the incentive.''
On March 6 of this year, PhRMA's Alan Goldhammer, PhD, wrote a
letter to FDA stating, `` [I]f consensus between a sponsor and the
Agency is reached that the diseases are the same in adults and
children, then there should not be any requirement to conduct efficacy
studies in children. Rather, information on pharmacokinetics to
establish the appropriate dosing regimen, relevant formulations, and
safety in children should be sufficient.'' If the requirements are so
limited, why should the incentives be so large?
Contrary to these positions articulated by PhRMA, GPhA believes
that the FDA should have the authority to require the timely addition
of label revisions for pediatric uses and that brand companies should
be required to conduct serious and original clinical studies in
children in order to qualify for this large of an incentive. We urge
Congress to consider these important issues in the reauthorization
process.
Question 5: According to an January 2001 FDA report, between 1991
and 1996 (prior to pediatric exclusivity), only 11 pediatric studies
were completed by the industry at the request of FDA. Since 1998 (after
pediatric exclusivity), the industry has agreed to perform 411
pediatric studies. Don't you agree that significant progress is being
made on behalf of children due to pediatric exclusivity?
Response 5. Again, it is GPhA's position that the quality of
information and its relevance to the pediatric community, and not the
number of studies, are the appropriate standards to use in determining
the success of the pediatric exclusivity program. An additional concern
on this front is that an over-reliance on sheer numbers as an indicator
of success can cloud the fact that clinical trials are a form of
experimentation. With experimentation comes considerable risk. The
deaths that resulted from the diprovan experience tragically
illustrated just how severe the risk can be.
Question 6: The January 2001 FDA report estimated that lower
hospitalization costs due to better pediatric dosing information can
save up to $228 million per year for five diseases alone. Do you agree
that by that measure alone the pediatric exclusivity provisions are
having a positive impact?
Response 6. Reducing hospitalization costs was surely one of the
objectives in creating a pediatric research incentive. Generating an
annual $228 million savings over 5 years would, in turn, be a positive
aspect of the pediatric incentive program. Allow me to again reiterate
that GPhA strongly supports the continuation of some kind of incentive
for pharmaceutical companies to conduct pediatric research. Having said
that, GPhA believes that it is vitally important to accurately
determine whether or not the current incentive is disproportionate to
the cost. This concern is rooted in the belief there may be more cost
efficient ways to create a pediatric incentive. Regrettably, a
disproportionate financial incentive could encourage the exploitation
of children. Combined, these two reasons make a powerful argument for
considering alternatives to the current system that could better
protect children with less of a cost to the public.
Question 7: You claim that pediatric exclusivity has been in place
for four years, but that there is no well-defined system for measuring
its success. However, in the five years before the provision was passed
by the pharmaceutical industry conducted 11 pediatric studies at the
request of the FDA, and since its passage they have agreed to conduct
411 pediatric studies. Isn't this proof enough for you that the
provision is working?
Response 7. No. As discussed in earlier responses, GPhA believes
the success of the provision should be measured by the quality and
impact of the data it is generating and not just by the increase in the
number of pediatric studies following the passage of the law in 1997.
Question 8: You mention in your testimony that the FDA claims the
cost of the provision will amount to $695 million per year in higher
costs of prescription drugs. That very same report says that better
pediatric dosing could save $228 million in lower hospitalization and
utilization costs for five pediatric diseases alone. It's entirely
possible that this provision may save health care dollars, isn't that
right?
Response 8. It is possible that this provision my save health care
dollars but I would reiterate the points I made in my response to
question 6.
Question 9: The generic industry will benefit by being able to
label their drugs for pediatric indications when the brand name which
conducted the pediatric studies comes off patent, correct?
Response 9. That is true if there is no patent and no exclusivity
other than pediatric exclusivity associated with the drugs in question.
One of the unintended repercussions of the pediatric exclusivity
incentive is that as brand companies do pediatric studies, they may be
seeking patents surrounding and protecting these concepts. The
existence of a patent(s) that a generic company cannot use in its
labeling raises an entirely different public health issue.
Exclusivities may be prolonged beyond six-months as it is conceivable
that additional patents could be issued.
______
Medical Device Manufacturers Association
June 19, 2001
The Honorable Michael Bilirakis
Chairman
Subcommittee on Health
Committee on Energy and Commerce
United States House of Representatives
Washington, District of Columbia 20515-6115
Dear Chairman Bilirakis: I have enclosed my responses to the
questions you submitted to me for the record of your subcommittee's May
3 hearing on the implementation of the Food and Drug Administration
Modernization Act of 1997.
Thank you for the opportunity to testify before the subcommittee
and for your continued interest in the issues that affect the ability
of the medical device industry to make new and advanced technologies
available to patients who need them.
Very sincerely yours,
Stephen J. Northrup
Executive Director
Attachment
Question 1. The FDA is on average reviewing 510(k) submissions in
77 days, and the premarket approval review time has been cut in half,
though its still roughly twice what is required by law. Are the FDA's
successes a result of FDAMA, FDA leadership, or both?
Response. Most of the credit for the reduction in medical device
review times goes to the U.S. Congress for both their oversight of CDRH
and their legislative efforts during FDAMA to ensure the necessary
procedures took place to streamline the review process. The Center for
Devices and Radiological Health (CDRH) and its own re-engineering
efforts also deserve special recognition for reducing approval times by
creating a more efficient and streamlined device review process.
Question 2. Have the collaboration measures contained within FDAMA
improved the working relationship between manufacturers and the FDA?
Has this come at the expense of patient safety?
Response. Overall the collaboration measures in FDAMA have improved
the general communications between the medical device industry and the
FDA. A survey conducted in 1999 by PricewaterhouseCoopers LLP and
CONNECT, the University of California at San Diego's Technology and
Entrepreneurship Program, found that communications between life
sciences companies and the FDA have improved significantly since 1995,
when the organization first began their bi-annual survey.
Unfortunately, the ``formal collaborative meetings'' between the
Agency and industry as proscribed in the FDAMA provisions are
underutilized, in large part because they are new and the industry has
not developed a full body of positive experience to which others
considering the merits of such meetings can refer. We nevertheless
encourage the FDA to continue to implement these provisions, especially
the collaborative meetings between the agency and industry to determine
the type of evidence needed to support a PMA approval. It is beneficial
for both industry and FDA to determine together the nature of the
information needed for the industry to include in the device
submission, as this will reduce the likelihood of arbitrary changes at
a later date. This type of meeting helps to streamline the review
process, thus ensuring that unnecessary regulatory requirements do not
delay patients' access to new technologies.
There is no evidence to suggest that a more collaborative
relationship between industry and the FDA has come at the expense of
patient safety. The goal of FDAMA was to increase the regulatory
efficiency of the FDA, not lower its standards.
Question 3. The FDA recently issued a Draft Guidance on the ``least
burdensome'' provision contained within FDAMA. While I am concerned
that it took FDA three and one-half years to develop this Guidance,
could you explain for the Committee industry's general thoughts on this
Guidance?
Response. As noted in my testimony, we are pleased that the FDA
published this draft guidance on the ``least burdensome'' provisions of
FDAMA in time for the May 3rd hearing. We believe this document
captures the intent of FDAMA by defining ``least burdensome'' to mean
an approach to addressing a premarket issue ``that involves the most
appropriate investment of time, effort, and resources on the part of
the industry and FDA.'' When finalized, this guidance should have
beneficial effects on the overall medical device review process.
Question 4. Even if the ``least burdensome'' Guidance is ideal from
a public health and industry perspective, isn't it true that there will
be little improvement in device reviews if the concept isn't thoroughly
explained to the main line device reviewers?
Response. Everyone at FDA involved in the medical device approval
process, from the division directors to branch chiefs to the front-line
reviewers, must fully understand and adopt ``least burdensome''
principles in their day-to-day work to ensure its full implementation.
We trust the agency will continue to train its reviewers and its
advisory panels in the application of these concepts and principles.
Training activities are crucial to promoting the greater consistency we
seek in the FDA's review process.
Before the guidance can be put into effect, it must be published in
final form. Therefore, it is important that CDRH expeditiously review
and incorporate the appropriate comments and issue the final guidance
in an accelerated fashion.
Question 5. Why did industry react so slowly to the third-party
review process created within FDAMA? I understand that in the first 17
months after passage industry only used this process 54 times.
Response. It is true that this program has been used infrequently
so far by the medical device industry, in large part because the FDA
has streamlined its own review processes. However, we also believe
industry underutilization of third-party review can be attributed in
part to the manner in which FDA has implemented this program.
The FDA took more than three years to fully implement the third-
party review provisions of FDAMA. The FDA's internal policy, as
described in October 1998 and November 1998 guidance documents,
permitted third-party review of class II devices only if device-
specific guidance or recognized consensus standards existed. In our
opinion, limiting the use of the program through requiring the
existence of guidance documents for the products in question was too
restrictive and not in accordance with Congressional intent under
FDAMA.
We argued to the FDA that products for which no guidance documents
or consensus standards exist are exactly the types of products for
which third-party review would be most attractive to manufacturers and
most beneficial to the FDA. In January 2001, the FDA expanded this
program to include any device regulated by CDRH that is not prohibited
from third party review under FDAMA.
Question 6. Do you expect utilization of the third-party review to
increase due to FDA's recent actions to expand the number of devices
eligible for such review?
Response. According to the latest statistics released by the
Agency, FDA has already received more third-party review applications
in 2001 than were received in all of 2000. We believe this is directly
related to the expansion of the program, and we look forward to its
continued growth.
Question 7. Is there any evidence whatsoever that third-party
review in any way compromises patient safety?
Response. According to FDAMA, the FDA accredits the independent
organizations that are eligible to review the applications, and the FDA
also has final authority whether to reject or accept the determination
by the third party before the submission is cleared. The FDA would be
in a better position to answer this question, but we are not aware of
any situations in which a third party has recommended to the FDA that
the agency clear an unsafe product. We also are unaware of any
widespread compromising of patient safety in Europe, where non-
governmental third parties conduct all premarket reviews of medical
devices.
Question 8. Why did it take the FDA Centers so long to establish
the dispute resolution procedure mandated by FDAMA? Do you have any
idea when the Device Center's dispute resolution committee will hear
its first dispute? Are companies willing to use such a procedure?
Response. As I noted in my written testimony, the FDA's first
response to this provision of FDAMA was to publish a direct final rule
on June 16, 1998. Under this rule, the FDA would have permitted drug
and device manufacturers to request review of scientific controversies
by an appropriate advisory committee. However, the FDA ended up
withdrawing this rule after our industry and others complained that the
rule was not consistent with the intent of FDAMA. As the FDA eventually
acknowledged, the rule did not contain critical information, such as
the process for selecting members of an advisory committee convened to
resolve a dispute, the timeframes for conducting the reviews, the
standards for granting or denying a review, and the weight to be given
to advisory committee recommendations.
In the end, the FDA chose to allow each of its centers to develop a
center-specific approach to implementing dispute resolution. For its
part, the Center for Devices and Radiological Health (CDRH) has
published a draft guidance document outlining how its dispute
resolution process will work and has hired an ombudsman to oversee the
workings of a Medical Devices Dispute Resolution Panel, which held its
first organizational meeting in October 2000.
On June 4, 2001, the CDRH dispute resolution panel was scheduled to
hear its first case, but the meeting was indefinitely postponed. As I
understand it, the meeting was postponed because the FDA and the
company had major disagreements about materials that were distributed
to panel members shortly before the meeting.
I believe that companies are willing to use this procedure if they
believe they will be guaranteed a fair hearing. With respect to the
postponed June 4 meeting, the company involved may have been concerned
that the materials the panel members received from the FDA would have
biased the panel against the company and its case.
For the most part, companies usually try to resolve disputes at a
lower level by going through normal administrative channels or the
recently established CDRH ombudsman's office. Nevertheless, it is
important for companies to have a mechanism like this dispute
resolution panel available, provided that the panel and its decisions
are independent and free of any agency bias. We will continue to
monitor the implementation of this FDAMA provisions and will report our
findings to you.
Question 9. Is the industry availing itself of the collaborative
meetings, whether on a pre-IDE or pre-PMA basis, which are provided for
in FDAMA? Have these meetings proved beneficial?
Response. Overall, industry has found the collaborative meetings
mandated by FDAMA to be productive and useful, although as I mentioned
earlier, they have been underutilized to date in our opinion. Most of
the meetings in which the FDA and industry have participated have
resulted in agreements, although some of our members report that the
FDA for some reason has been reluctant to engage in 180-day meetings on
major premarket approval application (PMA) amendments.
Questions from Anna Eshoo
Question 1. Despite extensive scientific evidence demonstrating
serious risks associated with reprocessing of single-use medical
devices--including several studies conducted by the Agency itself--FDA
has failed to meaningfully enforce key patient safety provisions of the
Food, Drug and Cosmetic Act. It took substantial Congressional and
public pressure to force FDA to finally publish enforcement guidance on
regulation of this potentially dangerous practice. Yet, I remain
concerned that this guidance, while a step in the right direction,
continues to permit the use of many unsafe reprocessed devices on
American patients.
Mr. Northrup, I know your organization has been actively involved
in working with FDA to develop a strategy to regulate the reprocessing
of single use medical devices. Would you comment on FDA's progress in
implementing its strategy to regulate this practice?
Response. On August 14, 2000, the FDA released a guidance document,
titled ``Enforcement Priorities for Single Use Devices Reprocessed by
Third Parties and Hospitals.'' The guidance document, if properly
implemented, will require reprocessors of some single use devices to
fulfill substantially the same pre-market submission requirements as
original manufacturers of single use devices. While the guidance
document represents a step forward in the enforcement of the Food,
Drug, and Cosmetic Act (``FDC Act'') on some reprocessors, it also
presents new risks to patient health and perpetuates the regulatory
inequity between reprocessors and original manufacturers by exempting
reprocessors from fulfilling premarket requirements for certain
devices.
According to the guidance document, FDA intends to subject
reprocessed single use devices to pre-market submission requirements
based on their original device classification (Class I, II, or III).
Under this classification scheme, FDA and its expert panels have
``exempted'' certain new devices from 510(k) and PMA requirements
because these requirements were not deemed necessary to ensure the
safety of the devices for one use. Instead, the FDA intends to extend
blindly these pre-market exemptions to reprocessed devices even though
the original expert panels never considered the reuse of these devices,
and even though these exemptions will not consider the new questions of
safety and effectiveness raised by reprocessing devices designed for
single use only.
The FDA broadly extends these pre-market exemptions to hundreds of
reprocessed single use devices while at the same time admitting that
many of these devices, although exempt (e.g., non-electric biopsy
forceps), may present a greater risk to patients when reprocessed. The
FDA's answer to this dilemma is to examine at some point in the future
``high-risk'' devices such as non-electric biopsy forceps on a case-by-
case basis to determine whether the exemption should still apply. Thus,
the FDA inappropriately presumes the safety and effectiveness of these
reprocessed single use devices.
Moreover, the FDA shifts the burden to original manufacturers who
design, develop and manufacture these devices to demonstrate the need
to revoke exemptions on a case-by-case basis rather than requiring
reprocessors to meet the burden for obtaining an exemption or filing a
510(k). This position is inconsistent with the FDC Act, the FDA's
regulations, sound policy, and patient safety. The burden of
affirmatively demonstrating safety should be placed on the party that
always has the burden under the FDC Act: the party that wishes to
market the device. Patient safety and consistent, sound policy,
therefore, require that reprocessors meet the burden of demonstrating
safety and effectiveness of a reprocessed single use device in a 510(k)
or a petition for exemption.
Question 2. Can you give me a specific example of a product where
you feel that FDA has failed to take appropriate steps to ensure
patient safety? What can FDA do in this instance to ensure the reuse of
this product does not pose a public health risk?
Response. A specific example of a product for which the FDA has
failed to take appropriate steps to ensure patient safety is
reprocessed single-use non-electric biopsy forceps. These devices are
currently exempt under the new regulatory scheme, and reprocessors are
not required to demonstrate their safety and effectiveness through the
510(k) clearance process prior to placing these devices on the market.
Non-electric biopsy forceps are used to obtain deep patient tissue
samples in various gastroenterology procedures in order to diagnose the
presence of such diseases as colon cancer, Crohn's, ulcerative colitis
or Barrett's esophagus. Single-use biopsy forceps break the mucosal
barrier and come in contact with the blood stream and are difficult, if
not impossible, to thoroughly clean or adequately sterilize for safe
reuse without adversely affecting the structural integrity of the
device. The very design of non-electric biopsy forceps impedes adequate
cleaning and sterilization after use. In addition, the harsh conditions
of reprocessing diminish the performance and structural integrity of
the device.
Single-use non-electric biopsy forceps are comprised of two long,
thin steel wires that are surrounded, at the distal end, by a
lubricious-coated plastic sheath. The wires and inner sheath are
located inside a tightly wound metal coil which is then encased in an
outer polymer sheath up to 240 cm long with an outer diameter as small
as 2.2 mm. These long, narrow lumens are one of the hallmark features
that make this device difficult to reprocess. The coil that surrounds
the inner plastic sheath creates many difficult-to-access interstices
in which debris accumulates during use.
The jaw assembly of the device often includes a needle for
anchoring the biopsy into the mucosa. The needle is also used to stack
biopsy samples for detainment in the jaw assembly. The needle directly
penetrates the mucosal layer of the GI tract and should be considered
in the same manner as all medical device ``sharps'' classification.
Because biopsy forceps break the mucosal barrier and come in
contact with the blood stream, sterility is critical. However, the
results of several studies have consistently demonstrated that a
significant number of reprocessed single use biopsy forceps contain
residual debris and fall below the sterility assurance level
established by the FDA as appropriate for most medical devices.
Specifically, in Boston Scientific Corporation-sponsored studies
performed by independent laboratories, more than 64 percent of
reprocessed devices randomly selected from hospital shelves failed the
sterility tests and over 94 percent tested positive for the presence of
residual tissue.\1\ Furthermore, in studies conducted by the FDA's
Office of Science and Technology using three types of single-use
gastrointestinal biopsy forceps, researchers found that, in cleaning
the devices with a sequence of bleach, ultrasonic bath with detergent
and enzyme, and water rinse, residual water remained in the devices.
This inability to dry the device lumen decreases the effectiveness of
sterilization.\2\ Thus, even when debris can be removed from these
devices, the existence of residual water compromises the ability to
sterilize them.
---------------------------------------------------------------------------
\1\ See BSC Citizen Petition, at 6-8 (FDA Docket No. 00P-1535)
(Sept. 20, 2000).
\2\ See CDRH, ``Reprocessing Single Use Biopsy Forceps for Reuse,''
Abstract for the 2000 FDA Science Forum from OST.
---------------------------------------------------------------------------
In FDA's initial draft guidance to regulate the practice of
reprocessing, FDA listed biopsy forceps on its list of products that
are frequently reprocessed. Interestingly, due to concerns regarding
the sterility and efficacy of the product after reprocessing, the
agency classified reprocessed biopsy forceps as a Class III ``high-
risk'' product, a decision which, if implemented, would have subjected
the reprocessed device to the agency's most stringent pre- and post-
market regulatory controls.
In short, reprocessing of biopsy forceps designed and labeled for
single use, with its potential for residual debris, non-sterility, and
compromised functionality, presents an increased risk to patients. This
risk necessitates rigorous review by the FDA via 510(k) clearance to
ensure that these single-use devices are in fact safe and effective for
reuse after reprocessing. The FDA must require reprocessors to provide
data demonstrating the efficacy of cleaning and sterilization of biopsy
forceps and verify their functionality before allowing these devices
back into the marketplace. The FDA, therefore, must immediately revise
its regulation that exempts all non-electric biopsy forceps from pre-
market notification procedures and require 510(k) clearance for these
devices, prior to these reprocessed devices being placed on the market
and used on a patient.
Question 3. Mr. Northrup, you testified to the importance of
``fair, predictable, and consistent regulatory actions'' during the FDA
approval process. When we wrote FDAMA, we included a provision
mandating that the evidence required for FDA approval be the ``least
burdensome'' needed to meet safety and effectiveness standards. In your
opinion, has the FDA implemented this ``least burdensome'' requirement
in a timely manner?
Response. In my opinion, the Agency has not implemented the ``least
burdensome'' requirement in a timely manner. It took the FDA until May
1, 2001, to release the draft guidance document on this subject. This
delay of more than three years since the passage of FDAMA is a critical
shortcoming of the agency's implementation efforts, as these provisions
capture best the true spirit of FDAMA--ensuring that unnecessary
regulatory requirements do not delay patients' access to new
technologies.
Upon review of the recent draft guidance document on ``least
burdensome'', we believe it upholds the basic principles outlined in
the FDAMA provisions, and we will be recommending to the FDA that they
accelerate the finalization of this guidance.
______
Children's Mercy Hospitals & Clinics
Division of Pediatric Pharmacology and Medical Toxicology
7 June 2001
Hon. Michael Bilirakis
Chairman, Subcommittee on Health
U.S. House of Representatives
Committee on Energy and Commerce
Washington, D.C. 20515-6115
Dear Congressman Bilirakis: Thank you for your letter of 01 June
2001 concerning my testimony of May 3, 2001 to the Subcommittee on
Health regarding the Food and Drug Modernization Act. It was truly a
distinct honor and privilege for me to have been invited to share my
perspectives and recommendations with the Congress pertaining to the
pediatric provisions of this Act. I also sincerely appreciated the
hospitality that was extended to me by you, the members of the
Subcommittee on Health and the Committee staff as it made my experience
both enjoyable and memorable.
Enclosed with your letter was a list of three questions for me to
consider and provide responses to. It is with great pleasure that I do
so at this time. As per the instructions contained in your letter, each
of the three questions and my responses to them are provided in the
enclosed document.
Again, thanks so much for inviting me to participate in the hearing
on FDAMA and by doing so, affording me an opportunity to serve. If I
can ever be of assistance to you and/or the other members of the
Subcommittee on Health, please do not hesitate to call upon me.
Sincerely,
Gregory L. Kearns, Pharm.D., FCP
Chief, Division of Pediatric Pharmacology and Medical Toxicology
Encl.
Question 1: In your testimony, you claim that ``in four short
years, pediatric exclusivity has done more to improve the health and
welfare of children than any other pediatric therapeutic initiative in
the history of our country''. Could you explain the hazards of not re-
authorizing this legislation?
Response: Failure to reauthorize the pediatric provisions of FDAMA
would dramatically reduce the number and scope of pediatric clinical
drug trials of marketed prescription drug products and thus, prevent
the generation of objective, scientifically-based information required
(and requested by physicians) to insure the safety and efficacy of drug
treatment in neonates, infants and children. For example, since FDAMA
was enacted, a total of 154 different therapeutic drug moieties have
been the subject of 409 carefully controlled clinical investigations
performed consequent to 189 formal written requests issued by FDA.
These clinical investigations, all of which were conducted with the
rigor that accompanies FDA oversight, have involved well over 50,000
pediatric patients spanning in age from birth through adolescence with
a variety of common (and potentially serious) medical conditions (e.g.,
asthma, hypertension, diabetes, pain, anxiety, sepsis) seen in
pediatric and adult patients alike. Thirty three of these drug products
studied in pediatric patients under the provisions of FDAMA have been
granted extended marketing exclusivity; 17 of which have produced
significant changes in product labeling (i.e., the prescribing
information made available to physicians) that have the potential to
prove both the safety and efficacy of these drugs in infants, children
and adolescents. In stark contrast, only 11 drugs were formally (i.e.,
under the aegis of the FDA) studied in pediatric patients in the 10
year period preceding the enactment of FDAMA. In conclusion, failure to
renew FDAMA and its pediatric provisions would return infants and
children to the status of ``therapeutic orphans'' and thus, deny them
the same rights to drug treatments which are proven to be safe and
effective as we afford adults through the formal process of drug
development mandated by the FDA.
Question 2: Is it your belief that FDA's Written Requests for
pediatric studies can be overly burdensome and impractical at times,
resulting in manufacturers deciding not to conduct pediatric studies?
Response: In some instances, this has indeed been the case; the
reasons for which are multifactorial. Some of these reasons are as
follows:
The process of consultation, collaboration and negotiation
between a pharmaceutical sponsor and the FDA that ultimately
results in the issuance of a Written Request may take anywhere
from 6 to 18 months. For drug products where patent life is
limited with respect to when the Written Request is issued, the
sponsor may not have sufficient time to conduct the required
pediatric studies in a manner that is safe (for the subjects)
and ethically defensible.
The FDA may require the study of a drug in a specific subgroup
of pediatric patients (e.g., neonates and infants) despite the
fact that the drug product being considered for study under a
Written Request may not have substantial therapeutic use in
these particular patient groups. This markedly increases the
time required to complete a pediatric clinical study program if
the FDA mandates that for any drug that is the subject of a
Written Requests, the entire pediatric age range (i.e., birth
through adolescence) must be included in the clinical trials.
The decision by the FDA whether or not to include formal
studies to prove drug efficacy (e.g., phase III clinical
trials) has been liberally interpreted by the Agency in several
instances by the Agency despite the fact that a pharmaceutical
company may not be seeking an indication-based label claim
(i.e., a recommendation for treatment of a specific pediatric
disease/condition) as part of a pediatric study program
conducted under a formal Written Request. In many instances,
``bridging studies'' to determine age-specific drug dose,
provide demonstration of drug effect and provide limited
safety/tolerability information are more than sufficient to
produce significant improvements in product labeling and
thereby, enhance the safe and effective use of drugs by
pediatric practitioners. These studies can generally be
accomplished without compromise in relatively small numbers of
well selected patients and in a reasonable time frame (e.g.,
12-18 months) as opposed to the 2 to 3 years that generally is
required to conduct clinical trials that are sufficiently
designed and powered to prove drug efficacy. To insure the
treatment benefits of FDAMA for children and that no more
pediatric patients than is absolutely necessary are subjected
to the risks and rigor associated with any clinical trial, the
FDA must only require pharmaceutical companies to obtain
information that is required to fill the information gaps
necessary to improve pediatric drug use. The Agency must not be
in a position to complicate the process of pediatric clinical
drug trials by asking pharmaceutical companies and in turn,
clinical investigators and the parents/guardians of the
research subjects (i.e., patients) to provide data that may
well be ``interesting'' but because of study limitations, are
inconclusive. Many of the aforementioned problems/challenges
during this first chapter of FDAMA can be minimized or
prevented by creation of an Office of Pediatric Therapeutics
within FDA and insuring that this new Office is appropriately
funded and staffed so that it might truly serve as a focal
point of expertise and operational capability for all pediatric
clinical trials being considered and/or reviewed by the Agency.
Question 3: In its report to Congress, the FDA noted that the
pediatric exclusivity provision does not create adequate incentives for
conducting studies in newborn infants. Why do you believe neonates are
not being studied as much as other pediatric age groups? What can be
done to ensure that neonates are studied in the future?
Responses: Neonates (i.e., infants less than one month of life)
represent a small segment of the entire pediatric population and
account for a relatively small proportion of pediatric drug use in
general. Despite this fact, approximately 20% of all pediatric clinical
drug trials conducted as part of a Written Request issued by FDA in the
first four years of FDAMA involved neonates. As well, with the possible
exception of drugs used to treat infections (e.g., antibiotics,
antifungal agents, antiviral agents), the 10 most common conditions
that afflict neonates are managed with fewer than 25 different
therapeutic drugs. Thus, relative to older infants and children, the
therapeutic ``need'' for drug products in the neonatal population is
focused and somewhat limited in scope. Hence, I know of no evidence
suggesting that neonates are routinely being excluded from
participation in clinical drug trials
Clearly, the ``need'' to include neonates in a clinical trial
should be driven by a demonstrated therapeutic need for a given drug
product in this particular pediatric sub-population. It should not be
driven by some mandate to include them simply because they are part of
the pediatric population when patterns of drug use and/or clinical
standards of care do not support substantial use of a given drug in
neonates. When there is a therapeutic need for a drug in the neonatal
population, it is imperative that these patients be included in
clinical trials that are appropriately designed for neonates, taking
into consideration that these subjects will be sick patients that have
a host of physiologic and disease-associated constraints that influence
what can and should be done. Appropriate scientific oversight afforded
by effective collaboration between pharmaceutical companies, FDA and
academic experts will insure that neonatal studies are done only when
therapeutically, necessary and in a manner that is safe, effective and
scientifically rigorous so as to produce the kind of information that
clinicians who care for sick newborn infants demand and deserve.
______
Eli Lilly and Company
June 7, 2001
Michael Bilirakis
Chairman--Subcommittee on Health
Committee on Commerce and Energy
U.S. House of Representatives
Washington, DC 20515-6115
Dear Chairman Bilirakis: On behalf of the Pharmaceutical Research
and Manufacturers Association (PhRMA) of America, I express our
appreciation for the opportunity to share our perspectives on the Food
and Drug Modernization Act (FDAMA) at the May 3rd hearing of the
Subcommittee on Health.
In response to your correspondence of June 1, 2001, including
questions from your members, the attached material represents PhRMAs
position on those matters in the format which you stipulated, and is
submitted within the June 10, 2001 deadline which you requested.
Please contact Drs. Bert Spilker or Alan Goldhammer at PhRMA or me
directly should there be any questions about this or other material, or
if we can be of any other service.
Sincerely,
Tinothy R. Franson, MD
Vice President, Clinical Research
and Regulatory Affairs-U.S.
Enc.
Question #1: Some today have claimed either in their written or
oral testimony that by allowing drugs to be introduced in the U.S.
before the rest of the world,, somehow the American people are being
used as ``guinea pigs.'' I believe it's better to have drugs introduced
in the U.S. first. Do you agree?
Response to #1: PhRMA strongly agrees that American patients
benefit from first global approvals in the United States. Most of the
research on new drugs is conducted in the United States and in the
past, notably pre-PDUFA American patients have had to wait, sometimes
for significantly long periods of time before they could benefit from
these new medicines. New drugs provide incremental or breakthrough
advantages to patients in need, and it is clearly in the interest of
public health to expedite such access. The volume and quality of
information provided by NDA (new drug application) sponsors to FDA, and
the degree/quality of scrutiny provided by FDA for such submissions
continue to be the global standard. Over the past decade, FDA has
consistently added new safety and efficacy requirements for drug
researchers to study during the development process indicating an
enhancement of the regulatory process rather than any diminution as
their critics might have you believe. Finally, all newly approved drugs
have a justification summary (termed ``Integrated Summary of Benefits
and Risks'') that summarizes the attributes of new products to make
assessments transparent.
Question #2: Have the reforms contained within FDAMA led to better
collaboration between the FDA and the regulated industry?
Response to #2: FDAMA has remarkably improved multiple aspects of
drug development processes, including roles and responsibilities for
sponsors and FDA. As such, the regulated industry and FDA have worked
toward improved, clear, commonly defined (improved) standards that the
respective parties execute independently. Therefore while FDA and
industry representatives collaborated with Congressional staff in 1996-
97 to refine standards, resulting in FDAMA, and while industry and FDA
may collaboratively plan studies to ensure expectations of all
stakeholders, actual development work and reviews are pursued
independently to assure process integrity.
Question #3: Since FDAMA was enacted, there have been 108 requests
for designation as a ``fast track'' drug, and 69 of these requests were
granted. Has this procedure led to quicker approval for drugs intended
to treat serious or life-threatening diseases?
Response to #3: While we have observed that there have been some
rapid approvals of oncology and AIDS medications, PhRMA is not in a
position to generalize how effective this provision has been. We
suggest that the Committee may want to contact the FDA to obtain the
actual approval data.
Question #4: Part 1--How has the pediatric exclusivity provision
affected drug companies internal decisions about whether to test new
molecular entities in pediatric populations?
Response to #4: Part 1--There is no question that this provision
has had aprofound positive effect on the pharmaceutical industry. Many
of the studies required new formulation development to cover younger
age ranges of patients, as well as the development of novel clinical
trial designs and tools to evaluate safety and/or efficacy. Requests
have covered drugs in a wide range of therapeutic areas from common
problems such as treatment of fever and simple skin infections, to
cardiac disease, endocrine problems, gastrointestinal disorders,
serious infections including HIV, seizure and other neurologic
disorders, and management of pain. Studies have included pediatric
patients across all ages. The range of conditions addressed, the
variety of drugs being studied, and the nature of the scientific data
requested all suggest that FDAMA is successfully addressing unmet
therapeutic needs in children. No other approach, legislative or
regulatory, has had such a profound impact on the evaluation of
medicines in children.
Question #4: Part 2--Has it elevated pediatric drug development in
the eyes of Research and Development directors?
Response to #4: Part 2--Yes it has. It is critically important to
remember that research resources are finite. Pediatric studies are
always in competition with studies of important new medicines for large
numbers of adult patients. By establishing a financial incentive,
Section 111 of FDAMA raises the priority for pediatric studies. By
focusing on the needs of children, and recognizing fundamental
impediments to pediatric drug development, the legislation is
accomplishing the goals set forth by Congress.
Question from Bart Stupak:
Dr. Franson, in your testimony, you mentioned that post-market
surveillance is mandatory. It is actually voluntary. Would you support
mandatory postmarket surveillance?
Response to Bart Stupak:
The testimony comment was to illustrate that post-market
surveillance ``activities'' regarding drug safety are mandatory--that
is, any sponsor holding an approved NDA is required by FDA regulations
to capture and report any and all post-approval adverse events to FDA
in timely fashion. 21 CFR Part 314.80 outlines the specific regulatory
requirements that pharmaceutical companies are required to follow.
Companies must report any serious or unexpected adverse event to the
FDA within 15 days of receiving such information. Companies also follow
up these reports to better understand what has occurred with the drug.
There is also a requirement to submit, at quarterly intervals during
the first three years the product is on the market and annually
thereafter, any adverse drug experience that doesn't fall into the
serious or unexpected category. Furthermore, PhRMA companies devote
extensive professional staff to not only adverse event collection--but
also event trend analysis and proactive, independent safety labeling
changes.
There are also selected circumstances in which various extents of
post-market surveillance programs (from simple registries to restricted
access) may be useful, depending on the benefit/risk characteristics of
a product. It would not be advisable to mandate post-introduction
surveillance studies for all--or most--new products without a well-
defined plan, expected yield and patient cost-benefit projections
supportive of such interventions.
______
Department of Health & Human Services
Public Health Service
Food and Drug Administration
June 29, 2001
The Honorable Michael Bilirakis
Chairman
Subcommittee on Health
Committee on Energy and Commerce
House of Representatives
Washington, D.C. 20515-6115
Dear Mr. Chairman: Thank you for your continued interest in the
Food and Drug Administration's (FDA or Agency) successful
implementation of the Food and Drug Administration Modernization Act
(FDAMA). This letter is in response to the Committee's additional
questions raised in your letter of June 1, 2001. Thank you for making
this a part of the public record. The response to question 24 contains
information not releasable to the public and we ask that the Committee
not make public or publish that information.
Your questions will be restated, followed by our response.
Question 1. What impact have user fees had on the information
technology systems within FDA? Are we closer to a paperless system of
review?
Response. As you know, FDA collects user fees for a limited number
of product review activities primarily drug and biologics review and
color additive petitions. FDA's Center for Drug Evaluation and Review
(CDER) has been able to improve its infrastructure to accept more
electronic applications. Following is a summary of the initiatives that
CDER has undertaken to be able to move to a paperless system.
Expanded the Electronic Document Room (EDR) to manage the
receipt and handling of full electronic new drug applications.
Around 75 percent of original new drug applications received in
CDER now include sections that conform to the electronic
submission guidance. In Fiscal Year (FY) 2000, CDER received
over 500 electronic submissions, including full new drug
applications, supplemental new drug applications (NDA), and
amendments. There has been a 50 percent decrease in the average
number of paper volumes per NDA submission since the start of
electronic submissions in 1997.
Accepting expedited postmarketing adverse event reports
without attachments in electronic format. A number of sponsors
have successfully sent reports electronically that have been
directly transferred to a database. The Agency is also
preparing regulations to require all adverse event reports from
industry to be submitted electronically.
Implemented the Division Files System, which provides document
management, tracking, archiving, electronic signature, and
search capabilities for internally generated review documents.
Developing guidance for submission of postmarketing expedited
safety reports, drug registration and listing information,
investigational new drug (IND) applications; NDA annual
reports, drug master files (DMF) in electronic format.
Finalizing a proposed rule that would require NDAs to submit
final printed labeling content electronically to the Agency for
review. Interested parties will have an opportunity to comment.
Since 1997 user fees have significantly impacted the Information
Technology (IT) systems in FDA's Center for Biologics Evaluation and
Review (CBER). User fee support has made it possible for CBER to have
the technology infrastructure in place to store, retrieve and review
electronic documents. Before the IT investments of the second
reauthorization of the Prescription Drug User Fee Act (PDUFA), CBER's
ability to receive and use electronic submission material was non-
existent. CBER's electronic mail (e-mail) system did not support
attachments and staffs found themselves limited by antiquated and
sometimes obsolete technology. Most CBER computers could not support a
business software suite, Internet browser, or other common place
business products.
The FDAMA and PDUFA reauthorization mandates the creation of a
paperless submission and review environment within FDA by the year
2002. In accordance with the Paperwork Reduction Act (PRA), Information
Technology Management Reform Act (ITMRA), Electronic Freedom of
Information Act (E-FOIA), and National Performance Review (NPR), FDA
has created strategic plans and programs to reach the intended goals.
Following is a summary of the CBER projects initiated to meet the goal
of a paperless environment in 2002.
An EDR has been designed and built to support the required
performance goals and international standards, enabling a
paperless submission and review environment. This electronic
repository was constructed using the requirements of CBER's
Managed Review process, which defines a systematic approach to
submission review. The EDR provides an electronic receipt point
for volumes of electronic submission material, the capability
to securely view regulatory submissions, the ability to
communicate electronically with Industry, and the ability to
manage electronic records and archiving of regulatory
submissions.
To meet the electronic submission review timetables and
milestones, a network, software and computer infrastructure was
constructed. This infrastructure is standardized across the
Agency and has increased the data transfer speed from 1.45mbs
to 100mbs. In addition, redundancy has been added to the
network to ensure reliability.
CBER issued Biologics License Application (BLA) regulations
and guidance to industry through the Federal Register
(``Biological Products Regulated Under Section 351 of the
Public Health Service Act: Implementation of the Biologics
License; Elimination of the Establishment License and Product
License,'' 10/20/99) Existing Product License Applications
(PLA) and Establishment License Applications (ELA) or their
Supplements were merged into a single BLA as a consequence of
the final rule since it provided that applicants who already
had an approved ELA and PLA for a product would not be required
to make additional submissions to comply with the new
requirements.
A new Regulatory Management System to track and report on BLA
status was developed. This system was designed to satisfy new
business rules and approximately 900 requirements associated
with BLAs and to merge pre-licensing and licensing components
of an older legacy system. BLAs replace ELAs and PLAs that have
been submitted to CBER separately in the past.
Today, CBER's entire workflow process has changed with the
technological enhancements made possible by user fees. CBER now uses a
robust e-mail system as a part of its standard software suite and has
the computer and network infrastructure to support a host of new
systems developed specifically to manage submission material and help
CBER meet its goal of a paperless review environment in 2002. User fees
made it possible for FDA to develop guidance documents and databases to
track the status of submission reviews. As a result, the review process
is well defined, accountable, and scientifically sound. Since 1994, FDA
has submitted an annual Performance and Financial report to Congress on
progress in meeting performance goals and the use of fees. (See http://
www.fda.gov/oc/pdufa/reports.html.)
For FDA's Center for Food Safety and Applied Nutrition (CFSAN), the
only user fees authorized to be collected involve its Color
Certification Program. The fees are collected to certify color batches
and enable CFSAN to keep the IT systems for the Color Certification
Program current and state-of-the-art. The Color Certification Program
has developed a database system that allows Agency analysts to enter
analyses of color batches into the Color Certification Tracking System
(CCTS) as they are completed. FDA's CCTS provides industry with real-
time information about their color samples as they are being processed.
The CCTS also provides the industry with timely final certification
data that allows them to sell a color additive days before they receive
the hard-copy certificate. CFSAN is working to develop in 2002 an
automated system that will allow industry to submit electronically its
requests for certification of color batches.
The medical device program does not have user fees, however, the
Agency encourages device manufacturers to provide device submissions
electronically. The Center for Devices and Radiological Health (CDRH)
received 113 electronic submissions in FY 2000. Instructions for
submitting electronic submissions can be found on FDA's home page at
the address http://www.fda.gov/cdrh/elecsub.html.
The CDRH does, however, under its radiological health statutory
charge, collect user fees as part of the Mammography Quality Standards
Act (MQSA) of 1992. The collection of MQSA user fees has enabled the
program to develop and maintain specialized databases (Mammography
Program Reporting Information System [MPRIS]) that track inspections,
inspection results, and facility billing for the approximately 9,700
facilities that are inspected annually. Using the MPRIS database,
findings and trends can be analyzed and used for program management.
User fees allowed the division to procure the services of an IT
contractor to assist in the design, development, and support of the
system. Thus, FDA was able to meet very tight statutory deadlines,
without utilizing already overburdened CDRH resources. A laptop and
printer are used on site by each inspector to record inspection data,
upload to headquarters, and leave a post inspection report with the
facility.
Question 2. In January of this year, the FDA issued a glowing
report in favor of reauthorizing the pediatric exclusivity provision.
In the report, FDA claimed that ``the pediatric exclusivity provision
has done more to generate clinical studies and useful prescribing
information than any other regulatory or legislative process to date.''
Why has this provision proved so successful when others have failed?
Response. We believe this provision has done more to generate
clinical studies and useful prescribing information for the pediatric
population than any other regulatory or legislative process to date
because the legislation provides financial incentives to the sponsors.
Even though this provision has been successful, there are gaps in the
success story we would like to bring to your attention as follows:
Exclusivity is granted for submitting pediatric studies not
for label changes incorporating pediatric information. Thus,
there have been some delays in getting information in drug
labels, particularly adverse information.
There are drugs with no remaining patent or exclusivity that
are not eligible for the financial incentive that makes it more
difficult to obtain pediatric studies.
Studies in some of the youngest children, particularly
newborns and young infants, are often delayed due to scientific
and ethical reasons. Obtaining these studies is difficult, as
there is no sufficient, additional financial incentive.
Question 3. As of today, 28 drugs have received pediatric
exclusivity, and 18 of these have had pediatric label changes. Out of
the ten, which have not had label changes, is it expected that many if
not all of these will eventually have label changes?
Response. We believe that eventually most of the drugs that have
been granted exclusivity will have label changes. Since the grant of
pediatric exclusivity is not tied to a requirement that label changes
be made, there may be cases in which information will not make it into
the label. In FDA's experience, delays in obtaining label changes are
more likely when the study has produced negative information about the
drug's use in children. Delays in getting this kind of information into
the drug label may jeopardize children's health.'
Question 4. In its January 2001 Report the FDA claimed that the
pediatric exclusivity provision added one-half of one percent to the
national pharmaceutical bill. The FDA also found that the provision
could lead to substantial health care savings due to lower
hospitalization rates for children. Is it possible that the pediatric
exclusivity provision may in fact save health care dollars, like the
Tufts Center for the Study of Drug Development suggested?
Response. We believe that the benefits of the pediatric provision
include savings of health care dollars due to lower hospitalization
rates. The lower hospitalization rates can be predicted from the
significant dosing and safety information already obtained and
incorporated in the first 18 products labeled with pediatric use
information. For example, the information showing proper dosing for
gabapentin for children three years to 12 years old should result in
fewer seizures and the need for fewer additional medications. The
appropriate dosing of fluvoxamine will lead to fewer medication changes
and potentially the prevention of suicide attempts in adolescents
because of poorly controlled obsessive compulsive disorder. For
etodolac, patients with juvenile rheumatoid arthritis will experience
better relief of their pain and improved mobility now that we know
children need higher doses than adults do. While we do not have
sufficient information to quantify these benefits, it is theoretically
possible that the savings from these benefits are greater than the
costs to consumers, pharmacists, and generic drug companies.
Question 5. The 9th Circuit Court of Appeals recently held pharmacy
compounding provisions of FDAMA unconstitutional due to their
restrictions on commercial speech. Will the FDA challenge this decision
all the way to the Supreme Court? If not, will it enforce the FDAMA
provisions outside of the 9th Circuit?
Response. As you know, on February 6, 2001, the U.S. Court of
Appeals for the Ninth Circuit issued a ruling. They affirmed in part
and reversed in part a decision of the U.S. District Court for the
District of Nevada involving a challenge to the constitutionality of
two speech-related restrictions in section 503A of the Federal Food,
Drug and Cosmetic (FD&C) Act (pharmacy compounding).
Section 503A, which was enacted as part of FDAMA, exempts
compounded drugs from the FD&C Act's new drug approval, adequate
directions for use, and good manufacturing practice requirements if
specified conditions are met. The provisions at issue provide that in
order to qualify for the exemption, the compounded drug may not be
based on a solicited prescription, section 503A(a), and the pharmacy,
pharmacist, or physician may not advertise or promote the compounding
of a particular drug, class of drug, or drug type, section 503A(c).
The enforcement of these two conditions has been enjoined since
December 18, 1998, although the rest of section 503A remained in
effect. The appellate court agreed that section 503A's restrictions on
commercial speech violate the First Amendment. The appellate court,
however, concluded that the speech restrictions in section 503A(a) and
section 503A(c) may not be severed from the rest of the provisions in
section 503A, and held that section 503A is invalid in its entirety.
The court's mandate issued on May 7, 2001. As a result, section 503A is
invalid in the States and territories that comprise the Ninth Circuit
(California, Oregon, Washington, Arizona, Montana, Idaho, Nevada,
Alaska, Hawaii, Guam, and the Northern Mariana Islands).
The Solicitor General's Office in the Department of Justice is
responsible for determining whether petitions for certiorari should be
filed in cases involving constitutional challenges to Federal statutes.
The matter is under consideration, and the deadline for filing a
petition for certiorari in this case is July 26, 2001. Because the
question of Supreme Court review remains pending, FDA has not yet
determined how the Ninth Circuit's decision will affect FDA's
enforcement of section 503A in the States and territories outside the
Ninth Circuit.
Question 6. FDAMA allowed for data from one adequate and well-
controlled clinical investigation to serve as substantial evidence of a
drug's effectiveness. Are you aware of any instance in which only one
clinical trial was used to prove effectiveness?
Response. FDAMA allowed for data from one adequate and well-
controlled clinical investigation and confirmatory evidence to serve as
substantial evidence of a drug's effectiveness. CDER and CBER have
approved several products based on this provision.
For example, CDER has approved:
Lamictal (lamotrigine) was approved on August 24, 1998, for
the treatment of Lennox-Gastaut Syndrome based on a single
adequate and well-controlled trial and confirmatory evidence.
Femara (letrozole) was approved on January 10, 2001, as a
first line treatment of postmenopausal women with hormone
receptor positive or hormone receptor unknown locally advanced
or metastatic breast cancer on the basis of a single, adequate
and well-controlled trial and confirmatory evidence.
In order to meet the requirements of FDAMA, FDA issued a Guidance
for Industry entitled, ``Providing Clinical Evidence of Effectiveness
for Human Drug and Biological Products.'' This guidance demonstrates
FDA's willingness to work with sponsors to help them plan drug
development programs that are sufficient to establish effectiveness
without being excessive in scope.
CBER has approved:
TNKase (Tenecteplase, licensed June 2, 2000) for reduction of
mortality associated with acute myocardial infarction.
Synagis (Palivizumab, licensed June 19, 1998) a monoclonal
antibody indicated for preventing serious lower respiratory
tract infections caused by respiratory syncytial virus (RSV) in
premature infants and those with lung disease.
Question 7. It seems that the drug manufacturing changes provisions
of FDAMA have been used extensively by both drug and biologics
manufacturers. Is it your belief that this will reduce the cost of
producing drugs without compromising safety and effectiveness?
Response. Yes, we believe that the manufacturing changes provision
has allowed the industry to produce products more efficiently thereby
reducing costs, without compromising the safety of the products.
Question 8. Has there been much dissemination of off-label
information pertaining to drugs and devices, or has litigation
discouraged this?
Response. We do not have a systematic method to track the trends in
the dissemination of off-label information and, therefore, do not know
if dissemination of this information has been discouraged.
Question 9. Recently the FDA finally came out with its ``least
burdensome'' Draft Guidance which should lead to more predictability in
medical device reviews because FDA must demand no more than the ``least
burdensome'' scientific proof for effectiveness. Why did it take the
FDA three and one-half years to develop this Draft Guidance when it was
such an integral part of FDAMA?
Response. The recent draft guidance that FDA issued is the latest
of a number of documents the Agency has shared with the public to
describe its approach to implementing the principles and concepts of
the least burdensome provisions. Earlier documents were revised and
modified in response to industry concerns and this latest draft
guidance is partly the result of Agency participation in an industry-
working group. Although this draft guidance was issued recently, CDRH
has been working to put least burdensome processes and procedures into
place every since FDAMA was passed. See response to number 10 below.
Question 10. What steps will FDA take to ensure that device
reviewers are consistently implementing the least burdensome concept
when conducting device reviews?
Response. The Agency has worked diligently with industry and staff
toward the goal of obtaining the right information to support
submissions--no more, no less. Activities have included a CDRH-wide
working group on least burdensome issues, development of a web page
containing up-to-date information, http:\\www.fda.gov/cdrh/modact/
leastburdensome.html, a CDRH-wide (the first) web cast was held to
engage staff and training has been held for all device review staff and
advisory panel members.
Furthermore, CDRH internal tracking documents and correspondence
have been changed and continued to be updated to embrace this concept,
a working level appeals process has been established and a
questionnaire for customer feedback has been developed. Finally, as you
stated, the draft guidance entitled, ``The Least Burdensome Provisions
of FDA Modernization Act of 1997: Concept and Principles'' has been
posted on the web.
Question 11. Since passage of FDAMA, how many medical devices have
been assigned expedited review? What steps do you take internally to
ensure that these devices designated for priority review receive the
resources necessary for a timely review?
Response. The Agency continues to maintain a high level of
premarket performance with all of its application types. Of the
applications reviewed, many involved medical breakthrough devices that
will provide significant improvements in-patient care. Since passage of
FDAMA, CDRH has assigned 26 applications for expedited review. FDA
always places special emphasis on getting these novel products through
the process as soon as possible without compromising patient safety.
Question 12. Has the FDA taken advantage of its authority under
FDAMA to contract out to appropriate experts parts of submission for
review of devices? If the FDA has not contracted out part of device
reviews, why not?
Response. When funding levels and circumstances permit, FDA has
used its authority to contract with outside technical expertise when
such expertise was needed. For example, in FY 2000, FDA hired 70
Special Government Employees to participate on the medical devices
advisory committees. FDA has also contracted with the Oak Ridge
Institute for Science and Education fellowship program to recruit
experts to participate in reviews. The Agency will continue to contract
with other experts when the need arises.
Question 13. The FDA just recently expanded the third-party review
provisions of FDAMA to every class 11 device allowed under the law. Why
was this decision only recently made? Is it true that since FDA made
this change the number of companies seeking third-party review has
increased?
Response. FDA met all its statutory requirements in implementing
the third party provisions of FDAMA. This included publishing standards
for third party review, reviewing applications for third party review,
accrediting third party reviewers, and publishing guidance about
devices that were eligible. FDA determined that the initial list of
devices should be those that met the statutory criteria and had
guidance or consensus standards that could support review. This was to
develop experience with the program to ensure that there was
consistency among third party reviewers and timely review by FDA
following the third party recommendation. FDA has been working with
industry trade groups to encourage wider use of this provision. Since
implementation, devices eligible for third party review has grown to
674 eligible devices. Preliminary numbers for 2001 indicate that the
number of third party reviews will increase to about 90.
Question 14. Could you explain in greater detail how the Sentinel
System for medical device user facility reporting worked, and whether
this pilot pro gram proved effective?
Response. The pilot for the sentinel system was called DeviceNet.
After recruitment of a purposeful sample of user facilities in the
Washington D.C. metropolitan area, North Carolina and Boston, eighteen
hospitals and six nursing homes agreed to participate in the pilot.
Facilities were trained in the requirements of the Safe Medical Devices
Act (SMDA) and in participation in the project. Barriers to reporting
(identified in earlier focus groups) were eliminated or reduced as much
as possible. For example, all reports went to a third party
(contractor); the participants were given regular feedback in the form
of a newsletter, direct contact with FDA as desired, and other FDA
communications; participants were allowed to report via phone and given
assistance in completing the form and the coding. Participants were
asked to report as required under SMDA (mandatory reports) but also to
report incidents that had the potential for harm (near miss).
During the year long pilot, CDRE received approximately 300
reports, but only from the hospitals. This averaged about 16 reports
per hospital. (Currently, FDA receives, on average, less than one
report per hospital per year.) About half of the reports were
``voluntary''--not required under SMDA--and a third of those
``voluntary'' reports were considered ``urgent'' as rated by FDA nurse
analysts. This suggested that eliminating or reducing barriers to
reporting could increase reports and that voluntary reports are
important for FDA in carrying out our public health mission.
These results and additional detail and discussion can be found in
the Agency's report submitted to Congress in August of 1999,
``Designing a Medical Device Surveillance Network.'' (This report is on
FDA's website at http://www.fda.gov/cdrh/postsurn/medsun.html). CDRH
has also done some pilot work to further investigate how to overcome
the apparent resistance of nursing homes to reporting to FDA.
In addition, the Medical Device Surveillance Network (MeDSuN) is
being designed to benefit from what we learned in the DeviceNet. We
hope to begin data collection on this project in 2002.
Question 15. Is it FDA's opinion that greater collaboration between
FDA and industry has in any way compromised patient safety? Do you feel
that the collaboration embodied within FDAMA has led to better
decision-making within FDA?
Response. Greater collaboration between FDA and the industry has
been very helpful. It ensures that the industry research is
scientifically sound, relevant to the regulatory issues that must be
addressed, and is consistent with human subject projection
requirements. It provides FDA with a better understanding of the
scientific base used in regulatory decisions. Such collaboration has
enhanced consumer protection and safety; not compromised it.
Increased collaboration has resulted in clinical studies that are
more likely to yield readily interpretable data, thereby limiting the
number of individuals needed for study. Such collaboration helps assure
adequate attention to safety issues; for example, because the numbers
of meetings with manufacturers has increased, the quality of
submissions has improved.
Good decision making relies on the best available information and
on a clear understanding of the issues. To the extent that FDAMA has
improved communication between industry and the Agency, it has
facilitated Agency decisions.
Collaboration also has enhanced patient safety and led to better
management of risk while still providing benefits to consumers. The
Agency has collaborated with industry on a case-by-case basis to
develop systems to manage risk for drugs that have higher risk
potential but clearly offer benefits to patient groups that have no
alternative therapies available.
One example would be Propulsid (cisapride) that was approved in
1993 for the treatment of nocturnal heartburn due to gastroesophageal
reflux disease (GERD). The sponsor worked with the Agency to implement
labeling changes and develop educational programs to help assure the
safe and appropriate use of Propulsid after receiving reports of
serious adverse events associated with the use of the drug. After
seeing no decrease in adverse events after these changes had been
implemented, in April 2000 the sponsor announced that the product would
no longer be available through pharmacies after August 2000. This
provided physicians and patients time to explore other treatment
options to control the patient's disease. The sponsor and the Agency
collaborated on structuring a program whereby patients who failed other
treatment options and who met the criteria would be eligible to receive
the product through an investigational limited access program.
Question 16. Are you aware of any petitions for health claims filed
after passage of FDAMA which were published in the ``Federal Register''
but not finalized within 18 months of FDA's receiving the petition?
Response. To date, all health claim petitions filed after passage
of FDAMA for which a proposal was published in the Federal Register
have been finalized within 18 months of FDA's receipt of the petition.
Two such petitions are currently pending. Both were submitted to FDA in
February 2000. Because of their similarity of subject matter and
proximity of submission, they are being handled in a single rulemaking
action. FDA published an interim final rule for both of these
petitions, rather than a proposal. Hence, manufacturers are currently
able to use the claim even though rulemaking has not been completed.
Question 17. In early 1999 the FDA issued and advanced notice of
proposed rulemaking to revise regulations regarding the labeling of
foods treated with ionizing radiation. When will the FDA undertake and
complete the rulemaking on labeling of irradiated foods?
Response. FDA received over 5500 comments on the labeling Advance
Notice of Proposed Rulemaking (ANPR) and is currently in the process of
evaluating the comments. The Agency intends to conduct focus groups and
gather information from other contemporary surveys and studies. The
purpose is to help the Agency better understand how the current label
is perceived by consumers and what messages would be perceived as
properly informative but not as a ``warning,'' with the goal of
developing alternative labeling that can reasonably be proposed. If
these efforts are successful, FDA's goal is to develop a proposed rule
on food irradiation labeling.
Question 18. Do you believe the ``radura'' symbol which is used on
irradiated foods gives rise to consumer anxiety,
Response. Based on our preliminary review of comments received to
the ANPR, the ``radura'' symbol in the absence of accompanying
irradiation information had no specific meaning to commenters. The
Agency intends to further explore consumers understanding of the
``radura'' symbol in its focus group research (noted above).
Question 19. What action has the FDA taken to assess and evaluate
the impact on human health from dairy products produced by cattle
injected with recombinant bovine growth hormone? Please provide a
detailed explanation of your analyses and conclusions about the safety
to humans from such dairy products.
Response. In 1993, following an extensive review of the data to
support the safety and effectiveness, FDA approved the first animal
drug containing recombinant bovine growth hormone (rhGH)--Posilac. A
copy of a report FDA's Center for Veterinary Medicine (CVM) published
about that approval can be found on the FDA website at
http:\\www.fda.gov/cvm/index/bst/RBRPTFNL.htm.
Since that approval, the Agency has no new data to indicate any
negative impact on human health from using rhGH in dairy cattle. In
fact, last year, FDA responded to a citizen petition filed, requesting
that Posilac be removed from the market ``based on new evidence'' that
the produce poses ``serious health consequences for human consumers.''
In our denial of the petition, the Agency affirmed there was no
evidence that the use of Posilac posed human health concerns. A copy of
the Agency's response can be found on FDA's website at http:\\www.cvm/
gov/efoi/citpet.pdf.
In very brief summary, the petitioner charged that:
1) a published study demonstrated that IGF-1 (a normal component of
both human and bovine milk) was absorbed from milk and posed a
risk of cancer;
2) the sponsor of Posilac altered the manufacturing process for the
product after approval, thus invalidating the safety and
effectiveness data in the application; and,
3) FDA had failed to review a food safety study or a portion thereof,
which demonstrated that rbGH was unsafe.
In response, the Agency reviewed the study submitted by the
petitioner and concluded that his interpretation of the study was
inconsistent with other published and unpublished data, as well as the
findings of the Joint Expert Committee on Food Additives of the World
Health Organization which had found rbGH to be safe in two separate
reports in 1992 and 1998.
The Agency rereviewed portions of the manufacturing component of
the rbGH application and collected records from the sponsor related to
investigational batches of Posilac. The rereview confirmed that the
manufacturing change did not invalidate the safety and effectiveness
data because it resulted in inconsequential changes to the formulated
rbGH product. That is, the product that FDA approved was the same as
the product on which the safety and effectiveness studies were
conducted. The purportedly unreviewed portion of the food safety study
had, in fact, been previously reviewed by the Agency and had been
determined not to demonstrate any lack of safety of rbGH and the Agency
reaffirmed that finding in the response to the petition. In addition,
FDA responded to a second citizen's petition related to rbGH that can
be found at http:\\www.fda.gov/ohrms/dockets/dailys/00/jun00/062700/pnd
0001.pdf.
Question from Ms. Eshoo:
Question 20. Despite extensive scientific evidence demonstrating
serious risks associated with reprocessing of single-use medical
devices - including several studies conducted by the Agency itself -
FDA has failed to meaningfully enforce key patient safety provisions of
the FD&C Act. It took substantial congressional and public pressure to
force FDA to finally publish enforcement guidance on regulation of this
potentially dangerous practice. Yet, I remain concerned that this
guidance, while a step in the right direction, continues to permit the
use of many unsafe reprocessed devices on American patients. Now that
FDA has made its intention clear to conduct pre-market reviews of
reprocessed medical devices, has the Agency received any submissions
from reprocessors or hospitals?
Response. On February 15, 2001, CDRH received five premarket
approval applications (all from third party reprocessors) for cardiac
ablation catheters. CDRH is currently reviewing and intends to apply
the same standards to these submissions as it does to all others. To
date, we have not received submissions from any hospitals.
Question from Mr. Strickland:
Question 21. This question relates to the inability of clinicians
to gain FDA approval for the use of thrombolytic therapy for peripheral
vascular indications. These agents (Urokinase, rt-Pa and Reteplase)
were each indicated for coronary artery problems (although Urokinase
has been unavailable and will not be released until 2002). However,
clinicians have been forced to use thrombolytic agents ``off-label''
for peripheral artery problems. The clinical trials 'required by the
Center for Biologics have relied upon statistical assumptions that
obligate the study of thousands of patients. Although such trials are
possible for coronary artery problems, the smaller market and greater
complexity of the procedures in the peripheral vessels renders such
trials impossible to execute. Moreover, thrombolytic therapy is
considered to be a ``standard of care'' for many patients with
peripheral arterial occlusions. In this regard, it is difficult to
enter such patients into the randomized trials required by CBER.
FDA has allowed devices a PMA pathway for device trials that are
not randomized and based on comparisons to what constitutes little more
than ``historical controls.'' For example, the approval process for the
Ancure and AneuRx endovascular grafts. CBER has not been so
conciliatory for thrombolytic drugs.
Given that other decisions of the Agency have allowed approval
based on less rigorous statistics, is it possible to allow the trial
with relaxed criteria to serve as a foundation for approval of agents
already in use for other indications?
Response. While it is true that different trial designs, sample
sizes, and statistical analyses may be used to satisfy the legal
standard for approval of a drug, in all cases the data must meet the
standard of substantial evidence from adequate and well-controlled
trials that the drug is safe and effective. It undoubtedly is easier to
meet the legal standard for approval for some products and indications
than for others. Where meeting the approval standard is particularly
difficult, careful exploration of proposed approaches to meet the
standard is warranted, however, the standard remains and the approach
used must be scientifically valid.
Differences in approaches to studying different products frequently
arise due to differences in the indication or the products. Thus, a
design or analysis that is suitable for one product and indication may
not be suitable for another. For example, historical control designs
may be useful where the historical control patients are well
characterized and well matched to the study patients, concomitant
therapy has not changed over time, the historical outcomes are highly
consistent and predictable, and the drug effect is large. However,
historical control designs may not be useful when these criteria are
not met.
The experience with devices, cited in the question, involved very
different settings. One of two specifically mentioned devices is the
``Ancure'' device, marketed by Guidant. This Class II device is a
balloon catheter for use in illiac arteries. It is marketed under a
510(k)-notification mechanism, as being ``substantially equivalent'' to
a marketed predicate device, a standard very different from that for
new drug approval. The other specifically noted device is ``AneuRx,''
marketing by Medtronic is a Class III device. The medical indication,
infrarenal aortic aneurysms, is quite different from the indication
being sought by thrombolytics, peripheral arterial obstruction (PAO).
FDA is quite interested in having the use of thrombolytics for PAO
appropriately assessed and, if appropriate, labeled so that physicians
and patients can know they are using a safe and effective regimen. CBER
has worked actively for many years with several manufacturers of
thrombolytic agents developing clinical research programs for this
indication. CBER has been open to a variety of approaches to
demonstrate clinical efficacy in this setting. These approaches include
randomized, placebo-controlled studies, randomized dose-ranging
studies; studies which seek to demonstrate a clinical benefit of the
most major importance (death and/or amputation) and studies which seek
to demonstrate benefits of a somewhat less compelling nature. While
CBER has had discussions with manufacturers to consider the use of
historical controls in this setting, no manufacturer has come forth
with adequate evidence to date to establish that a trial with a
historical control comparison would provide valid evidence of efficacy
in this setting.
Clinical trials to date have largely had no concurrent controls and
drawing clear conclusions is difficult or impossible. While there is a
general impression in the medical community that thrombolytics are
likely to be useful in this setting, the data on any specific dose-
regimen with any specific agent are rather limited. The published
literature makes clear those elements of safety, and likely efficacy,
may be very dependent upon dose and regimen.
Questions from Mr. Waxman:
Question 22. During FDA rulemaking on pediatric studies and during
hearings and deliberations on this rulemaking, a number of drugs were
noted by witnesses, committee members, and the FDA as important drugs
needing pediatric study. How many of the on-patent drugs have received
a written request for pediatric studies? IF not all have received such
a request, please explain why not.
Response. Enclosed is a copy of the ``10 drugs most widely
prescribed in pediatric age groups in 1994 for which the label carried
no directions for use'' (Pediatric Exclusivity Report to Congress,
Appendix B, Table 7, page 37).
Table 7
10 Drugs most widely prescribed in pediatric age groups in 1994 for which the label carried no directions for
use
----------------------------------------------------------------------------------------------------------------
Study
proposal Exclusivity
Drug Treatment Use Number of uses submitted or patent
by life
sponsor
----------------------------------------------------------------------------------------------------------------
Albuterol Inhalation solution........ asthma.................. 1,626,000 times to No\1\ No
pediatric patients
under 12.
Phenergan............................ allergic reactions...... 663,000 times to No No
pediatric patients
under 2.
Ampicillin Injection................. infection............... 639,000 times to No No
pediatric patients
under 12.
Auralgan otic solution............... ear pain................ 600,000 times to No No
pediatric patients
under 16.
Lotrisone cream...................... topical infections...... 325,000 times to Yes Yes
pediatric patients
under 12.
Prozac............................... depression and obsessive 349,000 times to Yes Yes
compulsive disorder. pediatric patients
under 16.
Intal................................ asthma.................. solution prescribed Yes Yes
109,000 times to
pediatric patients
under 2; aerosol
prescribed 399,000
times to pediatric
patients under 5.
Zoloft............................... depression.............. 248,000 times to Yes Yes
pediatric patients
under 16.
Ritalin.............................. attention deficit 226,000 times to No No
disorder and narcolepsy. pediatric patients
under 6.
Alupent.............................. asthma.................. 84,000 times to No No
pediatric patients
under 6.
----------------------------------------------------------------------------------------------------------------
\1\ Currently labeled for patients >2.
Of the top ten drugs, six products had no existing exclusivity or
patent protection and four products (Prozac [fluoxetine], Intal
[cromolyn sodium], Lotrisone [betamethasone/clotrimazole] and Zoloft
[sertraline]), had existing exclusivity or patent protection. The
Agency has issued Written Requests (Aa) for these latter four products.
Question 23. Of the most complete list of ``approved drugs for
which additional pediatric information may produce health benefits in
the pediatric population'', how many of the on-patent drugs have
received a written request for pediatric studies? If not all have
received such a request, please explain why not.
Response. The most current list of ``approved drugs for which
additional pediatric information may produce health benefits in the
pediatric population'' updated in May 2001, identifies 426 drugs on the
priority section of the list. Of these, 103 have existing patent
protection or exclusivity and have received a written request. Of the
remaining products on the list, many have existing patent protection or
exclusivity. To use our resources in an effective manner, we generally
issue a written request after a sponsor submits a proposed pediatric
study request. In some cases, we have issued written requests to an
entire class of drugs after a template for a request was developed, for
example, anti-hypertension drugs, drugs for depression/OCD, HIV drugs.
Question 24. Please provide a list of all approved drugs to which
FDA has issued a written request for pediatric studies. Please note the
manufacturer of the product and the date on which the request was
issued. Please note whether the manufacturer has agreed or disagreed to
the written request and the date on which the manufacturer responded.
If the manufacturer has not responded please note that as well.
Response. As of May 2001, 157 approved active moieties have
received a written request. We are providing at Tab B a list that
identifies the active moieties, the manufacturers, and the dates on
which the written request was issued. Manufacturers are not required to
alert FDA as to whether or not they plan on pursuing the studies.
However, based on our informal discussions with the manufacturers, we
estimate that approximately 80 percent plan on conducting the studies.
This list contains confidential information not releasable to the
public, and we ask that the Committee not make public or publish as
part of this hearing record, the enclosed information.
Question 25. What is FDA's estimate of the mean, median, and mode
of the cost of the pediatric trials requested in a written request for
a company?
Response. As of May 2001, 191 WRs have been issued. In these WRs,
421 studies have been requested. The types of studies and number of
each requested are as follows: efficacy/safety--138; PK/safety--125;
PK/PD--36; safety--83; and other--39. While we are unable to provide
you with a mean, median, and mode for the cost of the studies, we can
estimate that the cost ranges from $500,000 to $4,000,000 per study.
Efficacy studies would be at the top of the range while the cost of a
PK study would be at the lower end of the range. In addition, some
sponsors have to create the necessary infrastructure to do these
studies, and this adds to the sponsor's costs.
Question 26. What is the FDA's estimate of the mean, median, and
mode of the number of trial participants requested in the studies
requested in a written request for a company?
Response. Again, while we are unable to provide you with a mean,
median, and mode of the number of trial participants, we can tell you
the following. As of May 2001, the Agency has requested 421 studies. Of
these 421 studies, 233 specified the number of patients to be studied.
The projected total number of patients for these 233 studies is >23,
536 patients. The remaining 188 studies requested a sufficient number
to meet the study's objective, e.g., sufficient number to characterize
the pharmacokinetics, powered to demonstrate a specified difference. We
have not projected the total number of patients for these other
studies.
Question 27. How much additional funding and how many additional
personnel would it require for FDA to process SNDA's for pediatric use
at the same pace as NDAs? How much additional funding and how many
additional personnel would it require for FDA to process all SNDA's at
the same pace as NDA's? How much additional funding and how many
additional personnel would it require for FDA to process all ANDA's at
the same pace as NDA's?
Response. All pediatric clinical supplements are currently reviewed
at the same pace as NDAs (12 months for a standard review or six months
for a priority review). Any additional resources would allow us to more
efficiently review the applications we currently receive, including
pediatric supplements, abbreviated NDAs, and all other supplemental
applications.
Question 28. Inasmuch as the approval of ANDA's can greatly reduce
the cost of prescription drugs to the Nation in general and to
government programs in particular, why has the Administration not
requested sufficient funding and personnel to process all ANDA's at the
pace of NDA's?
Response. The generic drug program was granted a $1.2 million
increase in FY 2001. In addition,we continue to refine the review
process to increase efficiency. The number of new staff hired in the
last fiscal year are now fully trained and are demonstrating high
levels of productivity. There are, however, certain factors outside of
our control that would prevent complete adherence to the 180-day time
frame. These factors include the need to adhere to the review queue
review structure, timeliness of inspections of the manufacturing
plants, and legal issues such as lawsuits and Citizen Petitions. All
chemistry reviewer vacancies are currently filled. We continue to
examine every aspect of the review process to try to identify problem
areas to be addressed. We also plan to revise the current system for
amendment designation (major versus minor) to improve total review
times. Other changes are also being explored. While we did not request
a specific increase for generics in FY 2002, this office will benefit
from the requested increase for pay raises of approximately $2,000,000.
Question from Mr. Whitfield:
Question 29. Would FDA be amenable to employing a mandatory
premarket GRAS notification procedure, modeled on the voluntary GRAS
notification procedure already being implemented, as a means of
expanding the permitted use of a food substance affirmed as GRAS with
specific limitations under 21 CFR sec. 184.1(b)(2)? What would be the
most expeditious way of effectively implementing such a new procedure?
Response. The rulemakings that established Sec. 184.1(b)(2) itself,
as well as the specific regulations promulgated in accord with
Sec. 184.1(b)(2), were put in place through notice-and-comment
rulemaking. FDA must follow its own regulations, and must evaluate the
safety of a new substance currently subject to Sec. 184.1(b)(2) using
notice-and-comment rulemaking.
Generally recognized as safe (GRAS) ingredients, unlike food
additives, are not subject to statutory premarket approval
requirements. When the Agency affirmed as GRAS the current uses of
ingredients under Sec. Sec. 184.1(b)(2), it determined that other uses
outside the scope of the approval would be food additive uses. Thus,
FDA would need to consider whether the new uses of substances currently
subject to Sec. 184.1(b)(2) are GRAS and, if so, consider whether it
would be appropriate to amend Sec. 184.1(b)(2) and/or the current
approvals under Sec. 184.1(b)(2). The Agency would be open to discuss
with any interested party the best way to approach a given review.
Thank you again for making this a part of the public record. If you
have further questions, please let us know.
Melinda K. Plaisier
Associate Commissioner for Legislation
Enclosures
cc: The Honorable Sherrod Brown
Ranking Minority Member
Subcommittee on Health
Committee on Energy and Commerce
______
National Organization for Rare Disorders, Inc.
June 11, 2001
The Honorable Michael Bilirakis, Chairman
House Energy and Commerce Subcommittee on Health
United States House of Representatives
2369 RHOB
Washington, D.C. 20515
Attn: Brent Del Monte
Dear Mr. Chairman: Thank you for the opportunity to respond to
questions arising from my testimony before the House Committee on
Energy and Commerce Health Subcommittee on May 3, 2001 regarding the
reauthorization of the Food and Drug Administration Modernization Act
(FDAMA), as well as the pediatric exclusivity provision, which in
January 2002.
Question 1: In your written testimony you lament the fact that more
new drugs are being introduced in the United States before they're
introduced in the rest of the world. Is it your belief that individuals
with rare disorders would benefit from having drugs to treat their
conditions introduced elsewhere before they're introduced in the United
States?
Response: In my May 3rd testimony to the Subcommittee, I pointed
out that in 1988 only four percent of new drugs were first approved in
the United States, but by 1998, that figure had risen to 66%. I did not
``lament'' that fact, but simply pointed out that there are fundamental
risks associated with being ``first out of the gate." In her defense of
the many drug withdrawals ordered by the FDA, Dr. Janet Woodcock, FDA's
Director of CDER, has blamed those withdrawals on the fact that we are
now the first country to market most new drugs and therefore adverse
events tend to appear here before in the rest of the world. Inherent in
this fact, however, is my argument that none of the withdrawn drugs
were life saving drugs, and they probably should not have been rushed
to the American without additional FDA review.
Regarding whether individuals with rare disorders would rather see
``orphan drugs'' marketed in other countries before the United States,
obviously the answer is no. However, it is important to note that most
orphan drugs are lifesaving medicines for largely untreatable diseases
that have been afforded priority review from the FDA, and they have
been approved first in the United States (since the Orphan Drug Act was
enacted in 1983).
NORD has always advocated for speedy review of lifesaving drugs,
both orphan and non-orphans. My testimony does, however, lament the
fact DUFA has expedited review of many nonessential drugs that are not
important medicines for serious and life threatening diseases. We feel
strongly that the FDA should take more time to review non-essential
drugs because they may represent risks to relatively healthy people, or
to those who have other satisfactory treatment alternatives.
Question 2: In your testimony, you criticize the fact that the FDA
negotiates drug labels with manufacturers, and you say the FDA should
be given authority to order immediate labeling changes. But isn't it
true that the FDA already has this authority? The FDA already has the
ability to keep off the market new drugs if the FDA doesn't approve the
label, and they have the ability to seize any drugs which are
misbranded, don't they?
Response: Before responding to this question, I would like to
reiterate NORD's strong support for the testing of drugs used in the
pediatric population. NORD will work with members of the Subcommittee
to ensure reauthorization of the pediatric exclusivity provision, but
we do have some concerns regarding specific problems that have arisen
since 1997.
In response to Question 2, of course the FDA has authority to keep
drugs off the market if they do not agree with the manufacturer's
labeling. The agency also has the authority to seize misbranded drugs
when warranted. But the fact remains that of all the pediatric studies
submitted, only about 14 actually have been relabeled.
To solve this problem we suggest that the FDA be given authority to
require manufacturers to relabel their drugs for pediatric use within a
very specific timeframe even if the company does not agree with the
language that the agency believes is scientifically justified.
Alternatively, the FDA could be given authority to withhold exclusivity
if a manufacturer refuses to add pediatric information to the drug's
label. We feel it is critically important for pediatricians to have
access to pediatric prescribing information, and exclusivity should be
directly tied to the labeling requirement.
Question 3. The Elizabeth Glaser Pediatric AIDS Foundation, in a
letter signed by Dr. David Kessler, says the pediatric exclusivity
provision should be reauthorized because a one-half of one percent
increase pharmaceutical costs ``is a legitimate price to pay to ensure
our children's well being.'' Do you disagree that a one-half of one
percent increase in pharmaceutical costs is a legitimate price to pay
for our children's well being?
Response. The legitimacy of a one-half of one percent price
increase depends on the person who is paying. To an insured person, the
price may not be significant, but to an uninsured person or an elderly
Medicare recipient who pays cash for prescriptions, any increase would
be catastrophic. If Medicare paid for prescription drugs, this probably
would not be an issue, except for insurance companies who blame their
annual price increases on the escalating costs of prescription drugs.
The real issue is that some drug companies receiving pediatric
exclusivity are reaping rewards far greater than their investment in
pediatric clinical trials. The financial rewards can sometimes be so
great that they focus on their research on only the most lucrative
drugs, rather than the drugs children need most. Nevertheless, my
testimony clearly supports reauthorization of the pediatric exclusivity
law with some modifications.
I hope these answers to your questions are satisfactory. I will be
pleased to answer any further questions you may have.
Sincerely,
Abbey S. Meyers
cc: Diane Dorman
Sherrod Brown, Ranking Member
John Ford, Minority Counsel