[House Hearing, 107 Congress]
[From the U.S. Government Publishing Office]
REAUTHORIZATION OF THE PRESCRIPTION DRUG USER FEE ACT
=======================================================================
HEARING
before the
SUBCOMMITTEE ON HEALTH
of the
COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED SEVENTH CONGRESS
SECOND SESSION
__________
MARCH 6, 2002
__________
Serial No. 107-93
__________
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
RICHARD BURR, North Carolina BART GORDON, Tennessee
ED WHITFIELD, Kentucky PETER DEUTSCH, Florida
GREG GANSKE, Iowa BOBBY L. RUSH, Illinois
CHARLIE NORWOOD, Georgia ANNA G. ESHOO, California
BARBARA CUBIN, Wyoming BART STUPAK, Michigan
JOHN SHIMKUS, Illinois ELIOT L. ENGEL, New York
HEATHER WILSON, New Mexico TOM SAWYER, Ohio
JOHN B. SHADEGG, Arizona ALBERT R. WYNN, Maryland
CHARLES ``CHIP'' PICKERING, GENE GREEN, Texas
Mississippi KAREN McCARTHY, Missouri
VITO FOSSELLA, New York TED STRICKLAND, Ohio
ROY BLUNT, Missouri DIANA DeGETTE, Colorado
TOM DAVIS, Virginia THOMAS M. BARRETT, Wisconsin
ED BRYANT, Tennessee BILL LUTHER, Minnesota
ROBERT L. EHRLICH, Jr., Maryland LOIS CAPPS, California
STEVE BUYER, Indiana MICHAEL F. DOYLE, Pennsylvania
GEORGE RADANOVICH, California CHRISTOPHER JOHN, Louisiana
CHARLES F. BASS, New Hampshire JANE HARMAN, California
JOSEPH R. PITTS, Pennsylvania
MARY BONO, California
GREG WALDEN, Oregon
LEE TERRY, Nebraska
-- -- (Vacancy)
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:
Crawford, Hon. Lester M., Deputy Commissioner, Food and Drug
Administration; accompanied by Janet Woodcock, Director,
Center for Drug Evaluation and Research; and Catherine
Zoon, Director, Biologics Evaluation and Research.......... 30
Franson, Timothy R., Vice President of Clinical Research and
Regulatory Affairs, U.S. Eli Lilly Research Laboratories... 52
Pendergast, Mary K., Executive Vice President, Elan
Corporation................................................ 60
Wood, Alastair J.J., Assistant Vice Chancellor for Research,
Vanderbilt University School of Medicine................... 57
Material submitted for the record by:
Food and Drug Administration, responses for the record....... 78
(iii)
REAUTHORIZATION OF THE PRESCRIPTION DRUG USER FEE ACT
----------
WEDNESDAY, MARCH 6, 2002
House of Representatives,
Committee on Energy and Commerce,
Subcommittee on Health,
Washington, DC.
The subcommittee met, pursuant to notice, at 10:09 a.m., in
room 2322, Rayburn House Office Building, Hon. Michael
Bilirakis (chairman) presiding.
Members present: Representatives Bilirakis, Deal, Burr,
Ganske, Norwood, Bryant, Buyer, Pitts, Tauzin (ex officio),
Brown, Waxman, Strickland, Barrett, Capps, Towns, Pallone,
Eshoo, Stupak, Wynn, Green, and Dingell (ex officio).
Staff present: Brent DelMonte, majority counsel; Steve
Tilton, health policy coordinator; Eugenia Edwards, legislative
clerk; John Ford, minority staff counsel; and David Nelson,
economist.
Mr. Bilirakis. I call this hearing to order. Good morning.
I would like to thank all of our witnesses for being here today
to discuss the reauthorization of the Prescription Drug User
Fee Act, which we fondly refer to as PDUFA, another one of
those beautiful acronyms that we come with up here.
I know that many of you have been working around the clock
to develop a set of recommendations for the Congress to
consider in our deliberations. I want you to know that we
appreciate the work you have put in so far, and would like to
thank you in advance for your cooperation with the committee
and Congress as we move forward quickly and cleanly to
reauthorize this important program.
PDUFA as we know was first enacted in 1992, and then
reauthorized in 1997 as part of the Food and Drug
Administration Modernization Act, FDAMA. It is completely fair
to say that this program has been a tremendous success.
In 1992, when the program was created, innovative
treatments were taking far too long to reach patients. Since
the creation of PDUFA, patients have been able to access
breakthrough therapies more quickly and to improve their lives
immeasurably.
In fact, many new drugs are available to American patients
first. PDUFA has been so successful because it is a partnership
between the agency, the industry, and patients.
The PDUFA statute allows the agency to collect fees that it
in-turn uses to ensure timely review of drug products.
I think it is important to state that this program was not
created to ensure approvals. I repeat, it was not created to
ensure approvals. The FDA and Congress strongly believed that
products should only be approved by the agency when they proved
to be safe and effective.
The payment of user fees in no way guarantees approval of a
product. The fees are merely used to help the agency facilitate
timely reviews. Today the FDA can use the fees to hire more
reviewers, build its information technology capacity, and for
other administrative issues that facilitate the drug and
biologic review process.
The fees are not intended to replace the FDA's
appropriations and therefore do not constitute a tax. Our
subcommittee would like to reauthorize PDUFA cleanly, and
quickly, and I might add clearly.
This hearing will help us gain more insight into an
important component of PDUFA, which is the performance goals
letter. The performance goals letter represents agreements
between the FDA, industry, and Congress, and the letter
outlines goals that the agency must meet, which help frame the
basis to judge the user fee program success.
Congressional review of the goals letter is critical
because we must be certain that these extra PDUFA funds are
used in the most appropriate fashion. Some have asked why is it
so important to reauthorize PDUFA.
One reason that we need to move quickly and cleanly is that
the agency by law cannot collect user fees unless Congress
reauthorizes PDUFA. In effect, this means that the FDA would be
forced to eliminate a large portion of its work force.
This would have devastating consequences for the prospects
of continuing to ensure timely access to life saving products
for patients. I know that none of us want to adversely effect
patients' ability to access new life saving products. I believe
that it would be more efficient for Congress to quickly enact
the PDUFA reauthorization, and if we do so in as clean a manner
as possible.
There are many issues that impact patient's access to new
drug products. There is no question about that. Last week, we
held a hearing on the uninsured, and we are continuing to work
on solutions for that problem. Obviously, another issue that is
at the top of my agenda, and this committee's agenda, and the
President's agenda, is prescription drug coverage for our
Nation's elderly.
I know that our committee will be working diligently to
address many of these issues. I assure you that we will. We
already are.
However, I would argue that PDUFA reauthorization is
separate and apart from these issues. I think it is incumbent
upon our committee to examine each of these issues thoroughly,
and I am committed to doing so as soon as possible, and I have
made a commitment to Mr. Brown in some of these areas.
I know that many members of other areas have concern with
the FDA, and again I believe that our committee will examine
these issues as needed. Reauthorizing PDUFA is vitally
important to patients.
We sometimes fail to reauthorize in a timely fashion up
here, but they are certain types of programs that are
appropriated money, and they continue. NIH is in that category,
and so many others.
PDUFA obviously as you know is in a different situation. We
have got to ensure quick, clean, reauthorization of it. Our
actions will guarantee patient's continued access to innovative
drugs, and meet our country's gold standards of safety and
efficacy.
Again, I thank our witnesses for being here today, and I
look forward to their testimony, and now I yield to Mr. Brown.
[The prepared statement of Hon. Michael Bilirakis follows:]
Prepared Statement of Hon. Michael Bilirakis, Chairman, Subcommittee on
Health
Good morning, I now call this hearing to order. I would like to
thank all of our witnesses for being here today to discuss
reauthorization of the Prescription Drug User Fee Act (PDUFA). I know
that many of you have been working around the clock to develop a set of
recommendations for the Congress to consider in our deliberations. I
appreciate the work you all have put in so far, and I would like to
thank you in advance for your cooperation with the Committee and
Congress as we move forward to quickly and cleanly reauthorize this
important program.
PDUFA was first enacted in 1992 and then reauthorized in 1997 as
part of the Food and Drug Administration Modernization Act (FDAMA). It
is completely fair to say that this program has been a tremendous
success. In 1992, when the program was created innovative treatments
were taking far too long to reach patients. Since the creation of
PDUFA, patients have been able to access breakthrough therapies more
quickly and improve their lives immeasurably. In fact, many new drugs
are available to American patients first.
PDUFA has been so successful because it is a partnership between
the agency, the industry and patients. The PDUFA statute allows the
agency to collect fees that it in turn uses to ensure timely review of
drug products. I think it is important to state that this program was
not created to ensure approvals. The FDA and Congress strongly believe
that products should only be approved by the agency when they prove to
be safe and effective. The payment of user fees in no way guarantees
approval of a product. The fees are merely used to help the agency
facilitate timely reviews. Today, FDA can use the fees to hire more
reviewers, build its information technology capacity, and for other
administrative issues that facilitate the drug and biologic review
process. The fees are not intended to replace the FDA's appropriations,
and therefore do not constitute a tax.
Our Subcommittee would like to reauthorize PDUFA cleanly and
quickly. This hearing will help us gain more insight into an important
component of PDUFA, the performance goals letter. The performance goals
letter represents agreements between the FDA, industry and Congress.
The letter outlines goals that the agency must meet, which help frame
the basis to judge the user fee programs success. Congressional review
of the goals letter is critical because we must be certain that these
extra PDUFA funds are used in the most appropriate fashion.
Some have asked why is it so important to reauthorize PDUFA? One
reason that we need to move quickly and cleanly is that the agency by
law cannot collect user fees unless Congress reauthorizes PDUFA. In
effect, this means that the FDA would be forced to eliminate a large
portion of its workforce. This would have devastating consequences for
the prospects of continuing to ensure timely access to life saving
products for patients. I know that none of us want to adversely affect
patients'' ability to access new life saving products. I believe that
it will be more efficient for Congress to quickly enact PDUFA
reauthorization if we do so in as clean a manner as possible.
There are many issues that impact patients' access to new drug
products. Last week, we held a hearing on the uninsured and we are
continuing to work on solutions to that problem. Obviously, another
issue that is at the top of my agenda, the Committee's and the
President's is prescription drug coverage for our Nation's elderly. I
know that our Committee will be working diligently to address many of
these issues. However, I would argue that PDUFA reauthorization is
separate and apart from these issues. I think that it is incumbent upon
our Committee to examine each of these issues thoroughly, and I am
committed to doing so as soon as possible. I know that many Members
have other areas of concern with the FDA. Again, I believe our
Committee will examine these issues as needed.
Reauthorizing PDUFA is vitally important to patients. It is
incumbent upon us in Congress to ensure a quick, clean reauthorization
of this legislation. Our actions will guarantee patients continued
access to innovative drugs that meet our country's gold standards of
safety and efficacy. Again, I thank our witnesses for being here today
and look forward to their testimony.
Mr. Brown. Thank you, Mr. Chairman. I want to raise two
sets of issues this morning, and I would be remiss if I did not
raise both sets of these issues. One set is specific to PDUFA.
We need to make sure that the legislation and related
agreements strike the proper balance between speedier drug
approvals and drug safety, the main charge of the Food and Drug
Administration safety.
We need to evaluate whether FDA is overreaching in its
performance goals, and ensure that the agency is devoting
sufficient resources to pre-and-post market safety activities.
We also need to make sure that this law strikes the proper
balance between speedier drug approvals and drug efficacy.
We need to be sure that the drug companies are completing
all the clinical studies they commit to. Absent complete data
and proper drug labeling, faster drug approvals could simply
hasten improper use, or inappropriate substitution of new drugs
for existing ones. No one here wants that.
We need to make sure that the trigger mechanism in the bill
isn't doing more harm than good. FDA's Center for Drug
Evaluation should not have to starve critical functions, like
the review of generic drug applications, and the review of
direct to consumer advertising, and ongoing drug surveillance
in order to meet the PDUFA spending trigger.
The fact that the President' budget happens to increase
funding for some of these functions is no guarantee that future
budgets will do the same. The other set of issues that I want
to raise this morning is right before our eyes, yet we look
past these issues when it is time to hold hearings, and time to
write legislation.
There are pressing concerns for consumers for businesses,
for other third-party payers in both the public and the private
sector. Yet, we never seem to get around to addressing them.
I am referring to prescription drug pricing and
prescription drug advertising, to prescription drug inflation.
The three are related with the peculiar synergism to them, and
they are a lethal combination for a U.S. health care system.
Mr. Chairman, I don't doubt the benefits of PDUFA. You and
I have always worked well together and I don't doubt your
interest in seeing patients continuing to have timely access to
new medications.
But what I can't overlook are the drug issues that this
Congress and this committee do not address, the ones we appear
to be afraid to take on. With all due respect to this committee
and this Congress, and especially its Republican leadership,
jump when the drug industry says jump, and whether it is
pediatric exclusivity, whether it is PDUFA, whether it is a
whole host of issues.
It rushes to past registration when the drug industry wants
us to pass legislation. We don't challenge drug industry
pricing prices, even though these companies charge Americans 2,
and 3, and 4, and in a few cases 10 times what they charge
people in other wealthy industrialized countries for the same
prescription drugs even though our taxes pay nearly half of the
drug industry's R&D costs.
And even though the industry itself gets more tax breaks
than any other major industry. Yet, we on this committee, and
we in this Congress, Republican leadership, refuses to address
the issue of pricing.
The drug industry knows that not only do U.S. consumers pay
more than consumers in other countries for the same medicines,
we are also the only industrialized country that doesn't
guarantee access to health care.
This industry knows that 70 million Americans, many of them
seniors, have no coverage for drugs. The uninsured have the
distinction of paying the highest prices in the world with no
insurance for their medicines.
We don't take the pricing issue seriously, even though I
bet that every member on this committee, Republican and
Democrat alike, has spoken to seniors living on a social
security check that increased 3.5 percent last year, but are
paying for drugs that jumped 10 percent during that period,
drugs that cost hundreds of dollars per prescription.
I sponsor regular bus trips to Canada, and the seniors on
those trips are literally--save literally thousands of dollars
in some cases on their prescription medicines, money that can
buy food, money that can pay for heat, and other necessities.
We don't talk about that in this institution. When the drug
industry wants us to move quickly to ensure that FDA doesn't
hold their products up from getting to the market, we move with
lighting speed to do their bidding.
Spiraling prescription drug costs are what is preventing
Congress from adding a drug benefit to Medicare. We had better
not talk about drug pricing or the impact of direct to consumer
advertising on the Health Care Utilization Bill. Those topics
seem to be taboo.
The European Union doesn't permit direct to consumer
advertising, and Japan, Canada, Israel, don't permit direct to
consumer advertising. Only one other country in the world, New
Zealand, besides us, does allow it.
That is because direct to consumer advertising skews health
care costs toward the newest, the most expensive drugs,
regardless of whether these drugs are actually the best
alternative for patients, regardless of the impact on
American's health care bill.
The drug industry claims that it is doing consumers a
favor. The DTC advertising is a breakthrough in consumer
education. In 2000, last year, or 2 years ago, the drug
industry advertised 1 percent of the newly 10,000 prescription
drugs available to consumers.
And 95 percent of all DTC advertising was spent on 50
drugs, .5 percent of the 10,000 drugs on the market. The drug
industry claims that its advertising is highly educational. DTC
advertising is more highly profitable than it is highly
educational. But we don't talk about that here.
Mr. Chairman, I will continue to work with you on a
bipartisan basis on the Prescription Drug User Fee Act. I will
work with you to ensure that we bring the best possible bill to
the floor.
But I hope that this committee and this Congress will not
continue to limit our focus to those issues that the drug
industry wants us to consider. Our complacency already is
taking far too great a toll on our constituents. Thank you.
Mr. Bilirakis. I thank the gentleman. With all due respect,
I would suggest that probably the patients out there also would
like to see us streamline this process, and the Chair now would
yield to the chairman of the full committee, Mr. Tauzin.
Chairman Tauzin. Thank you, Mr. Chairman. Let me commend
you for holding this hearing, and I look forward to working
with you and the rest of the subcommittee in ensuring that the
Prescription Drug User Fee Act or PDUFA is reauthorized cleanly
and quickly.
I would further like to congratulate the FDA and the
industry for completing their negotiations on the performance
side agreements which must accompany this legislation. As you
know that was a predicate to our moving and I want to thank all
of you for moving as quickly as you did.
I look forward now to learning more about the substance of
those agreements. I think it is import to start by noting
certain facts which will guide the committee's consideration of
PDUFA.
The first is that the Act has worked extraordinarily well.
Since the Act was first passed in 1992, drug review times have
decreased dramatically, and the rate of drug withdrawal has
remained constant.
Now, you can only conclude one thing from that. That means
that necessary drugs are reaching patients who need them much
more quickly without drugs being approved that have to be
withdrawn at any greater rate than before.
That is a great success story. Not for drug companies, but
for patients in America, who need these drugs to sustain their
lives, and prevent illness, or to protect against damaging
ravages of those illnesses.
Now, half of all new drugs are first made available in the
United States; and 80 percent of all of the new drugs are
available to American patients within a year of the first
approval.
In short, PDUFA is working, and it must be renewed, and if
we fail to renew it, we will have failed American patients
across this country.
Second, if the Act is not authorized by the end of this
fiscal year, there are no carryover balances which would allow
the FDA to continue to pay the reviewers that are funded by
PDUFA.
This means that these reviewers will have to be laid off if
we do not reauthorize this bill, and the layoffs could come in
the middle of this year. We know it. If we don't complete our
work on this bill prior to August the FDA will begin the
process of notifying employees that their positions may be
eliminated.
I think this should not be allowed to occur as it would be
harmful not only to the employees and their morale, and the
work that they do in reviewing drugs, but again to the patients
of America that would depend upon these reviews.
Last, the committee and Congress have a very aggressive
health agenda this year. We have promised the House leadership,
and the House, working together with Ways and Means, that we
are going to produce a Medicare Reform and Drug Benefit Act by
late April to early June.
If we are going to get that work done, we have to complete
this work on PDUFA very quickly. And because of these factors,
I believe it is essential that the committee produced a clean
reauthorization this year.
I do not deny that there are other FDA reforms that frankly
I would like to see enacted this year. For example, I am very
interested in the Greenwood-Eshoo Device Reform Bill, as well
as some of the other reforms.
Mr. Burr has one of them, in that I am very interested, and
some of which may not sit very well with my friends on the
Democratic side of our committee. And I know that there are FDA
reforms that some on the other side may wish to add to this
bill that may not sit well with members of this side.
But if we weigh this bill down with those kinds of debates,
if we continue to fight old battles over issues in which
everybody had a fair chance to debate them and offer amendments
on the floor, and if we continue to fight those old battles and
add new battles to this issue, we just won't get our job done,
and this committee will have failed America's patients.
My message is that this is not the vehicle for
consideration of all of these matters. We can't allow this
reauthorization to be turned into some kind of a Christmas
tree.
If we do this, we increase the likelihood that the
hardworking FDA employees, critical to American patients, will
be presented with RIF notices later this summer, and we can't
let that happen.
So let's deal with PDUFA now, and then turn our attention
to the other FDA reforms. It is my every intent to see the
committee consider these other FDA matters later in this
session, if the members will continue to cooperate as they have
done so willingly in a bipartisan fashion to keep on our
schedule.
And I intend to work with the chairman of this committee,
and you, Mr. Brown, to see to it that those issues are
addressed in good order, and I yield back the balance of my
time.
[The prepared statement of Hon. W.J. ``Billy'' Tauzin
follows:]
Prepared Statement of Hon. W.J. ``Billy'' Tauzin, Chairman, Committee
on Energy and Commerce
Mr. Chairman: I commend you for holding this hearing, and look
forward to working with you and the rest of the Subcommittee in
ensuring that the Prescription Drug User Fee Act, or PDUFA, is
reauthorized cleanly and quickly. Further, I'd like to congratulate
both the FDA and industry for completing their negotiations on the side
agreements which will accompany the legislation, and I look forward to
learning more about the substance of the agreement.
I think it's important to start by noting certain facts which will
guide the Committee's consideration of PDUFA. One, PDUFA has worked
very well. Since the Act was first passed in 1992, drug review times
have decreased markedly, and the rate of drug withdrawal has remained
constant. Roughly half of all new drugs are first made available in the
United States, and 80% of all new drugs are available to American
patients within a year of first approval. In short, PDUFA is working
and must be renewed.
Second, if the Act is not reauthorized by the end of this Fiscal
Year, there are no carry-over balances which will allow the FDA to
continue to pay the reviewers funded by PDUFA. This means that these
reviewers will have to be laid off if we do not reauthorize the bill
this year. Further, if we do not complete work on this bill prior to
August, the FDA will begin the process of notifying employees that
their positions may be eliminated. I think this should not be allowed
to occur as it would be so harmful to employee morale.
Last, the Committee and the Congress have a very aggressive health
care agenda this year. Because this Committee is going to dedicate so
much time to creating a Medicare prescription drug benefit and enacting
structural Medicare reforms, it is absolutely essential that the
Committee address PDUFA reauthorization now.
Because of these factors, I believe it is essential that the
Committee produce a clean reauthorization this year. I do not deny that
there are other FDA reforms I would like to see enacted this year. For
example, I am very interested in the Greenwood/Eshoo device reform
bill, as well some other reforms which may not sit well with those on
the Democrat side. And I know that there are FDA reforms that some on
the other side may have which would not sit well with me.
My message to all is that this is not the vehicle for consideration
of those matters. We cannot allow reauthorization of PDUFA to be turned
into a Christmas tree. If we do this, we increase the likelihood that
hard-working FDA employees will be presented with RIF notices later
this summer. We cannot allow this to happen. Let's deal with PDUFA now,
and then turn our attention to other FDA reforms. It is my every intent
to see the Committee consider other FDA matters later in this Session,
so let's produce a clean PDUFA reauthorization now.
Mr. Bilirakis. Thank you. The Chair yields to Mr. Dingell.
Mr. Dingell. Mr. Chairman, I thank you, and I commend you
for scheduling this hearing today. We will soon be considering
for the third time legislation to provide user fees for
prescription drug approvals.
I have supported these user fees from the beginning, and
will continue to do so. I would like to tell a little bit about
the history of this. The Subcommittee on Oversight and
Investigations of this committee conducted a series of
investigations on behavior at Food and Drug with regard to a
major part of the pharmaceutical industry, namely the generic
drug industry.
We found massive scandal there. We found serious
misbehavior in the Agency, picking and choosing, and making
judgments on who would be considered. Because the docket of the
Agency was clogged, and because there were not enough people,
and the people were not properly paid to do the kind of work
that was necessary to see to it that the business of the agency
was conducted speedily and that the concerns of persons and
corporations interested in new drug applications was handled
speedily, well efficiently, and honestly. The result of these
investigations were several things.
First, there were a lot of people who went to jail as they
very well should. Second of all, there were a number of changes
in the administrative procedures at the agency. Third of all,
the agency found as everybody knew that it needed to beef up
its business, because it was proceeding far too slowly in terms
of making the necessary clearance.
The industry was waiting 7 to 10 years and more for a new
application to be cleared. There is only one way that we can
address the root of these problems, and that was to see that a
sufficient number of properly paid and adequate in number
employees at Food and Drug would address these problems.
The industry understood it, and the committee understood
it, and the Congress understood it, and we passed PDUFA as a
result thereof.
The result of this was that we got good people to do the
work that needed to be done. The Food and Drug Administration
cleaned up its act, and as I said a number of deserving people
did go to jail.
The result was that industry, because of the user fees that
were imposed, and to which they agreed, and to which they
supported, made it possible for FDA to hire enough people from
essentially a dedicated fund to provide the services that the
industry needed.
The result was that the consumer benefited. The industry
has been happy, and the industry has honored its commitments,
and the Food and Drug has provided excellent service in these
matters. The review time has speeded up, and industry is able
to get its new drug applications more speedily processed.
The result has been everybody has profited. The result has
been that this committee has defended these user fees, and has
not allowed the budgeteers who in their enthusiasm of run
around and grab any loose nickel in the government till to
apply to some purpose that they happen to believe is in the
public interest, has not been able to prevail.
It is time for this legislation to be extended because to
go back to the situation that it was before would be
intolerable from the standpoint of everybody; the industry, the
committee, the Congress, FDA, the consuming public, which is
dependent upon getting these drugs speedily and thoroughly, and
carefully, and honestly processed.
And of course the business and the economic activity, and
not just of the pharmaceutical houses, but of the United
States. This is a good piece of legislation and it should move
rapidly, and I hope that my colleagues are keeping in mind the
history of this and will understand why it is necessary for us
to proceed speedily.
I ask therefore that the entirely of my statement be
inserted in the record, and I urge the speedy, favorable, and
friendly consideration to an important piece of legislation
upon which everyone has agreed, and I thank you for your
courtesy to me, Mr. Chairman.
[The prepared statement of Hon. John D. Dingell follows:]
Prepared Statement of Hon. John D. Dingell, a Representative in
Congress from the State of Michigan
Mr. Chairman, thank you for scheduling today's hearing. Soon we
will consider for the third time legislation to provide user fees for
prescription drug approvals. I have supported user fees from the
beginning, and continue to do so. I will repeat here what I said on the
floor of the House in November 1997 when we passed the current user
fee: ``These user fees, and FDA's own commitment to excellence, help
make this agency the finest of its kind in the world.''
But this program can be improved. I join my colleagues,
Representatives Stupak and Brown, in their desire to improve the
current program's post market safety features. More drugs than ever are
first launched in the United States. Modern marketing and advertising
practices result in more consumers using more drugs in a shorter period
of time after FDA approval than ever before. Our population is more
diverse than ever. Diseases and drug therapies to treat them present
new challenges. These factors argue in favor of an enhanced post market
surveillance system that tracks drugs after they have been approved so
that we know drugs are safe and effective in the real world and not
just at the moment they leave FDA's door after clinical trials. I know
that we will hear encouraging testimony about improvement in this area.
The legislative text, plus any related side agreements, will need to
implement safety improvements.
Also, concerns have been raised about PDUFA's role in the drug
review process, so I look forward to today's testimony on these as
well. Mr. Chairman, I ask unanimous consent to have included in the
record the Patient and Consumer Coalition's PDUFA paper, which outlines
many of these concerns. This coalition includes many consumer
advocates, patient groups, including the International Union, UAW. I
further request that Dr. Crawford review this paper and provide us with
a response or comment to the points and concerns raised in that
document.
Finally, I want to echo the request of our Ranking Member, Mr.
Brown, that this Subcommittee consider drug price and access issues
this year. While I support the effort to produce a bipartisan PDUFA
bill, we all know that there is a great deal of interest in these other
issues, and we must begin to address them.
Mr. Bilirakis. We are going to try to continue on here, and
I am not sure that we will be able to do it. Dr. Ganske, the
Chair exercises its preoperative under the rules to limit
additional opening statements to 3 minutes. Dr. Ganske.
Mr. Ganske. Thank you, Mr. Chairman, and I will be much
briefer than that. I share the concerns of you and Chairman
Tauzin. There come sometimes in Congress where you need to
agree on what you can agree on, and move on with contentious
issues in other forums.
This is a very important bill, and you can see from the
data that has been gathered that the approval times have been
reduced by more than half in many instances. I think that is a
testimony that, as Chairman Tauzin has pointed out, we have not
seen an increase in drug withdrawals we were dealing with when
PDUFA was first passed. There was a general consensus, a
bipartisan consensus, that it was just taking too long, and we
needed to streamline the process, and maintain safety
standards, but try to help to get this process moving because
lives were at stake.
Patients needed their drugs, and it has been making a
difference in their health and maybe even in staying alive. And
delays were causing people their health and their lives.
So let's move to a resolution on this in an expeditious
manner. I look forward to reviewing the testimony by the people
on the panels today, and thank you for coming.
Mr. Bilirakis. Thank you, Dr. Ganske.
Mr. Waxman.
Mr. Waxman. Thank you very much, Mr. Chairman. The
Prescription Drug User Fee Act has achieved its primary goal to
speed the review of new drugs in the U.S. New drugs are now
available in the U.S. faster than anywhere else in the world.
This is an important achievement, and we should make every
effort to ensure that people have access to safe and effective
new medicines as quickly as possible. This achievement,
however, has come at a cost. That cost is an under-funded drug
review staff working on too many drugs, and too little time.
Even the FDA has called the working environment there a
sweat shop; hours are long, and salaries and training
opportunities are poor, and turnover is high.
Speeding drug approvals has had another cost as well. It
has siphoned off essential funds for post-market safety
programs, for review of direct to consumer ads, and for generic
drug approvals.
All of these FDA programs are critical to ensuring that
drugs are safe, and affordable, and all are severely under-
funded. Most importantly, the cost of faster approvals has been
a loss of public confidence in the safety of new drugs.
And as this has been happening, we have witnessed a large
increase in direct to consumer advertising of prescription
drugs, ads that were not permitted at the time that PDUFA was
first enacted.
It has been demonstrated that these ads are extremely
successful at fueling both demand by consumers and prescribing
by physicians. What is so troubling is that many of these ads
are often misleading and unbalanced.
We should have a system that ensures that direct to
consumer drug ads are adequate and fair. The FDA has only 13
staff to review over 37,000 pieces of prescription drug
advertising each year.
Speeding the review of new drugs is important, but ensuring
the public that drugs are safe and effective demands more, and
we cannot sacrifice safety for speed. User fees paid by the
pharmaceutical companies have provided the means to turn a slow
approval process into one of the fastest in the world.
It could provide the means to build a program that provides
assurance to the public that new drugs are safe and effective,
and that the advertising is truthful. Until now the
pharmaceutical industry has resisted paying user fees for any
purpose other than speeding approvals.
I understand that this agreement that has been worked out
with the FDA would have some of the user fees go to a post-
market, as well as a premarket review of drugs. I applaud this
beginning, but much more is needed. In closing, let me note
that today's hearing covers only one of the prescription drug
issues confronting us.
The most critical of these is the high price of
prescription drugs causing hardship to the poor, and to our
seniors, and to driving up the cost of health care for all of
us. And adding to the crisis in affordability, we know that
there have been serious abuses of the Hatch-Waxman law by
brand-name manufacturers trying to keep generic drugs off the
market. We owe it to the public that this committee address
these issues as well, and I look forward to working with my
colleagues on the committee to solve thee pressing problems.
And I hope that we can do so in a fair and bipartisan
manner, and be sure that we consider all of these issues as
carefully as possible. Thank you.
[The prepared statement of Hon. Henry A. Waxman follows:]
Prepared Statement of Hon. Henry A. Waxman, a Representative in
Congress from the State of California
The Prescription Drug User Fee Act has achieved its primary goal--
to speed the review of new drugs in the US. New drugs are now available
in the US as fast or faster than anywhere else in the world. This is an
important achievement. We should make every effort to ensure that
people have access to safe and effective new medicines as quickly as
possible.
This achievement has come at a cost, however.
That cost is an underfunded drug review staff working on too many
drugs in too little time. Even FDA has called the working environment
there a ``sweatshop.'' Hours are long, salaries and training
opportunities are poor, and turn-over is high. Under those conditions,
it is difficult to have complete confidence in the approval decisions
they reach.
Speeding drug approvals has had another cost as well. It has
siphoned off essential funds for post-market safety programs, for
review of direct-to-consumer ads, and for generic drug approvals. All
of these FDA programs are critical to ensuring that drugs are safe and
affordable, and all are severely underfunded.
Most importantly, the cost of faster approvals has been a loss of
public confidence in the safety of new drugs.
As this has been happening, we have witnessed a large increase in
direct-to-consumer advertising of prescription drugs--ads that were not
permitted at the time PDUFA was first enacted. It has been demonstrated
that these ads are extremely successful at fueling both demand by
consumers and prescribing by physicians.
At the same time, many believe that these ads are often misleading
and unbalanced. Whatever your view of whether these ads should be
allowed (and frankly I don't believe they should), most of us would
agree that we should have a system that ensures that direct-to-consumer
drug ads are accurate and fair. We do not have such a system. Right
now, FDA has only 13 staff to review over 37,000 pieces of prescription
drug advertising each year.
Speeding the review of new drugs is important. But ensuring the
public that drugs are safe and effective demands more. We cannot
sacrifice safety for speed. And we must be vigilant in our oversight of
prescription drug ads to be sure that misleading ads do not prompt
unsafe or inappropriate use of drugs.
User fees paid by the pharmaceutical company have provided the
means to turn a slow approval process into one of the fastest in the
world. And they could provide the means to build a program that
provides assurance to the public that new drugs are safe and effective,
and that their advertising is truthful.
Until now, the pharmaceutical industry has resisted paying user
fees for any purpose other than speeding approvals.
They have fought proposals to use their fees to ensure that the
safety and effectiveness of their drugs is monitored and validated
after approval.
They have been unwilling to allow their fees to be used to ensure
that their advertising is fair and truthful.
I believe that the industry has been short-sighted. It is in the
interest of manufacturers to support programs that give Americans
confidence that prescription drugs can be safely used as advertised.
This week we learned that the industry has agreed to pay increased
fees to adequately fund the premarket review of drugs and a small
amount to support a post-market safety program. I applaud this
beginning. But much more is needed.
Right now, the pharmaceutical industry spends one tenth of one
percent of its revenues on user fees. Meanwhile, faster approvals have
saved the industry billions of dollars per year. I don't think it's too
much to ask that the industry pay what is necessary to ensure the
safety and effectiveness of their drugs before and after approval. I
don't think it's too much to ask that the industry help FDA ensure that
direct-to-consumer ads are accurate and balanced. Continued public
confidence in prescription drugs is in the balance.
While I have concerns about some of the details of this
reauthorization, I believe that good progress is being made and I look
forward to working with my colleagues on both sides of the aisle on
this important legislation.
In closing, let me note that today's hearing covers only one of the
prescription drug issues confronting us. The most critical of these is
the high price of prescription drugs--causing hardship to the poor and
to our seniors and driving up the cost of health care for all of us.
Adding to the crisis in affordability, we know that there have been
serious abuses of the Waxman-Hatch Amendments by brand-name
manufacturers trying to keep generic drugs off the market. We owe it to
the public that this Committee address these issues. I look forward to
working with my colleagues on the Committee to solve these pressing
problems.
Mr. Bilirakis. I thank the gentleman. Mr. Bryant.
Mr. Bryant. I thank the chairman, and I will be brief in
light of the pending vote, as well as the need to begin to hear
our outstanding panels of witnesses.
And I simply will echo and adopt those statements of my
colleagues on either side of the aisle that are in support of
moving this bill expeditiously, and in an unencumbered fashion,
and not getting into these contentious issues that seem to
always crop up that are legitimate in some ways, because they
are contentious.
But there are certainly different sides to the issue that
need to be fully aired at some point in the future. The issue
today is this bill, and we need to move it quickly. Second, and
I will close by recognizing my happiness in having a Tennessee
doctor here today testifying from Vanderbilt, Dr. Wood, who
will be on the second panel.
And I welcome him, especially as I do all the other
witnesses, and look forward to his testimony. Many of us are in
other committees, and I have another committee marking up a
bill which requires votes, and so I will be in and out of this
hearing.
But, Mr. Chairman, thank you for having it nonetheless, and
I yield back my time.
Mr. Bilirakis. I thank the gentleman, and I think it is
only fair that we give everyone who wants to make an opening
statement a fair opportunity to do so. I am afraid in wanting
to go and vote that you are liable to miss out.
Dr. Norwood is coming back to sort of take over, but I
would like to think that we would hold it open, the opening
statement period. Let's see. Mr. Pallone for an opening
statement.
Mr. Pallone. Thank you. Thank you, Mr. Chairman. I will try
to be brief. I just wanted to say that I think it is sort of a
no-brainer that we are going to reauthorize PDUFA before its
sun sets, and I obviously agree with that.
But I just wanted to reiterate what some of my Democratic
colleagues have said, is that we know that this is coming up,
and this is another bill that the brand name pharmaceutical
industry supports, but we don't get the attention focused on
some of the other issues that we consider important.
I have to say that I was at--you know, I went and bought a
prescription for my cat. I guess it was Monday night. Today is
Tuesday or Wednesday, as I forget, but when we were back in the
District and I was waiting in line as the pharmacy in my
hometown and everybody at the counter was considered about the
pricing issue.
You know, how much they were paying, and how the prices
were going up, and then I bought the prescription for the cat,
which was probably the lowest prescription that was being sold
at that counter that evening.
And it is so amazing to think--you know, because we talk
about this as sort of a joke, but the fact of the matter was
that I was paying less for the cat than most of the people at
the counter were paying for the prescription drugs that they
had to buy for themselves for human beings.
And when you talk about the pricing issue, it just seems
that our Republican colleagues are reluctant to bring it up.
Even the President, over the week, he rolled out this drug card
again, and he is talking about the drug card and how that is
going to do all these wonders.
And everybody in my district tells me that the drug card--
you know, they already have it, and maybe they will get a 10 or
15 percent reduction, but they already have it. And so why is
this Administration promoting that, rather than dealing with
the pricing issue.
But of more immediate concern when you talk about PDUFA is
my concern that PDUFA in fact underscores the need for generic
drugs to enter the market. As resources within the FDA are
allocated to approving drugs in accordance to user fees, it has
been reported that limited FDA resources are taken away from
other important areas within the agency, particularly an area
within the FDA that are responsible for evaluating and
approving generic drugs.
And I really think that generics in many ways are the keys
of trying to reduce prices. We need statutory and legislative
initiatives that allow timely access to availability of generic
drugs.
However, today we are preparing to reauthorize legislation
that guarantees timely approval of brand name drugs, while
leaving behind necessary generics from potentially entering the
market.
So once again it is not just a question of what we roll out
and what bills we deal with first, which clearly favors the
brand names and not these other issues. But it is also the fact
that even this legislation I think short changes generics,
which I think is a major issue that we want to deal with if we
are going to deal with the pricing issues.
So I am concerned, and I know that the time is short, but I
am not concerned that although this bill needs to be
reauthorized, and we are here to do it, let's get to some of
these other issues.
Let's not shortchange generics and let's deal with the
pricing issues, and at least have some hearings on it. Thank
you, Mr. Chairman.
Mr. Bilirakis. We have 5 minutes before the vote is up. All
right. When Dr. Norwood returns, he will just have to wait
until we return. We are in recess.
[Brief recess.]
Mr. Bilirakis. Shall we continue?
Dr. Norwood.
Mr. Norwood. Thank you, Mr. Chairman, and especially thank
you for holding this hearing. It is very timely and very
appropriate for us to consider PDUFA reauthorization.
And in the interest of getting to our witnesses, I will be
uncharacteristically brief. Mr. Chairman, PDUFA has worked.
It's just of that simple. It is a program that is getting new
drugs to Americans who need them, and it is getting those drugs
to Americans far faster than before we passed PDUFA in 1992,
and in a safe manner.
We are approving drugs much faster, but yet drug safety
doesn't seem to have been compromised. And I am very heartened
by the work that the FDA is doing to improve on the original
model, and I am looking forward to their comments on their
efforts to date.
However, Mr. Chairman, I have serious concerns about the
cost and pricing of drugs, and I have some strong opinions
about areas that I think we need to give oversight to FDA.
But I want to point out that I am not going to press any of
those things as part of a conversation with PDUFA because I
agree with you and Chairman Tauzin that we need to have a very
clean reauthorization bill, and do it sooner rather than later.
It doesn't need to have things tacked on it that are
controversial, and so I support you 100 percent. But I do hope
as the chairman said that we will return to the subject of drug
costs later this year, and give us all an opportunity to
discuss that and look at that very closely.
I would like to encourage frankly my colleagues on this
committee to do the same, and let's get this reauthorized
because it is the right thing to do for the American patient,
and then let's have our discussions that we need to have. Thank
you, Mr. Chairman.
Mr. Bilirakis. I thank the chairman. Mr. Stupak.
Mr. Stupak. Thank you, Mr. Chairman, and with 3 minutes,
let me get right to the gist of my opening statement. We have
heard a lot about how PDUFA works, but at what cost? What have
we sacrificed?
What we have sacrificed under PDUFA is honesty, accuracy,
and informative labels. These are the duties and
responsibilities that affect every American consumer.
Therefore, we must be very careful to make sure that we do not
compromise safety or effectiveness that the American public has
come to expect.
Now, I have heard a lot about this tentative agreement, and
we don't know what it is because it is not in writing. It is
verbal. Now we were briefed yesterday by FDA officials, and
here are some of my concerns from that briefing.
First of all, the FDA is financially dependent upon an
industry that it regulates, and because under the new agreement
user fees are dramatically increased, dependence will grow
dramatically.
Instead of using industry funds, Congress should
appropriate enough money to ensure FDA's regulatory authority
is completely independent, above approach, and free of undue
pressure from the drug industry.
Second, it is more than clear that the approval of the drug
or device based on a relatively short term information does not
always give us complete information about a drug.
The number of drugs pulled off the market in the last 4
years is 12.
Now, I agree that three were pre-PDUFA, but nine drugs that
raced through an accelerated PDUFA approval process with
incomplete information brings me to my third point, Phase IV
studies, also known as post-marking surveillance, are
nightmarishly inadequate, and neglected to a shameful extent by
both the FDA and drug manufacturers.
In 1997, we did PDUFA-2, and we ordered a study from the
FDA that would summarize how well the industry complied over
the past 5 years with mandates to do Phase IV studies.
This report, which was due to Congress by October 1, has
been sitting in the Office of the Secretary of Health and Human
Services, even though by law we are supposed to receive it 5
months ago so we can do PDUFA reauthorization. Why the hold-up?
I believe the results of this study will show the vast
majority of drug companies do not do their mandated post-
marketing surveillance studies. According to some estimates, 90
percent of them were never completed. Ninety percent. So how do
we enforce it?
I understand that PDUFA-3 as negotiated thus far comes a
long way to address the major concerns with post-marketing
surveillance, but without any enforcement, there will be no
post-marketing surveillance as we see in PDUFA-2.
So I suggest that we put civil monetary penalties pegged to
the sales of drugs as one option that we should consider.
Another area of concern is the ability of the drug
manufacturers to game the system.
While waiting for requested and required information from
the manufacturer, the FDA should be able to stop the clock on
the time constraints that PDUFA imposes. Due to extremely tight
deadlines in PDUFA, manufacturers know that they can delay
their response to FDA's request for information long enough so
that the FDA is forced to make a decision without being able to
do a thorough review, and double-check data.
We had one breast cancer drug, and the FDA got the
information 1\1/2\ weeks before the PDUFA deadline would run.
My final concern is subpoena power. The FDA is one of the
few health and safety regulatory agencies that does not have
subpoena power.
Subpoena power would give the FDA the authority it needs to
inspect manufacturers' documents in a timely fashion. This is
one issue that we need to explore in this context.
And last, but not least, safety, adequate labeling, and
compliance with Federal regulations always seem to fall by the
wayside when we rush through PDUFA or whatever it might be.
We did pediatric exclusivity here recently, and we are
still waiting for studies. While this committee may have
defeated pediatric exclusivity, it is going to come back under
PDUFA.
I recently wrote a letter to Bristol-Myers SQUIB last month
about a drug called Serzone. Sixteen other members joined me.
That was a drug that did a pediatric exclusivity in 1994. We
are still waiting for the results of that study.
We have young people who have suffered liver damage from
this drug, and we can't even get anyone to tell us what the
results of that study was for pediatric exclusivity 6 years
ago. That's ridiculous, and it has to stop.
We want to make sure that drugs are safe, and we want to
make sure that we have adequate labeling, and we want to make
sure that the FDA has adequate information. Therefore, Mr.
Chairman, from subpoena power to enforcement power, the
pediatric labeling under the pediatric exclusivity issue, these
are all issues that must come up.
I know that you and the chairman have said don't cloud up
this bill with other issues. Mr. Chairman, this is the only
vehicle we will probably see this year. On this side of the
aisle, some of us are going to work to make safety, accuracy,
honesty, and labeling, is put back in to the Food and Drug
Administration and the Cosmetic Act of this country.
Mr. Bilirakis. Mr. Pitts for an opening statement.
Mr. Pitts. Thank you, Mr. Chairman, for holding this
important hearing today on PDUFA reauthorization. I look
forward to hearing from our witnesses. Since I have got two
hearings going on at the same time, I may miss some
questioning.
I want to up-front mention my concern that the plasma
industry be represented as the dialog on performance standards
moves forward. As you may know the plasma industry provides
unique life saving therapies, and also pays substantial user
fees.
I learned just recently that the CBER director has agreed
to meet with the plasma industry to discuss performance
standards, and I am hopeful that these discussions are
productive. Mr. Chairman, the new medicines approved by the FDA
in recent years include innovative treatments for many life
threatening diseases, and patients and their families will
benefit from the industry's innovation and so will the health
care system.
As we all know, recent research shows new medicines can
help keep people out of the hospital and help them avoid costly
surgery and other treatments.
Mr. Chairman, while we may have many ineffective programs
in our Federal Government that some would like to see expire,
PDUFA is certainly not one of them. Our committee should act as
quickly as possible to reauthorize this act, and I yield back
the balance of my time. Thank you.
[The prepared statement of Hon. Joseph R. Pitts follows:
Prepared Statement of Joseph R. Pitts, a Representative in Congress
from the State of Pennsylvania
Thank you, Mr. Chairman for holding this important hearing today on
the Reauthorization of the Prescription Drug User Fee Act.
I look forward to hearing from our witnesses today about whether
the Act has met its purpose of speeding the review of drugs and
biologics without compromising patient safety.
From my preliminary reading, it is clear that PDUFA has decreased
the review time for drugs and biologics.
It is gratifying to see the positive results of PDUFA that occurred
almost immediately after passage. The fact that the review time for
standard drug applications has been reduced from 26.9 months in 1993 to
less than 12 months in 2001 is great progress.
Mr. Chairman, since we all share the goal of getting life-saving
drugs to patients as quickly as possible, I am hopeful that we can
reauthorize this important Act as soon as possible.
I hope that this committee can finish our business on this by
August, 2002, so that the FDA does not have to begin the process of
notifying PDUFA-funded employees that they may be laid off.
I am also interested hearing from our witnesses today about the
recent agreement between FDA and industry on the goals they have
developed that will pave the way for us to reauthorize PDUFA III.
Since I have another hearing right now in another committee, I may
miss my chance to ask questions. Therefore, I want to mention my
concern that the plasma industry be represented as the dialogue on
performance standards moves forward. As you may know, the plasma
industry provides unique life-saving therapies and also pays
substantial user fees.
I learned just recently that the CBER Director of FDA has agreed to
meet with the plasma industry to discuss this issue. I am pleased that
this has been arranged and hopeful these discussions are productive.
Mr. Chairman, the new medicines and biologics approved by the FDA
in recent years include innovative therapies for many life threatening
diseases. Patients and their families will benefit from the industries'
innovation, and so will the health care system. As you know, recent
research shows these new treatments can help keep people out of the
hospital and help them avoid costly surgery and extensive medical care.
Mr. Chairman, while we have many ineffective programs in our
federal government that some of us would like to see expire, PDUFA is
certainly not one of them. Our committee should act as quickly as
possible to reauthorize this Act.
Mr. Bilirakis. Ms. Capps for an opening statement. Ms.
Eshoo for an opening statement.
Ms. Eshoo. Thank you, Mr. Chairman, along with all of my
colleagues from the committee for having this important
hearing. I am very proud of the PDUFA program and how it has
revolutionized the prescription drug approval process.
So reauthorizing this legislation is one of the most
important things that I think our committee can do this year,
and we must do it this year.
Prescription drugs and biologics are changing health care
on a daily basis. I am constantly amazed by the science and
what products have done to make our lives better. Twenty years
ago, a patient with chronic diabetes could expect extended
hospital stays, shorter life span, and higher health care
costs.
Today, prescription drugs allow diabetics to manage their
illness from the comfort of their own home, and they have
expectations of a much fuller and better life. PDUFA has gone a
long way toward ensuring the drugs to treat diabetes, and other
illnesses, reach the patients that so desperately need them in
a timely and responsive manner.
Prior to the initial passage of PDUFA, it often took years
for drugs and biologics to be reviewed by the FDA. The agency
was strapped for both financial and human resources, and was
unable to devote enough time and energy to the review process.
And that's really where the rubber meets the road. It is
the review process. In the 10 years since it was passed, PDUFA
funding has revamped and revitalized the review process, and
allowed the FDA to increase its staff and its expertise, and
upgrade its IT systems, and better structure the management of
the review process.
So clearly this is an example of legislation that has
worked, and is working very well. So we have to seize this
opportunity, and we need to reauthorize, and we need to do it
in an expeditious manner.
The FDA and the drug biotech industries have been working
closely to draft what is known as a side agreement that always
accompanies PDUFA. I am glad that they have come to an initial
consensus, and I look forward to reviewing the agreement soon.
I do want to take this opportunity to stress to the
chairman and my colleagues the importance of reviewing this
agreement before, and not after, but before we mark up the
legislation.
Given that this agreement is not bound by statute, it is
important that members be given ample time to review and have
any concerns addressed by the stakeholders. We shouldn't let a
desire for expeditious action overtake good, sound
policymaking.
So, in closing, I would like to once again reiterate my
support for PDUFA, the user fee program, and in hearing
Chairman Tauzin make his opening statement, I, too, am proud of
the work that we did in reauthorizing in 1997.
But we also have part of PDUFA, and I understand the
complications of not joining them this time, because that is
the chairman's view and wish, and I think that he obviously has
very good reasons for it.
We are not going to issue with notices, but the
reauthorization of FDAMA is a very, very important step for
this committee and the Congress to take this year as well. As
we talked about he reliance of patients across the country on
prescription drugs, they are also increasingly reliant on the
medical devices that not only give them hope, but bring them
good and improved health day in and day out.
So I think that it is very important for the committee, and
Mr. Chairman, for you, to start thinking about that, and that
we have a hearing on the bill, and you know that I will work
closely with you in order to accomplish that.
So thanks again for having this, and I look forward to the
review of the side agreement and legislation moving so that we
can get this done. It is good legislation, and it has worked
well, and it has served the American people well. That's the
reason that we are all here. Thank you, Mr. Chairman.
Mr. Bilirakis. Thank you. Mr. Deal for an opening
statement.
Mr. Deal. Thank you, Mr. Chairman.
Just a couple of thoughts. I would like to thank Dr.
Woodcock for your willingness to meet with me in the past on
the issues that are related to your agency's functions.
And to Ms. Pendergast, to say that Elan Pharmaceutical,
which is headquartered in my district, we are always pleased to
have representation here. Certainly the issue is an important
one, and one that many of us have looked forward to this
hearing, and I thank the chairman for holding it.
Certainly the issues that will make the availability of
drugs in a more responsive and quicker fashion is certainly
something that I think all of our constituents want.
But at the same time the concerns voiced by many of my
colleagues about safety are concerns that I think this hearing
hopefully, and others, will reinforce to assure us that we have
the best and safest products on the market. And with that, I
yield back my time, Mr. Chairman.
Mr. Bilirakis. I thank the gentleman.
Ms. Capps for an opening statement.
Ms. Capps. Mr. Chairman, I appreciate the opportunity that
you are giving the subcommittee to review the Prescription Drug
User Fee Act. Prescription medications have radically changed
health care, and improved the lives of millions of Americans.
They have become an essential component of what is now
standard medical care, at least for those that can afford it.
This committee has often struggled with issues relating to
prescription drugs.
And whether we are talking about seniors on Medicare or
pharmaceuticals for children, there are basically three
questions that we asked when we address prescription drugs. How
fast can a patient get them, and how safe and effective are
they, and how much do they cost.
We want them to be quick to market, save to use, and
affordable to patients. PDUFA has addressed the first matter by
significantly improving FDA's ability to review and approve new
medications.
These medications that are quicker to market seem to have
helped many Americans enjoy a higher quality of life. That
being said, PDUFA raises some questions about the issue of
safety, and may contribute to some of our problems addressing
cost.
In theory, while PDUFA accelerates the approval process for
new drugs, these drugs still must be safe before they are
approved, and there is some concern that the performance goals
of PDUFA may end up putting drugs on the market before they are
sufficiently tested and reviewed.
That is what we must examine.
Post-market surveillance is supposed to catch anything like
this, but with the resources for these surveys, and FDA's
authority to insist on them, are limited. This is certainly
something that we need to correct as we move toward
reauthorization of PDUFA.
I am also worried that PDUFA may help keep the cost of
prescription drugs inflated. The fees themselves, of course,
add the cost to medications, but more importantly PDUFA also
forces the FDA resources toward the approval of brand name
drugs, denying those resources for the review of generic drugs.
Generics access to the market is given to lower the cost of
prescription drugs dramatically, but the effect is limited
because the FDA is so slow to approve them. In 2001, the
average time it took to review and approve a new brand name
drug was 12 months.
The FDA took nearly twice that long, 22 months on average,
to approve generic drugs. I think this is appalling. And even
when these generics are approved, it does not necessarily mean
that they are going to get to the market right away.
Brand name pharmaceutical companies find various legal ways
to extend their patent or market exclusivity to block generic
competition. So as we review PDUFA, it would be beneficial to
consider these related issues and look for ways in which we
might adjust PDUFA to address them.
I understand that we expect two studies from the
Administration on safety and effectiveness of PDUFA to be
released later this year, and I think it would be a disservice
to act on PDUFA for reauthorization without the benefit of
those studies.
So I hope, Mr. Chairman, that you will not schedule a mark
up until we have them in-hand, and to this end, I look forward
to hearing our witnesses' testimony on this subject, and I look
forward to working on this with you, Mr. Chairman, and I yield
back my time.
[The prepared statement of Hon. Lois Capps follows:]
Prepared Statement of Hon. Lois Capps, a Representative in Congress
from the State of California
Mr. Chairman I appreciate the opportunity you are giving the
subcommittee to review the Prescription Drug User Fee Act.
Prescription drugs have radically changed health care and improved
the lives of millions of Americans. They have become an essential
component of what is now standard medical care, at least for those who
can afford it.
This committee has often struggled with issues relating to
prescription drugs.
But whether we are talking about seniors on Medicare or
pharmaceuticals for children there are basically three questions we ask
as we discuss prescription drugs: How fast can a patient get them, how
safe and effective are they, and how much do they cost.
We want them to be quick to market, safe to use, and affordable to
patients.
PDUFA has addressed the first matter by significantly improving the
FDA's ability to review and approve new medications.
These medications' quicker access to market seems to have helped
many Americans enjoy a higher quality of life.
That being said PDUFA raises some questions about the issue of
safety, and may contribute to some of our problems addressing cost.
In theory, while PDUFA accelerates the approval process for new
drugs, these drugs still must be safe before they are approved.
But there is some concern that the performance goals of PDUFA end
up putting drugs on the market before they are sufficiently tested and
reviewed.
Post market surveillance is supposed to catch anything like this,
but the resources for these surveys and FDA's authority to insist on
them are limited.
This is certainly something we need to correct as we move towards
reauthorization of PDUFA.
I am also worried that PDUFA may help keep the costs of
prescription drugs inflated.
The fees themselves of course add cost to medications, but more
importantly PDUFA also forces FDA resources towards the approval of
brand name drugs, denying those resources for the review of generic
drugs.
Generics access to the market is proven to lower the cost of
prescription drugs dramatically, but the effect is limited because FDA
is so slow to approve them.
In 2001, the average time it took to review and approve a new brand
name drug was 12 months. FDA took nearly twice that long, 22 months on
average, to approve generic drugs. This is appalling.
And even when these generics are approved, it does not necessarily
mean that they get to market right away.
Brand name pharmaceutical companies find various legal ways to
extend their patent or market exclusivity to block generic competition.
As we review PDUFA, it would be beneficial to consider these
related issues and look for ways we might adjust PDUFA to address them.
I understand that we expect two studies from the administration on
the safety and effectiveness of PDUFA to be released later this year.
I think it would be a disservice for this subcommittee to act on
PDUFA reauthorization without the benefit of those studies, and I hope,
Mr. Chairman, that you will not schedule a markup until we have them in
hand.
To this end I look forward to hearing our witnesses' testimony on
this subject and I look forward to working on this with you Mr.
Chairman.
Mr. Bilirakis. Mr. Buyer for an opening statement.
Mr. Buyer. I have just a couple of thoughts, Mr. Chairman.
I think it is very valuable to America's society that our drug
companies lead the world in the cutting edge in science and
biologics.
I don't think we want to do anything that would dull that
innovation and creativity of the greatest minds of the world.
And there are so many countries out there that their
governments have imposed systems that have had a detrimental
impact upon those industries.
And they look to the United States and the great minds of
the world come here. And we have to be very careful in what we
do. So, sure, there are the pressures that different members
receive from their constituencies to gain access to these great
drugs because of what it can do for the quality of life or
their loved one who is sick or ailing.
But Congress, and the industry, and the agency, did
something right. You know, someone who is critical toward
government, you also have to compliment when something was done
right.
In 1992, something was done right. I think it is thoughtful
for us to sort of look back now over the last 10 years and say,
okay, what are some of the lessons learned. I believe that our
process here in reauthorization should be the maintenance of
something that works.
And not trying to change something, and not bring political
agendas in an election year into something that is very
critical and is something that we have to do, and that is
reauthorize a successful program.
I will accept recommendations from the agency, and the
industry will have some, and I think that is part of the
oversight function of Congress to do. But we have to be very
careful here not to miss something that is so successful. With
that, I yield back.
Mr. Bilirakis. I thank the gentleman.
Mr. Strickland for an opening statement.
Mr. Strickland. I want to thank you, Mr. Chairman, and
Ranking member Brown, for this hearing today. I was pleased to
read in the submitted testimony of the success since 1992 in
speeding FDA's review times for drug applications.
The numbers are impressive. Median review times for
priority drugs have decreased from a median of 20.5 months to 6
months, and the median review time for standard new drug
applications fell from 26.9 months to about 12 months. PDUFA
has meant that more Americans have access to new remedies
faster, and I am glad that we will reauthorize the program to
continue these successes. However, I hope that we use the
opportunity this reauthorization gives us to strengthen PDUFA
and ensure that the program has not sacrificed safety for
speed.
Since drugs are getting to the market and American
consumers more quickly, we should consider the effects of this
faster time line on drug safety and dedicate a portion of
PDUFA's resources for FDA to track post-market outcomes of
drugs.
Similarly, I believe we should take this opportunity to
consider the effect of direct to consumer advertising on
prescription drug use and cost. If PDUFA's triggers cause the
FDA to devote less resources to functions like post-market
tracking, and the review of direct to consumer ads, we should
we think the way these triggers operate for the limits on the
use of PDUFA funds.
This debate would not be complete without a consideration
of the effects of faster review times on the cost of
prescription drugs. I hear every day from Medicare
beneficiaries, in particular, who are struggling to afford the
cost of their prescription drugs.
Put in this context, even the shortest possible FDA review
will not help those Americans who lack drug coverage to access
the drugs. They need to live healthy and productive lives.
And that is an issue that this Congress must address and
should address this year. I want to thank you, Mr. Chairman,
and I yield back the remainder of my time.
Mr. Bilirakis. I thank the gentleman. I ask for unanimous
consent, first of all, that the opening statements of all
members of the subcommittee be made a part of the record, and
without objection, that will be the case.
[Additional statements submitted for the record follow:]
Prepared Statement of Hon. Fred Upton, a Representative in Congress
from the State of Michigan
Mr. Chairman, thank you for holding today's hearing on the
reauthorization of the Prescription Drug User Fee Act. I am sure that
we will hear a lot of statistics this morning about the impact that
this important law has had on improving both the quality and the
timeliness of the review and approval of new drugs and biologics. But I
want to focus on the difference that this law has made in the lives of
individuals--of friends and family members who have greatly benefited
by the FDA's ability to give timely review and approval to potentially
life-saving drugs and biologics.
Just about a year ago, a call came into my district office from a
constituent asking if we could do anything to speed the FDA's review of
a very promising new drug--Gleevec--for the treatment of the rare form
of leukemia with which her husband was suffering. Like very many in the
Kalamazoo community, my staff and I have known and valued the
friendship of this couple for many years. As was typical, her husband
``didn't want to bother us'' with their problems, our constituent
reported, but she was very worried. We knew he had been suffering from
leukemia, but until that call, we didn't know that the medication he
was taking was no longer effective in controlling it and that his
condition was deteriorating. This drug may well have been his last
hope.
We checked with the manufacturer and learned that the FDA appeared
to be very close to approving the drug. That proved to be the case.
Within a week or so of the call, the FDA approved Gleevec, and we
worked with Novartis to get the drug to our constituent's hospital
pharmacy. It has proved to be the miracle we were all praying for. He
is back on his feet enjoying life, and my life and the lives of so many
in our community who know them and treasure their kindness and
friendship are the richer for his recovery, too.
In all likelihood, this would not have happened before we enacted
user fees and the FDA Modernization Act, which together give the FDA
the flexibility and resources it needs to review and approve Gleevec
and similar, breakthrough drugs. Recognizing the promise of this drug,
the FDA reviewed the marketing application in less than three months
under its accelerated approval regulations. That is a record--the
fastest ever approval for an oncology drug.
I know we will hear today from those who are concerned that perhaps
the agency is moving too fast on new drug approvals. But had the agency
not acted with the speed and expertise it did on Gleevec, my friend and
constituent would probably not be with us today. There is a human
cost--a great cost--in delaying this reauthorization.
______
Prepared Statement of Hon. Barbara Cubin, a Representative in Congress
from the State of Wyoming
The Prescription Drug User Fee Act (PDUFA) is, in large part, what
separates the United States from the rest of the world when it comes to
consumer access to innovator drugs.
No one rivals this country in the manufacturing, approval, and
distribution of innovator pharmaceutical products and devices--thanks
to PDUFA. I would like to see that continue.
The issue we face at this point is how do we do it even better?,
especially since funds needed for the drug approval process at FDA
outweigh the revenue coming in through drug application fees.
The last thing any of us wants is to see drug safety and approval
time slip because FDA does not have what it needs to get the job done.
PDUFA must be reauthorized this year, not only for the sake of
patients everywhere but for the continued high standard of innovation
set by this country.
My interest today is to better understand the recent agreement
reached between the FDA and industry on application fees and
performance standards.
Since this agreement is paramount in any PDUFA reauthorization we
attempt, it is important we give our full attention to our witnesses
today.
With that, Mr. Chairman, I yield back my time.
______
Prepared Statement of Hon. Robert L. Ehrlich, Jr., a Representative in
Congress from the State of Maryland
Mr. Chairman, thank you for holding this important hearing to
discuss the reauthorization of the Prescription Drug User Fee Act
(PDUFA).
PDUFA, which was first enacted in 1992, authorizes FDA to charge
pharmaceutical companies user fees to expedite the review process for
human drug and biologic applications. There are three types of fees: 1)
application fees are paid when human drug applications or supplements
are submitted; 2) product fees are due annually for each marketed
prescription drug product; and 3) establishment fees are also due
annually for each establishment manufacturing prescription drugs.
Mr. Chairman, reauthorization of this legislation is critical. The
federal government must have in place at the FDA an effective procedure
with sufficient resources, personnel, and expertise to review new drugs
to ensure that the American population receives speedy access to the
cutting-edge drugs available to treat so many health conditions today.
PDUFA has worked to significantly reduce approval times.
For their part, the biotechnology and pharmaceutical companies
should have the guarantee of an expedited, streamlined administrative
review process to ensure that their innovations are reviewed thoroughly
and sent to market as soon as possible for safe consumption. To ensure
speedy review, companies must pay the costs of the application,
product, and manufacturing fees so FDA has the resources to do its job
right.
Mr. Chairman, as Co-Chair of the Congressional Biotechnology
Caucus, and recognizing the over 270 biotechnology companies in
Maryland, I know that it is critical that new drug treatments receive
expeditious, thorough scrutiny of their latest products.
Ultimately, this legislation is about patients, and as we work with
all groups to ensure an effective review process, we must keep patient
safety and speedy access to medical innovations in mind.
I look forward to the testimony today as we consider reauthorizing
this important legislation.
Thank you, Mr. Chairman.
______
Prepared Statement of Hon. Ed Towns, a Representative in Congress from
the State of New York
Today's hearing gives us another opportunity to promote a unique
relationship between government and industry: the reauthorization of
the Prescription Drug User Fee Act (PDUFA). PDUFA is a successful
partnership that allow the F.D.A. to collect user fees from the
pharmaceutical industry in order to hire additional drug reviewers and
accelerate the drug review process.
By all accounts, the program has been extremely successful in
bringing new drugs to market in a more reasonable timeframe. For
example, before this legislation was enacted by this committee in 1992,
review times for new drug entities averaged about 2.5 years. By 1999,
the average review time had been reduced to 12.6 months. I am aware
that some have criticized this legislation as compromising F.D.A.'s
independent review authority. It is important to ensure that the
enhanced efficiency of the drug review process has not compromised drug
safety. Therefore, I am anxious and eager to learn whether drug
withdrawals can, in fact, be traced to faster approval times.
Finally, Mr. Chairman, we should remember that the reauthorization
of PDUFA will not only determine whether 1,000 drug reviewers will keep
their jobs past July of this year but it could also well determine how
quickly we approve a new treatment for diabetes, lupus or cystic
fibrosis or many other diseases. Certainly, we should examine proposals
to strengthen ``post-market surveillance.'' The F.D.A. has designed a
new proposal which allows the drug sponsor to design the appropriate
studies to monitor and assess potential risks. This approach process
allow quality to be built in from the beginning of the review process.
We should also remember that this law, in its current form, has been
remarkably effective in bringing additional resources to the F.D.A. as
well as reducing the market approval time for drugs. I am hopeful that
this committee can continue to provide the kind of policy leadership
which has resulted in new, faster drug approvals with the safety and
efficacy standards which has previously characterized F.D.A. reviews. I
look forward to hearing from today's witnesses.
______
Prepared Statement of Hon. Gene Green, a Representative in Congress
from the State of Texas
Thank you Mr. Chairman for holding this hearing today on the
Prescription Drug User Fee Act.
When the PDUFA program was first authorized in 1992, there were
many critics who worried that it would be a conflict of interests for
the FDA to accept user fees in order to expedite the review of
pharmaceuticals and biologics.
And while there are still critics of the PDUFA program, the
evidence indicates that the FDA and the industry can work together in a
fashion that gets life-saving medicines to the public in an efficient
and safe manner.
In 1993, the median review time for a standard new drug application
was almost 26 months.
For an individual dying of a serious illness, this was far too long
of a wait.
Since PDUFA's implementation, however, there has been a dramatic
decrease in the length of time it takes to have a new drug approved.
Today, the median has dropped to just twelve months.
More importantly, for priority new drug applications--which are the
life-saving therapies that often represent the last hope for people
with serious terminal illnesses--the median approval time was six
months in 2001.
As Dr. Crawford points out, the life-saving breast cancer
treatment, Herceptin, was approved by FDA in less than five months.
This is exactly the kind of result that the Congress intended when
it passed this law a decade ago.
PDUFA is not without its problems, however, and that is what we are
here today to discuss.
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.
Many have 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.
Mr. Chairman, these are important issues and I am glad that we are
holding a hearing to learn more about them.
It is certainly of importance to all of my constituents that the
FDA has the resources it needs to review pharmaceuticals to ensure
their safety and efficacy.
But I would be remiss if I did not raise other concerns about
prescription drugs--the costs of these vital medications, the affects
of direct-to-consumer advertising, and the absence of a Medicare
prescription drug benefit.
Last year, the National Institute for Health Care Management
Foundation stated that spending on retail outpatient prescription drugs
rose by almost 19% in 2000, from $111.1 billion to $131.9 billion.
Approximately half of that spending increase can be attributed to
just 23 drugs.
Among those drugs are blockbuster drugs like Vioxx, Lipitor,
Celebrex, and Glucophage the very drugs that seniors rely on every day
to treat chronic, long-term illnesses like diabetes, arthritis, and
high cholesterol.
It is no coincidence that these are the same drugs that are so
heavily advertised in direct-to-consumer marketing.
We must ensure that patients understand what these drugs do--and
don't do--and the risks associated with taking them.
But most importantly, after decades of rhetoric, the Congress must
act to provide a meaningful, comprehensive prescription drug benefit
under Medicare.
A full one-third of Medicare beneficiaries--more than 14 million
seniors--have no prescription drug coverage at all.
We need a prescription drug benefit that makes sure that seniors,
who have worked hard and paid taxes their whole lives, have access to
these life-saving medications.
The Congress has been slow to act on this issue, and it is
inexcusable.
But I have to give credit where credit is due. Recently, various
companies in the pharmaceutical industry have announced discount cards
and programs for low-income seniors who do not have access to a
prescription drug benefit.
Just yesterday, Eli Lilly joined the ranks of Pfizer, Novartis and
GlaxoSmithKline and announced the creation of their prescription drug
discount program.
These programs are by no means a solution to the Medicare
prescription drug problem but these companies have made an effort to
help the poorest seniors get access to the drugs they need.
I thank them for their efforts in this regard, and hope that they
will prompt Congress to do the same.
With that, Mr. Chairman, I yield back the balance of my time.
Mr. Bilirakis. I also ask for the unanimous consent that a
couple of documents here, one entitled, ``Patient and Consumer
Coalition, Background of Prescription Drug User Fee Act,`` and
also a letter to the four chairmen and ranking members from a
group of organizations, and it doesn't have a date on it, but
these have been shared with the minority, that they be made a
part of the record. That being the case, and without objection,
they are so made a part of the record.
[The information referred to follows:]
The Honorable W.J. Billy Tauzin
Chairman
Energy and Commerce Committee
The Honorable John Dingell
Ranking Member
Energy and Commerce Committee
The Honorable Mike Bilirakis
Chairmnan
Health Subcommittee
The Honorable Sherrod Brown
Ranking Member
Health Subcommittee
Dear Chairmen and Ranking Members: We, the undersigned patient
advocacy organizations implore you to consider a swift and clean
reauthorization of the Prescription Drug User Fee Act (PDUFA) that has
been of enormous benefit to patients with all types of diseases in all
parts of our country.
The user-fee law has been an unqualified success--a poster child
for Congressional achievement. Before the law was first enacted ten
years ago, review of new drugs took about 2\1/2\ years and the
timeliness of drug review was a big concern to patients who were not so
patiently waiting for their life-saving medicine.
Countless thousands of patients have benefited from Congress'
leadership in enacting the first PDUFA law in 1992, and supporting its
reauthorization in 1997. Since that time, life-saving drugs have been
made available to patients sooner, and without in any way compromising
the gold standard of drug approval upon which patients rely. According
to the FDA, the rate of drug withdrawal has remained constant at 2.7
percent before 1992 and 2.7 percent today.
The result: the average review time for new drugs has been cut
almost in half from 30 months to less than 18 months--for some
patients, that's a lifetime. And today, about half of all new drugs are
approved first in the U.S.
The law is working. Patients are not waiting as long for their new
medicines--and Congress must act without delay to ensure that patients
continue to receive new cures and treatments as expeditiously as
possible. Moreover, it is vital that PDUFA, which is set to sunset on
September 30, be reauthorized by July so FDA does not have to begin
laying off reviewers and the drug approval process is not disrupted in
other ways.
Our organizations represent literally millions of American patients
and their families. We are all depending on your leadership to
reauthorize PDUFA cleanly and quickly.
The ALS Association; Leukemia and Lymphoma Society;
Parkinsons Disease Foundation; American Association of
Clinical Endocrinologists; Pancreatic Cancer Action Network;
Kidney Cancer Association; Cancer Research Institute;
Association of Clinicians for the Underserved; National Alliance
for Hispanic Health; National AIDS Treatment Advocacy Project;
Cancer Research Foundation of America; American Liver Foundation;
Pulmonary Hypertension Association; American Foundation
for Urologic Disease; Cystic Fibrosis Foundation;
and National Coalition for Women with Heart Disease
______
Patient and Consumer Coalition
BACKGROUND ON THE PRESCRIPTION DRUG USER FEE ACT
The Prescription Drug User Fee Act was enacted in 1992 to address
concerns about the length of time it took for new drugs treating life-
threatening and disabling conditions--especially AIDS--to be reviewed
and approved by the FDA. The authors of PDUFA recognize that Congress
was not going to provide enough in new appropriations to support the
increased staff that a shorter approval process would require. PDUFA
mandated that drug manufacturers pay user fees when they filed a New
Drug Application for review and approval of a product.
PDUFA was reauthorized in 1997 as part of the Food and Drug
Administration Modernization Act. However, this iteration included more
stringent ``performance goals'' requiring that the FDA meet very tight
review deadlines. These faster deadlines were insisted upon by the
pharmaceutical industry, which argued that these ``measurables'' were
necessary to ensure that the user fees they paid were not dispersed to
fund other agency activities. For the first time, PDUFA II also
included stipulated time frames for the scheduling of meetings and
response to industry requests (``management goals'').
As a result of PDUFA I and II, the FDA has both dramatically
increased the amount of resources it devotes to new drug and biologics
review and decreased the review time. But this has come at a price.
PDUFA requires that the agency increase funding from non-user fee
revenues for drug reviews by an inflation-adjusted amount every year.
But, Congressional appropriations for the FDA have not kept pace with
inflation and with the increased mandates on and responsibilities of
the agency. As a result, the only way the FDA can comply with PDUFA's
requirements to increase non-user fee funding for the drug review
process is to take resources away from other essential activities, such
as post-market research and surveillance, on-site inspections, and
regulation of medical devices. Moreover, the agency has said that user
fees generate less than the total expenditures the agency must make to
satisfy PDUFA performance and management goals. As Former Commissioner
Jane Henney said, ``. . . 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.'' \1\
---------------------------------------------------------------------------
\1\ FDA Consumer Magazine, ``User Fees for Faster Drug Review: Are
They Helping or Hurting the Public Health?,'' September-October 2000.
---------------------------------------------------------------------------
The short review times mandated under PDUFA II have had other
negative effects. The director of FDA's Center for Drug Evaluation and
Research, Dr. Janet Woodcock, has expressed a great deal of concern
about the high rate of turnover among review staff, which means that
the agency has had difficulty retaining experienced, competent
reviewers. Dr. Woodcock has said that the intense timelines under PDUFA
have created a ``sweatshop environment that's causing high staffing
turnover.'' \2\
---------------------------------------------------------------------------
\2\ Ibid.
---------------------------------------------------------------------------
There have also been concerns about a series of high-profile drug
withdrawals over the last few years. According to the Pulitzer Prize-
winning investigation by David Willman of the Los Angeles Times, seven
of these drugs--Lotronex, Propulsid, Rezulin, Raxar, Posicor, Duract
and Redux--are suspected in 1,002 deaths.\3\ While FDA officials claim
that these safety problems were not necessarily linked to PDUFA, the
withdrawals raise troubling questions about whether the agency
performance goals mandated by the Act may be overriding its public
health responsibilities.
---------------------------------------------------------------------------
\3\ David Willman, ``How a New Policy Led to Seven Deadly Drugs,''
Los Angeles Times, December 20, 2000.
---------------------------------------------------------------------------
In fact, several former FDA employees told the Los Angeles Times
that they were under a great deal of pressure to approve drugs quickly.
Bill Schultz, former deputy commissioner at the FDA said, ``You can
meet the [performance] 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.'' \4\
---------------------------------------------------------------------------
\4\ Ibid.
---------------------------------------------------------------------------
reauthorization of the prescription drug user fee act
The undersigned members of the Patient and Consumer Coalition
believe that the upcoming re-authorization of PDUFA offers an important
opportunity to increase the safety of prescription drugs and devices in
this country and to insure that the protection of the public's health
is the FDA's top priority under the Act. We urge Congress to:
Hold balanced hearings on PDUFA reauthorization and drug
safety concerns. The hearings should include testimony from
patients who have been harmed by problem drugs--or their
representatives--and consumer advocates who are knowledgeable
about PDUFA. Such hearings would send a vital signal to FDA
from Congress that what the public wants and deserves is a
thorough review and oversight process for drugs and biologics,
not just speedy approval of new products.
Adequately fund the entire range of FDA's approval and safety
oversight activities from general revenues. There is an urgent
need for increased funding for post-marketing surveillance and
other safety-related activities not covered by current user
fees. User fees are not a substitute for adequate federal
funding of these vital and growing public health functions.
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.
Give the FDA total control over all review and surveillance
activities. If an unwillingness to appropriate adequate funds
leads Congress to consider the expansion of user fees, it is
absolutely essential that the FDA alone determine their usage,
without the kind of inappropriate control over the use of these
fees (through mandated decision-making deadlines) that the
industry has exercised with new drug approvals.
Address drug safety concerns created by PDUFA's excessive and
inappropriate focus on swift approval over public health. PDUFA
III should include new safety protections that, to the greatest
extent possible, protect the public from potential harm caused
by adverse reactions, side effects and adverse events related
to pharmaceutical products and biologics. Decision-making
deadlines for drug review should be redefined to focus on the
FDA's responsibility to guarantee safe drugs, not only on the
speed with which reviews are conducted. The agency's antiquated
and under-funded adverse event reporting system (for drugs,
biologics and devices) should also be modernized.
1. Restructure User Fees
Eliminate the linkage between appropriated and user fee funds.
The current law results in disproportionate funding for the
drug approval process compared to most other research,
regulatory, and public education functions. At a minimum, the
program must be re-designed in such a way as to prevent the
draining of funds from vital FDA functions.
Require that user fees support the life cycle of the review
process. Presently, FDA staff hold numerous pre-New Drug
Application meetings with manufacturers before the agency
receives any PDUFA fees for the intended application. While
these meetings benefit sponsors greatly by improving their
understanding of FDA expectations and the quality of their
applications, they also divert FDA staff time from other review
functions and increase the cost and difficulty of meeting PDUFA
goals. In other words, the required meetings are an un-funded
mandate on the agency.
2. Eliminate or Overhaul Performance Goals
Although PDUFA's deadlines are for decision-making on drugs and
biologics, not approval, these goals put the FDA under tremendous
financial pressure to move very quickly on the overall approval
process. By requiring that decisions must be made within the same
timeframes for priority and standard reviews,\5\ these goals force the
agency to take an unvarying, ``cookie cutter'' approach to approvals.
Congress should eliminate these required goals. If this does not occur,
the agency should be given greater flexibility to set its own
priorities and/or extend the goals, including:
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\5\ PDUFA II establishes deadlines that require FDA to review 90
percent of priority (``fast track'') new drug Applications within 180
days and 90 of standard applications within ten months.
Consult All Stakeholders--If performance goals are not
eliminated in PDUFA III, consumers and patient representatives
should be involved in developing them.
Grant FDA a ``Scientific Override''--When the FDA requires
additional information or clarification from the manufacturer
as part of the review process, the FDA should be allowed to
``stop the clock'' on review deadlines while waiting for this
information to be provided.
Eliminate Rigid Management Goals--These goals require the
agency to set up meetings with the industry within specific
timeframes. They should be replaced by a more flexible system
that allows the FDA to prioritize these requests, thus
decreasing undue burden on the agency.
Allow FDA More Flexibility For Standard Reviews--There is no
public health justification for requiring the FDA to decide on
a ``me too'' drug that duplicates therapies already on the
market at the same speed as a drug that might offer therapeutic
advantages to some patients. The FDA should be granted greater
authority to prioritize the review of standard drug
applications.
Create Safety Goals--FDA should establish performance goals
oriented toward protecting the health and welfare of consumers,
such as tracking and reviewing Phase IV trials, improving the
collection, analysis and response of adverse event reports, and
enhancing the speed and quality of review of direct-to-consumer
advertisements.
3. Enhance Drug Safety Measures and FDA Enforcement Authority
Grant FDA Civil Monetary Fine Authority and Subpoena Power--
When companies fail to complete Phase IV confirmatory trials or
when companies repeatedly violate prescriber and direct-to-
consumer advertising guidelines, the agency should be given the
authority to levy significant monetary penalties.\6\ The agency
should also have the power to compel companies to produce
relevant documents.\7\
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\6\ As a condition of approval of a new drug by the agency, drug
companies often commit to doing post-marketing or Phase IV studies.
These studies can help to identify previously unknown dangers presented
by a new drug so that its safety labeling can be updated or if
necessary the drug can be withdrawn. According to a Public Citizen
report released in 2000, of the 88 new drugs that were approved between
1990 and 1994 with the understanding that the sponsor would complete at
least one post-marketing study, only 13 percent (11 of 88) had
completed all of the studies they had agreed to as of December 1999.
\7\ According to a 1990 Congressional Research Service study,
almost every other U.S. health and safety regulatory agency has
subpoena power. Without the ability to subpoena company records, the
FDA's efforts to assure drug safety are hamstrung. The case of the
FDA's post-approval investigation of the drug Halcion demonstrates the
problems the agency faces. In that case, the agency could not subpoena
the company's records even though it had suspicions of criminal
wrongdoing. At one point in that investigation, the agency even went so
far as to ask for the intervention of a federal judge to modify a gag
order in a tort action against the maker of Halcion so that the agency
could have access to crucial documents.
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Launch Independent Drug Withdrawal Investigations--An office
or agency independent of the FDA should investigate the
circumstances surrounding the withdrawal of medical products
from the market, as the National Transportation Safety Board
does for plane crashes.
Increase Monitoring and Review of Phase IV Trials--Require the
FDA to track Phase IV trials, strictly monitor and enforce the
informed consent and protection of human subjects in those
studies, and, in a timely manner, review the quality of the
studies and the accuracy of the findings.
Improve Adverse Event Reporting--Hospitals, HMOs, nursing
homes and other healthcare providers should be required to
automatically report (the present system is voluntary) serious
adverse drug events, adverse reactions and medical errors to
the FDA, CDC, and/or other relevant agencies. Appropriations
for FDA's oversight of adverse event reporting should be
dramatically increased.
Utilize the Centers for Education and Research on
Therapeutics--CERTS should examine the feasibility of: (1)
implementing a patient self-monitoring reporting system for
signaling possible adverse drug reactions;\8\ and, (2)
expanding the use of medical registries to follow patients who
may be at risk of serious reactions
---------------------------------------------------------------------------
\8\ Under this system, suggested by Seymour Fisher and Stephen G.
Bryant, patients would be given information about how to report adverse
drug reactions by their pharmacist. This system would make it possible
to compare the rates of adverse drug reactions to a new drug with drugs
already on the market for the same indication. (S. Fisher, S.G. Bryant,
``Postmarketing surveillance of adverse drug reactions: patient self-
monitoring'' Journal of the American Board of Family Practice, 1992;
5:17-25.)
---------------------------------------------------------------------------
Broaden Distribution of medication Guides--Consumers should be
given power to make informed decisions about drugs and devices
and to avoid preventable harm. It is time to mandate that
medication guides with scientifically accurate, unbiased and
clearly worded information about the risks and benefits of a
treatment be included with every dispensed drug (as proposed by
the FDA in 1995.) Such medication guides would also, for the
first time, provide a mechanism for notifying consumers
directly when new safety concerns about a drug emerge that
require a change in a drug's approved labeling.
Provide Consumers with More Post-Market Drug Safety
Information--Section 506B of the Food, Drug and Cosmetics Act
should be amended to expand the scope of information made
available to the public to include information as study
protocols, patient accrual rates, reports of unexpected, i.e.,
unlabeled, suspected adverse reactions, and study results.\9\
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\9\ Under its proposed rule of December 1999 implementing FDAMA's
requirement for the industry to report its progress on completion of
phase IV tests to the agency this information would have been made
available to the public. However the industry objected, claiming that
FDAMA did not give the agency the authority to make this information
public and this requirement was removed from the final rule, which was
published in October of 2000. Legislation is needed to clearly give the
agency the authority it needs to disclose this information.
---------------------------------------------------------------------------
Scrutinize Single Controlled Clinical Studies--An increasing
number of drug manufacturers have indicated that they will
begin submitting new drug applications using data from only one
controlled clinical study, which is now allowed by law, rather
than multiple studies. An independent study should be conducted
at an appropriate time to assess the effectiveness of single
controlled studies in assessing the safety of drugs and
biologics.
Examine Comparative Safety Data--Manufacturers should be
required, as part of their application to the FDA to market a
new drug or biologic, to submit the results of tests comparing
the safety and efficacy of their product to others already on
the market that are used to treat the same indication.
This position paper is endorsed by the following members of the
Patient and Consumer Coalition: the Alpha I Foundation; Center for
Medical Consumers; Consumer Federation of America; Gray Panthers;
International Union, UAW; the National Consumers League; the National
Organization for Rare Disorders; the National Center for Policy
Research for Women & Families; the National Women's Health Network; and
the Title II Community AIDS National Network.
Mr. Bilirakis. And having waited very patiently, is Dr.
Lester M. Crawford, Deputy Commissioner of the Food and Drug
Administration. Dr. Crawford, thank you very much for being
here, and proceed, sir.
We are going to set the clock at 10 minutes, and you do
what you can, and we won't worry about the clock.
STATEMENT OF HON. LESTER M. CRAWFORD, DEPUTY COMMISSIONER, FOOD
AND DRUG ADMINISTRATION; ACCOMPANIED BY JANET WOODCOCK,
DIRECTOR, CENTER FOR DRUG EVALUATION AND RESEARCH; AND
CATHERINE ZOON, DIRECTOR, BIOLOGICS EVALUATION AND RESEARCH
Mr. Crawford. Thank you very much, Mr. Chairman, we thank
you and the other members for scheduling today's hearing. I am
joined at the table by Dr. Janet Woodcock, who is the Director
for the Center for Drug Evaluation and Research; and Dr.
Catherine Zoon, who is the Director of the Center for Biologics
Evaluation and Research.
I have a written statement for the record, and I will
confine my remarks to within the 10 minutes. In my oral
remarks, I will describe the Agency's success in implementing
the Prescription Drug User Fee Act, identify priorities for
PDUFA-3, and emphasize the importance of reauthorizing this law
in advance of its September 30, 2002 expiration date.
PDUFA has been a remarkable success. Since PDUFA was
enacted in 1992, the FDA has met the highest expectations for
performance, while continuing to adhere to rigorous standards
for safety and effectiveness.
We now have 8 years of data on our efforts to achieve PDUFA
goals. During this period the FDA faced a total of 73
performance goals. We met or exceeded 71 of those goals.
If you add procedural goals to that total, the Agency met
or exceeded 86 out of 92 PDUFA goals. The result has been a
dramatic reduction in product approval times. 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.
With the enactment of PDUFA, U.S. companies have overtaken
their European counterparts, and now have a commanding lead in
world markets. A July 2001 report found that the European share
of the world pharmaceutical market fell by 10 percent over the
past decade, while the U.S. market share rose by more than 10
percent.
During the same period U.S. research and development
increased a remarkable five-fold, and that is why the Tufts
University Center for the Study of Drug Development declared
that the U.S. environment for pharmaceutical innovation since
PDUFA is nothing short of remarkable.
The membership of this Subcommittee deserves a large share
of the credit for championing PDUFA and for making this record
of achievement possible. Your efforts have produced significant
benefits for public health.
The public has gained access to 717 new drugs and biologics
under PDUFA. These include important new products to treat
cancer, AIDS, cardiovascular disease, and to fight infection.
Every day the lives of patients are immeasurably improved
as a result of the great emphasis on priority review that we
instituted under PDUFA. While our experience under PDUFA-2 has
generally been good, significant issues have surfaced that
undermine the program's financial foundation.
During the final 3 years of PDUFA-2, fee revenue has been
less than the cost of performing review activities. The FDA has
been able to sustain its review effort by spending fee revenue
collected in previous years that has been held in reserve.
However, unspent revenues from previous years will be
depleted by September 30. A top priority will be to establish a
fee structure to ensure that income covers the cost of PDUFA
enhancements to the drug and biologic review process.
Funding a program of risk assessment for PDUFA drugs and
biologics is a second priority. While drugs and biological
products are under development, clinical testing is usually
limited to small, carefully selected populations.
After approval, when the drug reaches a much larger and
diverse population, adverse events not seen during clinical
trials may emerge. I want to emphasize that there is no
evidence that drugs are being withdrawn from the market for
safety reasons at a greater rate during the PDUFA era.
In fact, the withdrawal rate for new drugs approved prior
to PDUFA is identical to the withdrawal rate for drugs approved
since PDUFA was enacted. However, a more effective program of
risk management for new drugs that improve patient safety is
warranted by the reality that more drugs are launched for the
first time in the U.S.
Mr. Chairman, PDUFA-2 expires on September 30, 2002. I want
to emphasize again the importance of achieving a timely
reauthorization of this law. If we are to sustain our record of
accomplishment under PDUFA-2, it is critical that
reauthorization occur without a gap between the expiration of
the old law and the enactment of PDUFA-3.
Retaining FDA's skilled employees is essential to the
success of PDUFA-3. A delay in the reauthorization of this
program may precipitate an erosion in our work force,
particularly among senior reviewers, whose skills are in very
high demand.
The repercussions of such a loss would be with us for years
to come, and rebuilding the infrastructure that we would lose
in such an event would be very difficult indeed. Thank you for
your commitment to the mission of the FDA, and to the continued
success of PDUFA.
Thank you very much.
[The prepared statement of Hon. Lester M. Crawford
follows:]
Prepared Statement of Hon. Lester M. Crawford, Deputy Commissioner,
Food and Drug Administration
INTRODUCTION
Mr. Chairman and Members of the Subcommittee, I am Lester M.
Crawford, Deputy Commissioner of the Food and Drug Administration (FDA
or the Agency). I am pleased to be here today to discuss the Agency's
success in implementing the Prescription Drug User Fee Act and to
emphasize the importance of reauthorizing this law in advance of its
September 30, 2002, expiration date.
BACKGROUND
In 1992, Congress enacted the Prescription Drug User Fee Act (PDUFA
I). This law provided additional resources to hire more medical and
scientific reviewers to conduct premarket reviews, to hire support
personnel and field investigators to speed up the application review
process for human drug and biological products, and to acquire and
support critical information technology infrastructure.
In 1997, after the success of PDUFA I, Congress reauthorized the
program for an additional five years. With this reauthorization (PDUFA
II), came higher expectations for reviews and additional goals designed
to reduce clinical drug development times. The President's budget
request for Fiscal Year (FY) 2003 recommends that PDUFA be reauthorized
through FY2007, and we have been engaged in discussions with consumers,
health providers, and industry over the past year to develop proposals
for PDUFA III. These discussions have been very useful, and we hope to
complete the consultation process in the very near future and forward
our PDUFA III recommendations to the Department of Health and Human
Services.
PDUFA ACHIEVEMENTS
During PDUFA I and PDUFA II, FDA met the highest expectations for
performance while continuing to adhere to rigorous standards for safety
and effectiveness. We now have eight years of data on our efforts to
achieve PDUFA goals, and the Agency's record of achievement is
impressive. The Agency faced a total of 73 performance goals during
this period. These goals governed the review of priority and standard
new product applications, resubmitted applications, and supplements.
During this eight-year timeframe, FDA met or exceeded 71 of 73 PDUFA
performance goals.
In addition to the 73 performance goals, procedural and processing
standards were instituted under PDUFA II. A total of 19 goals governing
meetings, clinical holds, dispute resolution, and special protocols
were established when the law was reauthorized. FDA met or exceeded 15
of 19 procedural and processing goals. If you combine our performance
and procedural accomplishments, the Agency met or exceeded 86 out of 92
PDUFA goals.
Not only has FDA significantly reduced application review times
under PDUFA, it also has significantly reduced product approval times,
and therefore, the time for new drugs to reach the market. Review time
is the time it takes FDA to review original or resubmitted new product
applications, efficacy supplements, and manufacturing supplements and
issue an action letter. Approval time is measured from the date an
application was initially submitted to the date an approval letter is
issued. Approval time includes the period of FDA review, as well as the
time a sponsor may spend responding to deficiencies identified by the
Agency during application review. Because of these deficiencies, some
products require more than one review cycle. While PDUFA established
goals for review times, and faster reviews tend to produce quicker
approvals, the quality and completeness of an individual application
and the public health priority of the product significantly affect time
to approval.
The result of our efforts has been a dramatic reduction in product
approval times. The median approval time for priority new drug and
biologic applications dropped from 13 months in FY1993 to only six
months in FY2000. We do not have complete data for FY2001, but median
approval times are projected to remain at six months.
For standard new drug applications, the median approval time was 22
months in FY1993. By FY1999, however, median approval times had
declined to 12 months. For a variety of reasons, such as competing
PDUFA goals and priorities and unanswered questions that must be
addressed within some applications, we may experience a slight increase
in approval time in FY2000 for this category of applications. The data
for FY2000 are only preliminary, however.
THE WORLD LEADER
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. Between FY1993 and FY 2001,
pharmaceutical firms have introduced 285 new molecular entities (NMEs)
and 73 biologics into the market, a dramatic increase compared to any
other period of time.
Ten years ago, European pharmaceutical companies were the industry
leaders. With the enactment of PDUFA, however, U.S. companies have
overtaken their European counterparts and now have a commanding lead in
world markets. According to a July 2001 report in the Financial Times,
the European share of the world pharmaceutical market fell from 32 to
22 percent over the past ten years while U.S. market share rose from 31
to 43 percent. During this period, pharmaceutical R&D investment
doubled in the European Union, while U.S. R&D increased a remarkable
five-fold.
This turn-around prompted the Tufts Center for the Study of Drug
Development to describe the U.S. environment for pharmaceutical
innovation since PDUFA as ``nothing short of remarkable.''' The members
of this Subcommittee deserve a large share of the credit for
championing PDUFA and for making these successes possible.
PDUFA RESULTS
Your efforts have produced significant benefits for public health.
The public has gained access to 717 new drugs and biologics under
PDUFA, including 174 that represent significant therapeutic
advancements. During the PDUFA era, FDA reviewers have approved:
30 new medicines for cancer;
37 new medicines for AIDS;
29 medicines to fight infection; and
18 medicines for cardiovascular disease.
Every day, the lives of cancer patients are measurably improved as
a result of the greater emphasis on priority review that we instituted
under PDUFA. For example, Herceptin', a biological product
to treat breast cancer, was approved by FDA in less than five months.
In Europe, the approval process took 18 months. Because of FDA's
priority review, 10,000 American women with advanced breast cancer had
earlier access to this drug. These patients will gain an estimated
2,300 additional years of life because of early access to this
important new therapy.
The pharmaceutical industry also enjoys significant R&D savings as
a result of shorter review times. Under PDUFA, FDA reduced new drug
review by 12 months. Each month of reduced review results in an average
saving of $2.5 million, or $30 million in R&D cost savings over 12
months. Given that FDA approves an average of 40 NMEs and biologics per
year, the savings to industry represent $1.2 billion annually. The
program represents a bargain in light of the $133 million that industry
paid in user fees in FY2001.
Finally, PDUFA has also brought significant benefits for FDA:
Performance goals have helped streamline and harmonize the
management of drug and biological product review.
The program's requirement for comprehensive product reviews
and responses has resulted in improvements to the quality of
the application review process.
Most importantly, the fees have enabled the Agency to hire
additional medical reviewers and other specialists, and upgrade
the technology that is essential for the success of the
program.
FDA GOALS FOR PDUFA III
1. Sound Financial Footing
While our experience under PDUFA II has generally been good, a
number of significant issues have surfaced that undermine the program's
financial foundation. In PDUFA III, we are working to address these
issues and ensure that the Agency has a sound financial footing to
conduct essential review and approval activities.
During the final three years of PDUFA II, the amount of fees
collected has been substantially less than the cost of performing
review activities. FDA has been able to sustain its review effort only
by spending fee revenue collected in previous years that has been held
in reserve--an arrangement permitted under the Act. In FY2001 and
FY2002, spending from fee revenues will exceed fee income by about $30
million each year. FDA is reducing operations in FY2002 to adjust to
this revenue shortfall. However, unspent revenues from previous years
will be depleted by the end of this fiscal year and there will be
little or no fee balances available after September 30. Establishing a
fee structure to ensure that income covers the cost of enhancements to
the drug and biologic review process authorized by PDUFA is an issue
that we are working to address in PDUFA III.
Another problem is that PDUFA application fees are only paid on new
drug and biologic applications and efficacy supplements. Yet the review
of fee-paying applications represents only a fraction of FDA's actual
review workload. There are many activities associated with the process
for the review of human drugs and biological products that are not
covered by PDUFA fees. These activities continue to grow steadily and
demand more resources each year, while the number of fee-paying
applications, and the revenue they generate, fluctuates considerably.
This dynamic was not taken into account when the fee formula was
established.
The uncertainty about fee revenue is further complicated by the
relationship between application fees and the product and establishment
fees that also we collect under PDUFA II. The law directs that
establishment and product fees rise and fall based upon the number of
fee-paying applications, yet the volume of work associated with these
activities has little or no relationship to the number of applications.
The reality of this situation is inconsistent with the expectation that
product and establishment fees were intended to be a stable element of
PDUFA revenue in order to insure a consistent and predictable source of
fees.
2. Risk Management
While drugs and biological products are under development, clinical
testing is usually limited to small, carefully selected populations of
5,000 or less. After approval, however, millions of patients may be
exposed to the drug. When the drug is exposed to a much larger and
diverse population, adverse events not seen during clinical trials
often emerge in the first few years after a new product is on the
market. PDUFA has fostered a dramatic reduction in product approval
times, and the U.S. market is increasingly the country where drugs are
first launched.
There is no evidence that drugs are being withdrawn from the market
for safety reasons at a greater rate during the PDUFA era than prior to
the enactment of this landmark legislation. In fact, the withdrawal
rate for new drugs approved prior to PDUFA is identical to the rate of
withdrawal for drugs approved since PDUFA was enacted (2.7 percent).
However, the need to institute a more effective program of risk
management for new drugs, and thereby ensure greater patient safety, is
clearly warranted by the intrinsic limitations of drug development
programs (particularly the size of clinical trials) and the reality
that more drugs are launched for the first time in the U.S. Where risks
can be effectively managed, we avoid the need to withdraw drugs that
are highly beneficial to many patients, though harmful to some.
CONCLUSION
As you know, PDUFA II expires on September 30, 2002, and I want to
emphasize again the importance of achieving a timely reauthorizion of
this law. FDA is ready to work with you to accomplish this.
I have described the status of FDA's user fee account--Agency
carryover balances will be exhausted by the end of the current fiscal
year. If we are to sustain our record of accomplishment under PDUFA II,
it is critical that the reauthorization occur without a gap between the
expiration of the old law and the enactment of PDUFA III.
Timely reauthorization is a priority for the pharmaceutical
industry, the American public, and the many talented staff at FDA that
we rely upon to conduct human drug and biologic reviews. Retaining
FDA's skilled employees is essential to the success of PDUFA III. Any
hesitation or delay in the reauthorization of this program could
trigger sudden erosion in our work force, particularly among senior
reviewers whose skills are in very high demand. The repercussions of
such a loss would be with us for years to come.
Thank you for your commitment to the mission of FDA, and to the
continued success of PDUFA. I am happy to answer questions you may
have.
Mr. Bilirakis. Thank you very much, doctor. Dr. Crawford,
when might we expect to receive in writing the goals
performance letter, the agreement that was reached?
Mr. Crawford. The goals performance letter is in draft, and
I will ask Dr. Woodcock to comment to the extent that she is
able to do so, when it might be delivered. However, I have seen
it and have reviewed it, and I would say it is quite far along.
Mr. Bilirakis. All right. Before Dr. Woodcock speaks, I
would like to say that I requested that FDA meet with the
committee staff of minority and majority. They did so a couple
of days ago.
Then of course there was a members meeting yesterday and
Dr. Woodcock was there, with others. Dr. Zoon was there. I
wanted to express our appreciation for that.
Dr. Woodcock, please tell us something good. You might also
address the goals performance study, because as you heard
members say here, before we go into a mark-up, we need to have
that documentation to give you further cooperation.
Mr. Crawford. I can address that. It is correct that it is
being reviewed in the department. However, it is my
understanding that both the FDA and the department share in the
reasons for the delay.
It is very close to release, and I would say it is a matter
of days. I communicated personally with the department
yesterday and I expect that it will be released very soon
indeed.
Mr. Bilirakis. Very soon? Can you give us an idea of what
very soon is?
Mr. Crawford. Days.
Mr. Bilirakis. Days? That's good. That is the goals
performance study. Dr. Woodcock.
Ms. Woodcock. The letter, as Dr. Crawford said, is
written--a draft is written and it must be reviewed by the
original parties who have been negotiating this, as well as up
the line.
We understand the need for urgency in getting this letter
to you, and we will have it in a matter of weeks.
Mr. Bilirakis. Weeks?
Ms. Woodcock. Yes. We will make every effort to get it to
you as soon as possible.
Mr. Bilirakis. The letter?
Ms. Woodcock. The letter, in a week or weeks.
Mr. Bilirakis. Week or weeks?
Ms. Woodcock. Yes.
Mr. Bilirakis. That is a little better.
Mr. Crawford. It is a letter that is more like a novella.
It is very large, and we want to make sure that it is right.
But it should be--it is in very good shape now, I think, and it
just needs to be reviewed by some more people.
Mr. Bilirakis. Okay. Well, please review. I understand
sometimes that haste makes waste, but we need to have that
documentation here as soon as we can so that we can continue.
We have an awful lot of things on our plate as you know,
and as you heard, for example, prescription drugs and Medicare.
We would like to get this thing on course.
Doctor, you have heard people up here state they are
concerned that PDUFA may have resulted in a reduction in
safety. PDUFA-2's trigger, is the requirement that PDUFA funds
must augment and not replace the amount of reviews paid for by
appropriated funds. A concern is that money is being diverted
from other FDA centers, and that has been said here more than
once.
Can you tell us what in the FDA-industry agreement, the
performance goals agreement, will make this situation better?
Has it in fact been a concern? Has there been a reduction in
terms of safety, efficiency, et cetera?
Mr. Crawford. In reviewing the record of PDUFA, going back
to the first one a number of years ago, over the past few days,
I have personally been very interested in what the record is,
and I believe it is safe to say that PDUFA-1 or PDUFA-2 have
decreased risks.
The rate of withdrawal of drugs is essentially the same as
it was before then. The agency is always extremely concerned
about safety, and we will continue to be. With respect to what
will be done in the new package to deal with the trigger, I am
going to ask Dr. Woodcock once again to comment.
However, I know that that was a priority consideration and
one that continues, and that I will follow up with that.
Ms. Woodcock. First, to set the record clear on one thing.
We have increased our resources over the past 8 years devoted
to drug safety within the agency. However, perhaps this has
come at the expense of other programs.
The PDUFA trigger that you are talking about forces us to
maybe overspend a little, because if we got down--if we went
below the trigger, we could not collect user fees, and we would
have to immediately lay off our staff.
We have tried in this agreement to build more flexibility
into that, and that will allow us to be much closer, and not
overspend in this program. Any time there is a decreasing
resource environment overall for the FDA, some programs have to
become smaller.
Mr. Bilirakis. Are we saying that PDUFA results in other
programs being hurt?
Ms. Woodcock. If there is an overall decrease in
appropriations to FDA, or the cost of living is not given to
the program, then our number of staff must shrink. Just as if
you were to give a raise, and you have 10 employees, and you
gave a raise to all of them, and you didn't have any more
revenues, you would have nine employees, and that is what has
happened to the FDA over the last decade.
Mr. Bilirakis. In other words regardless of PDUFA, the same
thing would have taken place because the money has not been
there the way you would have liked to have had it?
Ms. Woodcock. But the trigger exacerbated that situation
because we could not have nine employees in the user fee
program. We had to maintain that program.
Mr. Bilirakis. My time is expired, but Dr. Crawford, very
quickly you could compliment that.
Mr. Crawford. I was just going to say that one of the
things that Dr. Woodcock refers to is the fact that over the
last few years that we have gotten raises for the FDA and we
have had to absorb them from our budget.
This year, things are different as you well know, and we
are grateful for that.
Mr. Bilirakis. All right. Thank you. Mr. Brown.
Mr. Brown. Thank you, Mr. Chairman. Dr. Crawford, in light
of what I have heard this morning, and especially what I will
say as well on what we heard in the briefing yesterday from
some of your fellow colleagues at the FDA, I am concerned about
sort of the evolution of the FDA mission.
I hear some of your people calling industry its customer,
and I heard yesterday talk and today about the launch of new
products into the market. You have talked about a term that you
learn in Marketing 101.
Industry uses the term launch, but the FDA using that term
concerns me. Discussing the success of PDUFA, in terms of
changes in the U.S. drug industry's market share, I guess I
grew up thinking the FDA was there to protect safety and not to
play a role in enhancing the U.S. market share.
And then coming yesterday and bragging about it with great
enthusiasm, and coming in today and talking about that, and I
just didn't know that that was the mission of this government
agency to help U.S. companies' enhance market share.
Then I hear you quote Tufts, the Tufts' drug center or
whatever it is called, which is always the group of experts
that the drug industry both fires and then quotes for their
drug studies.
It is mostly funded by them and I am just concerned about
where the separation is. You are a regulatory body, and you are
not a subsidiary of the drug industry. I am not accusing you of
that.
But I just wondered where the separation is. I understand
that one of the new agreements in the goals document is does it
require the FDA to hire an outside consultant if the drug
industry wants it to as long as criteria are set out in the
agreement?
I understand the agreement requires the FDA to review its
management practices because the industry is unhappy with these
practices? I mean, I wonder where is the separation, and who is
in control?
Is the FDA in control or is the industry that regulates in
control? Then I hear that the stakeholders, when it comes to
new drug reviews, and in a goals document, it includes industry
and consumers.
But while the FDA held private negotiations with the
industry, as I understand it the public forums were for patient
and consumer groups. So the industry met behind closed doors,
and the public meeting was with patients and consumers.
Then I read in the Congress Daily today that a landmark
deal brokered by the prescription drug industry and the FDA,
and it goes on and on, as if there are no other interested
parties in this.
I realize that the industry funds PDUFA, but it is for a
public purpose is what we were told 5 years ago and 10 years
ago, and both public dollars and private dollars, fund new drug
reviews.
Why were the stakeholders in this case, specifically why
were they treated differently? Why the private negotiations
with the industry, and then the public forum with the rest of
us?
Mr. Crawford. The FDA treads a tightwire of remaining
correct, but aloof, in terms of its enforcement and in its
consideration of the industry. Referring to the industry as a
client or as a customer is sort of part of the new emphasis on
stakeholder involvement.
And in the two public hearings that we held, where patient
organizations and consumer groups came in, as you may recall,
we had 28 different groups that came in to discuss their
positions, and all made testimony.
And 23 of those were non-industry sources, and so that base
was in fact covered. But I am sure they were----
Mr. Brown. That was the public hearing, Dr. Crawford.
Mr. Crawford. That's right.
Mr. Brown. The private meetings, any of those 23 groups in
there?
Mr. Crawford. No. No. Now one of the----
Mr. Brown. Then what am I missing here?
Mr. Crawford. One of the reasons that it was necessary to
meet with industry is because of a couple of things in my view.
One is we have to be apprised of what the pipeline is; how many
drugs are being developed, and what the needs are.
One of the goals, stated goals in the bill of PDUFA-1 was
to speed up the drug approvals. And the second one as you know
better than I was the same thing, plus performance standards
that we would meet.
In order to set both of those, we needed a dialog with the
industry. Many of the things that we discuss in these kinds of
meetings are or have a lot to do with both the stock market and
also the future of the industry, and how many things are there.
We have no way in FDA of knowing that until we have
communication with industry.
Mr. Brown. Well, perhaps then, Dr. Crawford, if those were
public, then you might not be able to trot out that really cool
chart of increasing and enhancing U.S. market share for the
drug industry. Is that connected somehow?
Mr. Crawford. Well, let me address that. Again, it is
delicate, and I grant you that for sure. But the lesson that we
have learned over the many years of the FDA Act is that each
new generation of drugs is safer and more effective.
If we keep them off the market, or if we are not----
Mr. Brown. Let me interrupt you there--I'm sorry--because I
only have 5 minutes, and now I have no minutes. If each new
generation is safer than a previous generation, why did you
come in here a minute ago and brag about how you are taking no
fewer percentage off the market. You are taking no more off the
market than before.
In other words, PDUFA has worked well. But if these drugs
are generally safer anyway, then there ought to be fewer
recalls with these drugs that you approve. So in that way,
PDUFA is not--PDUFA is working to get drugs to the market, and
that is good for our consumers, and our patients, and our
constituents.
But its primary object is safety, and it is failing on
safety then if it is only the same rate as it was back when
drugs weren't as safe as they were 10 years ago.
Mr. Crawford. Well, we won't think it is failing on safety.
There are more of them being approved, that's for sure, and Dr.
Woodcock would like to make a comment.
Ms. Woodcock. There is a countervailing force, which is
that more U.S. patients are the first in the world to be
exposed to these drugs now. It used to be that Europeans, or
Australians, or many people around the world, those
populations, were the first to be exposed.
Mr. Brown. And I might add in much higher numbers because
of this extravagant launch in this huge use initially of these
drugs, in part because of the FDA's assistance with this launch
in direct to consumer advertising. But go ahead, I'm sorry to
interrupt.
Ms. Woodcock. Mr. Chairman, may I finish?
Mr. Bilirakis. Are you really sure?
Mr. Brown. I'm sort of sorry, yes. Sorry.
Mr. Bilirakis. Please do it briefly, Dr. Woodcock.
Ms. Woodcock. Yes. Back when other populations were
exposed, in those people the problems were discovered, and the
drug was pulled off the market, and the application was
withdrawn from the U.S. approval process before it got on the
U.S. market.
Now that situation has totally changed, and that's why we
feel that we need more of an emphasis on risk management.
Mr. Brown. Okay. Thank you.
Mr. Bilirakis. Mr. Deal to inquire.
Mr. Deal. Thank you, Mr. Chairman. My previously alluded to
contact with Dr. Woodcock was quite the opposite. It was a
complaint by a constituent of mine who had a drug pulled off
the market, and they felt that it was a drug that needed to be
there, and was considered lifesaving from their standpoint.
So there are points of view many times that the removal of
drugs from the market is maybe overly zealous by some people's
points of view. So I would simply make that point.
One of the concerns that we have heard expressed is that
because of the so-called second trigger or the funding
mechanism that funds are being diverted away from other
functions within FDA.
Would you comment on that and is the agreement going to
resolve that issue?
Mr. Crawford. Well, of course it is our job to make sure
that nothing that we are mandated to do gets compromised as a
result of this or any other legislation. So we believe that
PDUFA-3 will better address that problem.
We also as we mentioned a little bit ago, as long as we
don't have to pay for the pay raise increases and some of these
other things, we are more able to predict resources and do a
better job.
And that issue has been dealt with very effectively in this
Congress, and we are happy about that.
Mr. Deal. Thank you. Since we have other members who have
questions, I will waive the rest of my time, Mr. Chairman.
Mr. Bilirakis. Well, thank you. You caught me unawares
here. Mr. Stupak.
Mr. Stupak. Well, thank you. Dr. Crawford, I want to pick
up where my friend, Sherrod Brown, left off. We talk about the
mission statement of the FDA, which is safety and consumer
protection is it not, or is it speed and more drugs?
Mr. Crawford. It is not speed and more drugs, no.
Mr. Stupak. Okay. On page eight of your testimony, you
compare the withdrawal of pre-PDUFA and during PDUFA, and
conclude that drug safety has not suffered because the
withdrawal rates are basically the same 2.7 percent.
Out of those 12 drugs that have been withdrawn, only one
was a life threatening drug, and the other 11 were for things
like upset stomach and other things, correct?
Mr. Crawford. Yes, I believe that is correct.
Mr. Stupak. And you have over a thousand deaths, correct,
with those 12 withdrawals?
Mr. Crawford. We can----
Mr. Stupak. To be exact, 1,012.
Mr. Crawford. Well, we can submit that for the record. I am
not prepared to say that.
[The following was received for the record:]
The Adverse Event Reporting System (AERS) maintained by the Center
for Drug Evaluation and Research contains information on adverse events
that may be associated with pharmaceutical drugs. AERS is a
computerized information database designed to support the FDA's post-
marketing safety surveillance program for all approved drug and
therapeutic biologic products. The reports in AERS are evaluated by FDA
clinical reviewers to detect safety signals and to monitor drug safety.
In evaluating AERS data, it is important to keep a number of
considerations in mind. First, there is no certainty that the drug in
question caused the reported deaths. A given death may actually have
been due to an underlying disease process, use of a concomitant drug,
or other unknown factors. The report rarely provides any basis for
assessing whether the product caused the death. Second, since more than
one health professional or other individual may file a report there may
be duplicate reports filed on a single incident. Third, since many
factors influence reporting for a particular drug, reliable comparisons
between drugs cannot be made from this data. Fourth, AERS does not
provide us with data on actual numbers of patients using the drugs in
question. Therefore the ratio of deaths to the number of users cannot
be calculated.
Finally, the decision to withdraw a product is complex and based on
the totality of available evidence, including risks of potentially
life-threatening adverse events, availability of alternative therapies,
etc. The decision is not driven solely by reports of death, although
such events are of most concern.
With these considerations in mind, the following list identifies
the numbers of U.S. death reports in AERS from the time that a drug is
marketed to the date of withdrawal, for drugs recently withdrawn from
the market:
Pondimin-46
Redux-19
Seldane-354
Posicor-28
Hismanal-14
Duract-5
Raxar-3
Rezulin-188
Propulsid-288
Lotronex-7
Baycol-93.
Total number of death reports in AERS associated with these 11
products is 1,045.
Mr. Stupak. Well, besides that, can you comment on the drug
safety that are of concern the FDA that does not include
product withdrawals?
By that I mean, provide us with the pre-PDUFA and PDUFA
comparison of such post-market drug safety matters, such as
warning letters, dear doctors letters, package inserts, black
boxes, and other action taken by the FDA?
Those have dramatically increased under PDUFA, as opposed
to pre-PDUFA, is that not correct Dr. Crawford. I don't believe
so. I am going to ask Dr. Zoon to answer your question from the
standpoint of biologics, and then Dr. Woodcock to add whatever
she would like, and they will give you a historical response,
as well as an up-to-date response, and then I will follow
through.
Ms. Zoon. Thank you. For biologics----
Mr. Stupak. Excuse me. I don't want to spend my whole
minutes talking by biologics. I just want to know about
prescription drugs; pre-PDUFA and post or during PDUFA. Do you
have more black boxes, and more warning letters, more dear
doctors?
[The following was received for the record:
A report to the Commissioner of FDA from the Task Force on
Risk Management entitled, ``Managing the Risks from Medical
Product Use'' was issued in May 1999. Appendix A of the
enclosed report provides a comparison of post-approval risks
for drugs and biological products approved before and after the
implementation of PDUFA. This report was also provided in its
entirety in response to questions for the record.
Ms. Zoon. The withdrawal rate for biologics is actually
less post-PDUFA than pre-PDUFA. The issue of the warning
letters and other labeling instances we would be happy to get
back to you.
Mr. Stupak. So you don't have an answer? Okay.
Ms. Zoon. I don't have the numbers right here with me.
Mr. Stupak. Well, let me ask you this. In the goals and
performance letter that we are going to get either in a week or
weeks, whatever it might be, what mechanism is there in the
performance letter to make sure that these performance and
goals are actually met by the pharmaceutical industry?
Or are we going to have a situation like PDUFA-2, where you
do your post-marketing, and 90 percent of it isn't done, and
here you want to reauthorize PDUFA-3, and 90 percent of the
goals were met in PDUFA-2?
Mr. Crawford. Well, we believe that this goals letter does
represent the newest science, and we feel that we will do a far
better job because of that. One of the things that we have come
to deal with is risk management and also the problems with the
peri-approval process.
Just as the product is about to enter the market, as we
have talked earlier about direct to consumer advertising, the
label itself, and all these sorts of things, which make a lot
of difference.
In other words, the product has been reviewed, and it is
getting close to labeling and market entry, and we are going to
emphasize that a great deal more. It helps us, I think, to
think in terms of pre-market activities, and also to think of
the approval and review activities, and then the peri-approvals
time.
The time was when the agency quite frankly approved the
drugs, and allowed them on the market, and then unless we got
adverse event reports, adverse reactions, we didn't do very
much.
Mr. Stupak. Doctor, with all due respect, how are you going
to enforce it? What is the enforcement mechanisms? Why are we
here? You have no subpoena power, and you can't fine anybody,
and you can't subpoena anybody.
For Serzone, we have been waiting for over 6 years for the
pediatric exclusivity study. Over 6 years. They got a 6 month
extension, and we are still waiting for that. What power do you
have to get the pharmaceutical company to give you that study?
And in another drug, in accutane, you have been waiting
since 1985 for the raw data from the manufacture. Tell me how
you are going to enforce that?
Mr. Crawford. Well, we have certain enforcement activities.
Mr. Stupak. Tell me one.
Mr. Crawford. I am going to ask Dr. Woodcock, because I
don't know what happened in the 1994 thing, if I may be
permitted to do so, and then I will follow up.
Ms. Woodcock. Well, first of all, under the new--your first
question, under this agreement, under a proposal that we have,
we will be substantially increasing our post-marketing staff
and our risk management staff. That was your first question.
Your second question----
Mr. Stupak. So you have more staff, and that doesn't mean
enforcement. You have more staff. Go ahead.
Ms. Woodcock. Currently for many of the--as you know, for
many of the post-marketing problems that we encounter, our
major authority and major step that we can take is to pull the
drug off the market.
Mr. Stupak. How many have you ever pulled when you didn't
get a study or report that you have been demanding? Serzone is
still there, and still pediatric exclusivity, and granted by
the way, and should not be used for minors, but it is still out
there.
Doctors are still prescribing, and they still don't know
after 6 years what it is safe or not for adolescents. That is
not pulled. Accutane, 1985, and we are still waiting for the
raw material, and there have been repeated requests of the
manufacturer. That has not been pulled.
Have you ever pulled a drug because they have not complied
with your request for studies for data, for information, that
is critical to the safety of a drug? Have you ever done that?
Ms. Woodcock. I think only when that was coupled with a
safety problem, a severe safety problem that warranted pulling
it off.
Mr. Stupak. So there has to be something more or there is
no enforcement?
Mr. Bilirakis. The gentleman's time has expired.
Mr. Stupak. Thank you, Mr. Chairman.
Mr. Crawford. Mr. Burr.
Mr. Burr. Thank you, Mr. Chairman. Dr. Crawford, and Dr.
Woodcock, and Dr. Zoon, welcome. Thank you for all the work
that you do. I apologize, Mr. Chairman, that I wasn't here for
opening statements, but I would like to reinforce something
that I understand that the chairman said in his opening
statement.
I think that the FDA has done an extremely good job of
meeting with the industry and trying to put together a goals
letter. I very much would like to see that in a matter of days,
signed, and a copy delivered, and I think that weeks is not an
option here. And I hope that you will take that back----
Mr. Bilirakis. If the gentleman would yield. As significant
as it is to get this thing reauthorized before the time
expires, I don't know how I in good conscience can set up a
mark-up unless we have the goals performance agreement in
writing, as well as the study. This should be presented to us
in adequate time.
Please proceed, Mr. Burr.
Mr. Burr. I thank the chairman for that. In an effort to
try to keep our efforts focused, as your efforts are, and that
is to a very valuable tool in the process of processing
applications, and bringing new drugs to the market in a timely
fashion, I hope that as we move through this mark-up period
that my colleagues on this subcommittee, as well as the full
committee and the House, understand the importance of this
reauthorization.
Sure, we can chicken out and stick it on the appropriations
bill later this year, and not talk about some of the things
that are legitimate in this debate, but at the end of the day
reauthorization of user fees mean that we bring potential new
products to the marketplace that have a tremendous quality of
life effect on the individuals that are waiting for these
drugs.
And, yes, we potentially bring down long term health care
costs because we eliminate the in-patient stays. And I think
that is the real work of this committee as we try to sort out
the health care marketplace in the future.
Let me ask you if I could relative to the goal sheet. I
understand that a risk management program was agreed to by the
industry and the FDA that will effectively double the number of
FTEs dedicated to drug and biologic safety. What type of
advance is this for the American people and does the industry
support the FDA's risk management plan?
Mr. Crawford. Yes. We believe that they do and they will.
This is an extension of what I was talking about, this peri-
approval process. We are going to devote more effort, and more
resources of other types to that, not the least of which will
be electronic information technology.
And as I mentioned earlier, I believe that in FDA's history
there was a time when we sort of put the drug out there and we
didn't worry that much about it. And that time is changing, and
we recognize that this kind of surveillance, once a product is
on the market, is a very real and sacred trust that we have.
And we will be working hard on that.
Mr. Burr. Dr. Crawford, in your testimony, I think you
alluded to the fact that there was a--I call it a disparity, a
difference between the review and approval times for drugs,
versus biologics. Why does that disparity exist between the two
centers?
Mr. Crawford. Well, I will give a general response and then
ask Dr. Zoon if she has comments. Drugs, as you well know, are
chemical entities, and many of them are similar to drugs that
have already existed, and that simply have another molecule on
them or something like that.
And we are able to have a body of information, and we have
had even the most advanced drugs like anti-cancer drugs and
antibiotics now for many, many years. So we have a residue or
body of understanding about them that enables us to review them
more carefully.
With biologics, many of them are bioengineered drugs of one
sort or another, and they are also--there is gene therapy that
is covered in biologics, and this is something new for us, and
we have to do it very, very carefully indeed. And it just takes
a little more time.
Ms. Zoon. There are a number of issues, particular speaking
about biologic supports and solicitation of getting to the
marketplace for consumers, safe and effective therapies as
quickly as possible.
And in fact the Center for Biologics has met all of its
PDUFA goals. All of them were exceeded, all of its PDUFA goals.
The issue then comes down to what is the reason why the times
are longer. And there is multiple reasons, and it is not all
related to one single issue.
One deals as Dr. Crawford said with the complexity of
biological products, and many of these are cutting edge
technologies, and a lot of the issues with large complex
molecules need to be dealt with, and things can go wrong with
them.
Sometimes in the manufacturing and the ability to be able
to make these products consistently, and other times they deal
with manufacturing and facility issues, and being able to
prepare them in a way to ensure that they meet GMP compliance.
And then other issues surrounding the clinical efficacy
data, and safety data with many of these ground breaking
products. We tried to work very hard with the companies to work
out these issues.
I think in the context in the future of PDUFA-3 that there
will be more support for those interactions, and to try to deal
with those problems proactively by having additional resources
to facilitate those issues.
Mr. Bilirakis. The gentleman's time has expired.
Mr. Burr. I thank you for that progress and I thank you for
the time, Mr. Chairman.
Mr. Bilirakis. Again, that is why we are very anxious to
see the results of all of your negotiations and your
discussions. Ms. Eshoo.
Ms. Eshoo. Thank you, Mr. Chairman, and I want to thank you
for what you said just a few moments ago, and that is how
important it is to have the side agreement come to us sooner
rather than later.
And I have to tell you that if you want to see this thing
move, weeks is not good. Weeks means more than a month, and
what we have to do--this Congress is not going to bump up to
Christmas. There are elections this year, and so we are going
to be getting out in October.
So we have a very limited timeframe here, and so thank you,
Mr. Chairman, for setting that down as a priority. It is an
important one. I want to pursue with Dr. Zoon if I might the
whole issue of outcomes. How do you explain the differences--
well, first of all, to set the stage.
Most of the companies that we are dealing with relative to
the special protocol reviews and that are small. And so they
really need help navigating this process. So in many ways they
are more agency reliant than others are, than the big guys are.
How do you explain the differences in special protocol reviews?
It is 129 for the CDER, which for my colleagues if the
scrambled letters don't make that much sense to you, that is
the Center for Drug Evaluation and Research. It is 129 for the
CDER and one for the Center for Biologic Evaluation, and
Research.
And given that these reviews as I said are supposed to help
the smaller companies negotiate the complicated process,
wouldn't you expect the reverse? I would expect the reverse to
be true. Can you enlighten us about this?
Ms. Zoon. Well, I can say that I don't know all the
answers. I think there are some explanations at least that I
can give, and perhaps our colleagues when they have a chance
can also elaborate on that.
Many of the issues of concerns to biologic manufacturers
are generally arranged during our planned meetings that have
been scheduled under the PDUFA program.
So one does not actually need to utilize the special
protocol in order to discuss important clinical trial design
issues or manufacturing issues, or other items of importance in
product development.
So many of those issues are addressed during those meeting,
and the meeting minutes are generated and agreed to.
Ms. Eshoo. Well, let me just interject something though. As
we listen to constituents and what they say, I am always
mindful that if you only pick up on what one person says, and
put a multiplier on it, you may be causing a boomerang on a
hundred others.
But there is a common thread of complaint in this area. So
if this were being taken care of in the consultation, or what
did you just refer to what it is?
Ms. Zoon. Our meetings?
Ms. Eshoo. Your meetings. Why would there be these
complaints? I mean, if it is already being taken care of, and
it is a lopsided number. Maybe you can't give the answer, and
maybe subsequent panels will speak to it, panel members. But it
is an area that is a rub.
Are you pleased with it, and do you have something from
inside the agency where you are trying to beef this up and
improve upon this outcome?
Ms. Zoon. Well, I think the answer is that if in fact this
particular vehicle under PDUFA-2 was made available for
everyone--the question is how many people actually know about
it and utilize it to the extent perhaps they may wish to, or
want to, in other areas.
Ms. Eshoo. Let me ask you this. What is the agency doing to
proactive if you think that people don't know, and you see it
as being highly workable and a problem solving arena?
I have a sense that there is a shortcoming here, and I am
not trying to pick on you or find something. In our review of
when we reauthorize this, it is always about making something
good even better.
So I am mindful of that and I think that this is an area
where there is a shortcoming, and the approval times that
CBER--I think that seriously when you look at the numbers, they
seriously lag behind those at the CDER.
So that is up to the agency to tell us why this is so.
These are the numbers that you have created, and that's why I
raised them.
Mr. Crawford. If I could respond. These meetings are as Dr.
Zoon indicated optional, but the reason that we--we need to
find out the reason that they are not taking advantage of them.
So there is some sort of shortcoming.
Ms. Eshoo. But have you raised them from inside the agency
to take a look at it, or is it the Congress through these
hearings weighing in that is making you aware of it?
Are we both doing it at the same time, or have you looked
at it, looked at this number, 129-to-1, and said, all right,
now we see that this isn't all that it should be, and this is
what we are doing.
Or is this news to you today, or is it something that you
have not had time to take a look at, even though you are aware
that the numbers aren't so great?
Mr. Crawford. This is not new to us. It is something that I
have not had time to take a look at, but I will, and I
appreciate that.
Ms. Eshoo. Is there any news about the appointment of the
Commissioners at the FDA?
Mr. Bilirakis. Why don't you ask Dr. Crawford very briefly
Ms. Eshoo. Dr. Crawford, do you want to comment on that? You
know, I raised that because--I know that people are thinking I
am raising it because of political sensitivity or whatever.
The FDA is one of the most important Federal Agencies in
our entire Nation. My constituents bank on the FDA protecting
them. I mean, they feel very strongly about it, and I know in
the past when there were attacks and whatever, they said, look,
don't destroy or take the whole thing down.
And so for an agency to be--well, I shouldn't say
rudderless, but not to have a person at the top I think is why
I raise it. What can you tell us?
Mr. Bilirakis. Very briefly, Dr. Crawford.
Mr. Crawford. Unfortunately, I can't tell you anything, and
I will be honest with you.
Ms. Eshoo. All right. Thank you. Thank you, Mr. Chairman.
Mr. Bilirakis. Dr. Zoon, do you have something to add to
that?
Ms. Zoon. The only thing, and just to further address one
of the issues is that one of our thoughts is, and we actually
are going to be doing some proactive outreach to make sure that
people understand what PDUFA offers to them in a outreach
program as part of our center initiatives.
Because I think we saw the numbers, and we are trying to
understand them, but we think one thing we can do is do more
outreach to make sure that people understand the options open
to them.
Mr. Bilirakis. All right. Thank you, doctor.
Ms. Eshoo. Thank you, Mr. Chairman.
Mr. Bilirakis. Dr. Norwood to inquire.
Mr. Norwood. Thank you, Mr. Chairman, and I do thank all
the panelists for being here, particularly Dr. Crawford, who is
a former professor at the University of Georgia, and at
Georgetown University, a couple of my favorite universities out
there.
So welcome one and all. The questions have all been good it
seems to me for once, and we are all sort of on the same page,
but I want you to tell it to me. Do you believe PDUFA-3 needs
to be preauthorized?
Mr. Crawford. I do believe it needs to be authorized. It is
very important for the public health of this country.
Mr. Norwood. It is very important for the public health of
this country, and I would say that in some ways that it is
pretty important for the FDA, too, wouldn't you agree with
that?
Mr. Crawford. Absolutely, yes, sir.
Mr. Norwood. Well, since you were down in Georgia long
enough, we can have some straight talk. Dr. Crawford, we need
that performance goal letter by 5 p.m. Monday. There is
absolutely no reason that all of us are going to work next
weekend, and you put your people to work, too.
If you want to have this thing authorized, you get that
letter to the chairman. We have problems, too. Now, get it
done. And if you can't get it done on Monday by 5 p.m., tell me
right now why; or just better yet tell me you will get it done.
Mr. Crawford. It pains me to beat around the bush here,
but----
Mr. Norwood. Please don't. Please don't do that.
Mr. Crawford. But we will make every effort to get it as
soon as we possibly can, and that is----
Mr. Norwood. No, that is not an answer. It is not
reasonable for you not to answer the question. If you can't get
it by 5 p.m. Monday, when? The date. And then make it work.
This is critical.
Mr. Crawford. Okay. Well, you know, until we get into it,
we can't really say the exact date, but I hear you.
Mr. Norwood. Yes, you can. You set the date and make them
go to it. The chairman will not authorize this without that
document.
Mr. Crawford. We understand that, and we will get to work
on it, and that is a promise.
Mr. Norwood. Can anybody tell me if 5 p.m. on Monday is
okay?
Mr. Crawford. I think I am the one, and I do, too. I do
know that. Okay. I hear you.
Mr. Norwood. Well, I don't know how to say this any other
way, except to say that you are not answering the question, and
it is a good thing that we are friends, and all of that, but
you need to answer the question.
You need to commit yourself to when the chairman will have
the documents so we know what to do, because we all want to
look at the document, and we hope then from that that we can
reauthorize a critical issue. Now, set the darn time, and work,
and make it happen.
Mr. Crawford. We will surprise you.
Mr. Norwood. Well, I have a feeling that we will surprise
you back if you don't surprise the subcommittee.
Mr. Crawford. I am well aware of that, yes.
Mr. Norwood. Mr. Chairman, I think I am through.
Mr. Bilirakis. We have a series of votes. I had hoped that
we could finish up with Dr. Crawford before we left, but there
is just no way that we can do it. I think we are going to have
to break.
Please, let's get back just as soon as we cast that second
vote. I think there is two of them, and let's finish up. Thank
you.
[Brief recess.]
Mr. Bilirakis. Mr. Bryant to inquire of Dr. Crawford.
Mr. Bryant. Thank you, Mr. Chairman, and Dr. Crawford,
welcome. I just have a few follow-up questions, three to be
precise, and so I will try to squeeze those in about 5 minutes,
and so if you could take and consider that when you answer.
I have been in and out, but I know that the FDA has done
some studies in regard to the issue that perhaps some have been
about rushing these reviews, and in some respects compromising
safety.
I don't know how much you have talked about those studies,
but I would like to have those, if reasonable, attached to your
testimony. Is that a very large study, or is it feasible?
Mr. Crawford. No, we can give you some information on that
and attach it without exception.
[The following was received for the record:]
The Office of Inspector General (OIG) of the Department of
Health and Human Services is evaluating the efficiency and
effectiveness of the review process for new drug applications
under PDUFA II. We understand that the OIG is in the drafting
stages of their report.
Mr. Bryant. Can you give me a bottom line?
Mr. Crawford. Yes. The bottom line is that since PDUFA-1
went into effect, the number of drugs that have to be recalled
because of safety concerns has not changed, and although more
drugs are being approved, no higher percentage are having these
kinds of difficulties.
Mr. Bryant. You were about to answer a question earlier on
from someone, and you were cutoff a little bit, and you started
out if you can remember this that if you keep the drug off the
market, and you were kind of cutoff at that point.
I assume that this has some connection with the impact of
PDUFA on making drugs and biologics more available to the
American consumer? Could you explain that for me?
Mr. Crawford. Yes. What I was referring to was that each
new generation of drugs that FDA has regulated has genuinely
been safer and even more effective than the previous
generation.
So when a new drug, which is a breakthrough entity that has
real prospects for improving public health in the country comes
along, it is incumbent upon us in my view to review it as fast
and as accurately as we possibly can so that it can get on the
market and begin improving the public health of this country.
We can't compromise the safety and efficacy requirements
that we have, but if it isn't introduced expeditiously, and it
hasn't been too many years ago when it took 4 or 5 years to do
what we are doing now in about 6 months.
And people did suffer as a result of that, and so we have
done a variety of things, like PDUFA, and even some other
initiatives to try to be sure that the drug is safe, and be
sure it is effective, and then if it has the promise that many
of these do, try to get it on the market, or try to get it
approved as soon as we possibly can.
Mr. Bryant. My last question is has PDUFA had any effect on
pharmaceutical research and development?
Mr. Crawford. Well, actually, if you go back and look, and
all of us have been briefed on this, one of the goals was to
send a signal to the pharmaceutical industry, and the biologics
industry, that the FDA is shaping up its approval process.
We are changing as a result of PDUFA, and rather than
getting credit for turning down drugs, we are going to get
credit for approving drugs correctly.
And that message being sent to the pharmaceutical industry
was intended to spur innovation and development of these new
drugs, particularly those for diseases that no drug existed
for, and we think by and large that it has worked.
Mr. Bryant. I have no other questions, but just one comment
just in follow-up to Mr. Norwood. I think you received his
message clearly, and coming from an arena of law here I had to
negotiate quite a bit, and I understand the situation that you
are in with this letter, and there is some give and take on
this, but if one side is under a deadline, usually they are at
a disadvantage.
But I think in this case that neither side--I think that
both sides have a real interest in getting this done, and so
even though you are here and we are talking to you, I would
send that message out clearly to those in the audience that
represent the other side, and who very clearly have a strong
interest in this bill being reauthorized that we really need
agreement as quickly as possible, and maybe even as soon as
next Monday.
But it would help us in that regard. So I think that all
the parties agree that we need to have this done. Thank you,
and I yield back my time.
Mr. Bilirakis. I would expect that there are an awful lot
of representatives here from quote, the other side, who have
gotten that message. Mr. Waxman to inquire.
Mr. Waxman. Thank you very much, Mr. Chairman. Dr.
Crawford, rapid drug approval has put an extra burden on FDA to
watch for unexpected safety problems after marketing.
The FDA no longer has the luxury of a lengthy review period
to detect safety issues before approval, nor does it have the
advantage of watching the European experience with a drug
before it is marketed here.
At the same time the FDA's post-market surveillance system
is seriously flawed. It is based on voluntary reporting from
health care professionals, and I understand that the FDA
estimates that it hears of less than 1 percent of serious
adverse reactions.
And while the FDA allocates over 2,000 FTEs to premarket
reviews of new drugs, it has been able to assign less than 5
percent of that number to post-market safety monitoring.
I am concerned that the FDA's current post-market
surveillance system is not up to the challenge posed by rapid
drug approvals. What changes in FDA's post-market surveillance
program are needed to run an effective program, and will the
amount of money the industry has put forward pay for the needed
changes?
Mr. Crawford. That is one of the things that I am very
concerned about, and have been briefed on by Dr. Woodcock and
her staff. And I would if I may like to ask her to give the
bottom line of those briefings.
Ms. Woodcock. That is a complex question you are asking.
The recommendations that we have arrived at would actually
double the size of the review staff in drug safety at the
agency, and that would be a tremendous boost.
However, there are many drugs, of course, that are generic,
that are off patent, that have safety problems. Most of the
drugs on the market have not been newly approved, and as you
know, my feeling is that drug safety is a broad issue, and it
does not pertain to the first year or so after a drug is
approved.
It pertains to all drugs that are on the market. We find
problems years, sometimes decades, after a drug is on the
market.
Mr. Waxman. Well, you mentioned that this funding from user
fees will double the staff of post-marketing, but I understand
that is over a 5 year period.
Ms. Woodcock. Correct.
Mr. Waxman. Just tell us in your best professional judgment
what would FDA need to have in place to do a post-market
surveillance program that will accomplish what we would like to
see ideally to assure the public about the safety of drugs that
are on the market?
Ms. Woodcock. For drugs, we need money for access to data
bases, and the linked health care data bases that exist now,
and the health care organizations that link adverse reactions
to prescriptions, and outcomes, we need the money to do studies
so that when health problems are detected or suspected with
drugs, we can go out and confirm or evaluate whether or not
these are real, and if so, what to do about them.
Mr. Waxman. I assume the money that will be provided in
this agreement with the industry will not be sufficient to do
what ought to be done for a post-marketing surveillance
program.
Ms. Woodcock. In my judgment that is true, but that many of
these drugs are not new drugs.
Mr. Waxman. How much money and how many staff people in
your best professional judgment would be needed to do a good
post-marketing surveillance program? You might want to get it
for the record.
Mr. Crawford. Yeah, I think that is a good idea. Can we
submit that for the record?
Mr. Waxman. Yes, please. I understand in this agreement
with the industry that it authorizes the FDA to use a portion
of the user fees to gain approximately a hundred new FTEs
devoted to post-market safety over the next 5 years.
And while it is a good start, and welcome change, I am
concerned that though there is apparently nothing explicit in
the agreement about the number of FTEs that FDA can add to the
post-market surveillance program.
Instead, the only explicit part of the agreement is a goal
that is set for premarket review. And I would like to know how
we in Congress can be sure that the fees currently earmarked
for post-market safety will in fact be used for that purpose.
For example, if in a given year the FDA does not have
sufficient resources to meet its performance goals, which again
are only for pre-market approvals, what will stop the agency
from taking resources from the post-market safety program to
help meet performance goals for faster approvals?
Ms. Woodcock. We issue a report to Congress yearly, both a
performance report and a financial report. We would expect that
the yearly reports issued under this new program would have a
line item for how many dollars, and how many FTEs are devoted
in drug safety from user fees.
Mr. Waxman. Well, I guess what I want to try to focus on is
that the agreement, which could be the basis for legislation,
spells out a performance goal for premarket reviews, and no
performance goals for post-market safety activities.
Don't you guarantee that post-market safety will always be
sacrificed in order to meet pre-market review deadlines? And is
pre-market review speed more important than post-market safety
evaluation from a public health point of view. I think we would
both say no.
But can we be assured that we are not going to find
ourselves in a position where that money is going to be used
for pre-market instead of post-market if you fail to meet those
performance standards?
Ms. Woodcock. We have viewed it as an obligation to use the
money as it has been intended under the user fee program, and
that is laid out in the reports that we give to Congress. And I
don't think that we would change the money around.
Mr. Waxman. And will the people hired with user fee money
be allowed to work on non-PDUFA-3 drugs?
Ms. Woodcock. Could I answer that, because it is
complicated?
Mr. Waxman. Yes, sure.
Ms. Woodcock. It is a level of effort arrangement. We don't
have people with a star on their head saying user fee people,
and non-user fee people. So we would have to devote a certain
level of effort to the PDUFA-3 drugs, if that makes sense to
you.
But it would not be by individual, individually.
Individuals would work on whatever was appropriate.
Mr. Waxman. Can I ask just one last question, Mr. Chairman?
Mr. Bilirakis. Yes, but just briefly.
Mr. Waxman. My last question is this. I am concerned about
the fact that we have direct to consumer advertising by the
pharmaceutical manufacturers, and the FDA has a role to make
sure that it is not false and misleading.
I also understand that the FDA has very, very, little
resources to accomplish that goal. Perhaps for the record you
could tell us what you would need if you were actually going to
do the job that you have the power to do, but not the resources
to do, to supervise these consumer ads to be sure that they are
not false and misleading.
Mr. Crawford. May we submit that analysis for the record
also?
Mr. Waxman. And please submit the answers to my questions
about optimal staff and budget, in terms of your best
professional judgment, and not what is approved by every
politician around, but your professional judgment.
Mr. Crawford. Thank you, sir.
[The following was received for the record:]
The Division of Drug Marketing and Advertising (DDMAC) in
the Center for Drug Evaluation and Research (CDER) is
responsible for the regulation of prescription drug
advertising. This Division currently has assigned 39 full-time
equivalents (FTEs) positions. While DDMAC has worked to
maximize its productivity and is currently undergoing a
reorganization that is designed to further improve its
efficiency and effectiveness, the current staffing is not
adequate to keep pace with the rapidly increasing number of
professional and direct-to-consumer advertisements for
prescription drugs. It is estimated that CDER would need
approximately 35 additional FTEs and supporting operating funds
to fully staff the advertising review program.
Currently, the Center for Biologic Evaluation and Research
(CBER) has 4 FTEs to review all advertising and promotional
labeling materials submitted. In order to adequately assess
these materials and bring timely enforcement actions, a large
increase in staff would be required. Based on the projected
number of submissions for FY2003, and conservative estimates of
man-hours needed to review these submissions, 30 additional
review FTEs would be required. Additional management and
support staff would also be needed, for a total of 38 FTEs at a
cost of $5,130,000.00. An additional $550,000 would be required
for IT upgrade and support of a tracking system. This would
result in a total requirement of $5,680,000.00.
Mr. Bilirakis. We will be submitting, of course, a number
of questions to you. There are people here who have sat around
all morning long, and haven't had the opportunity to inquire of
you, Dr. Crawford.
Per usual, you will be responding to those in a timely
fashion. That being the case, we are going to finally excuse
you and express our appreciation to you, and Dr. Zoon, and Dr.
Woodcock, for the long delays and sitting in the chair as long
as you have.
Mr. Crawford. Thank you very much.
Mr. Bilirakis. Thank you very much. Again, help us to help
those who need to be helped.
Mr. Crawford. We shall do that.
Mr. Bilirakis. Thank you. Panel Number 2 will consist of
Dr. Timothy R. Franson, Vice President of Clinical Research and
Regulatory Affairs, U.S. Eli Lilly Research Laboratories; Dr.
Alastair J. J. Wood, Assistant Vice Chancellor for Research,
Professor of Medicine, and Professor of Pharmacology, at
Vanderbilt University School of Medicine; and Dr. Mary
Pendergast, Executive Vice President of Elan Corporation.
Welcome to all three of you. We can start off with Dr.
Franson. If you would, please. We are setting the clock at 5
minutes. Your written statement, of course, is a part of the
record.
We would hope that you would supplement or compliment it,
and let's do the best that we can.
Dr. Franson, please proceed.
STATEMENTS OF TIMOTHY R. FRANSON, VICE PRESIDENT OF CLINICAL
RESEARCH AND REGULATORY AFFAIRS, U.S. ELI LILLY RESEARCH
LABORATORIES; ALASTAIR J.J. WOOD, ASSISTANT VICE CHANCELLOR FOR
RESEARCH, VANDERBILT UNIVERSITY SCHOOL OF MEDICINE; AND MARY K.
PENDERGAST, EXECUTIVE VICE PRESIDENT, ELAN CORPORATION
Mr. Franson. Thank you very much. Chairman Bilirakis,
Ranking Member Brown, and members of the subcommittee, thank
you for the opportunity to discuss the reauthorization of
PDUFA.
My name is Tim Franson, and I am a physician, a pharmacist,
and Vice President of Clinical Research and Regulatory Affairs
at Eli Lilly and Company. And I am representing the views of
the Pharmaceutical Research and Manufacturers of America,
PhRMA.
Very few legislative initiatives have been as effective and
successful as PDUFA. The user fee program was created while
keeping two overriding and principled goals in mind. There must
be no real or perceived paying for a drug approval, and patient
access to new treatments must be expedited.
The results of the program are tangible. Since enactment of
the program in 1992, the FDA has approved 712 drugs, and 198 of
these being priority reviews, which have had a remarkable
positive impact on patients.
It is critical to note that the user fees are designed to
be added to FDA appropriated base funds. Congress wisely added
two triggers to assure that the FDA could not collect user fees
unless the base line appropriation for FDA was preserved, and
the necessary funds within the appropriations were spent on
drug review in the full sense.
The public health advantages of PDUFA cannot be overstated.
Patient access to new, safe, and effective medicines has been
expedited. Prior to the initial passage of the legislation,
drug reviews at FDA took on average over 30 months.
The review time has been cut in half over the past 9 years
that the program has been in effect. The FDA is now approving
new, life-saving therapies before other regulatory agencies in
the world, giving American patients first access to these
important medicines.
There is improved, appropriate communication between the
FDA and the companies developing these new drugs, and thus
facilitating the decisionmaking process. And according to FDA
statistics, the law has had no effect on market withdrawal
rate, which has remained at 2.7 percent, both pre-and-post-
PDUFA.
Clearly, this program is an excellent example of how to
structure a successful working relationship between the
regulator and the regulated without compromising safety and
efficacy standards.
The integrity of the program is in its simplicity;
incremental resources for FDA and measurable performance goals.
These goals have been kept out of the statute and dealt with in
a side-letter from the Secretary of HHS to Congress.
The statute is explicit about the use of user fee funds,
and they can only be used for the process for the review of
human drug applications. The retention of this limitation is
critical to the proper scope of PDUFA.
It focuses the additive resources on the activities that
best serve the broad public health goal of the law, the prompt
review of important new drugs.
PDUFA-1 focused solely on the drug review process, and
PDUFA-2 focused on improving interactions during the clinical
drug development phase. As we look forward to extending this
program, we identified several key objectives.
Continuing to assure a sufficient financial base for FDA.
Incorporating the most current information technology into the
review process. Exploring new concepts to bring additional
efficiencies to the process.
Improving performance management, and continuing to assure
that the safety of new drugs is of the highest priority. The
FDA has proposed a risk management program in which the agency
would gain additional resources to evaluate risk management
plans associated with new products.
These will address questions of what may occur as products
reached to a larger number of patients in the first 2 to 3
years of marketing, the time in which a vast majority of risks
are identified.
Additional user fees will be allocated for the risk
management program, and this will complement the extensive
programs that the FDA and PhRMA member companies have in place
to monitor post-market safety of new drugs.
In closing, I want to acknowledge the over 1,000
professionals at FDA, who are a large part of the success of
this program, and who are dedicated to doing their job to the
highest standards.
PhRMA hopes that Congress will act to reauthorize this
program, assuring these employees of the shared commitment of
all parties to continue the program for another 5 years, and to
assure continued, timely flow of new therapeutic advances to
waiting patients.
Thank you, and I will be happy to answer any questions that
members of the committee may have.
[The prepared statement of Timothy R. Franson follows:]
Prepared Statement of Timothy R. Franson, Vice President, Clinical
Research and Regulatory Affairs, Eli Lilly & Company on Behalf of The
Pharmaceutical Research and Manufacturers of America
Mr. Chairman and Members of the Subcommittee, I'm pleased to be
here on behalf of the Pharmaceutical Research and Manufacturers of
America (PhRMA) to present its views on the reauthorization of the
Prescription Drug User Fee Act (PDUFA). PhRMA represents the nation's
leading research-based pharmaceutical and biotechnology companies,
which are devoted to inventing medicines that allow patients to live
longer, healthier, and more productive lives. Investing more than $30
billion in 2001 to discover and develop new medicines, PhRMA companies
are leading the way in the search for cures. Right now, our companies
have some 30,000 researchers working on more than 1,000 potential new
medicines. We want patients to have access to safe and effective
medicines as soon as possible. That's why we're here today.
As members of this Subcommittee well know, opportunities to make a
real societal difference through legislation are unique and special.
PDUFA, enacted in September 1992, was clearly a central piece of
legislation that has affected the lives of many American citizens who
needed prompt access to important new medicines. The Energy and
Commerce Committee played a critical role at that time and the Commerce
Committee was key again in 1997 when PDUFA was reauthorized as part of
the Food and Drug Administration Modernization Act. As the members of
this Subcommittee are aware, PDUFA expires at the end of this federal
fiscal year. Prompt reauthorization is critical to all the
stakeholders: to industry, which seeks to maintain timely review; to
the FDA, which anticipates gaining important additional resources; and
most of all, to the American public, who await new advances that our
industry is developing to treat their diseases from cancer and AIDS to
Alzheimer's and diabetes.
The public health benefits of PDUFA cannot be overstated. Patient
access to new safe and effective medicines has been expedited. Prior to
the initial passage of the legislation in 1992, drug reviews at FDA
took on average over 30 months. The review time has been cut in half
over the past nine years that the program has been in effect. FDA is
now approving new life-saving therapies before other regulatory
agencies in the world, giving American patients first access to these
important medicines. There is improved appropriate communication
between FDA and the companies developing these new drugs. This leads to
a greater and timelier exchange of information, facilitating the
decision-making process. Finally, this program is a clear example of
how to structure a successful working relationship between the
regulator and regulated without compromising standards.
The results of this program are tangible. One need only look at the
number of drugs and biologics approved over the past nine years. FDA
has approved 712 drugs; 198 of these were priority reviews. Among the
examples of new treatments that American patients have access to are:
(1) Gleevec--A drug approved for the treatment of chronic myeloid
leukemia, which is a rare and deadly disease that affects some 25,000
Americans. A priority drug, it was approved in just over two months.
(2) Xigris--A drug approved for the treatment of adults
hospitalized with severe sepsis that are at a high risk of dying. Prior
to the approval of Xigris, about 1,000 people died of this condition
every single day. A priority drug, it was approved in under 10 months.
(3) Trisenox--A drug approved for the treatment of leukemia (acute
promyleocytic leukemia) in patients who have not responded to, or have
relapsed following all trans-retinoic acid and anthracycline-based
chemotherapy. A priority drug, it was approved in six months.
(4) Mylotarg--A drug approved for the treatment of a certain type
of leukemia (CD33 positive acute myeloid leukemia) for patients 60
years or older who have relapsed for the first time and are not
suitable candidates for the standard but poorly tolerated cytotoxic
therapy. A priority and orphan drug, it was approved in about seven
months.
(5) Zyvox--A drug approved for the treatment of bloodstream
infection, hospital-acquired pneumonia, and community-acquired
pneumonia. A priority drug, it was approved in six months.
The concept of a user fee program to augment FDA resources was
first proposed by the Agency. The lengthy time of drug reviews was
attributed to the lack of adequate resources, a view put forth by the
FDA and agreed to by the pharmaceutical industry. A distinct need for
supplemental resources on top of those appropriated by Congress was
established with one principal goal: there must be no real or perceived
``paying for a drug approval.'' Over the past nine years this goal has
been met. Although performance goals were established in both PDUFA-1
and PDUFA-2, these were kept out of the statute and dealt with in a
side letter from the Secretary of HHS to Congress. Thus, the PDUFA law
itself is rather simple, covering the fee structure, how fees can be
collected, and what they can be used for.
It is critical to note that the user fees are designed to be
additive to the FDA appropriated base funds. Congress, in its wisdom,
added two ``triggers'' to assure that FDA could not collect user fees
unless there was a baseline appropriation for all of FDA and the
necessary funds within the full appropriation were spent on drug review
activities. Collectively the two ``triggers'' emphasize the ongoing
public responsibility to provide FDA with adequate resources to carry
out its mission to advance the public health.
PDUFA-1 focused solely on the drug review process, reducing the
time to FDA action to six months for priority drugs and twelve months
for standard drugs. FDA also agreed to process the backlog of pending
applications within the first two years of the program. Both goals were
accomplished.
While PDUFA-1 focused on FDA review time, PhRMA stressed that the
FDA review of an application, while significant, is only a fractional
portion of the whole drug development time that was taking as long as
12 years. As the pharmaceutical industry looked toward the first
reauthorization of PDUFA in 1997, proposals were offered to the FDA
that would improve interactions during the clinical development phase
of drug development with the hope that improvements in this lengthy
process (6-8 years) could be realized with the same degree of success
that occurred with the FDA review phase. Agreement was reached on a set
of metrics that has made such interactions more predictable. In
addition, PDUFA-2 incorporated processes for resolving disputes,
assessing special protocols, providing prompt feedback when sponsors
submit information in response to a clinical hold, and simplifying the
action letter that the sponsor receives following the review of an
application. Collectively, these enhancements are beginning to improve
the drug development process.
As PhRMA began preparing for the PDUFA-3 reauthorization, we
recognized that this is a sound program that works and works well. The
integrity of the program is its simplicity: measurable performance
goals in return for the added incremental resources for FDA. The
statute is explicit about the use of user fee funds; they can only be
used for the ``process for the review of human drug applications.'' The
retention of this limitation is critical to the proper scope of PDUFA;
it focuses the additive resources on the activities that best serve the
broad public health goal of the law, the prompt review of important new
drugs. While no less important, the broad array of other FDA regulatory
activities that deal with a host of post-market issues are best funded
out of the federally appropriated budget. PhRMA recognizes the critical
role of these activities and the necessity for full funding of the Food
and Drug Administration.
One critical issue that surfaced back in 1992 was whether the
nature of the proposed legislation constituted a ``tax'' on industry.
It was argued at that time, successfully, that the program would not be
a tax, but rather a fee for service. Thus, Congress avoided a difficult
jurisdictional decision as to whether referral to the House Ways and
Means and the Senate Finance Committees would be required. PhRMA would
urge the Subcommittee to preserve the current language in the statute
to insure that PDUFA continues to meet the above-mentioned process
definition. In this manner, PhRMA hopes that Congressional jurisdiction
will remain clear and unambiguous.
The goals for the program over the next five years are
straightforward. We must preserve the significant process improvements
that have been made over the past nine years of PDUFA. PhRMA
consistently has complimented the FDA for meeting every established
performance goal, in most cases well ahead of schedule. Interactions
between the FDA and sponsors of new medicines have never been better.
The predictability of the regulatory process provides a degree of
certainty to companies' drug development programs.
There are some key aspects of the proposed PDUFA-3 program that are
worth discussion.
We need to continue to assure a sufficient financial base that
preserves the current services and achievements made during the
first two cycles of PDUFA. The current FDA budget that fully
funded the Agency's current cost of living increase was of
great assistance in meeting this goal.
We must continue to move toward incorporating the most current
Information Technology (IT) into the review process. Over the
five years of PDUFA-2, industry has provided over $80 million
of user fees to upgrade the IT infrastructure of both the Drugs
and Biologics Centers. By the end of this fiscal year, FDA will
be in a position to receive all regulatory submissions in
electronic format. This includes not only the New Drug
Application, but also the large amount of information that is
required during the clinical development process, the annual
reports that are required of all approved drugs, and the
reports of adverse drug reactions. Industry is willing to
continue this level of funding and add extra funds toward
targeted programs. We must remember that FDA is responsible for
managing large amounts of information and this ongoing IT
initiative is critical to the Agency's function.
We need to continue to explore new review concepts that will
bring additional efficiencies to the process. PhRMA has
proposed to pilot a ``cumulative marketing application'' in
PDUFA-3. Rather than waiting until the full application is
complete, FDA would begin to review defined modules of the
submission, as they are finished. This ``building'' of a
reviewed NDA may lead to marked improvements in the way drugs
are reviewed.
We need to develop a workload adjuster that reflects all of
the activities of the new drug review process, rather than just
the completed NDA submission. FDA allocates user fee resources
to the review of efficacy and manufacturing supplements as well
as all of the interactions with sponsors during the clinical
development time period. During PDUFA-2, workload was
calculated only on the basis of fee-paying applications. By a
rough estimate this represents only about 40% of the net review
burden of the Agency. If the number of these applications dip,
as it has in the last couple of years, FDA's ability to carry
out all of its responsibilities will be hampered by
insufficient additional resources.
PhRMA and the FDA have been in agreement that the safety of
new drugs must continue to be one of the highest priorities in
the development and approval process. To this end, we have been
in frequent discussions with other PDUFA stakeholders to
improve this function. We all acknowledge that drugs are not
without risks. The basic premise of drug development is
managing the benefit/risk relationship. Additional information
on the safety of drugs emerges constantly, particularly in
early use following approval. PhRMA companies already dedicate
significant resources, both personnel and money, to pre- and
post-approval safety vigilance activities. While there has been
no increase in the rate of drug withdrawals during PDUFA
compared to pre-PDUFA periods, the FDA has proposed a risk
management program in which the agency would gain additional
resources for the purpose of evaluating risk management plans
associated with new products, and to address questions of what
will occur as products reach larger numbers of patients in the
first 2 to 3 years of marketing--the time in which the vast
majority of risks are identified. Additional user fees will be
allocated for the risk management program.
We should allocate a modest proportion of PDUFA funds for
improving performance management. By implementing ``good review
management principles,'' FDA can bring consistency throughout
the review divisions that are located within both CDER and
CBER. Secondly, as the PDUFA program enters its third cycle,
PhRMA believes that this is an appropriate time for a major
management review focusing on process review and analysis
within the two Centers. This review should be comprehensive,
involving a thorough analysis of IT utilization, review
management, and activity cost. The resultant process map should
enable FDA to make far greater use of its principal resource,
people power.
Finally, we must not lose sight of the dedicated employees at the
Food and Drug Administration who are a large part of the success of
this program. User fees now support well over 1000 men and women who
are dedicated to doing their job to the highest professional standards.
PhRMA believes that Congress needs to act with all due speed to
reauthorize this program, assuring these employees of the shared
commitment of all parties to continue the program for another five
years and the continued timely flow of new therapeutic advances to
waiting patients.
Mr. Bilirakis. Thank you very much, Mr. Franson.
Dr. Wood.
STATEMENT OF ALASTAIR J.J. WOOD
Mr. Wood. Mr. Chairman, Representatives, and Ladies and
Gentlemen, thank you also for giving me the opportunity to
testify today. As you already heard, I am Alastair Wood from
Vanderbilt University, where I am Assistant Vice Chancellor,
and Professor of Medicine, and Professor of Pharmacology.
But I am also the drug therapy editor of the New England
Journal Of Medicine. Prescription drug user fees have provided
the FDA with additional resources to allow effective therapies
to reach patients faster.
The program has clearly been a great success and has
achieved its goal. And with respect to that, I would like to
highlight a number of points from my written testimony that
addressed the future under PDUFA.
We are at a time when the potential for innovative drug
development has never been greater. While that innovative
potential is enormously exciting, it will put extraordinarily
new demands on the FDA.
If only a percentage of the genes discovered by the Human
Genome Project reveal new drug targets, this will provide
thousands of new drug classes, and I am not just talking about
new drugs. New drug classes never before seen.
Facilitating such innovative therapies to market will
require paradigm shifts in the way that we think about
evaluation of safety and efficacy. Some of these new challenges
are already apparent.
The old models used to demonstrate efficacy may not be
optimal for the therapies of the future. Drugs are being
developed, for example, to enhance immune function in HIV AIDS.
The reduction in viral load, which is the current standard
measure of efficacy, may not be the optimal efficacy end point
for such drugs. In the cancer area, a number of novel
therapeutical strategies are in development.
Here, too, the old measures of effectiveness based simply
on reduction in tumor size may need reevaluating.
Pharmacogenetics, defined as the effect of genetics on drug
response, has the potential to identify patients whose
particular genetic backgrounds made them either more likely to
respond to therapy, or put them at particular risk from side
effects.
If it is an early stage in the drug development process, we
can identify patients who, because of their genetic make-up,
respond to a drug. And then by including only such patients in
clinical trials, we could substantially reduce the number of
patients that we need to study.
The agency needs to work with industry to identify the
issues related to the use of these more efficient trial
designs, and ensure that their use does not result in overly
restrictive labeling.
Questions have been raised this morning about the effects
of PDUFA on drug safety. The issue is framed sometimes in
different ways. Sometimes the question has been posed are we
approving drugs too quickly.
I think the answer is clearly no. We are not approving
drugs too quickly. In fact, I would go further and say that
there is no intuitive reason to imagine that slowing the
approval process will enhance safety.
Drugs are not like wines; they don't improve with keeping.
An additional way that the question has been posed is are we
withdrawing more drugs because of safety concerns since PDUFA.
Again, the data do not appear to support that conclusion.
Another question that has been raised is how should PDUFA
influence post-marketing surveillance? As someone has already
said, the answer is complicated.
First, it is worth saying that effective post-marketing
surveillance is not and should not be the enemy of industry.
Poorly performed post-marketing surveillance may result in the
needless removal, as we have already, of safe and effective
drugs from the market on the basis of invalid data.
Fortunately, the information technology revolution is about
to radically change the way physicians prescribe drugs. At
Vanderbilt Medical Center, all physician's orders for in-
patients must now be entered by computer.
Dosage, interaction risks, et cetera, are checked
automatically at the time of prescribing, and the results fed
back to the physician before direct transmission of the
prescription to the pharmacy.
The implications for improved patient safety are obvious
and compelling, but there are also substantial opportunities
for post-marketing surveillance.
We will have access to complete data sets on prescriptions
and outcomes, with positive implications for the drug approval
process. The greater our confidence in the post-approval data,
the earlier and faster we should be able to approve drugs.
These prescribing systems are moving forward rapidly, and
the FDA needs immediately to be a player in the development of
such systems.
In summary the upcoming challenges to the FDA are
substantial. These challenges can only be met if the agency has
the resources to hire and retain the quality scientific staff
it needs.
The salaries of FDA scientists need to be maintain parity
with academia, and should be tied to the NIH salary cap. If we
are to fulfill our hopes for novel therapies in the future, it
is essential that the FDA has the increased resources it needs
to participate as a full and credible scientific partner.
User fees alone cannot be expected to provide the required
increases in resources. Additional public funds are required to
adequately fund this critical public health agency. Mr.
Chairman, thank you for giving me the opportunity to present
these views.
[The prepared statement of Alastair J.J. Wood follows:]
Prepared Statement of Alastair J.J. Wood, Assistant Vice Chancellor,
Vanderbilt University School of Medicine
Mr. Chairman, Representatives, Ladies and Gentlemen, I am Alastair
Wood from Vanderbilt University where I am Assistant Vice Chancellor,
Professor of Medicine and Professor of Pharmacology. I have spent my
entire professional life studying and writing about drugs. I have
served on FDA advisory committees and have been the Drug Therapy Editor
of The New England Journal of Medicine for over a decade.
The purpose of the Prescription Drug User Fee Act was to provide
the FDA with the additional resources it needed to allow faster review
of NDAs and therefore have effective therapies reach our patients
faster. The program has clearly been a great success and has achieved
that goal. The success of the program and the occasion of its
reauthorization provide an opportunity to look into the future to
determine what actions are required to ensure that we can continue to
further enhance the drug approval process.
There has probably never been a time in drug development at which
the opportunities were greater. While these opportunities are exciting
they will also put extraordinary new demands on the FDA. It has been
estimated that all of the drugs currently on the market act on only 500
different molecular targets. If only a percentage of the genes
discovered by the Human Genome Project reveal new drug targets this
will provide thousands of new Drug Classes--Not just new Drugs--But
completely new drug classes never seen before. Facilitating such
innovative therapies to market will require, not more of the same but
paradigm shifts in the way we think about evaluation of safety and
efficacy.
Some of these new challenges are already apparent. The old models
used and demanded to demonstrate efficacy may not be optimal in the
future. New approaches from biotechnology drug development are already
posing new and unanswered regulatory questions. Drugs are being
developed to enhance immune function in HIV/Aids--Reduction in viral
load--the current standard measure of efficacy in HIV patients may be
inappropriate for such drugs. In the cancer area drugs are in
development to reduce the occurrence of metastatic cancer, to reduce
blood vessel supply to tumors, to increase drug entry into cancer
cells, while yet others will target the cell signaling processes that
are deranged in cancer cells. Here too the old models of effectiveness
based simply on reduction in tumor size may need re-evaluating. The
development of such new approaches will require all of the
stakeholders--Industry, regulators, academics and patients working
together to define robust, relevant and measurable end points for the
clinical trials of the future.
Pharmacogenetics--The effects of genetics on drug response has
considerable potential to enhance drug investigation and the approval
process. It will allow us to identify patients whose particular genetic
backgrounds either make them more likely to respond to therapy or put
them at particular risk from side effects. Such genetic information is
already being used to optimize drug dosage in the treatment of
childhood leukemia. Of particular relevance to our discussion today is
how this pharmacogenetic information could improve the drug approval
process. If at an early stage in the drug development process we can
identify patients who, because of their genetic makeup, respond to a
drug, then by including only such patients in our clinical trials we
could substantially reduce the number of patients who have to be
entered into the pivotal trials required for drug approval. Conversely
the ability to identify patients at particular risk of developing side
effects from a drug and the exclusion of such patients from treatment
or studies will also affect the risk benefit profile of such a drug.
Drugs, which might otherwise be considered too toxic for widespread
use, may be safely developed if we can exclude the patients at risk of
toxicity. The regulatory issues are enormous and will again require
substantial effort on the part of all the stakeholders. The Agency
needs to work with industry to identify the issues related to the use
of these more efficient trial designs and ensure that their use does
not result in restrictive labeling.
Concerns have been raised about the effects of PDUFA on drug
safety. The issue has been framed in various ways.
Sometimes the question is posed--``Are we approving drugs too
quickly?'' I think the answer is clearly--No--we are not approving
drugs too quickly in fact I would go further and say that there is no
intuitive reason to imagine that slowing the approval process will
enhance safety but such delays do prevent effective therapy reaching
our patients. Delay has no inherent safety value, but may simply
reflect indecision or lack of intellectual confidence.
An additional way that the question is posed is ``Are we
withdrawing more drugs since PDUFA?'' Again the data do not appear to
support that conclusion.
Another question that has been raised is ``How should PDUFA
influence post marketing surveillance?'' The answer is complicated. But
first it is worth saying that effective post marketing surveillance is
not, and should not, be the enemy of industry. Inadequate post
marketing surveillance will fail to identify drugs with unacceptable
risk/benefit profiles. However just as importantly poorly performed
post marketing surveillance is also dangerous because it may result in
the needless removal of safe and effective drugs from the market on the
basis of invalid data. Neither of these outcomes is acceptable. In
addition the greater our confidence in the ability to generate quality
post marketing data the greater should be our ability to approve drugs
earlier.
Fortunately changes in information technology may assist us.
Doctors still prescribe drugs much as they have done for 2,000 years.
With little assistance, they write out a prescription from memory
(sometimes still in Latin!), give the prescription to their patient who
carries it to a pharmacist, who tries to read it and dispense the
correct drug. That process is about to change rapidly. At Vanderbilt
Medical Center all physicians' orders for inpatients must now be
entered by computer. Dosage, interaction risks etc are checked
automatically at the time of prescription before direct transmission of
the prescription to the pharmacy. Such systems will soon also be
available and widely used in the outpatient setting. The implications
for improved patient safety are obvious and compelling. However the
introduction of such computerized prescribing systems also have huge
implications for post marketing surveillance--For the first time we
will have access to complete data sets on prescriptions and outcomes.
Again I see these innovations as having positive implications for the
drug approval process. The greater our confidence in the post approval
data the earlier and faster we should be able to approve drugs and use
them to treat our patients. Issues of privacy need to be dealt with but
these systems are moving forward rapidly and the FDA needs to be
integrated into such systems now so that the information can be used to
push back the time to drug approval.
I list these examples of the exciting new challenges and
opportunities to you to emphasize that in the immediate future we are
going to have to undertake considerable rethinking of our approach to
the demonstration of drug safety and efficacy. Such innovative thinking
will need to involve all of the constituencies--industry, regulators,
legislators, academics and patients and will require considerable
effort from us all. Reducing the time to drug approval does not depend
solely on the review time for an NDA it also requires efficient trial
design and execution and enhanced sponsor confidence that innovations
in trial design and in definition of end points will be accepted at the
time of NDA review. The strategy to speed drug approval needs to extend
across the entire life cycle of development and use of a drug and
therefore demands investment not just in the review process itself but
also in developing and maintaining excellence in the pre and post
approval process. The speed of scientific change and development of new
knowledge requires a strategy to ensure that FDA's scientific staff
maintains cutting edge scientific skills. Such strategies will require
funding which will not come from user fees, yet the benefits should
flow directly to better reviews and more efficient drug development
strategies. Drugs can be developed faster if only meaningful high
quality studies are demanded and required to be performed.
Thus as we think about PDUFA reauthorization the opportunities
offered by drugs to relieve the diseases that have plagued mankind are
enormous. The challenges to the FDA to develop the new paradigms
required will be substantial. These innovations will only be
forthcoming if the agency has the resources to hire and retain the
quality scientific staff it needs. The FDA competes with both industry
and academia for such scientific talent. The salaries of FDA Scientists
need to maintain parity with academia and should be tied to the NIH
salary cap. If we are to fulfill our hopes for novel therapies in the
future it is essential that the FDA has the increased resources it
needs to participate as a full and credible scientific partner. User
fees alone cannot be expected to provide the required increase in
resources. Additional public funds are required to adequately fund this
critical public health agency.
Mr. Chairman thank you for giving me the opportunity to present my
views today.
Mr. Bilirakis. Thank you, Mr. Wood.
Ms. Pendergast.
STATEMENT OF MARY K. PENDERGAST
Ms. Pendergast. Mr. Chairman and members of the
subcommittee, I am Mary Pendergast, Executive Vice President of
Elan Pharmaseuticals, a member of the biotechnology industry
organization.
Thank you for letting me testify on behalf of BIO. Our
message today is simple and it echoes what you have heard
before. The Prescription Drug User Fee Act is an
extraordinarily successful piece of legislation, and we are
here to urge you to renew the program for another 5 years,
quickly, and without taking on other issues.
The additional resources provided to the Food and Drug
Administration through user fees have facilitated FDA's review
of new biotech therapies, many of which are life-saving,
without compromising the agency's ability to make sound and
scientific medical and regulatory decisions.
In fact, the proportion of drugs removed from the market
for safety reasons has not changed because of the user fee
program.
Yet, because safety is a paramount concern of industry,
consumers, and FDA, we are ready to provide the FDA with
additional resources to work with companies, physicians in and
academic medicines, such as Dr. Wood, and consumer groups, to
improve our understanding of the risks imposed by drugs and
biologicals.
And to find new methods to reduce those risks, companies
will also work with the FDA to develop specific risk management
plans for products that will be coming on to the market in the
next 5 years.
These new risk management efforts will buildupon the FDA's
already considerable powers to give the public an added margin
of safety. We also hope that the user fee resources will be
used to respond to a problem we see in the FDA's implementation
of the user fee program.
There appears to be significant differences among FDA
review divisions, as well as one center to the other, in both
their review processes, and the timeframes for their
application reviews.
We want to understand the reasons for these differences,
and we want to find ways to address them and hopefully reduce
or eliminate them. So we hope that the FDA will study how it is
conducting reviews now, devote both management attention and
user fee resources to improve their review processes.
And look at ways to enhance communication with companies
during reviews, and to minimize the inconsistencies between the
Center for Biologics and the Center for Drugs.
Finally, because we recognize that biotechnology products
are often novel and complex, we propose that FDA spend new and
additional user fees that we are willing to put forward to
bolster its access to the expertise crucial to the review of
biotechnology products.
We hope that user fees will be used when necessary to hire
outside experts to help determine how a company could
demonstrate safety and effectiveness. These experts would be
selected by the FDA and screened by the agency, and the agency
of course would have final decisionmaking authority.
Thank you for the opportunity to present BIO's views at
this meeting. We look forward to working with the subcommittee
and the committee to reauthorize this important program.
[The prepared statement of Mary K. Pendergast follows:]
Prepared Statement of Mary K. Pendergast, Executive Vice President,
Elan Corporation
Mr. Chairman and Members of the Subcommittee, I am Mary K.
Pendergast, Executive Vice President for Government Affairs at Elan
Pharmaceuticals Management Corporation. I am pleased to be here today
on behalf of the Biotechnology Industry Organization (BIO), to talk
with you about the Prescription Drug User Fee Program and to urge the
Subcommittee and the Congress to reauthorize this program, which
expires at the end of this fiscal year.
The Biotechnology Industry Organization, BIO, represents more than
1000 biotechnology companies, academic institutions, and state
biotechnology centers in all 50 U.S. States. BIO members are involved
in the research and development of health-care, agricultural, and
environmental biotechnology products. The companies BIO represents
range from large, multinational corporations to much smaller, emerging
companies. Since its establishment in 1993, BIO has worked with this
Subcommittee on a variety of issues, including the one we discuss
today--the product review and approval process at the Food and Drug
Administration (FDA). BIO was active during congressional deliberations
in 1996 and 1997 that led to the Food and Drug Administration
Modernization Act and, importantly, to the reauthorization of the
Prescription Drug User Fee Act (PDUFA).
I want to begin by thanking this Subcommittee and its Members for
your work over nearly ten years in creating and then continuing the
user fee program for drugs and biologics. You were there at the
beginning, with the first user fee bill sponsored by Mr. Dingell, Mr.
Waxman, and others on the Energy and Commerce Committee; you were there
five years later at the first reauthorization, with legislation
sponsored by you, Mr. Chairman, Mr. Burr, Mr. Greenwood, and others;
and here you are again. We greatly appreciate your support of this
critical program.
I also want to reiterate what already has been said here today: the
Prescription Drug User Fee Act has been and remains an extraordinarily
successful piece of legislation. Prior to enactment of PDUFA, FDA was
often behind other nations of the world in approving new pharmaceutical
products. What Congress and FDA repeatedly heard was that American
patients waited while patients elsewhere had access to important new
therapies. The drug and biologic user fee program reversed that
scenario. Because of the additional funding made possible through the
user fee program, the United States now leads the world, rather than
following it. Today, FDA is the world's leading regulatory agency, not
only in terms of the quality and safety of the products it approves for
marketing, but also in terms of ensuring that new products are
available to patients as soon as possible.
For BIO, two key measures of the success of PDUFA I were, first,
whether the law has facilitated FDA's review and approval of new
products without compromising the agency's ability to make sound
scientific, medical, and regulatory decisions and, second, whether the
law worked for patients.
By both of these measures, the initial user fee program succeeded.
User fees enhanced FDA's resources so the agency could hire additional
medical and scientific reviewers and function more effectively in its
review of new products. And that was accomplished without a diminution
in safety. Anyone who has worked with FDA knows they are now, as they
always have been, the toughest regulators in the world. User fees have
not changed that, nor has reducing average review times changed the
proportion of products withdrawn from the market for safety reasons.
Thus, when the time came to reauthorize the program in 1997, there
was a keen recognition that we were seeing something unusual--a newly
established program that had worked the way it was expected to work--
one that a wide variety of stakeholders were praising. PDUFA II also
has been successful by many measures. Communication between FDA and
application sponsors has continued to improve, leading to better
applications and more effective use of scientific resources in making
decisions. And, most importantly, the health of patients has improved
through access to new products like Herceptin for metastatic breast
cancer, Zevulin for non-Hodgkins lymphoma, Enbrel--the first disease
modifying agent for rheumatoid arthritis, Xigris--the first therapy for
life-threatening sepsis, and Synagis to protect newborns from
potentially fatal infections.
Mr. Chairman, as the Subcommittee moves forward with its work on
reauthorizing this program for a second time, we know you will build on
its successes. In particular, we are hopeful that in the next five
years of the user fee program, while FDA maintains the strong standards
it now requires, we will see enhanced efforts regarding product safety.
This enhanced product safety program--FDA's risk management proposal--
will be supported by user fees. With these additional user fees, FDA's
risk management program will hopefully prove to be an even better
pharmacovigilance system than that which already exists in the United
States.
We also hope that you will recognize that positive results do not
necessarily equate with perfection. As we have looked more deeply into
the statistics regarding what has occurred over the last four years, we
have recognized that some modifications in how the program is
implemented may be in order and may improve on successes already
achieved. The things we are looking at do not involve ways in which we
think the law needs to be changed. Indeed, it is BIO's view that minor,
largely technical, changes in the law may be called for, but that
fundamentally this statute works well and should remain essentially
intact. We also hope that this important legislation will not become a
magnet or a train to which many unrelated provisions will be attached.
Reports of PDUFA progress generally deal in averages across the
agency, and often do not separate these averages to allow examination
of whether different components of the agency are fulfilling the goals
of PDUFA at the same level. This kind of sub-analysis is of great
importance to the biotechnology industry, which often brings to FDA
products that are complex, unique, and the outgrowth of emerging
science. We are keenly interested in how the process for reviewing
these biotechnology products--which are the primary preserve of the
Center for Biologics Evaluation and Research (CBER)--and the time
frames in which they are reviewed, tracks the review process and time
frames for other pharmaceutical products.
When BIO has examined the data, we have seen what appear to be
significant differences among review divisions, as well as from one
center to another, in both the review processes and the time frames for
application reviews. We want to understand the reasons for these
differences and we want to find ways to address and even reduce or
eliminate them.
To achieve this goal, BIO is proposing some modifications that we
hope will enhance the FDA's review processes over the next five years.
These proposals would not require any change in the legislation, nor in
the standards for approval, but would be achieved within FDA through
the agency's modification of some of its existing processes.
First, BIO hopes to be able, through the user fee annual reporting
mechanisms already in place, to see more clearly where there are
differences among review divisions and between the two reviewing
centers, the Center for Drug Evaluation and Research (CDER) and CBER,
in terms of meeting the various goals of the user fee program.
Second, BIO wants to see a more structured allocation of user fee
resources to activities related to review process improvements, as well
as greater involvement by officials in the Office of the Commissioner
in evaluating these review processes, looking for opportunities for
improvements and efficiency gains, and taking steps to implement them.
Therefore, we propose that a small portion of user fee resources be
specifically dedicated to review process performance improvement
activities and that these resources and activities be overseen by the
Office of the Commissioner.
Third, we hope to improve further the level of communication
between FDA and sponsors during the first review cycle. As you know,
Mr. Chairman, the goal of PDUFA is for FDA to complete its review of an
application in a designated period of time--six months for a so-called
priority application, and ten months for a non-priority, or standard
application. FDA's action on an application may be a letter to the
sponsor requesting more data or information, a letter stating that the
application is disapproved, or a letter stating that the application is
approved. If FDA asks for more information, the sponsor generally
provides the information to the agency, and then FDA enters into a
second cycle of review, which can take several additional months. After
this, third, fourth, and even fifth review cycles may be needed,
depending on what additional information FDA requests after each of its
reviews. Our review of data in FDA's reports to Congress, and
information provided on the agency's web site, shows quite striking
differences between the centers in regard to their ability to reach
final decisions within one review cycle.
With reviews that both FDA and sponsors believe have worked well,
one of the common themes we have found is early and on-going
communication. Another factor that influences review processes--and,
consequently, review times--is inconsistency among divisions and
between centers in review practices. To address both of these factors--
communication and consistency--we propose that FDA look at ways to
enhance communication and to minimize inconsistency through the
development, articulation, and implementation among divisions and
between centers of effective review practices. We believe such sharing
of good practices will go a long way to resolving differences among
divisions and between the centers and will also contribute to greater
efficiency of review across the board.
Finally, BIO would like to encourage FDA to use another mechanism
for obtaining expert advice on cutting edge issues. BIO recognizes that
biotechnology products are often novel and complex so that only a small
number of research scientists and medical specialists have the
expertise to understand how the products' development should proceed.
Specifically, it is often the case with these products that appropriate
design of the clinical trials needed for product approval is more
difficult than it would be with more well-understood science. The
resources CBER currently devotes to its laboratory-based, scientific
studies do not address sufficiently this expertise shortage. We propose
that FDA initiate a mechanism whereby an outside expert could be
brought in to a meeting between the product sponsor and the FDA to
assist the sponsor and the agency in deciding how best to achieve the
data needed to demonstrate safety and effectiveness for the product.
Such an expert would, of course, be selected by the FDA and, as is
currently the case, would be screened by FDA, to ensure no conflicts of
interest and no breach of the confidentiality of proprietary
information. We propose that a company be provided one opportunity for
such an expert consultation, so this would not become overly burdensome
for the agency. As is always the case, the recommendations or views of
any consultant would be advisory to the FDA, which would remain the
final decision-maker.
In summary, BIO shares with FDA the goal of reauthorizing PDUFA in
a way that not merely maintains but strengthens the FDA's drug and
biologic review programs. We believe that the user fee program has
provided, and will continue to provide, the agency the user fee
resources it needs to do its work. Indeed, we propose that under PDUFA
III, FDA receive a substantial infusion of new resources. But we also
hope in the course of PDUFA III to achieve a better handle on review
process efficiency, especially as it relates to biotechnology products,
so we can look forward to even more enthusiastic support for the
program reauthorization in the year 2007.
Mr. Chairman, we share the belief that timing is critical in this
reauthorization process. FDA must, because of federal personnel rules,
initiate a Reduction in Force (RIF) unless the agency has the
legislative authority to continue providing the salaries and expenses
that are derived from user fees. Notices of the possibility of such a
RIF must be sent to FDA employees no later than August 1, 2002, 60 days
before the end of the fiscal year and detailed plans for any RIF must
be developed months earlier than that. BIO urges you, Mr. Chairman, and
the Subcommittee and Committee, to act with all appropriate speed to
ensure the future of this program.
Mr. Chairman, thank you for the opportunity to present BIO's views
at this hearing. BIO looks forward to working with the Subcommittee and
the Committee in your continuing role as the initiators and overseers
of this important and highly successful program. This program has
improved and even saved patients' lives, and has made the U.S.
biotechnology industry the most productive in the world.
I would be happy to answer any questions you may have.
Mr. Bilirakis. Thank you.
Well, Dr. Wood, and I will say Ms. Pendergast, how does the
FDA compare to other countries in terms of regulating drugs;
the efficacy, the safety, et cetera?
Mr. Wood. I think this is undoubtedly the gold standard
internationally and for drug regulation. It is the gold
standard in lots of ways, both in terms of scientific
expertise, in terms of the rigor with which drugs are reviewed.
But also importantly I think, and something that we tend
not to think about it in this country, the openness with which
that process operates. In many other countries the process is
much more secretive and advisory committees being held in the
open, and individuals' views being exposed to open criticism in
the public, and is not characteristic of the approach taken in
many other countries.
So I think we have an excellent system, but that doesn't
mean that we can't do better, and we can't improve many of
these things, but most countries I think would view this as one
to which they would aim rather than the opposite.
Mr. Bilirakis. Thank you. Ms. Pendergast.
Ms. Pendergast. I share Dr. Woods' views. The FDA is and
remains the gold standard for the rest of the world, and I
think this is especially true with regard to safety.
I feel as though the FDA has been unfairly criticized for
its safety record.
I think we need to remember that in the United States that
only approximately a tenth of the drugs are pulled from the
market as they are pulled in other countries. So I think that
while it is true that drugs do get pulled from the market from
time to time, the FDA has an enviable record compared to the
regulators in the rest of the world.
Mr. Bilirakis. Concerns have been raised by members of the
panel that PDUFA, or at least this is the way that I
interpreted their statements, that PDUFA may have hurt the
quality of FDA, particularly safety, and maybe shifting from
what was done previously to PDUFA because of the fees coming
in.
Do you have any comments regarding that, Ms. Pendergast?
Ms. Pendergast. I do not think that the prescription drug
user fee program has impacted safety. I think the data shows
that a lesser percentage of drugs have been pulled from the
market now than before.
I think we have studied twice as many patients before
putting drugs on the market than we did before the prescription
drug user fee program began, and I think we have a solid safety
base upon which the FDA can make decisions.
So I do not think that the user fee program, which has
given the FDA additional resources, has impacted adversely on
safety.
Mr. Bilirakis. Thank you. Dr. Wood you are an academic. I
would say you probably don't have any axes to grind, I am not
insinuating that anybody does, about your opinion.
Mr. Wood. Yes, I think that one of the things that we need
to do is we need to look at the safety of a drug throughout its
life cycle, and one of the things that we have focused on
today, I guess, has been PDUFA, which really focuses on the
narrow part of the life cycle of a drug, the time during which
an NDA, or a new drug application is being considered and
approved.
But really we need to--and of course that is the part for
which PDUFA fees are available--we really need to focus on the
breadth of the entire life history of the drug before the NDA
is filed during the appropriate--ensuring that the appropriate
studies are done, but not excessive studies are done.
And that requires an appropriate interaction to industry,
and FDA, and others. But also in the post-market, what I have
heard is the concerns about the post-marketing surveillance
being inadequate, and whether that should be wrapped up, and we
can talk about that, I guess, later.
Mr. Bilirakis. Dr. Wood, I want to go into one area very
quickly. These recommendations that you have just made in terms
of details, I understand that you touched on that in your
statement.
If you have any specific recommendations regarding these
areas, if you could give that to us in writing so that we can
take them all into consideration, and the sooner the better
obviously, so that we can do this on a timely basis, and
consider them.
Post-market surveillance. All of us agree that it is a
necessary function of the FDA. I don't know that anybody has
disagreed with that. Just comment, in terms of the user fees,
on whether user fees will be adequate for that, and if not,
should it be accomplished with appropriated dollars.
Mr. Wood. Well, I have not seen the specifics as you have
either.
Mr. Bilirakis. Well, we haven't either.
Mr. Wood. But the stories that are circulating include
statements which may not be correct. That the ability to use
these user fees will be restricted to some period after
approval, and 2 years for drugs without a black box warning,
and 3 years for drugs with a black box warning.
That seems to be inappropriate, and if----
Mr. Bilirakis. Inappropriate?
Mr. Wood. Inappropriate, given that for the first 6 months
of a drug's approval you usually have no data. It just does not
come in that quickly, unless something really bad is happening.
And then after that, and in the last 6 months of that 2
year period, people obviously are going to be distracted and
thinking about other things. So you are really looking at a
window of a year in there, and that seems inadequate, and seems
like an inappropriate restriction to put on it.
There are two problems in the post-marketing surveillance
area. One is for drugs where we already know the side effect
before the drug goes on the market. And the second one is where
we are looking for novel side effects that have not been
recognized prior to the drug going on the market.
And these are different problems, and that need different
solutions. In the first case, where we already know about the
side effects before the drug goes on the market, you are
talking about a management issue.
How do you educate doctors and others appropriately to use
these drugs, and we have done a relatively poor job of that. It
is not the FDA's fault entirely. It is people like me perhaps
that are to blame for that, academics and physicians, who
perhaps have not gotten that word out.
But uniformly when we have made labeling changes to drugs,
these labeling changes have not been widely incorporated into
physicians' practices. So where we have information on side
effects, we are not able to translate that readily into action.
In the other setting where we are looking if you like and
sort of drilling for oil, and we are looking for unexpected
side effects that have never been described before, that is
difficult, because we are better at identifying side effects
that have already been recognized.
For example, it is easy for a physician when a patient
develops a rash to say that might be the antibiotic that you
were taking, and to make that connection. It is much harder for
a physician to make a connection between some adverse event
that may be drug related, but has not been previously
described.
Now, that's where the opportunity of a computerized
prescribing really opens up tremendous opportunities. Quite
quickly, physicians are going to start prescribing drugs on
their Palm Pilots. And they are going to be prescribing the
drugs like that, and then sending it to the pharmacy.
We still prescribe drugs very much like we have done for
the last 2,000 years. You know, we get our pen out of our
pocket, and we get a bit of paper, and we try and remember the
dosage, and we try and remember the drug, and all the stuff
that goes with that.
And we write it down, sometimes in Latin still on a bit of
paper, and the patient carries that in their hand to a
pharmacy, and the pharmacy tries to read my writing, and
translate that and give the patient the drug.
And that really has been virtually unchanged in 2,000
years. Clearly that is going to change dramatically, and has
already changed in the in-patient setting at Vanderbilt, and
will change dramatically over the next 2 years.
This is not going to take long, and we need to have the
agency incorporated into these systems at the get-go for two
reasons. One is that we can use these systems to capture data
and totally transform the issues that were discussed earlier
this morning.
Somebody said that only less than 1 percent of adverse
reactions are reported. If we were capturing a hundred percent
of any particular dataset, we would have a totally different
perspective on drug safety.
Second, as we move to the computerized prescribing, drug
labeling is going to change. Drug labeling right now is a
paper-based system. It goes with the dispensing of the drug, or
it is put up in a book like the PDR.
Once we are prescribing drugs on our Palm Pilots, what is
on the Palm Pilot is going to be what my residents, or interns,
or physicians, see.
They are not going to be running around looking for bits of
paper anymore. We need to know what is on that Palm Pilot, and
we need to ensure that labeling is appropriate to that.
So there are huge opportunities, I think, to transform the
way that we do this, and the agency needs the funds, and it
needs the intellectual horsepower, and it needs the ability to
recruit people who can really do that.
And to do that in a collegial way with all of the
stakeholders--industry, academia, and others.
Mr. Bilirakis. Doctor, with the indulgence of my
colleagues, I let you go because----
Mr. Wood. Sorry.
Mr. Bilirakis. No, it is of great interest to me and to all
of us here. I know that Mr. Stupak, in particular, and you
might expand in writing on your comments regarding that
subject. I appreciate that very much. Mr. Brown.
Mr. Brown. Thank you, Mr. Chairman. Ms. Pendergast and Dr.
Wood, I had--Dr. Wood, you had said as we develop entirely new
medicines, particularly those rooted in pharmacogenetics, then
regulators in the drug development industries have to think of
how efficacy and safety should be demonstrated in entirely new
ways.
Most of us have visited biotech firms in our districts or
in our regions. I visited a firm called Athersis some time ago,
and saw the sort of exciting new things they are doing in
research development.
And you see that and you are given the revolution promised
by the expediential growth and understanding of how and why
disease occurs, and why drugs work in individuals.
Does it make sense, and if both of you would respond, to
continue or to separate the regulators into separate entities
in this CDER and CBER? Does it make sense to continue that
separation, and why?
Ms. Pendergast. We are not prepared to make recommendations
as the board management changes that the FDA might want to
make.
But we do see differences between how biotech products,
which are regulated by both the Center for Drugs, and the
Center for Biologics, are handled by the number of rounds of
review that they take, and the number of months that it takes
for the FDA to make a decision.
So what we are proposing in our performance management
assessment is that we give the FDA money so that they can do
the management, and so they can study what works, and what
doesn't work, and so they can develop consistency across the
agency.
We are not prepared to tell them what to do, or to manage
it. We are just saying please study it. We see major
differences. Please, take a look.
Mr. Brown. Dr. Wood.
Mr. Wood. I think innovation is going to occur across both
those areas, both in CDER and CBER, and I think we need to be
prepared to embrace innovation in both areas. And I am not sure
that it makes a lot of difference now whether the drug came
from a biological background, or came from a chemical
background.
Eventually they are going to produce the same novel
effects, and some of these effects that we are talking about
are going to be in drugs that may have exactly the same action,
and exactly the same target, but maybe generated in one case
from a biological background, and in the other case from a
chemical background.
It makes little sense to regulate these differently, I
think, and although there are some issues that obviously are
peculiar to biologics that need to be addressed on issues of
infection and so on.
Mr. Brown. Dr. Franson, we all know that prices in the
United States for prescription drugs are based in large part on
whatever the market will bear, whether you are negotiating with
an HMO or whether you are selling to the Federal Government.
And that is not really market will bear, but certainly when
you are selling individual drugs to individual consumers. Our
neighbor to the north as you know sells its drugs at their
pharmacies at much lower prices.
Could you tell me how Eli Lilly, how they sell drugs into
the Canadian market, and how those prices are determined?
Mr. Franson. Well, that is not an area that I have
expertise in, and I am sure that PhRMA or Lilly would be happy
to provide you information as you wish in writing.
But as a physician and regulator, I am not even allowed to
handle the checkbook at home. So certainly I am not prepared to
answer that.
Mr. Brown. Is that at the office or at home that you are
not?
Mr. Franson. Both.
Mr. Brown. All right. That's fine. Thank you, Mr. Chairman.
Mr. Bilirakis. Mr. Stupak, you may inquire.
Mr. Stupak. Well, thanks. Let me pick up where Sherrod left
off, Mr. Franson, or Dr. Franson. I realize that you came here
to testify on behalf of a trade association and not Eli Lilly,
but nonetheless your testimony presents me with an opportunity
to clarify just what Eli Lilly and other industry is prepared
to do about protecting the safety of patients when the FDA is
denied legal tools to compel compliance.
You know, if you take a look at it, post-marketing surveys
or risk-management as it is called. First of all, I want to ask
you a question that arose last year. The committee was
considering the reauthorization of a pediatric exclusivity
provision, and at that time the industry opposed it, and did
everything that they could to defeat my amendment.
Common sense requirements to require drug companies to make
changes in their labels to reflect the results of studies of
their drugs in children before they could take an advantage of
the 6 months additional exclusivity that you receive for
undertaking this important research, really got their 6 months
exclusivity for studying the effects of prozac in children.
You completed the study some time ago. In fact, you
received your exclusivity, I believe, last year, somewhere
between February and August. So generic was permitted on the
market, and so you had a chance to do another 6 months of
marketing, which is estimated to be worth $900 million to your
executives and your shareholders.
As of January 2002, Lilly still has not changed the label
for this drug, while consumers in this country continue to pay
for it. What is the status of the labeling change for pediatric
exclusivity with Lilly?
Mr. Franson. Well, I am happy to answer that, realizing
that it has no relationship to PDUFA, but I will tell you
that----
Mr. Stupak. No, no. You will see a pediatric exclusivity
fight again in PDUFA, and that's why I am bringing it up, just
to refresh your memory. You will see this fight again on
pediatric exclusivity.
Mr. Franson. I am happy to address that, and I will tell
you that I believe that four clinical studies and three
clinical pharmacokinetic studies were submitted to the FDA in
timely fashion, and those discussions as to labeling remain
under review.
So I believe that we have met our obligation and our
desire, and we are working with the FDA to expedite that.
Mr. Stupak. So as of January of this year then, you have
submitted your studies?
Mr. Franson. We actually submitted it well over a year
prior to that.
Mr. Stupak. A year prior to that? So if there is a labeling
change, we still don't know if there is a required labeling
change, even though you got your exclusivity last year, right?
Mr. Franson. Well, the provision of exclusivity is a
submission to data to FDA, with their acknowledgement that it
meets their standards.
Mr. Stupak. But, you know, in your statement, you said that
patients should have access to more drugs. But shouldn't
patients also have information, access to information? You have
the information, Lilly does, and it has been given to the FDA.
You get your 6 month exclusivity, and get $900 million more
in profit. All the while, we don't know if prozac, in the
dosage and the amount that the doctors have prescribed, is
appropriate for adolescents.
And yet you get your exclusivity and your 6 month patent
protection. Shouldn't we have that information before you get
the patent protection, the extra 6 months? Shouldn't the
labeling be done before?
Mr. Franson. Well, we certainly acknowledge the importance
of providing information to prescribers, and we also recognize
our obligations to comply with FDA in terms of labeling, and
the pharmaceutical manufacturer, be it my company or others,
cannot go out and talk about new uses and so forth, such as in
pediatrics, without the approval of FDA, and we respect FDA's
oversight.
Mr. Stupak. But you get the approval before you even have
the study completed and submitted, and a label change is even
made. That is part of the enforcement problem that we have.
Let's go to PDUFA-2, where you are supposed to do post-
marketing surveillance, okay? We here, even though the study
has been sitting on the Director's desk for 5 months, we hear
that 90 percent of the pharmaceutical companies did not do
PDUFA-2 post-marketing surveillance.
Is that a true statement, that 90 percent have not done it
under PDUFA-2?
Mr. Franson. I actually believe that that is seriously
flawed information.
Mr. Stupak. What is the number then? What is the number?
Mr. Franson. Well, I can tell you what our company's number
is, because----
Mr. Stupak. I thought you were on top, on the part of
PhRMA, the whole industry, and so I was hoping you would give
me that number.
Mr. Franson. I do not have an industry number because we
have not seen the report from the FDA, but I can tell you that
my understanding from colleagues and from the FDA is when their
data base was updated, that one is probably looking at 90
percent of studies being completed, and others pending.
So I believe that information was flawed because of poor
data submission, tracking and collection by both industry and
FDA.
Mr. Stupak. So that was updated recently then, within the
last 5 months, since the study has been sitting on the
Director's desk?
Mr. Franson. My understanding is that the update that has
been submitted would verify that, but I have not seen that, nor
have my colleagues. So I think it would be very important to
validate that information.
Mr. Stupak. Well, it is updated on the computer, and we
should just go to the computer and we can get the information,
and we don't have to wait for the director then do we?
Mr. Franson. I'm sorry, but to wait for----
Mr. Stupak. I mean, if it is all updated on the computer as
you said, the computer has been updated, and it is 90 percent
completion, and so we shouldn't have to wait for the director.
We should just be able to go to this computer. Do you have
the website where we could get this updated information,
because I would really like to know about it, because if I am
saying something wrong here, I would really like to know about
it.
Mr. Franson. I think it would be important to see this
report which is pending, and we are also anxious to see that. I
am certainly glad to verify as a company what kind of
commitments have been met.
Mr. Stupak. Well, you had indicated that it has been
updated and it is on a website.
Mr. Franson. I did not indicate a website.
Mr. Stupak. I'm sorry, that the computer was updated, that
the FDA updated their computer, I believe you said.
Mr. Franson. Our understanding was that that tracking
system had not been maintained because it was not a performance
goal or requirement.
Mr. Stupak. But now it is your understanding that it has
been updated?
Mr. Franson. That is correct.
Mr. Stupak. And the number is now 90 percent completed and
did not?
Mr. Franson. My understanding from colleagues with whom I
have spoken is that the companies with whom I am interacting
have that kind of compliance. We anticipate that would be it
broadly, but we have not seen the report.
Mr. Stupak. Can you tell me what computer has been updated
so that I can go there and get the most recent information on
this issue?
Because to a lot of us, when you talk about the integrity
of PDUFA, there is no integrity when 90 percent of the reports
have not been completed. That lessens the integrity of PDUFA.
Mr. Franson. I think it would be very important to see that
report, and our understanding is that with updates that
information is seriously outdated.
Mr. Stupak. Okay. Well, hopefully we see it before we have
any further mark-ups or hearings on this, because it is hard
for us on whether or not we should reauthorize PDUFA,
especially when we are trying to get to enforcement issues. Do
you agree that the FDA should have subpoena power to get to
your records, and access to reports?
Mr. Franson. I am not aware that the FDA has had any
difficulty obtaining any information on inspection, visits, and
so forth. So I am not sure what you are asking for.
Mr. Stupak. Really? Like Serzone, were you here for my
opening statement, where with Serzone in 1994, they did a
report, and the FDA has been asking for the report, and they
still don't have it? That is over 6 years old.
Mr. Franson. I am not aware of that situation. I am aware
of your reference to it, of course. PDUFA
Mr. Stupak. Do you believe that they should have subpoena
power to get information if it does take 6 years, or in another
case, 15 years? Do you think they should have subpoena power to
get that information as a regulatory agency concerned with the
safety for the American public?
Mr. Franson. I think it is important for any regulatory
body to be able to validate information that they receive. As
to the specifics here, since I have no knowledge, and since it
is to a degree a legal matter, I am over my head in that.
Mr. Stupak. You don't know the difference between subpoena
and not?
Mr. Franson. What I don't understand is what the gap is,
and whether it is a systematic gap.
Mr. Stupak. Would you support putting the PDUFA-3 agreement
in the Federal Register so the public can take a look at it
before we authorize PDUFA-3? Would you support that?
Mr. Franson. I think it would be very good for all parties
to have full knowledge of the kinds of things that have been
discussed by those who have directly been involved with PDUFA
processes, and probably can offer the best insight on what has
worked well, and what can be improved.
Mr. Bilirakis. The gentleman's time has expired.
Mr. Stupak. Thank you, Mr. Chairman.
Mr. Bilirakis. Mr. Waxman.
Mr. Waxman. Thank you, Mr. Chairman. Dr. Franson, in this
recommendation that the industry and the FDA is submitting to
Congress to review and to adopt in either form it is submitted
to us, or with changes that we might make, we have been told
that you pushed forward and got an agreement that requires the
FDA to retain an outside consultant whenever an applicant
requests one.
This consultant would advise the FDA on an outstanding
issue of the applicant's choice during review of a new drug
application. Now, it is my understanding right now that the FDA
voluntarily retains outside consultants to supply needed
expertise.
And, in fact, the FDA did so dozens of times last year in
its oncology division alone. It is also my understanding that
applicants are always free to bring their own outside experts
to meetings with the FDA.
Why do you feel it was necessary to remove FDA's discretion
about whether it should hire its own outside expert and place
that decision solely in the hands of the applicant; and what
was wrong with the voluntary system?
Mr. Franson. Well, all I can say is that on PhRMA's behalf,
and looking primarily at the Center for Drugs' processes, we
are comfortable that the dispute resolution and use of
consultants, and so forth, are very appropriate.
And we are comfortable with the FDA's oversight. However,
we respect the fact that there are other considerations that
are important to address in other centers. And I guess that I
would have to defer comment. That is not one that----
Mr. Waxman. But am I wrong in assuming that you personally
had asked for the mandatory outside consultants to be brought
in if an applicant requested it?
Mr. Franson. That was not PhRMA's proposal, no.
Mr. Waxman. That was not PhRMA's proposal. Ms. Pendergast,
was it yours?
Ms. Pendergast. Representative Waxman, there is no
mandatory requirement that the FDA engage the services of an
expert. Rather, the biotech companies have asked that for
biotech products only at the Center for Biologics, that a
company may ask once the agency to bring in an outside expert
into a meeting.
And we will pay for these expert consultancy fees, but the
choice of the expert is up to the agency.
Mr. Waxman. Why is there a mandatory requirement that the
agency must hire an outside consultant?
Ms. Pendergast. There is no mandatory requirement. It is
totally at the FDA's discretion, and we aren't given additional
funds so that they may do this when we ask, but they are under
no obligation to do it even when we ask.
Mr. Waxman. Thank you. Then that clarifies that issue. Dr.
Wood, it appears that even with the money that this agreement
will pay toward post-market safety programs, pre-market review
will receive far more resources than post-market safety. Do you
believe that post-market surveillance deserves fewer resources
than pre-market review?
Mr. Wood. No. I think it needs adequate resources. I can't
tell you that it should be fewer or more, and I would say what
I said earlier. I think it is important that we think about
drug safety as a continuum.
That there is a continuum that starts with the right
studies being done in the early stages before an NDA is filed,
and that continues through the relatively small number of
subjects or patients who are studied prior to an NDA being
filed, and often as few as 2,000 or 3,000 people.
Mr. Waxman. Well, back to the adequacy question. Do you
feel that that the post-market safety program agreed to under
the industry-FDA proposal is adequate to protect consumers from
the risk of marketed drugs?
Mr. Wood. My concern about the rumors, which is what they
are, and from what I hear about this agreement, is that there
seems to be excessive restrictions on both what these
additional FTEs can do, and what they can spend their time
doing, although I heard Janet Woodcock say that they won't be
people with a star on their hat.
And as specifically designated, there will still be some
expectation that at the end of a year that people have spent an
appropriate amount of time on PDUFA approved drugs. Drug safety
is an overall issue that involves not just the PDUFA drug.
Sometimes it is an interaction with a standard drug.
Sometimes the appearances of the toxicity has occurred because
of the longstanding, and long approved drug, when in fact it is
an interaction with the newly approved drug. So that kind of
rigidity seems inappropriate to me.
Mr. Waxman. Ms. Pendergast, it is my understanding that at
some point in the negotiations between the industry and the
FDA, a tentative agreement was reached that would allow user
fees to be used to support some drug advertising reviews. Why
was that tentative agreement withdrawn?
Ms. Pendergast. There was never a tentative agreement.
Rather, the FDA has the capacity to, and does use user fee
monies, to review advertising, and they are free to do that in
the future.
And nothing about this agreement changes either their
substantive ability or the standards they impose. The question
on the table was if industry gave the FDA more money to review
advertising, could the FDA review it quicker.
So the FDA cost it out on how much it would cost to get the
FDA to do it faster than it does now, and not better, and not
to a different standard, but just faster. And when the FDA came
back with how much it would cost to serve the industry by
getting their reviews done quicker, the industry looked at it
and said of all of the priorities of the things we have to
spend money on, this goes to the bottom of the list, or at
least below what people were willing to give additional
resources for.
So I don't think it is fair to say that in any way, shape,
or form, does this stop FDA's review. They are free to devote
whatever resources they wish to to it, but it is just speeding
it up didn't seem cost effective.
Mr. Waxman. Dr. Wood, just on the question of the----
Mr. Bilirakis. Just a very brief question and response.
Mr. Waxman. The others have had a little bit more time, and
I would like just another minute or so. Dr. Wood, do you
believe that mandatory use of outside experts is a good policy?
If you could answer just yes or no?
Mr. Wood. I think there are a number of problems with that.
First of all--and I will try and be brief.
Mr. Waxman. If you could just answer yes or no, and then we
can get--because I want to ask just one other question after my
time has already expired.
Mr. Wood. All right. I think it is complex, and I think in
an ideal world the answer is no, although there are lots of
opportunities. And I personally have served as an expert for
the FDA on occasion, and told them to get experts in. I think
that is a good thing.
And I think that should be a decision that should be left
to the FDA.
Mr. Waxman. My last question relates to Mr. Stupak's issue
that he raised, and it is my understanding that several of the
drugs that were recently withdrawn from the market for safety
reasons ran into problems because doctors prescribed them
against the label directions, and continued to do so even after
the label warnings were repeatedly strengthened.
It looks to me like doctors either don't read label
directions and warnings, or don't believe them. Do you believe
the FDA should continue to rely on label warnings to solve
known safety problems with drugs?
Mr. Wood. Can I take time to answer that?
Mr. Bilirakis. Take time, doctor.
Mr. Wood. That is a very complicated question, and I think
it does merit a longer answer. The issue is that frequently
drugs--a problem is identified which people believe can be
avoided by increasing the amount of testing that is done on
patients prior to them receiving the drug or while they are
receiving the drug.
An excellent example is an anti-diabetic drug called
Rezulin that caused liver failure, and increasingly frequent
liver function tests were ordered, and were suggested in the
labeling, to allow Rezulin to remain on the market.
And these were changed every few months, and rezulin was a
drug that was being used to treat diabetes. When patients were
being asked to return for a liver function test to be performed
every 2 weeks, or 3 weeks, that becomes an incredible
imposition on a patient's lifestyle, and is clearly
unrealistic.
We know that only 7 percent of the patients who were taking
Rezulin were actually following these instructions. It may be a
problem with physicians, but it clearly is an expectation
problem.
It is unreasonable to expect that a patient with a chronic
disease like diabetes can come back to the doctor's office on a
regular basis to have liver function tests drawn when they have
another life. They have got a job and so on.
So we need to work out how we are going to manage these
risks better, and this is a complex question, and it involves
education of physicians, and it involves setting reasonable
expectations.
It involves defining and making certain that introducing
these restrictions actually improves safety. That is not always
the case. And sometimes there is just a desire to do more.
And so I think it is a very complicated question, and I
think the answer is unclear, and I think it is something that
we need a lot more work on.
Mr. Waxman. Thank you, Mr. Chairman.
Mr. Bilirakis. All right. Mr. Green, do you have questions
of this panel?
Mr. Green. I will try and be brief, Mr. Chairman. I
appreciate it. I'm sorry I was not here earlier for the first
round, but it is the nature of the business. If any of the
panel could--one of the criticisms of PDUFA has been that some
of the drugs that are receiving priority are neither innovative
nor life-saving.
While we all appreciate the need for drugs to treat, for
example, male pattern baldness, we certainly want to make sure
that truly innovative drugs are receiving the highest priority
at the FDA.
And we understand that the FDA has a process whereby
certain NDAs receive priority in the review process. Can any of
you share some information about that concern that maybe some
of these pharmaseuticals are not necessarily life-saving or
innovative?
Mr. Wood. Well, male-pattern baldness sounds like a pretty
high priority for me.
Mr. Green. Well, I have to admit that I may be getting
there, but it is not life-saving.
Mr. Wood. I think if I could respond to that. I think one
of the things that we do at our peril is apply paternalistic
views to patients' suffering, and sometimes--and I plead guilty
to that, too.
And the drugs that have been used for diseases that
patients truly suffer from, but may not be life-threatening,
can still be very debilitating for patients. Novel therapies
for these diseases still should receive rapid review and
approval, because they can still be very debilitating for
patients.
I am only being a little facetious about male-pattern
baldness, but irritable bowel syndrome, for instance, which
doesn't sound such a serious disease to some patients, has
devastating effects in one's life.
It is clearly not life-threatening, but devastating effects
in one's life. So I think we need to be--and we meaning
experts, need to be careful about adopting an attitude that
views life-threatening as the only criteria for urgent
approval.
Mr. Green. And again it is a priority, I guess.
Mr. Wood. Right.
Mr. Franson. And I was just going to add that the category
of priority reviews are usually made on the basis of an unmet
medical need, which can include, but isn't limited to, life-
threatening illness.
And the determination on that is not made by the sponsor
submitting the application, but by the FDA.
Mr. Green. Mr. Chairman, just one more question. Ms.
Pendergast, in your testimony you presented about BIO, it makes
clear that your organization is concerned about both CDER and
CBER meet the review times set out in the performance goals.
The CBER takes longer and more cycles to approve biologic
based drugs; is that correct?
Ms. Pendergast. Yes, sir, it is. If we look at the data for
the last 4 years of PDUFA-2, what we see is that year in and
year out the Center for Drugs is able to organize itself such
that roughly half of all drugs are finally reviewed on the
first cycle.
Whereas, that percentage for the Center for Biologics is
only 20 percent. The differences are also striking in terms of
the number of months it takes for the FDA's consideration for
them.
Again, the Center for Drugs is simply faster than the
Center for Biologics, and we would like to understand the
reasons for those differences.
Mr. Green. I think some of us would also to see if there is
an interest in it. We are informed that the FDA also enacted
with PDUFA-2 when it was reauthorized provides for something
called special protocol reviews, whereby firms presumably
through the advantage of inexperienced companies that more
typically submit their applications, the CBER can take
advantage of the FDA expert assistance in designing that
special protocol that binds the FDA, absent scientific
breakthrough to accepting the terms of that protocol in the
review process. Is that correct?
Ms. Pendergast. Yes, there are certainly many more
companies that have availed themselves of this opportunity for
consultation with the agency, and the Center for Drugs than for
the Center for Biologics.
Again, we are not giving the reasons for this widely
disparate set of numbers, but we are offering to give the
agency additional resources so they can conduct studies to find
out why it is that companies are so hesitant to do it, and why
the FDA is so hesitant to offer this service for biotech
companies.
Mr. Green. How many members of BIO are also members of
PhRMA or not members? Is there----
Ms. Pendergast. The vast majority of the members of BIO are
not also members of the Pharmaceutical Manufacturers
Association. There are a few, and we would have to get that for
the record, but it is probably less than 10 percent.
Mr. Green. Okay. Do you believe that Dr. Zoon puts less
pressure on her reviewers than Dr. Woodcock, or do you want to
touch base on that?
Mr. Bilirakis. Are you going to withdraw that?
Mr. Green. I will withdraw it. Thank you, Mr. Chairman.
Mr. Bilirakis. Mr. Bryant to inquire.
Mr. Bryant. Thank you, Mr. Chairman. Dr. Wood, I have
rushed back here so that I could be sure to let you see me here
so that you could go back home to Tennessee and tell people I
am working.
Mr. Wood. I will be sure to tell them that.
Mr. Bryant. We don't work away from these rooms here. Let
me ask you, and I know that I am sort of catching up here, and
you have already given your testimony and answered a number of
questions, but the performance goals which accompany the PDUFA
focus on review times, I know that you are very interested in
finding ways to shorten the clinical developmental time or
development times.
Do you have any suggestions on how to best shorten clinical
development times?
Mr. Wood. Yes. I think we need to avoid doing studies that
are either of low quality--and I don't mean that they were not
performed right, but were done because somebody perceives the
FDA may ask for them later.
And we need an increased certainty that a package of
studies put together will indeed satisfy the agency when they
get there, and that was addressed a moment ago. And so I think
we need to work as a group with all the stakeholders to work
out what it is that we are going to need to do to get a drug
approved.
In many examples that are currently out there, we don't
know that right now. We are talking about novel therapies that
work by novel approaches, and that work in ways that have not
been seen before.
And we are going to have to put a lot of effort, and the
agency is going to have to spend a lot of time and effort in
working out what the best approach to these new drugs is. And
that is going to have to be done in a way that reassures
industry that if they follow that approach that they will
target approval if the studies come out the right way
obviously.
Mr. Bryant. In your written testimony, and I believe in
your oral statement today also, you speak about the need to
find new ways to measure efficacy. In the future should this
debate be a part of the PDUFA negotiations or should it be left
solely to the agency?
Mr. Wood. The reason that I emphasized that is that I think
it is important that the agency have sufficient funds
independently of PDUFA, and to allow them to make the
innovative changes that we are going to have to do.
That is going to take a lot of time, and it is going to
take a lot of consultations, and it is going to take a lot of
effort. And this should not become a distraction in NDA
approvals, but it will take effort, and that seems to be an
appropriate reason for funding to be increased.
The past is not going to be a prologue to the future here.
We are going to have to make paradigm shifts in the way that we
think about drugs, and that is going to take effort and
expenditure.
Mr. Bryant. You speak of pharmacogenetics, and I am not
pronouncing that correctly. Do you believe that we will ever
get to the point where drugs and biologics are only approved
for certain individuals with specific genetic makeups?
Mr. Wood. Well, that is a very interesting question,and one
that the FDA and industry really need to work on, because what
we don't want--we want to encourage the development of drugs
for identified patient populations.
We want to discourage patients who are not going to respond
to drugs getting drugs, and we want to discourage patients who
are going to develop adverse effects getting these drugs.
And industry on the other hand, and I shouldn't speak for
them, I guess, but industry is also worried that they don't get
an overly restrictive label for a drug, and that would restrict
the potential market for the drug.
So somehow we need to work to use the genuine benefits of
pharmacogenetics to allow us to better target drugs to our
patients without limiting the potential for these drugs in the
future.
Mr. Bryant. Do either of the other witnesses on the panel
have brief comments on any of those questions, or would like to
add to, or take away from?
Mr. Franson. I would just say that the notion of
pharmacogenetics, and the opportunity that it does offer is
exciting and probably will be a centerpiece for PDUFA-4, given
the time that it will take to evolve.
And I would just say that we would foresee the same high
standards of efficacy and safety being held in approval, but
perhaps different measures to get at those end points.
Ms. Pendergast. I would just like to say that while today
we are talking about the funding that the companies are
providing to the agency, I would like to underscore what Dr.
Wood said before.
In an era where we are doubling the NIH's budget, we know
that the products that they are studying and developing will
come to the FDA 5 years down the road. And there will be
paradigm shifts in terms of the impact of the genetic
revolution, pharmacogenomics.
And I urge the Congress to consider increasing the
appropriations for FDA and not rely obviously just on what bit
the companies can throw into the pot.
Mr. Bryant. Thank you, Mr. Chairman.
Mr. Bilirakis. Thank you, Mr. Bryant.
Mr. Brown. Mr. Chairman, I want to make sure that--and
again I think you had already done this, but any members that
have written questions for the panelist--Dr. Franson--I had
asked him about the Canadian pricing, and if you or the people
at PhRMA would answer that.
Mr. Bilirakis. Yes. Members have 3 days to submit questions
to the committee and we will submit them to you. I know that
you would be very pleased to respond to them.
Obviously your response being sooner rather than later
would be very helpful. The knowledge that you all have is just
terrific, stupendous, and it is going to be of great benefit to
us.
Again, I not only ask you to respond to the questions, but
submit to us any information voluntarily that might help us do
our job. Thank you very much. The hearing is adjourned.
[Whereupon, at 1:42 p.m., the subcommittee was adjourned.]
[Additional material submitted for the record follows:]
Responses of the Food and Drug Administration for the Record
questions submitted by chairman michael bilirakis
1. Is the United States now the country where most new drugs are
first-approved? Was this the case prior to PDUFA?
Yes, the United States (U.S.) is now the country where most new
drugs are first approved. A study by the Tufts University Center for
the Study of Drug Development confirmed that FDA's implementation of
PDUFA has helped enable American patients to be first in the world to
have access to many new drugs. During the years 1991-1995, drugs were
first marketed in the U.S. only 31 percent of the time. During the same
period, drugs marketed for the first time in other countries were first
marketed in the U.S. within a year of their foreign introduction only
43 percent of the time.
During the period 1996-1998, however, nearly 47 percent of all new
drugs marketed world-wide were first marketed in the U.S., and American
patients had access to 78 percent of the world's new drugs within the
first year of their introduction. (Kaitin, KI. ``Impact of the
Prescription Drug User Fee Act of 1992 on the Speed of New Drug
Development.'' Tufts University Center for the Study of Drug
Development, prepared for FDA Public Hearing on PDUFA, September 2000.)
2. I understand that after this year there will be no carry-over
funds available to pay FDA reviewers. That is, if the Congress doesn't
reauthorize the program, FDA will have to lay-off employees. Is this
the case? If so, how many reviewers will have to be laid off? When will
these employees first be notified of the possibility that they may be
laid-off if the program is not reauthorized?
Your understanding is correct, Mr. Chairman. FDA will have
virtually no carryover PDUFA funds available to pay our employees when
the fiscal year ends on September 30, 2002. FDA currently has about
2,400 staff-years devoted to the drug review process. Since
prescription drug user fees are used to support approximately 50
percent of the staff devoted to the drug review process, FDA will begin
planning for a furlough and/or a reduction in force (RIF) in June and
by August 1, 2002, we would issue a general notice of a possible RIF to
all 2,400 employees.
3. FDA has stated that increasing revenues and addressing risk
management were its top two priorities in the discussions with
industry. How successful was FDA in addressing these issues in the
negotiations?
FDA believes that both of these priorities are successfully
addressed in the proposed Goals Letter and proposed statutory changes
to PDUFA. If these recommendations are enacted into law, FDA will
receive a substantial increase in funding. Fee revenues would increase
from an estimated $148 million in Fiscal Year (FY) 2002 to $222.9
million in FY 2003. Ultimately, fee revenues would increase to $259.3
million in FY 2007. The increased fee revenues would enable FDA to
achieve both the letter and spirit of the performance goals. Increased
resources would be available for increased staffing, training, guidance
development, and other key aspects of the process for the review of
human drugs.
The proposed funding for risk management activities would allow FDA
to double its safety staff by FY 2007. The increase in staff and
resources would enhance FDA's ability to monitor new drugs for safety
problems that could emerge after their introduction on the U.S. market.
Enhancing this programmatic ability is especially critical now that
U.S. patients are increasingly the first population to receive new
drugs.
4. You state in your testimony that PDUFA performance goals have
helped harmonize drug and biologic product review. However, on January
25, 2002 FDA issued a report on review times, and it shows that CDER
reviews and approves priority drugs in six months, but that CBER
reviews priority biologics in 11.5 months and approved them in 13.2
months. Similar disparities existed for standard reviews. Why the
disparity between the two Centers?
The Center for Drug Evaluation and Research (CDER) and the Center
for Biologics Evaluation and Research (CBER) have met the performance
goal deadlines for review and action on priority (90 percent within 6
months) and standard (90 percent within 12 months) applications.
Approval times, on the other hand, have differed between the Centers.
Although there has been no systematic study of the reasons for these
differences, the Agency believes that they are the result of multiple
forces including the difficulties that applicants experience in
manufacturing the product. Another problem that occurs frequently with
biological products is the inability to ``scale-up'' the manufacturing
process. The sponsor can produce a batch of product for clinical
trials, but when larger scale production is initiated the product no
longer meets the same specifications as the product tested in trials.
These difficulties can lead to longer approval times.
5. What will be done under PDUFA III to lessen the disparity in
review and approval times between CDER and CBER?
The PDUFA III proposals recommended to Congress include several
initiatives to evaluate and address differences between Centers. The
First Cycle Review Performance initiative provides for increased
communication (e.g., of the early-identified deficiencies) to the
sponsor at the time of the filing review and the development of a
guidance document by review staff on Good Review Management Principles.
This initiative includes further training to implement those
principles, and a study to evaluate best practices on the part of both
FDA and industry during the first cycle of review. The Performance
Management initiative includes funding for a review and analysis of the
review process in both Centers.
6. I understand that one key component of the tentative agreement
made between FDA and industry relates to performance management.
Specifically, FDA has agreed to a study of internal management and
performance. Please describe for us the nature of the performance
management agreement and how your office will ensure that this
important piece of PDUFA III is fulfilled.
FDA's Office of the Commissioner will conduct a series of studies
to identify opportunities for enhanced program performance. These will
include a study through an outside consultant to perform a
comprehensive process review within CDER and CBER. The anticipated
outcome of this review will be a thorough documentation of the drug and
biological review process, a re-map of the process indicating where
efficiencies can be gained, activity-based project accounting, optimal
use of review tools, and a suggested path for implementing the
recommendations. FDA would anticipate delivery of a report of the
consultant's findings and recommendations in FY 2004-2005. The Agency
would consider these recommendations in planning any redesign or
process reengineering to enhance performance.
7. Recent data indicate that drug approval times have been
increasing. The approval times for novel drugs (``NCEs'') have
increased from 12.6 months to 17.6 months between 1999 and 2000. What
are the reasons for the upward trend?
The median total approval time for priority new molecular entities
(NMEs, i.e., drugs not previously approved by FDA) approved by CDER has
been approximately 6 months for the past 5 calendar years (1997-2001).
Over the same 5 calendar years, the median approval times for standard
NMEs approved by CDER have ranged from a low of 13.4 months in calendar
year 1998 to a high of 19.9 months in calendar year (CY) 2000. For
calendar year 2001 the median approval time for standard NMEs was 19.0
months.
While FDA has met or exceeded all of its performance goals for the
review of NME applications during PDUFA II, the median total approval
times for NMEs over the past three calendar years have been higher
compared to the all-time low of 13.4 months experienced in CY 1998
(16.3 months in CY1999, 19.9 months in CY2000, 19.0 months in CY2001).
There are many factors that may affect the total approval times for
standard NMEs in any calendar year including the quality and
completeness of the applications and the time required for the sponsor
to resolve any safety, efficacy, or manufacturing deficiencies
identified by FDA. However, FDA has noted that the trend of increased
total approval times for NMEs during the past three calendar years has
coincided with implementation of the increased procedural goals (e.g.,
meeting management goals) under PDFUA II. FDA believes that the
increased workload it has experienced during PDUFA II and the
implementation of FDAMA requirements may have contributed to this
trend. It is important to note that a similar trend has not been seen
for priority applications or for standard non-NME new drug applications
(NDAs).
8. When will the FDA issue its draft guidance on use of surrogate
markers in imaging?
The only guidance that FDA is developing on medical imaging is the
guidance for industry on Developing Medical Imaging Drugs and
Biological Products. This guidance for industry is being developed with
extensive input from the public. A first draft of the guidance was
issued for comment on October 14, 1998. FDA held public meetings on the
draft guidance on January 25 and March 26, 1999. After considering the
discussion and comments at the meetings and after reviewing all written
comments, FDA issued a second draft for comment on July 31, 2000. The
Agency has considered carefully the second round of comments, and the
final version of the guidance is currently moving through the clearance
process. We expect it to be released during the next month or two.
9. When will FDA address the cGMP requirements for PET products?
The Food and Drug Administration Modernization Act (FDAMA) directs
FDA to consult with patient advocacy groups, professional associations,
manufacturers, and physicians and scientists who make or use PET drugs
as we develop PET drug CGMP requirements and approval procedures. We
have taken extraordinary steps to develop the PET CGMPs with extensive
input from these groups. We presented our initial tentative approach to
PET drug CGMP requirements and responded to numerous questions and
comments about that approach at a public meeting on February 19, 1999.
In the September 21, 1999, issue of the Federal Register (64 FR 51274),
we published a notice of availability of preliminary draft regulations
on PET drug CGMP requirements. These preliminary draft regulations were
discussed at a public meeting on September 28, 1999. After considering
the comments on the preliminary draft regulations, FDA has decided to
make several changes to those regulations, to publish a notice of
availability of a revised preliminary draft proposed rule, and to
publish an accompanying draft guidance document. These documents should
publish very soon. We intend to hold another public meeting on May 21,
2002, after which we will evaluate the comments, make appropriate
changes, and publish a proposed rule for comment.
10. To what extent has CDER and CDRH worked to harmonize
requirements for drug and device manufacturers seeking similar
indications (e.g., perfusion indications for MR/US drugs and MR/US
machines)?
CDER, the Center for Devices and Radiological Health (CDRH) and the
FDA Ombudsman's office work together to assure that sponsors of similar
drug/device products are treated the same with respect to regulatory
requirements and review procedures. If any company believes they are
being treated differently than similarly situated competitors, they are
encouraged to bring the issues to the FDA Ombudsman or to the CDER or
CDRH Ombudsmen.
QUESTIONS SUBMITTED BY REPRESENTATIVE JOHN D. DINGELL
What is the legal status of the side agreement? Specifically, is
this a contract, a regulation, a guidance, or something else?
The document referred to as the ``side agreement,'' which is a
letter sent from the Secretary of the Department of Health and Human
Services (HHS) to the Committee on Energy and Commerce of the House of
Representatives and the Committee on Health, Education, Labor, and
Pension of the Senate (the ``Goals Letter''), is not a contract,
regulation, or guidance. The goals letter is a statement by the
Secretary about what the FDA intends and expects to accomplish with the
additional resources provided through the proposed legislation. This
letter is specifically referenced in the proposed PDUFA legislation in
the findings section (section 101) and in the section specifying annual
reports (section 104).
Does this side agreement create any enforceable rights on the part
of industry or FDA? If so, please describe these.
The Goals Letter does not create enforceable rights on the part of
industry or FDA. The PDUFA III legislation, if enacted, would provide
FDA the authority to collect and spend user fees as specified in the
enacted legislation.
Are the provisions of the side agreement enforceable in any way by
third parties?
No. However, there is substantial oversight of FDA's activities
under PDUFA that allows the Administration, Congress, the regulated
industry, and all other interested persons to evaluate FDA's
performance on a regular basis. The proposed PDUFA legislation, if
enacted, would direct the FDA to provide both an annual performance
report and an annual financial report setting forth its performance in
achieving the goals and its expenditures from PDUFA funds, as it has
during PDUFA I and II. Both of these reports are made available to the
public.
If enforceable by anyone, what are the available remedies?
As discussed above, while neither industry nor other interested
persons can file suit against FDA to enforce the performance goals
contained in the letter, the annual reports provide Congress, regulated
industry, and other interested persons with the information about the
Agency's accomplishments and use of funds collected under the PDUFA.
Is FDA free to modify or ignore any or all of the provisions of the
side agreement for any reason? Can it modify or ignore the agreement in
the name of public safety?
FDA fully intends and expects to perform in a manner consistent
with the Goals Letter. FDA's performance under PDUFA over the past 10
years demonstrates that this expectation is likely to be met. Under the
PDUFA legislation, FDA may only use user fees for health activities
related to the process for the review of human drug applications. If a
public safety emergency required FDA to shift resources away from the
process for the review of human drug applications, FDA could shift
resources, but would not be able to collect or spend user fees for any
activities not authorized by PDUFA.
On page eight of your testimony you compare product withdrawals pre
PDUFA and during PDUFA and conclude that drug safety has not suffered
because withdrawal rates are basically the same. Can you comment on
drug safety issues that are of concern to FDA, but that do not result
in product withdrawals? For example, could you provide us with a pre
PDUFA and PDUFA comparison of such post market drug safety matters as
warning letter, package inserts, black boxes and the like taken by FDA
other that withdrawals?
A report to the Commissioner of FDA from the Task Force on Risk
Management entitled, ``Managing the Risks from Medical Product Use''
was issued in May 1999. This report is enclosed as Appendix 1. Appendix
A of the enclosed report provides a comparison of post-approval risks
for drugs and biological products approved before and after the
implementation of PDUFA.
Could you outline in detail each element of the side agreement? I
realize that it is still undergoing departmental review, but it would
be helpful to us to have a run down of the agreement now. Will you
provide us with written text of the agreement as it currently stands?
Since the Subcommittee held its hearing on March 6, the
Administration has transmitted the Goals Letter to the Energy and
Commerce Committee. The full text of the Goals Letter appears in
Appendix 2.
Can you explain for us exactly why this side agreement needs to be
cleared by OMB. That sounds a lot like a regulation. If so, why aren't
APA notice and comment procedures being followed?
Regulations are not the only documents appropriate for the Office
of Management and Budget (OMB) clearance or review. OMB reviews budget
estimates as well as documents in support of pending or planned
legislative proposals. (See OMB Circular A-19 for the policy on
clearance of legislative proposals and Circular A-11 for the policy on
clearance of budget matters). The Goals Letter is, in part, a budgetary
matter since it involves Agency resource commitments. It is also
referred to in a legislative proposal that the Administration has
decided to advance for FY 2003. For these reasons it is appropriate for
OMB review. Because the Goals Letter is not a regulation, the
Administrative Procedure Act (APA) requirements for notice and comment
rulemaking are not applicable.
Could you explain the pros and cons of subjecting the side
agreement to notice and comment in the Federal Register before making
it final? Wouldn't such a procedure provide a broader base of input to
FDA and a greater assurance to all that the agreement is in the public
interest?
FDA believes that this process, as well as the legislative process
that Congress engages in, provides great assurance that the PDUFA
program will continue to be in the public interest. In order to receive
input from a broad range of interested persons on the concepts in the
proposed legislation and Goals Letter, FDA hosted a series of
discussions over the past 18 months. Since the fall of 2000, FDA has
engaged in a series of public meetings with patients, consumers and
other stakeholders to obtain their views on their issues and priorities
for PDUFA reauthorization. FDA has also engaged in a series of meetings
with representatives of the biotechnology and pharmaceutical industry
to discuss some of the more technical aspects of application review,
information technology in support of application review, and fee
collection and use.
RESPONSES TO THE RECOMMENDATIONS AND/OR CONCERNS RAISED IN THE PAPER
COMPILED BY THE PATIENT AND CONSUMER COALITION, AS REQUESTED BY
REPRESENTATIVE JOHN DINGELL.
Hold balanced hearings on PDUFA reauthorization and drug safety
concerns. The hearings should include testimony from patients who have
been harmed by problem drugs--or their representatives--and consumer
advocates who are knowledgeable about PDUFA. Such hearings would send a
vital signal to FDA from Congress that what the public wants and
deserves is a thorough review and oversight process for drugs and
biologics, not just speedy approval of new products.
FDA defers to the prerogatives of the Energy and Commerce Committee
to determine the choice of witnesses for its hearings.
Adequately fund the entire range of FDA's approval and safety
oversight activities from general revenues. There is an urgent need for
increased funding for post-marketing surveillance and other safety-
related activities not covered by current user fees. User fees are not
a substitute for adequate federal funding of these vital and growing
public health functions. 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 tot he regulator from
the regulated industry.
Administrations, both past and present, as well as Congress have
determined that the process for the review of human drugs and biologics
at FDA should be funded through a combination of appropriations and
user fees. FDA has been able to administer this policy without
compromising its integrity or the safety and efficacy of the products
it approves.
Give the FDA Total Control Over All Review and Surveillance
Activities--If an unwillingness to appropriate adequate funds leads
Congress to consider the expansion of user fees, it is absolutely
essential that the FDA alone determine their usage, without the kind of
inappropriate control over the use of these fees (through mandated
decision-making deadlines) that the industry has exercised with new
drug approvals.
Under PDUFA, fee revenues may be used by FDA to cover the costs of
the process for the review of human drugs. In the context of receiving
these additional revenues, FDA agreed to meet certain performance goals
for the review of applications and certain procedural and processing
goals. FDA retains the ability to allocate the fee revenues as it sees
fit in order to meet its public health obligations and to meet the
PDUFA performance goals. It is important to remember that the
performance goals in PDUFA relate to the timeliness of review and
processing of applications, not the approval of applications. FDA
believes that the current system works well and the PDUFA program has
overall been good for the public health.
Address Drug Safety Concerns Created by PDUFA's Excessive and
Inappropriate Focus on Swift Approval--PDUFA III should include new
safety protections that, to the greatest extent possible, protect the
public from potential harm caused by adverse reactions, side effects
and adverse events related to pharmaceutical products and biologics.
Decision-making deadlines for drug review should be redefined to focus
on the FDA's responsibility to guarantee safe drugs, not only on the
speed with which reviews are conducted. The agency's antiquated and
under-funded adverse event reporting system (for drugs, biologics and
devices) should also be modernized.
A report to the Commissioner of FDA from the Task Force on Risk
Management, entitled, ``Managing the Risks from Medical Product Use''
was issued in May 1999. That report (enclosed as Appendix 1) found
that, for drugs approved during the PDFUA era, the rate of drug
withdrawals for safety concerns was relatively unchanged from the rate
of drug withdrawals for safety concerns in the pre-PDFUA era. The most
recent data show that the percentage of PDUFA drugs withdrawn for
safety concerns is the same (2.7%) as the percentage of drugs withdrawn
for safety concerns during the pre-PDFUA period (2.7%). This finding is
particularly notable when one takes into account the fact that nearly
80% of newly approved drugs are either approved first in the United
States or are approved in the United States within one year of their
being approved anywhere else in the world.
The draft Goals Letter for PDUFA III includes no substantive
changes to the performance goals for review of applications compared to
those currently in place. The draft Goals Letter also includes a
proposal for an expanded risk management program for new drugs approved
under PDFUA III. FDA believes that this new risk management program
will significantly enhance its ability to detect risks of drugs early
and improve FDA's ability to work with the sponsor, health care
providers, and patients to manage the risks of new drugs more
effectively. The proposal for PDUFA III would allow FDA to use PDUFA
fee revenues to cover the costs of this new risk management program,
including activities that occur for up to three years after drug
approval. The availability of these new PDFUA fee revenues for risk
management would allow FDA to approximately double the staffing in its
drug safety program over five years.
Please refer to the response provided to the question below
relating to ``Improve Adverse Event Reporting'' for details relating to
adverse events.
Eliminate the linkage between appropriated and user fee funds. The
current law results in disproportionate funding for the drug approval
process compared to most other research, regulatory, and public
education functions. At a minimum, the program must be re-designed in
such a way as to prevent the draining of funds from vital FDA
functions.
During the period of FY 1994 to FY 2001, the effect of the
statutory triggers established under Prescription Drug User Fee Act
(PDUFA) on the availability of funding for non-PDUFA programs has been
less significant than the absence of additional appropriations to fund
the annual pay raises for Food and Drug Administration (FDA) employees.
During these years, FDA's appropriations failed to include increases to
cover the annual costs of mandated Federal pay raises. The cumulative
impact of absorbing the cost of the Federal pay raise during this
eight-year period was more than $200 million. This resulted in a
reduction in staffing for activities other than the process for the
review of human drug applications (e.g., compliance activities, review
of over-the-counter drugs, etc.) of more than 1,100 staff years since
PDUFA I was enacted.
Although the absence of additional funds to pay the cost of
mandated pay raises has had the greatest effect on non-PDUFA programs,
one of the PDUFA triggers has also had a significant effect. Section
736(g)(2)(B) requires that FDA annual spending on drug review from
appropriations be at least as much as the amount of appropriations that
FDA spent on drug review in FY 1997, adjusted for inflation.
The legislation that the Administration has proposed includes
modifications to the trigger (Section 736(g)(2)(B)) such that FDA will
no longer be compelled to spend amounts that are significantly greater
than the amount required by this trigger. The proposal would provide
FDA a margin of error in its effort to meet this requirement of the
law. Under this proposed modification, if FDA's spending from
appropriations on drug review is within 5 percent of the amount
required by this section of the law, the requirement is considered to
be satisfied. In cases where FDA's spending from appropriations is
within 3 percent of the trigger amount, no adjustment in fees will be
required. If the spending is between 3 percent and 5 percent below the
trigger amount, then FDA will, in a subsequent year, decrease user fees
by the amount of the shortfall that is between 3 and 5 percent (i.e., a
maximum of 2 percent).
The purpose of this change is to relieve FDA of the need to
overspend from appropriations each year, as has occurred consistently
since FY 1993. Spending from appropriations on the drug review process
each year is still expected to be at, or very close to, the amount
specified by this trigger, and may never be more than 5 percent below
the trigger amount.
Require that user fees support the life cycle of the review
process. Presently, FDA staff hold numerous pre-New Drug Application
meetings with manufacturers before the agency receives any PDUFA fees
for the intended application. While these meetings benefit sponsors
greatly by improving their understanding of FDA expectations and the
quality of their applications, they also divert FDA staff time from
other review functions and increase the cost and difficulty of meeting
PDUFA goals. In other words, the required meetings are an un-funded
mandate on the agency.
The financial provisions in the legislation that the Administration
has submitted should satisfy the concerns that prompt this issue.
First, it is important to note that PDUFA revenues come from three
fees--application fees, product fees, and establishment fees. The fees
from all of these sources can be used by FDA to enhance its activities
in any part of the drug review process, from the submission of an
investigational new drug application through the FDA decision to
approve or not approve a new drug application. Some of the revenue from
product and establishment fees is used to support the work FDA does at
the investigational new drug stage, before a marketing application is
ever submitted.
The Agency agrees that under PDUFA II, FY 1998 through FY 2002, fee
revenues were insufficient to adequately fund the work necessary to
meet the PDUFA II performance goals. The legislative proposal that the
Administration has forwarded to the Energy and Commerce Committee
addresses this problem by significantly increasing the revenue levels
from FY 2003 through FY 2007. This proposal calls for revenues of
$222.9 million in FY 2003--a 30% increase over revenue levels FDA
expects to spend in FY 2002. These revenue levels will rise to $259.3
million by FY 2006 and 2007--an increase of more than 50% compared to
FY 2002 spending levels. Further, these figures are in FY 2003 dollars,
and will be adjusted to account for the impact of inflation and
workload increases. FDA believes that this proposal would fully fund
the work obligations that would be required of the Agency over the next
5 years.
Finally, under the proposal, FDA would be allowed to use fee
revenues to fund some activities that the Agency will perform after a
drug is approved. For drugs approved on or after October 1, 2002, risk
management and epidemiological studies that may be needed in the first
two to three years after approval may be paid for from PDUFA fees. The
Agency expects that this provision will enable FDA to approximately
double its headquarters drug safety employment levels in CDER and CBER
by FY 2007. We believe that this is an important addition to the
resources available to FDA that helps to assure the safety of drugs in
their first two or three years of market life.
Question Consult All Stakeholders--If performance goals are not
eliminated in PDUFA III, consumers and patient representatives should
be involved in developing them.
FDA has conducted a fair and balanced effort to hear from all
parties that have a viewpoint about PDUFA. In preparation for
submitting the Administration's PDUFA III proposal to Congress, the
Agency engaged in a comprehensive initiative to involve all PDUFA
stakeholders--consumers, health providers, patient groups, and the
manufacturers of drugs and biologics--in the development of PDUFA III
proposals. This process included:
Two public hearings.
``Listening'' sessions with consumer and patient groups.
Consumer roundtables where PDUFA was a major topic of
discussion.
Meetings with drug and biologic manufacturers.
At our public hearings, FDA received 12 hours of testimony. Of the
total of 28 witnesses who provided testimony, 23 were representatives
from consumer, patient and health provider groups. Seventy-five
consumer, patient and health provider groups were also represented at
the ``listening'' sessions and roundtables. This is evidence of the
broad representation that served as a foundation for the
Administration's PDUFA III proposal and the development of the PDUFA
III performance goals.
Grant FDA a ``Scientific Override''--When the FDA requires
additional information or clarification from the manufacturer as part
of the review process, the FDA should be allowed to ``stop the clock''
on review deadlines while waiting for this information to be provided.
The fundamental premise of the performance goals for review of
applications outlined in the letter from the Secretary of HHS to
Congress is that sponsors are expected to submit a complete application
for FDA review and FDA will perform a complete review of the
application within a defined time (i.e., 6 months for priority
applications and 10 months for standard applications). If FDA
determines during the review of an application that additional
information is needed from the sponsor, FDA may request the information
from the sponsor while continuing its review of the application as
submitted. If the additional information is submitted to FDA during the
same review cycle, FDA has several options on how to handle the new
information. If there is sufficient time remaining on the review clock,
FDA may choose to review the new information without changing the
review clock. Alternatively, FDA may choose to extend the review clock
by up to three months if the new information constitutes a major
amendment to the application and is submitted within the last three
months of the review cycle. Finally, FDA may defer review of the new
information until the next review cycle. Thus, FDA already has a
significant degree of discretion in deciding how to process new
information submitted during the review of an application and FDA
considers these options sufficient to address issues that arise when
new information is submitted to an application during a review.
Eliminate Rigid Management Goals--These goals require the agency to
set up meetings with the industry within specific timeframes. They
should be replaced by a more flexible system that allows the FDA to
prioritize these requests, thus decreasing undue burden on the agency.
FDA is satisfied with the current prioritization of meetings into
three categories, such that a meeting about a critical issue takes
precedence over a more routine discussion. Type A meetings are
considered necessary for an otherwise stalled drug development program
to proceed (a ``critical path'' meeting). For example, a Type A meeting
would be held when FDA has placed an investigational new drug on
``clinical hold'' and the investigation cannot continue. Type A
meetings are held within 30 days. Type B meetings are usually held to
discuss anticipated submissions (pre-initial IND, end of Phase II, or
pre-NDA) and are held within 60 days. Type C meetings are any other
type of meeting and accordingly, have the longest timeframe of 75 days.
Fee revenues in the proposed statutory changes for PDUFA provided the
necessary resources to support these meetings.
Allow FDA More Flexibility For Standard Reviews--There is no public
health justification for requiring the FDA to decide on a ``me too''
drug that duplicates therapies already on the market at the same speed
as a drug that might offer therapeutic advantages to some patients. The
FDA should be granted greater authority to prioritize the review of
standard drug applications.
FDA has existing criteria by which decisions are made regarding
whether to prioritize the review of new drug applications based on the
therapeutic potential of the drug. The two review classifications and
their definitions are:
Priority review drug--The drug product, if approved, would be
a significant improvement compared to marketed products in the
treatment, diagnosis, or prevention of a disease. Improvement
can be demonstrated by, for example: (1) evidence of increased
effectiveness in treatment, prevention, or diagnosis of
disease; (2) elimination or substantial reduction of a
treatment-limiting drug reaction; (3) documented enhancement of
patient compliance; or (4) evidence of safety and effectiveness
of a new subpopulation.
Standard review drug--All non-priority applications will be
considered standard applications.
Under PDUFA, the review clock for priority applications is 6 months
and the review clock for standard applications is 10 months. FDA's
performance goals for a complete review of both types of applications
are 90% completed within the goal dates.
FDA believes that the current system for designation of products
for priority review and the current review clocks and performance goals
work well and allow FDA to prioritize its review work. The PDUFA III
proposal would not change the current performance goals.
Create Safety Goals--FDA should establish performance goals
oriented toward protecting the health and welfare of consumers, such as
tracking and reviewing Phase IV trials, improving the collection,
analysis and response of adverse event reports, and enhancing the speed
and quality of review of direct-to-consumer advertisements.
The PDUFA III proposal does not include performance goals for the
activities identified in this question. However, FDA has conducted, and
will continue to conduct, significant activities in the areas
identified in this question. Details of these activities follow:
Tracking and Reviewing Phase IV Trials
Following the enactment of FDAMA, FDA initiated a number of steps
to implement the provisions on postmarketing studies (section 130). In
addition, several procedural improvements were made and a data tracking
system was developed to improve monitoring and processing of annual
status reports and final study reports. The improvements include:
Updating staff operating procedures at CDER to clarify how
postmarketing commitments and the annual status reports will be
processed, reviewed, and archived.
Designating CDER personnel to be responsible for monitoring
the submission of reports. Target review timelines have been
established for annual status reports and for the review of
final study reports. These timelines will be tracked and
monitored.
Developing new CDER data systems to more efficiently capture
the existence of postmarketing commitments, the submission of
annual study progress reports, the submission of final study
reports, and final review determinations. This new database was
implemented in July, 2001.
Improving the Collection, Analysis and Response of Adverse Event
Reports
One of the objectives of the risk management component of the PDUFA
III proposal is to develop surveillance approaches in a directed and
well thought out manner that could yield the greatest value for the
particular drug. In circumstances where there are suggestions in the
pre-market database of adverse events of concern, risk management and
active surveillance approaches could be developed to manage and further
evaluate those concerns. In other situations where there are unexpected
events, the current reporting system has been able to detect signals of
an event of concern. Good pharmacovigilance requires evaluation of drug
safety from many perspectives and sources. In addition, the current
system depends upon the involvement of drug companies to ensure that
they conduct the initial follow up that is so important for full
evaluation of a report.
Enhancing the Speed and Quality of Review of Direct-to-Consumer
Advertisements
CDER currently has an active program focused on the timely review
of direct-to-consumer advertisements. CDER recognizes the importance of
insuring that such advertisements are accurate and provide balanced
information about the benefits and risks of the product. CDER is
currently implementing plans to reorganize its advertising review
division to improve its ability to review direct-to consumer
advertisements. CDER, however, has limited resources to apply to this
area in the face of an increasing number of direct-to consumer
advertisements.
Grant FDA Civil Monetary Fine Authority and Subpoena Power--When
companies fail to complete Phase IV confirmatory trials or when
companies repeatedly violate prescriber and direct-to-consumer
advertising guidelines, the agency should be given the authority to
levy significant monetary penalties. The agency should also have the
power to compel companies to produce relevant documents.
As part of FDAMA, Congress provided additional authority in section
21 USC 356b to monitor the progress of postmarketing studies that
sponsors have agreed to conduct. Congress also instructed FDA to
provide a report providing information on the status of postmarketing
studies that sponsors have agreed to conduct and for which annual
reports have been submitted. As indicated in the recent ``Report to
Congress on Reports on Postmarketing Studies,'' in implementing 21 USC
356b FDA has defined the content and format of annual progress reports
for postmarketing studies. The Agency has also modified a number of
internal operating procedures and programs to more efficiently track
and monitor the status of postmarketing studies. At this time, FDA is
not recommending any changes to legislative authority regarding
postmarketing studies since the Administration's proposals only relate
to PDUFA.
FDA has an active enforcement program to help ensure compliance
with the Act and regulations governing promotion and advertising. If
the Agency determines that the enforcement program governing these
activities is not resulting in sufficient levels of compliance with the
law, FDA will inform Congress and, if necessary, seek authority for
additional penalties.
A number of provisions both in the Act and the implementing
regulations enable FDA to gather information from manufacturers related
to drug safety. For example, FDA's inspectional authority is set out in
21 USC 374. Under this authority, FDA is authorized to enter and
inspect any factory, warehouse, or establishment where drugs are
manufactured, processed, packed, or held for introduction into
interstate commerce. New drug application (NDA) and abbreviated new
drug application (ANDA) holders are also required to establish and
maintain records and make reports to FDA of relevant data determined by
FDA to be ``. . . necessary to enable the Secretary to determine . . .
whether there is or may be ground for invoking subsection (e) . . .,''
the provision in the Act setting forth the procedures for the
withdrawal of approval of an NDA or ANDA on safety grounds. 21 USC
355(k)(1). NDA and ANDA sponsors are required to report adverse events
associated with the use of a drug in human to FDA. 21 CFR 314.80. NDA
and ANDA sponsors must report other safety-related information to FDA
under 21 CFR 314.81. Under 21 CFE 310.305, manufacturers, packers, and
distributors of marketed prescription products without NDAs or ANDAs
must also report serious, unexpected adverse events to the FDA. Under
the proposed PDUFA legislation, funds from user fees will be able to be
expended on pre- and peri-NDA/BLA risk management plan activities. This
change in the PDUFA program will help ensure that drugs approved for
use in the United States continue to be among the safest in the world.
As stated, if FDA determines that the tools currently in place are not
adequate to maintain the high degree of drug safety in the U.S., FDA
will inform Congress, and if necessary, seek additional authorities.
Launch Independent Drug Withdrawal Investigations--An office or
agency independent of the FDA should investigate the circumstances
surrounding the withdrawal of medical products from the market, as the
National Transportation Safety Board does for plane crashes.
The complex decision to withdraw an approved product from the
market requires multi-disciplinary expertise, often the same expertise
critical to the decision to initially approve the product. Since FDA's
mission is to protect and promote the public health, FDA believes that
the creation of a separate agency to evaluate product withdrawals is
unnecessary and would result in the duplication of functions that are
currently being performed, and must continue to be performed, by FDA.
Increase Monitoring and Review of Phase IV Trials--Require the FDA
to track Phase IV trials, strictly monitor and enforce the informed
consent and protection of human subjects in those studies, and, in a
timely manner, review the quality of the studies and the accuracy of
the findings.
Please see response to the question relating to creating safety
goals, above.
Improve Adverse Event Reporting--Hospitals, HMOs, nursing homes and
other healthcare providers should be required to automatically report
(the present system is voluntary) serious adverse drug events, adverse
reactions and medical errors to the FDA, CDC, and/or other relevant
agencies. Appropriations for FDA's oversight of adverse event reporting
should be dramatically increased.
At the present time, FDA does not have authority to require
hospitals, Health Maintenance Organizations (HMOs), nursing homes, and
other healthcare providers to report all adverse drug events to FDA. In
addition, to have all healthcare providers report every adverse event
directly to FDA would overtax the system without necessarily yielding
additional quality data. Part of the objective of the risk management
component of the PDUFA III proposal is to develop surveillance
approaches in a directed and well thought-out manner that could yield
the greatest value for the particular drug. In circumstances where
there are suggestions in the pre-market database of adverse events of
concern, risk management and active surveillance approaches could be
developed to manage and further evaluate those concerns. In other
situations where there are unexpected events, the current reporting
system has been able to detect signals of an event of concern. Good
pharmacovigilance requires evaluation of drug safety from many
perspectives and sources. The current system also depends upon the
involvement of drug companies to ensure that they conduct the initial
follow up that is so important for full evaluation of a report.
Utilize the Centers for Education and Research on Therapeutics--
CERTS should examine the feasibility of: (1) implementing a patient
self-monitoring reporting system for signaling possible adverse drug
reactions; and, (2) expanding the use of medical registries to follow
patients who may be at risk of serious reactions.
FDA is currently working with the Centers for Education and
Research on Therapies (CERTS) on a number of projects that relate to
risk management. A current area of active work is a series of workshops
that FDA, CERTS, and industry are conducting that address risk
communication, risk assessment, and risk management. The objective of
these workshops is the development of a research agenda to further
advance the science of risk management as it relates to
pharmaceuticals. In addition, the CERTS and FDA are beginning to look
at the feasibility of active surveillance in emergency departments for
adverse events related to drugs.
Broaden Distribution of Medication Guides--Consumers should be
given power to make informed decisions about drugs and devices and to
avoid preventable harm. It is time to mandate that medication guides
with scientifically accurate, unbiased and clearly worded information
about the risks and benefits of a treatment be included with every
dispensed drug (as proposed by the FDA in 1995). Such medication guides
would also, for the first time, provide a mechanism for notifying
consumers directly when new safety concerns about a drug emerge that
require a change in a drug's approved labeling.
As noted in the question, in 1995 FDA published a proposed rule to
increase the quality and quantity of written medication information for
consumers. FDA proposed requiring manufacturers to produce Medication
Guides for certain medications that pose serious and significant public
health concerns. In addition, the proposal encouraged that written
information be produced and distributed for all drugs, and set targets
for the distribution of such information with new prescriptions.
The following year a workshop was convened by FDA to discuss this
proposal and, subsequent to the workshop, Congress passed legislation
(P.L. 104-180) that asked interested parties to develop a plan which
would attempt to achieve in a voluntary manner the goals of FDA's 1995
proposal. A plan was developed in response to the legislation that
included identifying mechanisms and incentives to ensure voluntary
efforts to provide useful information to consumers. The target goals
established in P.L. 104-180 provided that by 2000, 75% of individuals
receiving a new prescription receive useful information. By 2006 the
target goal increased to 95%. FDA currently requires a Medication Guide
in certain circumstances, but for most drugs the distribution of
medication information to patients by a pharmacist is voluntary and is
accomplished using third party vendors of such information.
Regarding the voluntary distribution of information, FDA contracted
for a study of the quality and quantity of the information that was
being distributed in response to the year 2000 goals. FDA is currently
evaluating the results of this study and will be determining what
additional actions and public discussion may be needed in an effort to
ensure that the 2006 goals are achieved.
Regarding the required medication guides, these are a relatively
new risk communication tool that also requires further evaluation. In
particular, FDA is now working with the CERTS to develop projects
evaluating the effectiveness of medication guides as a risk management
tool. In addition, more study is needed of the degree to which
medication guides are distributed by pharmacists and how frequently
they are read and comprehended by consumers.
Section 506B of the Food, Drug, and Cosmetic Act should be amended
to expand the scope of information made available to the public to
include information [such] as study protocols, patient accrual rates,
reports of unexpected, i.e., unlabeled, suspected adverse reactions,
and study results.
As a public health agency, FDA supports making useful information
available to consumers regarding the safe and effective use of
regulated products. However, there are a number of considerations that
must be taken into account when a determination is made to make
information publicly available. Given the complex issues involved, the
Agency would need to examine the language of a specific proposal in
order to comment on whether or not it is advisable.
Scrutinize Single Controlled Clinical Studies--An increasing number
of drug manufacturers have indicated that they will begin submitting
new drug applications using data from only one controlled clinical
study, which is now allowed by law, rather than multiple studies. An
independent study should be conducted at an appropriate time to assess
the effectiveness of single controlled studies in assessing the safety
of drugs and biologics.
The usual requirement for more than one adequate and well-
controlled investigation reflects the need for independent
substantiation of experimental results. A single clinical experimental
finding of efficacy, unsupported by other independent evidence, has not
usually been considered adequate scientific support for a conclusion of
effectiveness. However, FDA has, under certain circumstances, approved
drugs on the basis of development programs that included only one well-
controlled clinical trial in addition to evidence from other studies
that confirmed its results. The Agency issued a ``Guidance for
Industry: Providing Clinical Evidence of Effectiveness,'' in 1998 to
specifically address this, as required by FDAMA. Situations in which a
single controlled clinical trial might be considered adequate (in
combination with confirmatory evidence) for drug approval include:
1. When the effectiveness of a new use can be extrapolated from
existing studies of an already approved use (e.g., a new dosage
regimen; pediatric uses).
2. When a single study for a new use is supported by data from related
adequate and well controlled trials (e.g., a different phase of
the same disease or a closely related disease, studies in a new
special population, studies in combination or as monotherapy;
studies in a closely related disease).
3. When a single controlled study includes multiple centers and is so
large that it, in effect, serves as multiple studies.
4. When the endpoint and results of the single controlled study are
such that the study could not ethically be repeated or the
statistical results are very persuasive, with consistency
across subsets of the analysis.
Although FDAMA encouraged the Agency to issue a Guidance on the
subject, FDA has applied these principles for many years and continues
to be actively engaged in discussions to further refine them. For
example, FDA participated in a meeting convened by the Center for Drug
Development Science at Georgetown University in January, 2002,
entitled, ``Confirmatory Evidence to Support a Single Clinical Trial
(SCT) as a Basis for Drug Approval.'' Participants included
academicians, leaders from FDA's CDER, CBER and CDRH and the
pharmaceutical industry. A written summary of the conference is
currently being drafted. Discussion topics included: 1) the nature,
sources and standards for evidence of effectiveness; current issues
concerning satisfactory requirements for ``confirmatory evidence;'' 2)
the standards for a single clinical trial itself, and; 3) current
issues in establishing an adequate safety database, assuming that
effectiveness is independently confirmed.
Discussions at the meeting were constructive and productive. In
general, at the meeting there was a great deal of reluctance on the
part of regulators and the pharmaceutical industry, as well as many of
the academicians, to apply the SCT model widely. This was felt to be a
model that should only be used in limited circumstances, such as those
already articulated in FDA's 1998 Guidance. It was generally
acknowledged that scientifically sound clinical studies should be the
goal of any drug development program, and simply conducting large
numbers of poorly designed or inefficient trials is not in the interest
of the public health. While most of the work at the conference centered
around clarifying the principles related to the single adequate and
well-controlled trial, it was widely agreed that one of the greatest
needs for data at the time of NDA review is regarding safety. This
point is often lost in discussions about single controlled trials and
must not be, particularly in light of recent public concerns about
drugs reaching the market prior to adequate safety testing.
Examine Comparative Safety Data--Manufacturers should be required,
as part of their application to the FDA to market a new drug or
biologic, to submit the results of tests comparing the safety and
efficacy of their product to others already on the market that are used
to treat the same indication.
FDA does not have the legal authority to require sponsors to submit
the results of clinical trials comparing the safety and efficacy of
their product to others already on the market that are used to treat
the same condition. While FDA does not have this legal authority, FDA
often encourages sponsors to conduct such comparative trials and in
many cases the sponsors do conduct comparative trials and submit them
for FDA review. If these trials meet FDA standards, the data are often
included in the approved labeling for the product.
FURTHER QUESTIONS SUBMITTED BY REPRESENTATIVE JOHN D. DINGELL
Dr. Woodcock, as Director of CDER, you have the responsibility of
assuring that new drugs approved under NDAs are safe. I understand that
clinical trials, even ones involving thousands of patients, cannot be
expected to pick up safety problems, less frequently occurring but
dangerous, even fatal, side effects, is that correct?
It is correct that clinical trials would not be expected to detect
rare adverse events due to the limited numbers of patients in such
trials. In addition, clinical trials are limited in duration and tend
to include carefully selected patient populations. For these reasons,
it is critical that we maintain careful vigilance over newly marketed
drugs to be able to detect such events. The new risk management program
in PDUFA III will be an important step forward toward this goal.
So safety is primarily evaluated through animal studies and
pharmacokinetic models is that correct?
No. The safety of a new drug is evaluated prior to approval based
on data available from a variety of studies. This includes data on how
the drug is manufactured and the drug's stability over time, an
analysis of safety of drug impurities, inactive ingredients, and
degradation products, data from an extensive battery of animal
toxicology and pharmacology studies, data from human pharmacodynamic
and pharmacokinetic studies, and data from the clinical trials of the
drug in humans. While the amount of safety data in humans varies
depending on the drug and the indication to be treated, for chronically
administered drugs, the International Conference for Harmonization
(ICH) standard for the minimum size of the clinical safety database is
1,500 volunteers/patients. In many cases, FDA may require that the
clinical safety database be far greater than the ICH minimum prior to
approval. FDA also considers any data available from foreign post-
marketing surveillance of the drug if the drug has been approved in
other countries prior to approval in the United States.
I understand that CDER is working on better early measures of liver
toxicity and heart toxicity both in animals and in humans so drugs that
product unacceptable side effects are detected earlier in the process.
Could you elaborate on you work in this area? When might we see more
sensitive tests leading to greater assurance of safety at time of
approval?
Regarding cardiac toxicity, FDA is addressing this issue from both
the pre-clinical and clinical standpoint. FDA is working to develop
guidances on appropriate pre-clinical assessment of drugs to screen for
cardiac toxicity, in particular prolongation of the QTc interval on
ECGs. This activity is still in its early stages and it may be some
time before a guidance is finalized. From the clinical standpoint, FDA
is working on developing guidance for industry regarding appropriate
cardiac evaluation of a drug during its development. In addition, it is
important for FDA to have direct access to ECG data as we evaluate
drugs, and so a public meeting has been held on the topic of submitting
ECG data electronically for analysis. Another public workshop is
planned for this spring following which draft guidance will be
developed.
Regarding hepatotoxicity, a public workshop was held in February
2001 at which time a White Paper on hepatotoxicity was written which
described the issues to be addressed. These included pre-clinical,
clinical and post-marketing issues. Since that time FDA has been
working with industry and others to further identify the issues to be
addressed and develop plans to address the various issues that are
identified. These include:
Examining the sensitivity and specificity of screening tests.
Examining the time course and patterns of hepatotoxicity
related to drugs to better inform future actions.
Determining background rates.
Determining the feasibility of active surveillance approaches.
further questions submitted by representative richard burr
When will the Agency issue the final ``Guidance for Industry on
Developing Medical Imaging Drugs and Biological Products''? The last
draft was issued in June 2000. This Guidance is necessary in order to
implement the radiopharmaceutical regulation directed by Section 122 of
FDAMA which was supposed to be effective almost 3 years ago under
FDAMA.
The guidance for industry on Developing Medical Imaging Drugs and
Biological Products is being developed with extensive input from the
public. A first draft of the guidance was issued for comment on October
14, 1998. FDA held public meetings on the draft guidance on January 25
and March 26, 1999. After considering the discussion and comments at
the meetings and after reviewing all written comments, FDA issued a
second draft for comment on July 31, 2000. The Agency has considered
carefully the second round of comments, and the final version of the
guidance is currently moving through the clearance process. We expect
it to be released during the next month or two.
FURTHER QUESTIONS SUBMITTED BY REPRESENTATIVE HENRY A. WAXMAN
It is my understanding that FDA has fewer than 15 FTEs to review
over 37,000 prescription drug ads each year, and the triggers in the
user fee program have been partly to blame because FDA has been forced
to drain resources from other programs, including drug advertising, to
meet its obligations under PDUFA. In your best professional judgment,
how many FTEs would be needed and how much would it cost to fund an
effective drug advertising review program and bring enforcement actions
against misleading ads in a timely manner?
The Division of Drug Marketing and Advertising (DDMAC) in CDER is
responsible for the regulation of prescription drug advertising. This
Division currently has assigned 39 FTEs. While DDMAC has worked to
maximize its productivity and is currently undergoing a reorganization
that is designed to further improve its efficiency and effectiveness,
the current staffing is not adequate to keep pace with the rapidly
increasing number of professional and direct-to-consumer advertisements
for prescription drugs. It is estimated that CDER would need
approximately 35 additional FTEs and supporting operating funds to
fully staff the advertising review program.
Currently, CBER has 4 FTEs to review all advertising and
promotional labeling materials submitted. In order to adequately assess
these materials and bring timely enforcement actions, a large increase
in staff would be required. Based on the projected number of
submissions for FY2003, and conservative estimates of man-hours needed
to review these submissions, 30 additional review FTEs would be
required. Additional management and support staff would also be needed,
for a total of 38 FTEs at a cost of $5,130,000.00. An additional
$550,000 would be required for IT upgrade and support of a tracking
system. This would result in a total requirement of $5,680,000.00.
Have statutory triggers in PDUFA adversely affected funding of
other FDA programs? If so, which ones?
As is mentioned above, during the period of FY 1994 to FY 2001, the
effect of the Prescription Drug User Fee Act's (PDUFA) statutory
triggers has had on the availability of funding for non-PDUFA programs
has been less significant than the absence of additional appropriations
to fund that annual pay raises for Food and Drug Administration (FDA)
employees. During these years, FDA's appropriations failed to include
increases to cover the annual costs of mandated Federal pay raises. The
cumulative impact of absorbing the cost of the Federal pay raise during
this eight-year period was more than $200 million. This resulted in a
reduction in staffing for programs other than the process for the
review of human drug applications (e.g., compliance activities, review
of over-the-counter drugs) of more than 1,100 staff years since PDUFA I
was enacted.
Although the absence of additional funds to pay the cost of
mandated pay raises has had the greatest effect on non-PDUFA programs,
one of the PDUFA triggers has also had a significant effect. Section
736(g)(2)(B) requires that FDA annual spending on drug review from
appropriations must be at least as much as the amount of appropriations
that FDA spent on drug review in FY 1997, adjusted for inflation.
There are two aspects of this trigger that may adversely affect FDA
programs other than drug review. These are:
(1) The minimum that FDA must spend from appropriations increases by an
inflation factor each year. In years when FDA does not receive
appropriated increases to cover the cost of the Federal pay
raise, FDA must increase the amount allocated for PDUFA drug
review programs by an amount sufficient to meet the adjustment
for inflation established in the PDUFA statute. The only means
of accomplishing this is to reduce the amount spent on non-
PDUFA programs. This aspect of the section 736(g)(2)(B) trigger
is directly related to whether or not FDA receives the
appropriations necessary to cover the cost of the Federal pay
raise.
(2) This trigger is based on FDA spending, an amount that cannot be
measured until after the fiscal year ends, when the accounts
are closed and final reports are produced. Failure to meet this
spending threshold would be catastrophic. Fee revenue collected
in the previous year would all have to be returned and this
loss in revenue would mean that FDA would have to lay off a
significant number of employees. To avoid these catastrophic
consequences, FDA must always err on the side of caution by
spending more on the drug review process than the minimum
amount required. This is necessary to be certain that, when the
final accounting is completed at the end of the year, FDA will
have met the minimum spending required.
The table below outlines this situation. It depicts:
(1) the minimum amount of spending required from appropriations each
year as a result of this trigger (Section 736(g)(2)(B));
(2) the actual FDA spending from appropriations each year on the drug
review process; and
(3) the amount by which FDA spending exceeded the minimum spending
mandated by the statutory trigger (i.e., the difference between
1 and 2.)
----------------------------------------------------------------------------------------------------------------
Minimum Spending
Required by Actual Spending Percent
Fiscal Year Section from Difference Difference
736(g)(2)(B) Appropriations
----------------------------------------------------------------------------------------------------------------
1993.................................... $120,057,253 $126,515,577 $6,458,324 5
1994.................................... $123,380,438 $129,337,138 $5,956,700 5
1995.................................... $126,958,144 $139,830,318 $12,872,174 10
1996.................................... $124,302,476 $152,289,387 $27,986,911 23
1997.................................... $125,872,166 $147,959,689 $22,087,523 18
1998.................................... $147,959,689 $151,836,635 $3,876,946 3
1999.................................... $150,083,954 $159,669,575 $9,585,621 6
2000.................................... $153,508,177 $167,646,122 $14,137,945 9
2001.................................... $158,213,295 $162,691,657 $4,478,362 3
----------------------------------------------------------------------------------------------------------------
Will your recommended alteration in one of the triggers ensure that
funding for other programs is no longer drained?
The most important action to assure that funding from other
programs is not drained in the future is an appropriation each year
that includes the full costs of the mandatory Federal pay raise. We are
pleased that for the current fiscal year the President requested, and
Congress appropriated, funds that specifically included amounts to
enable FDA to meet the costs of the mandatory Federal pay increase.
Further, the President's budget for FY 2003 that is now before Congress
also includes specific increases to cover the cost of the mandatory
Federal pay raise anticipated in FY 2003.
In addition, the legislation that the Administration has proposed
will include modifications to the trigger (Section 736(g)(2)(B)) such
that FDA will no longer be compelled to spend amounts that are
significantly greater than the amount required by this trigger. The
proposal will provide FDA a margin of error in its effort to meet this
requirement of the law. Under this proposed modification, if FDA's
spending from appropriations on drug review is within 5 percent of the
amount required by this section of the law, the requirement is
considered to be satisfied. In cases where FDA's spending from
appropriations is within 3 percent of the trigger amount, no adjustment
in fees will be required. If the spending is between 3 percent and 5
percent below the trigger amount, then FDA will, in a subsequent year,
decrease user fees by the amount of the shortfall that is between 3 and
5 percent (i.e., a maximum of 2 percent).
The purpose of this change is to relieve FDA of the need to
overspend from appropriations each year, as has occurred consistently
since FY 1994. Spending from appropriations on the drug review process
each year is still expected to be at, or very close to, the amount
specified by this trigger, and may never be more than 5 percent below
the trigger amount.
What changes in the triggers would be necessary to protect the
funding of the generic drug and advertising review programs?
The PDUFA statute does not apply to generic drugs or to post-
approval drug advertising. Since there are no user fee or non-user fee
amounts authorized for these programs under the PDUFA statute, it is
difficult to conceive of a modification to the PDUFA statute that would
accomplish this objective.
The best way to protect funding for these and other non-PDUFA
programs is to assure that they receive adequate appropriations each
year, including increases to cover the costs of mandatory Federal pay
raises.
In your best professional judgment, how many FTEs would be needed
and how much would it cost to fund a generic drug program that can
review generic drug applications in the statutory 180 days.
It is estimated that the Office of Generic Drugs (OGD) would need
approximately 55 additional FTEs at a cost of $9,570,000 above its
current base to meet the statutory review time of 180 days. This amount
includes salary, operating costs, and overhead to support these
additional employees.
In addition, other parts of the Agency, such as the Office of
Compliance, CDER, and FDA's Office of Regulatory Affairs and Office of
Chief Counsel, would need additional FTEs and budgetary support. These
other organizations provide essential inspection and legal support to
OGD's review activities. It is estimated that an additional 66 FTEs
would be needed to cover the increased workload in these organizations
in support of the Office of Generic Drugs for a total of $20,430,000.
This figure includes salary, operating costs, and overhead.
As I understand it, your agreement with the pharmaceutical industry
will include a performance goal of 6 months for reviewing any portion
of a cumulative marketing application. This is the same review period
as a priority drug; hence these partial applications are going to be
given as high as priority as priority drugs. I am concerned that this
will take resources away from needed drugs that are ready for approval,
and give them to drugs that may be far from approval. Does your
agreement include sufficient additional fees to cover the cost of
carrying out these additional high priority reviews? Can we be sure
that resources will not be diverted from the review of drugs that are
ready for approval to review CMAs?
FDA carefully considered the resources that would be necessary to
implement the two pilot studies of continuous marketing application
(CMA) review without taking resources away from the review of completed
new drug applications. The necessary resources have been included in
the PDUFA III proposals. It is also important to note that both pilot
CMA programs will be limited to Fast Track drugs--those drugs that are
intended to treat serious or life-threatening conditions and that
demonstrate the potential to address unmet medical needs. Additionally,
Pilot 1 is limited to Fast Track drugs that have already demonstrated
significant promise as a therapeutic advance in clinical trials and
Pilot 2 is limited to one application per review division over the
five-year period of PDUFA III. FDA believes the additional resources
and the limitations on the CMA pilot program will provide opportunities
to shorten drug development time for promising new drugs, while
ensuring appropriate resources are devoted to other new drugs that are
ready for approval. FDA proposes to conduct a formal evaluation of
these Pilot programs during PDUFA III in order to evaluate these and
other considerations.
After FDA has completed a review of a portion of a cumulative
marketing application, is the agency free to rereview all or part of
that portion when the full application is submitted, if the agency
believes a rereview is needed?
Yes. FDA plans to publish a guidance to industry on the cumulative
marketing application pilot programs by the end of FY03 and the pilot
programs will begin in FY04. FDA anticipates that the guidance document
will outline the procedures that FDA will follow with regard to any
changes that may occur to a ``reviewable unit'' from the time that it
was pre-submitted for review until the time that the complete
application is submitted. The pilot programs described in the PDUFA III
proposed Goals Letter do not preclude FDA from re-reviewing previously
reviewed ``reviewable units'' if that is felt to be necessary. The
pilot programs as described in the draft Goals Letter also make clear
that the deficiencies transmitted to the sponsor in a discipline review
letter on completion of review of a pre-submitted ``reviewable unit''
are ``not final, definitive decisions relevant to the NDA/BLA.''
At the hearing, the witnesses representing BIO testified that,
under the agreement, the decision whether to use an outside expert
requested by an applicant is completely within FDA's discretion. I was
pleased to hear this, because I believe that restricting FDA's
discretion raises serious questions about the integrity of the review
process. What are the specific terms in the agreement concerning the
use of outside experts that establish FDA's discretion to use them as
the agency sees fit?
Section IX of the Goals Letter provides for the use of independent
consultants for biotechnology clinical trial protocols. The text of
this section of the Goals Letter is reprinted below.
IX. INDEPENDENT CONSULTANTS FOR BIOTECHNOLOGY CLINICAL TRIAL
PROTOCOLS
A. Engagement of Expert Consultant: During the development period
for a biotechnology product, a sponsor may request that FDA engage an
independent expert consultant, selected by FDA, to participate in the
Agency's review of the protocol for the clinical studies that are
expected to serve as the primary basis for a claim.
B. Conditions
1. The product must be a biotechnology product (for example, DNA
plasmid products, synthetic peptides of fewer than 40 amino acids,
monoclonal antibodies for in vivo use, and recombinant DNA-derived
products) that represents a significant advance in the treatment,
diagnosis or prevention of a disease or condition, or have the
potential to address an unmet medical need;
2. The product may not have been the subject of a previously
granted request under this program;
3. The sponsor must submit a written request for the use of an
independent consultant, describing the reasons why the consultant
should be engaged (e.g., as a result of preliminary discussions with
the Agency the sponsor expects substantial disagreement over the
proposed protocol); and
4. The request must be designated as a ``Request for Appointment of
Expert Consultant'' and submitted in conjunction with a formal meeting
request (for example, during the end-of-Phase II meeting or a Type A,
meeting).
C. Recommendations for Consultants: The sponsor may submit a list
of recommended consultants for consideration by the Agency. The
selected consultant will either be a special government employee, or
will be retained by FDA under contract. The consultant's role will be
advisory to FDA and FDA will remain responsible for making scientific
and regulatory decisions regarding the clinical protocol in question.
D. Denial of Requests: Except in the most unusual circumstances
(for example, it is clearly premature) FDA will honor the request and
engage the services of an independent consultant, of FDA's choosing, as
soon as practicable. If the Agency denies the request, it will provide
a written rationale to the requester within 14 days of receipt.
E. Performance Goal Change: Due to the time required to select and
screen the consultant for potential conflicts of interest and to allow
the consultant sufficient time to review the scientific issues
involved, the performance goals for scheduling the formal meeting (see
section III) may be extended for an additional sixty (60) days.
F. Evaluation: During FY 2006, FDA will conduct a study to evaluate
the costs and benefits of this program for both sponsors and the
Agency.
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