[House Hearing, 110 Congress]
[From the U.S. Government Publishing Office]


 
     PROGRAMS AFFECTING SAFETY AND INNOVATION IN PEDIATRIC THERAPIES

=======================================================================

                                HEARING

                               BEFORE THE

                         SUBCOMMITTEE ON HEALTH

                                 OF THE

                    COMMITTEE ON ENERGY AND COMMERCE
                        HOUSE OF REPRESENTATIVES

                       ONE HUNDRED TENTH CONGRESS

                             FIRST SESSION

                               __________

                              MAY 22, 2007

                               __________

                           Serial No. 110-49


      Printed for the use of the Committee on Energy and Commerce

                        energycommerce.house.gov

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                    COMMITTEE ON ENERGY AND COMMERCE

    JOHN D. DINGELL, Michigan,       JOE BARTON, Texas
             Chairman                    Ranking Member
HENRY A. WAXMAN, California          RALPH M. HALL, Texas
EDWARD J. MARKEY, Massachusetts      J. DENNIS HASTERT, Illinois
RICK BOUCHER, Virginia               FRED UPTON, Michigan
EDOLPHUS TOWNS, New York             CLIFF STEARNS, Florida
FRANK PALLONE, Jr., New Jersey       NATHAN DEAL, Georgia
BART GORDON, Tennessee               ED WHITFIELD, Kentucky
BOBBY L. RUSH, Illinois              BARBARA CUBIN, Wyoming
ANNA G. ESHOO, California            JOHN SHIMKUS, Illinois
BART STUPAK, Michigan                HEATHER WILSON, New Mexico
ELIOT L. ENGEL, New York             JOHN B. SHADEGG, Arizona
ALBERT R. WYNN, Maryland             CHARLES W. ``CHIP'' PICKERING, 
GENE GREEN, Texas                        Mississippi
DIANA DeGETTE, Colorado              VITO FOSSELLA, New York
    Vice Chairman                    STEVE BUYER, Indiana
LOIS CAPPS, California               GEORGE RADANOVICH, California
MIKE DOYLE, Pennsylvania             JOSEPH R. PITTS, Pennsylvania
JANE HARMAN, California              MARY BONO, California
TOM ALLEN, Maine                     GREG WALDEN, Oregon
JAN SCHAKOWSKY, Illinois             LEE TERRY, Nebraska
HILDA L. SOLIS, California           MIKE FERGUSON, New Jersey
CHARLES A. GONZALEZ, Texas           MIKE ROGERS, Michigan
JAY INSLEE, Washington               SUE WILKINS MYRICK, North Carolina
TAMMY BALDWIN, Wisconsin             JOHN SULLIVAN, Oklahoma
MIKE ROSS, Arkansas                  TIM MURPHY, Pennsylvania
DARLENE HOOLEY, Oregon               MICHAEL C. BURGESS, Texas
ANTHONY D. WEINER, New York          MARSHA BLACKBURN, Tennessee       
JIM MATHESON, Utah                   
G.K. BUTTERFIELD, North Carolina     
CHARLIE MELANCON, Louisiana          
JOHN BARROW, Georgia                 
BARON P. HILL, Indiana               

_________________________________________________________________

                           Professional Staff

 Dennis B. Fitzgibbons, Chief of 
               Staff
Gregg A. Rothschild, Chief Counsel
   Sharon E. Davis, Chief Clerk
   Bud Albright, Minority Staff 
             Director

                                  (ii)
                         Subcommittee on Health

                FRANK PALLONE, Jr., New Jersey, Chairman
HENRY A. WAXMAN, California          NATHAN DEAL, Georgia,
EDOLPHUS TOWNS, New York                 Ranking Member
BART GORDON, Tennessee               RALPH M. HALL, Texas
ANNA G. ESHOO, California            BARBARA CUBIN, Wyoming
GENE GREEN, Texas                    HEATHER WILSON, New Mexico
    Vice Chairman                    JOHN B. SHADEGG, Arizona
DIANA DeGETTE, Colorado              STEVE BUYER, Indiana
LOIS CAPPS, California               JOSEPH R. PITTS, Pennsylvania
TOM ALLEN, Maine                     MIKE FERGUSON, New Jersey
TAMMY BALDWIN, Wisconsin             MIKE ROGERS, Michigan
ELIOT L. ENGEL, New York             SUE WILKINS MYRICK, North Carolina
JAN SCHAKOWSKY, Illinois             JOHN SULLIVAN, Oklahoma
HILDA L. SOLIS, California           TIM MURPHY, Pennsylvania
MIKE ROSS, Arkansas                  MICHAEL C. BURGESS, Texas
DARLENE HOOLEY, Oregon               MARSHA BLACKBURN, Tennessee
ANTHONY D. WEINER, New York          JOE BARTON, Texas (ex officio)
JIM MATHESON, Utah
JOHN D. DINGELL, Michigan (ex 
    officio)
  
                             C O N T E N T S

                              ----------                              
                                                                   Page
Hon. Frank Pallone, Jr., a Representative in Congress from the 
  State of New Jersey, opening statement.........................     1
Hon. Nathan Deal, a Representative in Congress from the State of 
  Georgia, opening statement.....................................     3
Hon. Henry A. Waxman, a Representative in Congress from the State 
  of California, opening statement...............................     3
Hon. Michael C. Burgess, a Representative in Congress from the 
  State of Texas, opening statement..............................     4
Hon. Anna G. Eshoo, a Representative in Congress from the State 
  of California, opening statement...............................     5
Hon. Marsha Blackburn, a Representative in Congress from the 
  State of Tennessee, opening statement..........................     6
Hon. Gene Green, a Representative in Congress from the State of 
  Texas, opening statement.......................................     7
Hon. Tim Murphy, a Representative in Congress from the 
  Commonwealth of Pennsylvania, opening statement................     8
Hon. Lois Capps, a Representative in Congress from the State of 
  California, opening statement..................................     9
Hon. Darlene Hooley, a Representative in Congress from the State 
  of Oregon, opening statement...................................    10
Hon. Edolphus Towns, a Representative in Congress from the State 
  of New York, prepared statement................................    12
Hon. Hilda L. Solis, a Representative in Congress from the State 
  of California, prepared statement..............................    14
Hon. Barbara Cubin, a Representative in Congress from the State 
  of Wyoming, prepared statement.................................    14

                               Witnesses

Rear Admiral Sandra L. Kweder, Deputy Director, Office of New 
  Drugs, Center for Drug Evaluation and Research, U.S. Food and 
  Drug Administration............................................    15
    Prepared statement...........................................    18
Donald Mattison, Chief, Obstetric and Pediatric Pharmacology 
  Branch and Human Development, National Institutes of Health....    34
    Prepared statement...........................................    36
Lori Reilly, vice president, policy and research, Pharmaceutical 
  Research and Manufacturers of America..........................    54
    Prepared statement...........................................    57
Marcia Crosse, Director, Health Care Issues, U.S. Government 
  Accountability Office..........................................    73
    Prepared statement...........................................    75
Richard L. Gorman, M.D., F.A.A.P., chair, AAP section of clinical 
  pharmacology and therapeutics, American Academy of Pediatrics..    91
    Prepared statement...........................................    93
Peter Lurie, M.D., M.P.H., deputy director, Public Citizen's 
  Health Research Group..........................................   112
    Prepared statement...........................................   115
Susan Belfiore, Princeton, NJ....................................   128
    Prepared statement...........................................   129
Ed Rozynski, vice president, global government affairs, Stryker 
  Corporation....................................................   131
    Prepared statement...........................................   133
Donald P. Lombardi, president and chief executive officer, 
  Institute for Pediatric Innovation.............................   138
    Prepared statement...........................................   140


    PROGRAMS AFFECTING SAFETY AND INNOVATION IN PEDIATRIC THERAPIES

                              ----------                              


                         TUESDAY, MAY 22, 2007

                  House of Representatives,
                            Subcommittee on Health,
                          Committee on Energy and Commerce,
                                                    Washington, DC.
    The subcommittee met, pursuant to call, at 10:15 a.m., in 
room 2322 of the Rayburn House Office Building, Hon. Frank 
Pallone, Jr. (chairman) presiding.
    Members present: Representatives Waxman, Eshoo, Green, 
Capps, Allen, Schakowsky, Hooley, Matheson, Deal, Murphy, 
Burgess, and Blackburn.
    Also present: Representative Markey.
    Staff present: Ryan Long, Nanden Kenkeremath, Chad Grant, 
John Ford, Bobby Clark, Jack Maniko, Virgil Miller, and Melissa 
Sidman.

OPENING STATEMENT OF HON. FRANK PALLONE, JR., A REPRESENTATIVE 
            IN CONGRESS FROM THE STATE OF NEW JERSEY

    Mr. Pallone. We have no amplification, so we urge everyone 
to speak loudly. There is no point speaking into the mic or 
turning it on. It is not working. We will have no Web cast, so 
for those who want to watch us from a distance, they are out of 
luck. We also have no transcript. I apologize, we are going to 
have a transcript. We are going to do the best we can. Thank 
you. It may not be a full transcript because we may not be able 
to hear everything; but yes, there will be a transcript, it 
just may not be complete. Other than that, we are following 
normal procedures. And the air-conditioning works, too, just so 
you know. So I will recognize myself for an opening statement 
initially.
    Today the subcommittee is meeting to hear about programs 
affecting safety and innovation in pediatric therapies. Today's 
hearing is of critical importance because above all else, we 
must ensure that the prescription medications and devices our 
children use are in fact tested appropriately and deemed safe. 
I believe that we all agree, regardless of our party 
affiliation, that we have an enormous responsibility to our 
children to ensure that they have access to the best possible 
medical treatment. And today we will hear about two existing 
programs designed to facilitate better testing of drugs in 
children. They are the Best Pharmaceuticals for Children and 
the Pediatric Research Equity Act. Combined, these two programs 
are often referred to a carrot-and-stick approach used by the 
FDA to encourage and direct drug manufacturers to test their 
products for pediatric use. We will also discuss the need to 
encourage better research and development of medical devices 
for pediatric populations. Under BPCA, in exchange for 
completing a pediatric study requested by the FDA, a drug 
manufacturer can receive a 6-month extension of market 
exclusivity for the product that is studied. This model has 
proven successful in providing new and valuable information 
about the appropriate pediatric use of many drugs. According to 
the GAO, who we will also hear from today, drug manufacturers 
agree to the pediatric studies requested by FDA for on-patent 
drugs 81 percent of the time. These studies have resulted in 
important labeling changes that help providers and parents 
determine the best course of treatment for a child stricken by 
a particular illness or chronic condition.
    In the past, I have raised concerns about the financial 
impact an additional 6 months of market exclusivity has on 
American consumers. While the incentive under BPCA is clearly 
working to encourage companies to conduct the studies that FDA 
requests, at the same time this type of patent extension serves 
as an obstacle that blocks access to generic drugs for 
consumers, forcing them to pay higher prices because lower-cost 
alternatives are kept off the market.
    In looking over how the program has worked over the past 5 
years, I am concerned about the amount of earnings drug 
manufacturers receive in exchange for completing these studies. 
The financial gain the drug makers receive from the market 
exclusivity under BPCA usually far exceeds the costs incurred 
in completing the pediatric trials requested by FDA. There may 
be a better way to balance the need to provide incentives for 
drug manufacturers who conduct pediatric studies and ensuring 
consumers have timely access to lower-cost prescription drugs.
    The Pharmaceutical and Research and Equity Act, or PREA, is 
the other component of this approach, and gives FDA the 
regulatory authority to require certain pediatric assessments 
for a particular drug in which a drug maker is submitting an 
application. The regulatory authority granted to FDA under PREA 
is linked to the expiration of BPCA and thus will also expire 
at the end of this fiscal year. This makes very little sense to 
me. Why should we put a timetable on providing the FDA with the 
regulatory power to ensure drug companies conduct research 
necessary to ensure that our children have access to safe and 
effective medicines? We don't place such limits on FDA when it 
comes to conducting research on adult populations, and so we 
shouldn't do it for our children, either.
    Aside from drugs, we also have a responsibility to ensure 
that children have access to appropriate medical devices. You 
know that we had a hearing on PDUFA last week, but today we 
also want to look at the children's aspect. The problems that 
we face in encouraging pediatric studies of drugs are parallel 
to the problems that we face in encouraging similar research in 
the device world. There are few medical devices designed to be 
used in kids. Instead, doctors are often forced to jury-rig 
devices that are designed to treat adults. We need legislation 
that will encourage device manufacturers to do their research 
and development necessary to provide our children with devices 
that will fit their small and growing bodies.
    Again, I can't emphasize enough that testing of drugs and 
devices for pediatric use is essential. As a father of three 
young children, I know how critical it is that we ensure our 
children with access to the treatments and therapies they need 
to live happy and healthy childhoods. I also want to say that I 
know how important these issues are to members of this 
subcommittee on both sides of the aisle. Ms. Eshoo, Mr. Waxman 
are the voices in the debate about encouraging pediatric 
studies for prescription drugs. Mr. Markey and Mr. Rogers have 
been strong advocates on the need for medical devices to be 
made available for kids, and I am going to work with all of you 
to ensure that we pass legislation that includes access to the 
medical treatment our Nation's children need.
    Again, I want to thank all of our witnesses for being here 
today even though we are dealing with certain limitations here 
in terms of the technology, and we are the technology 
committee. So I don't really know what to tell you.
    I will yield to our ranking member for 5 minutes. Thank 
you.

  OPENING STATEMENT OF HON. NATHAN DEAL, A REPRESENTATIVE IN 
               CONGRESS FROM THE STATE OF GEORGIA

    Mr. Deal. We are going to have to stop letting the 
Telecommunications Subcommittee use this room. Meeting medical 
needs of children in the innovative world of today's 
medications and medical devices presents a challenge because of 
their smaller share of the market and the typical focus on 
adults in the testing of any new product. The Best 
Pharmaceuticals for Children Act and the Pediatric Research 
Equity Act were important steps toward promoting research in 
pediatric education or medical therapies. I know our witnesses 
will highlight that the effect of a medication on a child is 
not necessarily the same as an adult, and further study is 
necessary to establish the safety and effectiveness of products 
for children.
    Developing medical devices for use by children also creates 
a unique challenge. As we evaluate the reauthorization of our 
current programs which focus on pediatric testing, I look 
forward to the testimony of the witnesses about their successes 
but also ways to improve these programs. I would also like to 
hear about what should be done in other areas of pediatric 
devices.
    I thank our witnesses for their attendance today, and I 
look forward to your testimony. I yield back my time.
    Mr. Pallone. Thank you. Mr. Waxman.

OPENING STATEMENT OF HON. HENRY A. WAXMAN, A REPRESENTATIVE IN 
             CONGRESS FROM THE STATE OF CALIFORNIA

    Mr. Waxman. Thank you very much, Mr. Chairman. When a 
pharmaceutical company gets a drug approved, for the longest 
period of time they never bothered to check what the dosage 
would be for children. And that frustrated parents and 
pediatricians because they didn't have that information. So 
originally we decided to give an incentive for that test by 
giving the pharmaceutical company an additional 6 months of 
exclusivity over their drug. Then Congress passed another law 
saying, well, at least when they come in for their first 
approval, we ought to require them to do the tests for 
children, and that should be a condition for approval. So we 
had both laws working now to make sure that we get the 
pediatric tests.
    The first law that requires that they test the drugs on 
children before approval of the drug at all has been sunsetted, 
and we ought to remove that sunset. It ought to be a permanent 
feature of our law.
    The second one which gives the exclusivity as a reward for 
these tests should be extended, but I think we need to think 
through a number of different issues. One, in many cases, 6 
months is too generous a reward. It, in some cases, over 100 
times rewards the company for the expenditure of money to do 
the test. And it is all at the expense of consumers because the 
consumers have to wait an additional 6 months after continuing 
to pay the high monopoly price for the drug. I think that we 
need to evaluate how generous we should be in rewarding the 
drug companies for doing something that quite frankly they 
should be doing anyway. We also ought to evaluate the way that 
FDA acts in providing this 6-month or any type of exclusivity. 
The FDA has a very short period of time in which to make a 
decision, and we ought to give them enough time to decide 
whether the company has done work that merits a reward of 
exclusivity.
    Some of the tests that the companies have done to gain this 
exclusivity really aren't all that targeted. They will do tests 
on a big-selling drug that really don't have the applicability 
for children, for example, doing tests on an anti-depressant 
that might never be used for children but by doing the test, 
they get a longer period of time for that particular drug which 
may be a very big-selling drug.
    So I think we need to calibrate the reward for the job that 
we want done. We all want the tests to be accomplished for 
pediatric doses of these drugs. We need now at this time of 
reauthorization of the legislation to figure out the best way 
to accomplish those goals without putting the consumers at an 
economic disadvantage.
    Mr. Pallone. Thank you, Mr. Waxman. Mr. Burgess.

OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A REPRESENTATIVE 
              IN CONGRESS FROM THE STATE OF TEXAS

    Mr. Burgess. Thank you, Mr. Chairman, and to Ranking Member 
Deal for holding this hearing. As we talk about the 
reauthorization of PDUFA, we come to some significant issues 
relating to their reauthorization with regard to the needs 
children. When it comes to children, drugs can react 
differently than they might in adults; and medical devices need 
to fit on their bodies that are still growing and bodies that 
are active in ways that many of us could no longer remember.
    My old professor of pediatric surgery, Dr. Vangy Brooks 
down in Houston, perhaps the patron saint of pediatric surgery, 
summed it up best one morning to a group of us medical students 
when she looked at us and said, you know what, kids are 
different. And indeed they are. I think we will hear that from 
several of our witnesses this morning that children are more 
than just little adults. They react differently to devices and 
drugs, and our Federal regulations should be crafted in a way 
that is sensitive and provides appropriate safeguards to 
protect their health and ensure their safety for their unique 
situation where an implant may be placed into a growing body 
and is active in ways that we can only vaguely remember.
    At the same time, overregulation can have a negative effect 
in the impact on the development and availability of drugs and 
devices for children, especially in the medical device realm in 
a pediatric environment where patient population can be small, 
both in number and literally, companies have huge incentives to 
enter the market. I believe that we need to expand on 
incentives that are currently available under the law such as 
the Humanitarian Device Exemption to encourage more companies 
to conduct research and more development in this important 
field.
    Now, we are going to be hearing from several witnesses this 
morning, and I am especially glad to be hearing from Mr. 
Rozynski from the Stryker Corporation. They have a big presence 
in my district down in Flower Mound, TX, but what really 
excites me is some of the work in Dr. Rozynski's testimony that 
Stryker has done absolutely changing the landscape of the 
treatment of pediatric bone cancer, changing the environment 
for diseases as diverse as CLEP and cranial synostosis. The 
non-healthcare expenses related to moving a child or getting a 
child treated at the Center of Excellence are big, but Stryker 
has stepped up to the plate and said we will bear some of those 
expenses not covered by traditional insurance. These are 
particularly exciting events that are occurring, and I 
certainly salute Stryker and their corporate benevolence for 
looking and recognizing that this is important.
    Additionally, we are going to hear from Dr. Gorman. His 
testimony will be illustrative of the clinical difficulties 
with treating children with outsized tools and medications that 
react differently in their bodies.
    Over the past several years, I believe the drug and device 
industry, medicine, and its regulators have made important 
strides in improving safety and efficacy of pediatric drugs and 
devices. As this committee works on legislation relating to 
both, I hope this hearing will be instructive and our 
legislation will be appropriately inspired.
    Thank you, Mr. Chairman. I will yield back.
    Mr. Pallone. Thank you. Ms. Eshoo.

 OPENING STATEMENT OF HON. ANNA G. ESHOO, A REPRESENTATIVE IN 
             CONGRESS FROM THE STATE OF CALIFORNIA

    Ms. Eshoo. Good morning, Mr. Chairman, and thank you for 
having this very important hearing. Despite our efforts, 
approximately 75 percent of drugs and a large majority of 
medical devices used by children have not been tested 
specifically for that use. So we have our work cut out for us. 
I think while the Congress has taken very, very important steps 
to turn these statistics around, understanding that children 
are not small adults. We recognized this fact in 1997 with the 
initial authorization of Best Pharmaceuticals for Children Act. 
I am very proud to be the Democratic sponsor of that, and again 
in 2003 with the enactment of Pediatric Research Equity Act. 
And together, I think that these two laws have established what 
might be called a carrot-stick approach to pediatric drug 
testing that has been I think very successful.
    Now, we are on the threshold of reauthorizing them, and as 
we reauthorize, we not only build on the successes of the past 
but I think having learned some things that we need to add some 
important things that will hopefully, when the next 
reauthorization comes around, that we can hail some more 
successes.
    I think that the successes are evident because the laws 
have generated important, new information about safety and the 
efficacy of drugs prescribed to children. Pediatricians now 
know more about what therapies work and don't work in children. 
Unfortunately, nearly two-thirds of drugs currently used in 
children are still not labeled for their use. We need these two 
laws as I said renewed and improved if we want progress to be 
continued.
    In the coming days, I am going to be introducing 
legislation to reauthorize both of these programs, and my 
legislation is going to make permanent the FDA's authority to 
require pediatric studies. This adjustment I think is 
consistent with FDA's permanent authority to require studies of 
adult formulations. I am also going to incorporate many of the 
recommendations of the GAO, the American Academy of Pediatrics, 
and the Elizabeth Glaser Pediatric AIDS Foundation; and I want 
to thank all of them, for all of these organizations for 
helping in the development of the legislation.
    Medical and surgical devices designed just for children 
also need to be developed, but experience tells me that it 
won't happen without legislation. I think the Pediatric Medical 
Devices Safety Improvement Act is an important step in that 
direction. So I am confident that we are going to reauthorize, 
and I think passage of not only the reauthorizations but the 
Pediatric Medical Device legislation is going to protect 
children, really our Nation's most vulnerable citizens. They 
can't do these things for themselves.
    I would also like to pay tribute to what Dr. Phil Pizzo, 
one time was at NIH. He is a pediatrician by background, and 
today heads up the Stanford Medical School; and he has been of 
great assistance to me, and I think without his steady, sure 
advice that we wouldn't have had the previous legislation and 
hopefully really sound legislation this time around.
    Thank you, Mr. Chairman, and I look forward to working with 
all the committee members on this. These are not partisan 
issues by any stretch of the imagination. So I have confidence 
that we will be a solid group here, reauthorize and reform at 
the same time. Thank you. Thank you to our witnesses.
    Mr. Pallone. Thank you. The gentlewoman from Tennessee.

OPENING STATEMENT OF HON. MARSHA BLACKBURN, A REPRESENTATIVE IN 
              CONGRESS FROM THE STATE OF TENNESSEE

    Mrs. Blackburn. Thank you, Mr. Chairman, and I do thank you 
and Ranking Member Deal for allowing us to engage in this 
discussion today with our witnesses, and we thank you for the 
time that you are giving to us for our hearing today. We know 
from so many different agencies and so many different 
participants that having this current pediatric exclusivity 
program has done quite a bit to spur some research and 
development and to generate some critical information about the 
use of medicines in pediatric patients. And it is done more 
than probably any other Government initiative, and so we are 
interested in how to best go about and how to best approach the 
reauthorization of the Best Pharmaceuticals for Children Act. 
And it does give us a unique opportunity, I think, to expand 
our knowledge about the safety, the effectiveness of the 
products that are used with our children and to certainly 
protect our children as they are a part of our medical 
community.
    Prior to passage of this legislation there was little 
incentive that existed to conduct clinical trails on pediatric 
use of medicines developed primarily for the adult population. 
The success of the BPCA has equipped doctors with accurate 
information about which drugs and which doses work best for our 
children. The pediatric exclusivity provision of the BPCA 
provides a critical incentive for our biopharmaceutical 
companies and for that research to invest in lifesaving drugs 
for our pediatric patients. This incentive has helped these 
companies, many companies of all sizes, to develop innovative 
medicines and protocols that would improve the lives of our 
children.
    We are so fortunate in Tennessee to have some wonderful 
work that is being done at St. Jude's and also at Vanderbilt 
with our children; and we have talked with these researchers 
and we talked with some of these innovators and the scientists, 
and we know the importance of this legislation to their work. 
We know also it is important to keep our attention to 
preserving their right to the intellectual property and the 
research that they do. And we will continue to focus on that.
    It is good legislation. As we move forward, I hope that our 
focus in our discussion will remain on how we preserve access 
to these protocols and therapies and formulations for our 
children.
    Thank you, Mr. Chairman. I yield back.
    Mr. Pallone. Thank you. Our vice chairman, Mr. Green.

   OPENING STATEMENT OF HON. GENE GREEN, A REPRESENTATIVE IN 
                CONGRESS FROM THE STATE OF TEXAS

    Mr. Green. Thank you, Mr. Chairman, for holding this 
important hearing on pediatric therapies and our efforts to 
ensure their safety and continued development. Most of the 
prescription drugs we give children to cure their illnesses or 
treatment received are actually drugs that are developed for 
adults and prescribed off-label for children. While this is a 
common practice, it is clear that children are simply not 
little adults. By treating children with drugs that were 
developed for adults, we run the risk of exposing them to 
ineffective drugs. Even worse is off-label use of drugs could 
result in improper doses of drugs or adverse reaction for 
children that would not necessarily appear in adults. Currently 
75 percent of drugs have not undergone studies in pediatric 
populations or even pediatric party populations. Any one drug 
is too small for a manufacturer to have the incentive to commit 
the resources or the testing. To provide that incentive, we 
enacted the Best Pharmaceuticals for Children Act which would 
provide an additional 6 months of market exclusivity for market 
products when their sponsor agreed to perform pediatric studies 
on the drug. In some respects it has been a success. In the 
drugs granted pediatric exclusivity, 87 percent saw the changes 
to their label as a result of pediatric studies. These changes 
suggest that labels now provide physicians with better 
information, specific to the drugs indication for children. On 
the flip side, however, there are one out of five manufacturers 
that received FDA requests for pediatric studies that declined 
to conduct the studies; and today, none of these drugs have 
been studied for pediatric populations.
    I look forward to hearing from our witnesses on how we can 
improve the Best Pharmaceuticals for Children Act and encourage 
even better prescriptions from drug sponsors. Any discussion of 
the Best Pharmaceuticals for Children Act should also be 
accompanied by the discussion of the Pediatric Research Equity 
Act which for all intents and purposes will expire at the end 
of this fiscal year along with the Best Pharmaceuticals for 
Children Act. In this statute, we give the Secretary the 
ability to require manufacturers to study drug safety and the 
effectiveness of children. If the manufacturer doesn't comply 
with the request, the Secretary can consider the product 
misbranded. However, the Secretary doesn't have any enforcement 
action short of--misbranded. I would like to learn what 
additional authority Congress can give the FDA to better align 
the research obligations and the appropriate enforcement 
effectiveness with the end result of better information on the 
safety and effectiveness of drugs involving our children. And 
again, like everyone else, I would like to thank our witnesses 
for being here today and thank you for what you do every day 
regarding the health of our children. I yield back.
    Mr. Pallone. Thank you. Mr. Murphy.

   OPENING STATEMENT OF HON. TIM MURPHY, A REPRESENTATIVE IN 
         CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA

    Mr. Murphy. Thank you, Mr. Chairman. As we look at 
reauthorizing this bill, one of the things that I want to make 
sure that we are working on here has to do with the issue of 
being very careful that we are not taking away incentives in 
order to develop new drugs. Any reauthorization that limits the 
money a company can make and suddenly says you are making too 
much, we need to take that away from you, concerns me if it 
ends up reducing money that is used to develop new drugs. Let 
me give some examples.
    When we look at a blockbuster drug that has emerged, we are 
looking at something that is the outcome of years of testing in 
which hundreds of millions of dollars may have been invested to 
that end, including funding many dead-ends along the way. There 
is also the issue about spin-off effects of profits that have 
funded the research of the past in other diseases as well and 
can be used for investments in researching other diseases in 
the future. But even when there is a blockbuster drug that 
emerges and one that may result in high profits, the risks do 
not end there. New problems may be found. For example, the news 
that came out about a drug called Avandia used to treat Type II 
diabetes, has had a big effect upon some of the profits and 
losses and stocks for GlaxoSmithKline. And although the outcome 
of that is being disputed, regardless of that, still it does 
have an effect upon the stock. It also has an effect then 
actually upon the profits and then the subsequent effects upon 
things with regard to lawsuits. So any time we begin to look at 
such things such as profits, I hope we look at what are some of 
the long-term effects on how to review that.
    Another area I want to make sure with this that we don't 
harm is the treatments and drugs that come for orphan diseases. 
There is an NIH office for rare diseases, and this helps us 
with advances in other areas so for those researching an area 
of a rare disease, it oftentimes helps us come up with 
treatments for other more common diseases that we didn't 
specifically know about in the first place. This is an area of 
such importance that in 1983 Congress passed the Orphan Drug 
Act to provide financial incentives for drug companies and 
biological manufacturers such as tax credits, Government 
grants, other research assistance, and 7-year exclusivity on 
development. Because these extremely rare diseases were ones 
that certainly didn't have the numbers to create profits big 
enough or the money even to invest in some of the research, 
these being infectious diseases, immune deficiency diseases, 
autoimmune diseases, analogies that could be exaggerated if the 
immune systems are compromised.
    Many of these areas are ones that I want to make sure we 
continue with this funding stream. So I hope whatever road we 
go down is one we are very careful to make sure that funding is 
still there in the future to come up with some of the 
medications we need, particularly for rare childhood disorders, 
as we proceed forward.
    Thank you, Mr. Chairman.
    Mr. Pallone. Thank you. Mrs. Capps.

   OPENING STATEMENT OF HON. LOIS CAPPS, A REPRESENTATIVE IN 
             CONGRESS FROM THE STATE OF CALIFORNIA

    Mrs. Capps. Thank you, Mr. Chairman, and good morning to 
you and to our witnesses for appearing with us today on this 
very important topic, pediatric therapies. I think it is so 
fitting we are holding this hearing at the same time our 
Speaker, Nancy Pelosi, is holding a national summit on 
America's children. Unfortunately, we can't be in both places 
at the same time, but several of us were at the kickoff at 9 
o'clock; and the first panel I think is also very appropriate, 
the panel under the topic ``the Science of Early Childhood----
    Mr. Pallone. Wait a minute. Mrs. Capps, just hold on a 
second. I am sorry. Go ahead.
    Mrs. Capps. Well, I will leave that--maybe that is the path 
where we should be. But this is more directly attuned to a 
topic of great importance to our committee, and if the 
Secretary had this second on children's health and I appreciate 
that and I think it is a good sign of things to come.
    As I mentioned in a hearing we had last week on a different 
topic, I am very concerned by the fact that research tends to 
focus on adult males while leaving out women and children; and 
we know that there are biological and physiological differences 
that need to be taken into account to best meet the needs of 
all men, women, and children separately; and of course, when it 
comes to testing medications and devices on children, we have 
to confront many additional ethical issues and some economic 
issues for the lack of testing on children for one. The lack of 
proper testing on children results in a lot of off-label 
prescribing and for a lack of access to potentially lifesaving 
treatment. As has been mentioned already, 75 percent of drugs 
have had no pediatric testing, yet we know many of them are 
being prescribed for children. This puts all of our children at 
risk.
    So our task becomes answering the question of how do we 
ensure safety. We have taken several steps to move forward in 
our quest to incentivize both the development of drugs and 
biologics for use in children. We also need to ensure that 
clinical testing in children is carried out to the highest 
ethically accepted standard. And as we move forward to find 
ways to improve existing frameworks developed through the Best 
Pharmaceuticals for Children Act and the Pediatric Research 
Equity Act, we need to put in place incentives for medical 
device manufacturers as well. And so I look forward to hearing 
today from our witnesses on the current status of pediatric 
development as well as testing and learning about areas that 
need improvement. This is a work in progress. And most 
importantly I believe we all need to be working to figure out 
how we can ensure that both the Government and biotechnology 
industry keep children in mind as we move forward in developing 
and improving new medications. Thank you. I yield back.
    Mr. Pallone. The gentleman from Utah.
    Mr. Matheson. I will waive.
    Mr. Pallone. Ms. Hooley, the gentlewoman from Oregon.
    Ms. Hooley. I guess it doesn't matter if I turn on the 
microphone?
    Mr. Pallone. It does not, although I should tell you we are 
trying to correct it, and we might have some luck. But right 
now, we are operating without.

 OPENING STATEMENT OF HON. DARLENE HOOLEY, A REPRESENTATIVE IN 
               CONGRESS FROM THE STATE OF OREGON

    Ms. Hooley. Well, first of all, Mr. Chairman, thank you; 
and I want to thank the witnesses for being here today. 
Ensuring that drugs and medical devices used by our children 
are safe and effective is a moral imperative for Congress and 
the FDA. The Best Pharmaceuticals for Children Act and the 
Pediatric Research Equity Act have enabled us to make 
significant strides toward improving the safety of drugs 
prescribed for children. For example, labeling changes have 
been made to 87 percent of the drugs that are used exclusively 
in pediatrics. That figure demonstrates a tremendous value in 
pediatric testing and the imperative for Congress to take 
additional steps to push for increased clinical testing of 
drugs prescribed for children. Because of the incentives 
provided under BPCA, labeling changes have resulted in more 
appropriate dosing for children and disclosure of previously 
unknown side-effects. PREA has ensured appropriate pediatric 
testing can be required for new drugs and BPCA has been 
successful in incentivizing studies for on-patent drugs. Drug 
companies have conducted pediatric studies under BPCA on over 
80 percent of FDA requests for on-patent drugs. I love all 
these initials. They are so wonderful. However, even with our 
successes, significant work remains to increase the prevalence 
of pediatric testing. Only four or five of the 10 most commonly 
prescribed drugs for children have ever undergone pediatric 
testing. To increase pediatric testing, the FDA's very limited 
success with getting off-patent drug sponsors to conduct 
pediatric studies deserves more careful consideration. The 
National Institutes of Health has not funded studies on more 
than half of the off-patent drugs on which drug sponsors have 
declined FDA-requested pediatric studies.
    The FDA must also reduce the amount of time between 
completion of its scientific review and approval of necessary 
labeling changes. Over 15 percent of drugs that require 
labeling changes under BPCA took more than 1 year from 
completion of the review process to a review of those labeling 
changes. The average time is nearly 9 months. Delays in making 
labeling changes may mean that children continue to receive 
inappropriate doses or that doctors remain unaware of potential 
serious side-effects for children. I hope the FDA does better. 
I also hope the FDA and the committee will look into the 2005 
Institutes of Medicine Report on Pediatric Medical Devices for 
Reform Recommendations. As a starting point, the Center for 
Devices and Radiological Health should follow the IOM 
recommendation to form a division with expertise on pediatric 
devices. I look forward to discussing more of the IOM's 
recommendation on pediatric devices with the panelists during 
my question time.
    Finally, it is imperative that as we take steps to expand 
testing of drugs and devices in pediatric populations that we 
do not produce unintended consequences that discourage 
development of products for children.
    Thank you, Mr. Chairman. I yield back my time.
    Mr. Pallone. Thank you. We are going to take just a brief 
break to see if we can test the equipment. It might be working 
again. OK. Sounds like we are in order so we can use the 
equipment again starting with Mr. Allen who is recognized for 5 
minutes.
    Mr. Allen. Mr. Chairman, I will waive my opening remarks 
and submit it for the record.
    Mr. Pallone. OK. I think that ends all the opening 
statements. Any other statements for the record will be 
accepted at this time.
    [The prepared statements follow:]

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    [GRAPHIC] [TIFF OMITTED] T1972.002
    
Prepared Statement of Hon. Hilda L. Solis, a Representative in Congress 
                      from the State of California

    Mr. Chairman, thank you for holding this hearing today to 
discuss safety and innovation in pediatric therapies. Children 
are sometimes forgotten and left out because some consider them 
a small, niche market.
    While the FDA's mission is to protect and advance the 
public's health, we must not forget that this must include 
children as well as adults. The FDA is also responsible for 
providing accurate, evidence-based information to the public so 
that individuals can make optimal health decisions. It is 
important to discuss and determine how we can increase the 
number and types of safe and effective medical devices and 
drugs designed for children. In order to do so, we must have 
accurate, scientific data on the safety and effectiveness of 
drugs and devices for children.
    Before the enactment of the Pediatric Research Equity Act, 
75 percent of the prescriptions that pediatricians wrote were 
for medications that had been found appropriate only for 
adults, even though their labels provided suggested children's 
dosages. As we know now, just because a drug has been proven 
safe and effective for an adult does not mean that it is 
equally safe and effective in a child. We must adjust 
medications and devices for children's small and rapidly 
growing bodies based on science, not guesswork. Improper 
medical treatments such as overdosing and underdosing can both 
lead to adverse health consequences. This is why medicines that 
will be used by children should be found safe for children.
    Just as there are difference between children and adults, 
there are also differences among children of color. For 
example, the incidence of diabetes disproportionately affects 
Latino and Black children. We should maximize the effectiveness 
of drugs for the entire population. This means that when 
determining effectiveness and safety, we must ensure that the 
process includes the diverse group of children who represent 
the racial and ethnic groups that will likely receive the drug. 
I hope that FDA can now efficiently identify the participation 
rates of children of color under the pediatric exclusivity 
provision and that drug sponsors are required to use standard 
definitions for race and ethnicity.
    Accurate data collection is essential in determining how 
children from different racial and ethnic react to specific 
drugs. We must enable providers and families to make the best 
possible decision about using medicines to improve their 
health.
    I hope we can work together in a timely manner to ensure 
that our children have improved access to life-saving drugs and 
devices.
                              ----------                              


Prepared Statement of Hon. Barbara Cubin, a Representative in Congress 
                       from the State of Wyoming

    As the mother of two boys, I have made my fair share of 
trips to the doctor's office, not to mention the occasional 
emergency room visit. No parent wants to find out that their 
child is sick. But when it does happen, you hope that your 
physician has the knowledge and resources necessary to treat 
the problem.
    In modern medical practice, pharmaceutical drugs have 
played an increased role in preventing, treating and curing 
disease. Yet federal drug safety policy fell behind in labeling 
these products for pediatric use. As few as 10 years ago, 
roughly 80 percent of medication labels in the Physician's Desk 
Reference were not labeled for children.
    Biologically, children are not simply miniature adults. 
Off-label drug prescribing can result in a child receiving too 
much of a drug, or not enough for it to be effective. There can 
also be side effects unique to children, including effects on 
growth and development.
    In 1997, Congress recognized this problem and granted a 6-
month market exclusivity period to drug manufacturers who 
conduct the pediatric studies necessary for pediatric labeling. 
In 2002, this incentive was reauthorized in the Best 
Pharmaceutical for Children Act, or BPCA.
    BPCA is arguably the most successful pediatric initiative 
the FDA has embarked upon. In conjunction with the FDA 
authorities granted in the Pediatric Research Equity Act, or 
PREA, the FDA has successfully spurred industry participation 
in the riskier pediatric labeling arena.
    Because of this robust carrot and stick approach, I am 
please to report that my two grandchildren will have more 
access to pediatric specific labeling than I or their parents 
ever did. Today there is a pediatric study infrastructure that 
before was nonexistent.
    I am confident that much of today's testimony will reaffirm 
the success of this approach. In reauthorizing BPCA and PREA, 
this committee ought to recognize the important role of both 
voluntary market incentives and the FDA's authority to impose 
mandated studies in certain circumstances.
    We still have a long way to go in fitting our treatments 
for pediatric settings. Nearly two-thirds of drugs used on 
children are still not labeled for children. We can, and 
should, do better than this. I am hopeful our panelists here 
today can share their suggestions for how Congress can best 
support our pediatric study infrastructure.
                              ----------                              

    Let me turn to our first panel today.
    First of all, welcome to all of you. Let me introduce each 
of you. We have, beginning on my left, Dr. Joanne Less who is 
Acting Director of the Office of Combination Products for the 
U.S. Food and Drug Administration; and then we have Dr. Sandra 
Kweder, Deputy Director, Office of New Drugs, Center of Drug 
Evaluation and Research at the FDA; and then last is Dr. Donald 
Mattison who is Chief Obstetric and Pediatric Pharmacology 
Branch of the National Institute of Child Health and Human 
Development at the National Institute of Health. Thank you all 
for being here.
    We start with 5-minute opening statements from each of you. 
Your statements become part of the hearing record, and each 
witness, each of you in the discretion of the committee, may 
submit additional brief or pertinent statements in writing 
afterwards if you like; and I will start with Admiral Kweder.

   STATEMENT OF REAR ADMIRAL SANDRA L. KWEDER, M.D., DEPUTY 
 DIRECTOR, OFFICE OF NEW DRUGS, CENTER FOR DRUG EVALUATION AND 
          RESEARCH, U.S. FOOD AND DRUG ADMINISTRATION

    Dr. Kweder. Good morning, Mr. Chairman, and members of the 
committee. I am Rear Admiral Sandra Kweder. I am a physician 
and the Deputy Director of the Office of New Drugs in the 
Center for Drug Evaluation and Research of the FDA. Dr. Joanne 
Less, the Acting Director of the Office of Combination 
Products, is accompanying me. She is here to respond to 
questions that you might have regarding pediatric devices. I am 
here today to share with you the real success of the pediatric 
exclusivity provisions that you have authorized and the 
Pediatric Research Equity Act. There is no question that they 
have expanded access to important therapeutics for children and 
importantly promoted safety and innovation in drug development 
for children.
    Before the enactment of the exclusivity incentive program 
that began in 1997, about 80 percent of medications in the 
Physician's Desk Reference, a big compendium, did not have any 
pediatric use information; and only about 20 to 30 percent of 
drugs approved by FDA were labeled for pediatric use. Most 
drugs used for children were considered to be used off-label; 
in other words, there was no data to establish the correct dose 
in children or to confirm their safety profile or if they even 
were effective in children, the pediatric population. In 1997 
you provided marketing incentives to manufacturers who 
voluntarily conduct studies of drugs in children. This law 
provides 6 months of additional market exclusivity for a drug 
in return for conducting pediatric studies in response to a 
very specific written request issued by FDA. The incentive had 
become the most successful pediatric initiative that we at FDA 
have ever participated in.
    In 2002, the pediatric exclusivity incentive was 
reauthorized as this BPCA, the Best Pharmaceuticals for 
Children Act. This statute added provision for safety 
evaluation of products once they had received exclusivity, 
public dissemination of study information, and additional 
mechanisms for the study of drugs in children. Shortly 
thereafter, Congress passed another important law to work in 
concert with BPCA, the Pediatric Research Equity Act. PREA 
provides FDA authority to require pediatric studies under 
certain conditions. Since 1997, the exclusivity program has 
generated labeling changes for 128 products. These labeling 
changes have significantly increased the information available 
to healthcare professionals to use in the treatment of 
pediatric patients. Eighty-three products have updated new 
information expanding the use of the product to a broader 
pediatric population and labeling. Twenty-five have had dosing 
adjustments, important for clinicians, put in labels for 
pediatrics, and 28 products had information added to labeling 
indicating that the products were found not to be safe or 
effective in children. Thirty-seven had newer enhanced 
pediatric safety information added to labeling. This 
exclusivity, or BPCA, process can be initiated in two ways. FDA 
can determine if there is a public health need for additional 
pediatric studies for a drug and issue a written request on our 
own. Alternatively, a sponsor can initiate the process by 
submitting a proposal for a written request to us. However, 
even if the sponsor issues such a proposal, we will not issue a 
written request unless we perceive there to be an important 
public health need for those studies to be conducted.
    Under BPCA, two review processes occur in parallel once we 
have data. One is the exclusivity review to determine whether 
the studies that the company actually did fairly respond to the 
terms we set forth in the written request that would therefore 
qualify the product for exclusivity. There is a separate 
process, a scientific review, to determine whether the NDA or 
supplement should be approved. And those two processes occur on 
different timelines. The scientific review is subject, however, 
to the same intense scientific rigor and administrative terms 
and conditions that we provide to any application that comes 
before the agency, and as part of that, we will decide whether 
changes to a product label are warranted at that time. 
Importantly, FDA includes both positive information and 
negative information from study reports done on pediatric 
studies in labeling because both types of information inform 
practitioners.
    BPCA did several other important things that really have 
taught us a lot about the study of drugs in children and 
monitoring the safety of drugs in general. First, it authorized 
us to establish a Pediatric Advisory Committee that also 
provides for post-marketing safety review on a regular schedule 
by that committee of information on adverse events for all 
pediatric products granted exclusivity. It also created our 
Office of Pediatric Therapeutics as part of the Office of the 
Commissioner. This office provides scientific expertise and 
important ethics advice as we work with companies to guide 
pediatric product development. In contrast to BPCA which 
provides this voluntary mechanism for attaining needed studies 
on approved or unapproved indications of a drug, PREA, 
Pediatric Research Equity Act requires pediatric assessment of 
certain products but only for the indications that are approved 
in adults. It is an important distinction, only for the 
indications that the sponsor is seeking adult approval for. FDA 
can defer or waive those pediatric assessments under certain 
circumstances. In contrast to BPCA though, PREA applies not 
just to NDA's or drugs, PREA also applies to biological 
products and biologic license applications. There have been 
about 40 labeling changes involving pediatric studies that are 
linked specifically to PREA.
    Despite the success of the statutes, there are 
unquestionably a large number of drug and biological products 
that remain inadequately studied for children. BPCA and PREA 
have acted in concert to provide important safety, efficacy, 
and dosing information on pediatrics. We at FDA want to build 
on these improvements with more studies to produce new labeling 
information that is a value to the children in this country as 
well as physicians taking care of them.
    We welcome the opportunity to work with you to ensure that 
the benefits of the incentive program continue in conjunction 
with our need for our continued authority to mandate studies. 
We are just getting on a roll, and Dr. Less and I will be happy 
to answer any questions.
    [The prepared statement of Dr. Kweder follows:]

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    Mr. Pallone. Thank you, Dr. Kweder. Dr. Mattison.

   STATEMENT OF DONALD MATTISON, M.D., CHIEF, OBSTETRIC AND 
 PEDIATRIC PHARMACOLOGY BRANCH AND HUMAN DEVELOPMENT, NATIONAL 
                      INSTITUTES OF HEALTH

    Dr. Mattison. Good morning, Mr. Chairman. I am Donald 
Mattison, Chief of the Obstetric and Pediatric Pharmacology 
Research Branch at the National Institute of Child Health and 
Human Development, the National Institutes of Health. We 
appreciate the opportunity to appear before you and the rest of 
the committee to discuss NIH's research activities in relation 
to implementation of the pediatric drug testing program under 
the Best Pharmaceuticals for Children Act.
    The BPCA legislation was enacted in 2002 to address the 
growing recognition that the great majority of pharmaceutical 
products prescribed for children have never been tested for 
pediatric use. Healthcare professionals were forced to depend 
upon experience and their best judgment in prescribing 
medications for their pediatric patients. However, without a 
strong evidentiary base, it becomes difficult for practitioners 
to work with children of various ages who are at various 
developmental stages to estimate what the correct dose should 
be. Since children metabolize or respond to a drug differently 
from an adult, that drug's effect may be variable with too high 
a dose producing toxicity, too low a dose being ineffective to 
treat the child's disease.
    Under current law, the NIH is directed to conduct research-
related activities in three general categories, identifying and 
prioritizing drugs needing study in children, developing new 
study requests in collaboration with the Food and Drug 
Administration and other pediatric experts, and supporting 
studies on priority drugs after manufacturers decline to do so. 
In most cases, the drugs under consideration for study by the 
NIH are for off-patent or older medications to which no 
marketing exclusivity can be granted. In some instances, these 
medicines have been used for over 30 years and yet, those same 
efficacy and safety information have not been compiled for 
children.
    This is a challenging area of research. The available data 
are mostly on adults. Some of the conditions that these drugs 
are used to treat are relatively rare, and effects on 
children's growth and development have largely been 
unrecognized and certainly can't be studied in adults. In 
addition, human subjects concerns with a critical focus on 
balancing risks versus benefits are of particular importance in 
pediatric research. Moreover, long-term follow-up of the 
possible effects on growth and development can be important but 
costly aspects of pediatric clinical trials. To conduct these 
studies and obtain generalizable data, we often need to enroll 
a larger number of pediatric patients than have previously been 
studied. In order to prioritize the drugs needing studies, 
NICHD has developed an annual cycle of data gathering, expert 
consultation, and critical analysis. The purpose of the process 
is to distill from the total number of off-patent drugs to a 
manageable number, five to 10, for study the following year. We 
look at whether dosing, safety, and efficacy data are already 
available from a reputable source and whether additional data 
are needed, whether new studies will produce health benefits 
for children, and the balance between how frequently the 
condition is to be treated and the severity of the condition, 
whether there is a need to reformulate the drug so that 
children will be able to use it. As an example, a drug that 
only comes in tablet form cannot be readily taken by a young 
child with cerebral palsy. Together with other NIH institutes 
and centers, the FDA and other pediatric experts, NICHD has 
made significant progress on this front as required by BPCA by 
developing and publishing an annual list of approved drugs in 
need of further study in pediatric populations. As of December 
2006, 106 total drugs have been addressed and discussed in 
scientific forums to decide if they should be listed or whether 
we need further review of medical literature or outside 
consultation. From this group of drugs, approximately 60 drug 
indication pairs have been listed as off-patent priority drugs, 
drugs that require further pediatric studies. I have provided a 
list of those drugs to the committee in table 1.
    From the list of prioritized drugs, the FDA, in 
consultation with the NIH, develops and issues written requests 
to the drug manufacturers. To date, 16 written requests have 
been developed and forwarded to the manufacturers by the FDA. 
All but one of those written requests have been declined by the 
manufacturer, and those drugs have been referred to the NIH for 
study. Since receiving the 16 written requests, we have 
implemented, as shown on table 2, 13 drug studies that we are 
currently conducting and funding with support from other NIH 
institutes and centers that have significant pediatric research 
programs.
    BPCA implementation is a trans-NIH collaboration with 19 
NIH institutes and centers investing more than $25 million 
annually. While many of the projects first funded after the 
enactment of the BPCA are in their final years of funding and 
results are expected in the next few years, we have learned a 
great deal of pediatric pharmacology and reach out regularly to 
the field to further understand the needs of clinicians who 
treat children. For example, research findings suggest the need 
for testing a variety of drugs and other approaches to address 
the increasing problem of obesity-related hypertension in 
adolescents and improving the health of these young people. We 
have also organized and invited experts to numerous workshops 
on a myriad of issues that surround pediatric studies, 
including formulations for use at different stages of 
development, the design requirements and ethics of clinical 
trials in this special population.
    Some of what we have learned has been unexpected. 
Information on a number of drugs which we thought initially 
would require only late phase III or phase IV clinical trials 
in children to provide the data we were seeking, proved 
completely inadequate; and we were forced to revise our plans 
and fund more preliminary studies on safety and efficacy. A 
number of those studies are underway.
    In summary, significant progress has been made to establish 
the infrastructure and support for pediatric drug studies that 
can provide critical information regarding the safe and 
effective use of these medications in children. We look forward 
to continuing to work with this important committee and would 
be happy to answer any questions you and other members of the 
committee might have. Thank you.
    [The prepared statement of Dr. Mattison follows:]

                    Statement of Donald Mattison, MD

     Good morning, Mr. Chairman. I am Donald Mattison, chief of 
the Obstetric and Pediatric Pharmacology Research Branch at the 
National Institute of Child Health and Human Development 
(NICHD), National Institutes of Health (NIH). We appreciate the 
opportunity to appear before you and the rest of the Committee 
to discuss NIH's research activities in relation to 
implementation of the pediatric drug testing program under the 
Best Pharmaceuticals for Children Act (BPCA).
     The BPCA legislation was enacted in 2002 to address the 
growing recognition that the great majority of pharmaceutical 
drugs prescribed for children had never been tested for 
pediatric use. Health care professionals were forced to depend 
upon experience and their best judgment in prescribing 
medications for their pediatric patients. However, without a 
strong evidentiary base, it becomes difficult for practitioners 
who work with children of various ages who are at a range of 
developmental stages to estimate what the correct dose may be. 
Since children may metabolize or respond to a drug differently 
from an adult, that drug's effects may be variable--too high a 
dose for a given child poses risks of toxicity, too low a dose 
may be ineffective.
     Under current law, the NIH is directed to conduct 
research-related activities in three general categories: 
identifying and prioritizing those drugs needing study in 
children, developing new study requests in collaboration with 
the Food and Drug Administration (FDA) and other pediatric 
experts, and supporting studies on priority drugs after 
manufacturers decline to do so. In most cases, the drugs under 
consideration for study by the NIH are for off-patent or older 
medications for which no marketing exclusivity can be granted. 
In some instances, these medications have been in use for over 
thirty years, and yet relative dosing, efficacy and safety data 
have yet to be compiled for children.
     This is a challenging area of research. The available data 
are mostly on adults; some of the conditions these drugs are 
used to treat are relatively rare; effects on children's growth 
and development have been largely unrecognized and certainly 
cannot be studied in adults. In addition, human subjects 
concerns, with a critical focus on balancing risks versus 
benefits, are of particular importance in pediatric research. 
Moreover, long-term follow-up of the possible effects on growth 
and development can be an important, but costly, aspect of 
pediatric clinical trials. To conduct these studies and obtain 
generalizable data, we often need to enroll larger numbers of 
pediatric patients than have been previously studied.
     In order to prioritize the drugs needing study, NICHD has 
developed an annual cycle of data gathering, expert 
consultation and critical analysis. The purpose of the process 
is to distill, from the total number of off-patent drugs 
(approximately 200) to a manageable number (five to ten) for 
study in the following year. We look at whether dosing, safety 
and efficacy data are already available from a reputable source 
and whether additional data are needed, whether new studies 
will produce health benefits for some subpopulation of 
children, the balance between how frequently the condition to 
be treated may occur and the severity of the condition, and 
whether there is a need to reformulate a drug so that children 
will be able to use it. For example, a drug that only comes in 
tablet form cannot readily be taken by an infant or by a young 
child with cerebral palsy.
     Together with other NIH Institutes and Centers, the FDA, 
and other pediatric experts, the NICHD has made significant 
progress on this front--as required by the BPCA--by developing 
and publishing an annual list of approved drugs in need of 
further study in the pediatric population. As of December 2006, 
106 total drugs have been discussed in a scientific forum to 
decide if they should be listed, or whether we need further 
review of the medical literature or outside consultation. From 
this group of drugs, approximately 60 drug/indication pairs 
have been listed as off-patent priority drugs that require 
further pediatric studies. These annual lists have been 
provided to the committee in Table 1.
     From each list of prioritized drugs, the FDA, in 
consultation with the NIH, develops and issues a series of 
Written Requests to the drugs' manufacturers; to date, all but 
one has been declined by the manufacturer, and the drugs have 
been referred to the NIH for study. Table 2 shows the 13 drug 
studies the NIH is currently funding and the status of each. We 
could not be conducting this work without the scientific 
expertise and financial support from the other NIH Institutes 
and Centers that have significant pediatric research 
portfolios. BPCA implementation is a major trans-NIH 
collaboration, as 19 NIH Institutes and Centers are investing 
more than $25 million annually.
     While many of the projects first funded after the 
enactment of the BPCA are in their final year(s) of funding and 
results are expected in the next few years, since the enactment 
of BPCA, we have learned a great deal about the field of 
pediatric pharmacology and reach out regularly to the field to 
better understand the needs of the clinicians who treat 
children. For example, research findings suggest a need for 
testing a variety of drugs and other approaches to address the 
increasing problem of obesity-related hypertension in 
adolescents (high blood pressure related to weight gain), and 
improving the health of these young people. We also have 
organized and invited experts to numerous workshops on the 
myriad of issues that surround pediatric studies, including 
formulations for use at different stages of development, the 
design requirements and ethics of clinical trials in this 
special population.
     Some of what we learned was unexpected. Information on a 
number of drugs, which we initially thought would require only 
Phase III or IV clinical trials in children to provide the data 
we were seeking, proved to be completely inadequate, and we 
were forced to revise our plans and fund more preliminary 
studies on safety and efficacy. A number of those studies are 
now underway.
     In summary, significant progress has been made to 
establish the infrastructure and support for pediatric drug 
studies that can provide critical information regarding the 
safe use of these medications in children. We look forward to 
continuing this important work, and I would be happy to answer 
any questions you or the other members of the committee may 
have.

                                Table 1

    2003:
    Ampicillin/Sulbactam: treatment of pediatric infections
    Azithromycin:
        Prevention of bronchopulmonary dysplasia in 
infants with Ureaplasma urealyticum
        Prevention and treatment of Chlamydia 
conjunctivitis and pneumonia
    Baclofen: treatment of spasticity in children with cerebral 
palsy
    Bumetanide: treatment of pediatric hypertension
    Diazoxide: treatment of hypoglycemia in children
    Dobutamine: treatment of hypotension and low cardiac output 
in children
    Dopamine: treatment of hypotension and low cardiac output 
in children
    Furosemide: treatment of pediatric hypertension
    Heparin: prevent blood clotting in children
    Isofluorane: produce general anesthesia in children
    Lindane: treatment of lice and scabies in children
    Lithium: treatment of mania in children with bipolar 
disorder
    Lorazepam:
        Treatment of status epilepticus in children
        Provide sedation for children in intensive care 
being treated with a respirator
    Meropenem: treatment of pediatric infections
    Metoclopramide: treatment of children with Gastroesophageal 
reflux
    Piperacillin/Tazobactam: treatment of pediatric infections
    Promethazine: treatment of nausea and vomiting in children
    Rifampin:
        Treatment of Methicillin resistant 
Staphylococcus aureus endocarditis in children
        Treatment of central nervous system shunt 
infections in children
    Sodium Nitroprusside: produce hypotension in children 
undergoing surgery to reduce blood loss
    Spironolactone: treatment of pediatric hypertension

    2004:--
    Ampicillin: treatment of pediatric infections
    Dactinomycin: treatment of pediatric cancer
    Ketamine: sedation of children for short procedures
    Metolazone: treatment of pediatric hypertension
    Vincristine: treatment of pediatric cancer

    2005:--
    Acyclovir: treatment of pediatric infections with herpes
    Clonidine:
        Treatment of autism in children
        Treatment of ADHD in children
    Cyclosporine: prevention of organ transplant rejection in 
children
    Ethambutol: treatment of children with tuberculosis 
infections
    Flecanide: treatment of cardiac arrhythmias in children
    Griseofulvin: treatment of Tinea capitis infections in 
children
    Hydrochlorothiazide: treatment of pediatric hypertension
    Hydrocortisone valerate: treatment of inflammatory skin 
conditions in children
    Hydroxychloroquine: treatment of connective tissue 
disorders in children
    Ivermectin: treatment of scabies infection in children
    Methadone: treatment of neonates undergoing opioid 
withdrawal
    Sevelamer: treatment of hyperphosphatemia in children with 
chronic renal failure
    Morphine: treatment of pain in pediatric patients

    2006:
    Albendazole: treatment of children with parasitic 
infections
    Amantidine: treatment of children with influenza
    Daunomycin: treatment of children with cancer
    Guanfacine: treatment of children with ADHD
    Methotrexate: treatment of children with cancer
    Mebendazole: treatment of children with parasitic 
infections
    Pralidoxime: treatment of children with organophosphate 
poisoning
    Rimantadine: treatment of children with influenza
    Hydroxyurea: treatment of children with sickle cell disease 
to prevent painful blood sickling crisis
    Methylphenidate: characterize safety in this drug used to 
treat children with ADHD



     Table 2
    The following pediatric drug studies currently are being 
supported with NIH funding:

        Lorazepam--Phase I, Phase II and Phase III 
clinical studies to support treatment for status epilepticus 
(NINDS)
        Lorazepam--Phase I, Phase II and Phase III 
clinical studies to support sedation of children on respirators 
in an intensive care unit
        Nitroprusside--Phase I, Phase II and Phase III 
clinical studies to understand use to reduce blood pressure 
during surgery to reduce blood loss
        Lithium-- Phase I, Phase II and Phase III 
clinical studies to define treatment of mania in children with 
bipolar disorder (NIMH)
        Baclofen--Phase I, Phase II and Phase III 
clinical studies to understand oral treatment of spasticity, 
most commonly from cerebral palsy
        Vincristine--Phase I, Phase II and Phase III 
clinical studies to enhance treatment for malignancies in 
children (NCI)
        Dactinomycin--Phase I, Phase II and Phase III 
clinical studies to enhance treatment for malignancies in 
children (NCI)
        Daunomycin--Pharmacokinetics, safety, efficacy 
of daunomycin to treat childhood cancers and relationship to 
body weight (NCI)
        Methotrexate--Phase II and Phase III clinical 
studies to improve treatment outcomes for pediatric patients 
with high risk acute lymphoblastic leukemia (NCI)
        Ketamine--Preclinical studies to evaluate the 
scientific and safety concerns about the use as an anesthetic 
in children
        Hydroxyurea--Preclinical, Phase I, Phase II and 
Phase III clinical studies to improve treatment of children 
with sickle cell disease (NHLBI)
        Methylphenidate--Preclinical and clinical 
evaluation of pharmacokinetics and safety to understand reports 
of cytogenetic toxicity (NIEHS)
        Morphine--preclinical basic science evaluations 
of the developmental expression of opioid receptors to better 
understand management of pain in children of different 
developmental stages and safety issues in treating pain in 
neonates
                              ----------                              

    Mr. Pallone. Thank you, Dr. Mattison. We will move to 
questions now, and I will start by recognizing myself for 5 
minutes.
    I wanted to talk about the pediatric exclusivity. Dr. 
Kweder, as you are aware, there is some concern within Congress 
that there are economic incentives associated with BPCA that 
encourage drug sponsors to provide pediatric studies on those 
drugs that are most widely used in adult populations, the so-
called blockbuster drugs. Furthermore, according to an article 
that appeared in the Journal of the American Medical 
Association, the value of the patent extensions under BPCA was 
often greater than the costs of conducting the pediatric 
studies requested by the FDA. Some of these drugs received as 
much as $508 million return because of the 6-month extension. 
The Senate, dare I mention the other body, included in their 
bill recently reauthorizing BPCA and PREA a provision that 
scaled back at the amount of exclusivity a company could get 
based on its earnings. For drugs whose annual earnings exceed 
$1 billion, they would get 3 additional months of exclusivity 
for conducting pediatric trials requested by FDA. I just want 
to know if that is something the administration supports and 
why or why not.
    Dr. Kweder. I can comment generally on this. I am well-
aware of the article that really set out to look at the cost of 
doing the trials themselves versus the exclusivity. What that 
study could not do and one of the things that we are faced with 
doing is before we issue such a request, we look very carefully 
to ensure that any written request that we issue, any specific 
request for a trial or set of trials, it is often more than 
one, that would lead to exclusivity is something that will have 
a meaningful public health benefit for children. The questions 
that will be answered in those trials will result in something 
meaningful to the public health. Unfortunately it is really 
difficult to assign a dollar amount to bump the public health 
benefit; and that is what we are faced with. Remember that in 
some cases, these are going to be for products that are 
manufactured by large companies that have wide use in adults 
and are being used for a number of different things that are 
different from adults than for pediatric patients. In other 
cases we are dealing with a company that has one drug that has 
a very small niche but we see an important pediatric need.
    We have not been in a position where we have had to make 
those determinations of what is the sponsor likely to get out 
of this.
    Mr. Pallone. You seem to be telling me that your decisions 
do not in anyway reflect whether----
    Dr. Kweder. Our decisions do not take into account how much 
money they make today or are likely to make in the future. If 
you were to decide that was something we needed to do, we would 
certainly have to work to obtain some expertise in helping us 
make those assessments. Our concern is that that may end up 
delaying the process in some ways.
    Mr. Pallone. All right. So you don't really want to link 
your decision to the money, but then you are really not taking 
a position on the 3 months it seems to me, right?
    Dr. Kweder. No, I am not taking a position. I will say to 
give you a flavor of how seriously we take this public health 
benefit, if you look at the numbers--I mentioned that sometimes 
a company can initiate a request. We have had well over 500 of 
those come from companies.
    Mr. Pallone. OK.
    Dr. Kweder. We have only issued like 350, 375, but for over 
700 studies, which tells you that we don't take the company's 
initial request at face value. We are really looking harder. 
They complain because our requirements are too tough.
    Mr. Pallone. OK. That is fair. Let me get to my next 
question. As I understand it, there are different labeling 
requirements that apply when a drug maker applies to FDA for 
approval to list a pediatric indication of a new drug versus 
when a manufacturer received exclusivity after conducting 
appropriate studies. Under the first case, pediatric use 
information is included in the labeling only if FDA approved 
the pediatric indication. If FDA turned down or the 
manufacturer withdrew a request for an indication, not only 
does pediatric use information not appear in the product's 
labeling the fact that the manufacturer had made an 
unsuccessful attempt and the research findings that blocked the 
approval--neither are noted in the label, nor made public in 
other ways. But under exclusivity rules, information goes on 
the label regardless of whether or not a drug is found to be 
appropriate for pediatric use. I am concerned by this 
disconnect. Shouldn't information regarding pediatric use be 
made available to the public regardless of whether we learn 
about it when a drug manufacturer applies for a pediatric 
indication or through the exclusivity rules? Wouldn't it be 
helpful for physicians or parents to know whether or not a drug 
maker applied to have their drug approved for pediatric 
indications and was denied and would the administration be 
supportive of changing the rules to accomplish that?
    Dr. Kweder. Let me say that we take the need for inclusion 
of information about use of a product in pediatrics very 
seriously, and where we have data that specifically suggests 
that there may be a risk in pediatrics or that a drug may not 
be effective in pediatric population, we will include that in 
the label, regardless of whether the request came to us under 
an exclusivity, through an exclusivity study, or as part of our 
general application. We are increasingly pushing the envelope 
on that and ensuring that the public has that information. That 
is for approved drugs.
    Mr. Pallone. Right.
    Dr. Kweder. Now, the difference under BPCA is that even if 
an application is not approved under BPCA, a study summary does 
appear on the web that lets people know about that oftentimes 
before we even get into the label. But we are increasingly 
successful in including all that important information for 
practitioners in product labels and the public in product 
labels.
    Mr. Pallone. But then if we change the law to make the 
information more available or to require it and to eliminate 
this disconnect, you don't have a problem with that?
    Dr. Kweder. We are strongly in favor of transparency.
    Mr. Pallone. OK. All right. Thanks a lot. Mr. Deal.
    Mr. Deal. When a manufacturer initiates the request, you 
don't take them up on the offer----
    Dr. Kweder. Sometimes we do but we usually modify a lot.
    Mr. Deal. Let us assume you don't take them up at all. Do 
you have any idea how many of them go forward on their own 
initiative at that point to do pediatric testing?
    Dr. Kweder. I do not have the answer to that question off 
the top of my head. That is information I can get you and 
follow up unless one of my colleagues knows. No, they don't 
know specifically. Very few. I would say, Mr. Deal, my best 
estimate is that very few, very, very few.
    Mr. Deal. So the exclusivity is a real useful tool?
    Dr. Kweder. It is an extraordinarily useful tool for us, 
yes.
    Mr. Deal. Dr. Mattison, let me ask you with regard to your 
off-patent further investigations, who makes the determination 
to select those drugs? Is there a scientific panel, is there 
public input into that process? How do you go about selecting 
those drugs?
    Dr. Mattison. We have established a process by which we 
work with the FDA to identify the drugs that are considered to 
be off-patent; and then on an annual basis, we have pulled 
together 30 to 50 experts in pediatrics to help us discuss the 
drugs that we think have the greatest potential for improving 
public health benefit, in children or have the widest gap 
between what we know and what we would like to know in terms of 
the use of those drugs in children. We rely very, very heavily 
in the set of activities that lead up to selecting drugs on 
input from experts from around the United States in pediatrics, 
our colleagues in the various institutes and centers of the NIH 
that participate in BPCA, as well as our colleagues at the FDA. 
So this is a very open, deliberative process that we believe 
helps us identify those drugs for which testing will have a 
substantial impact on children's health.
    Mr. Deal. With regard to those tests, are most of those 
tests conducted within the institute or are they contracted out 
through grant programs? How do you conduct them?
    Dr. Mattison. The tests are all financed by the institutes 
but conducted outside of the NIH through grants and contracts, 
and the choice of the mechanism that we use depends upon the 
nature of the study that we are interested in performing. For 
large clinical trials, we have used a contract as a way of 
assuring that the various institutions that participate 
understand what we specifically need from the clinical trial to 
improve how the drug is used or thought about in children. In 
some instances we have been surprised by the lack of even basic 
science knowledge about the drugs, and in that case we have 
used grants as the mechanism to build the scientific 
understanding that we need before we can actually design the 
clinical trail.
    Mr. Deal. Let us take a situation in which you have done 
one of these tests to further determine the applicability of a 
drug for pediatric usage that was not initially approved by 
FDA. Do you find at that point that the manufacturers of those 
drugs take your information and then go back to FDA for 
relabeling or new applications? What is the process that 
follows your research?
    Dr. Mattison. When the research is completed and the data 
has been analyzed from the clinical trials, that data is made 
publicly available as a part of the FDA docket system so that 
any investigator from around the United States or anywhere 
around the world could actually take a look at the outcomes of 
those clinical trials and determine whether or not they thought 
it was appropriate to use that drug in children. As I 
understand the current BPCA law, the manufacturers can't get 
additional exclusivity. We haven't encountered the issue of the 
manufacturers asking to use the data, but we make the data 
publicly available to anyone that would like to take a look at 
it.
    Mr. Deal. But it would seem to me to logically close the 
loop, they would go back to FDA and apply for new application 
for usage for pediatric purposes. Is that what happens, Dr. 
Kweder?
    Dr. Kweder. Yes, if it were important information to come 
from any of those studies, we absolutely would ensure that it 
made it to product labeling. Oftentimes you are dealing with a 
generic product that has multiple manufacturers, for example; 
but we would make sure that those data were widely available in 
a package insert.
    Mr. Deal. But is there enough interest on the part of 
either the initial innovator product or the follow-on generics? 
Do they have enough interest in this to initiate it?
    Dr. Kweder. Seek to initiate it? I think it is quite 
variable, particularly if there is a safety issue. They will 
usually see that it is in their best interest to include that 
information in their labeling, but we have managed to find ways 
to require them to include that information.
    Mr. Deal. OK. Thank you.
    Mr. Pallone. Mr. Waxman.
    Mr. Waxman. Thank you very much, Mr. Chairman. When we give 
the exclusivity, we are giving what could be a very rich 
reward, and it seems to me that we want to make sure that we 
are getting something well worthwhile in return. There are many 
drugs with annual U.S. sales in the billions, so when we are 
talking about an extra 6 months of exclusivity paid for by the 
uninsured, the Federal Government, businesses, and insurers in 
the form of higher monopoly drug prices, we want to see if that 
price tag was worth it.
    Dr. Kweder, in your testimony you said that since BPCA's 
inception in 1997, FDA has made 150 exclusivity determinations 
and has awarded exclusivity in 136 of those cases. Your 
testimony also describes the process by which FDA makes the 
decision to award exclusivity. Essentially you base that 
decision on a brief and cursory review of the submitted 
studies, looking only at whether they fairly respond to the 
terms of the written request. That decision is not based upon 
the latter and more thorough scientific review of the studies 
which forms the basis for your decisions about what FDA will 
actually do with the information contained in the studies. You 
obviously award exclusivity in most cases based on the first 
preliminary review, so I assume it is only companies who fail 
egregiously to comply with the terms of the written request 
that are denied exclusivity. Can you briefly give a couple of 
examples of cases in which FDA denied exclusivity?
    Dr. Kweder. One thing that I think is important to 
understand is the reason that we make that determination of 
exclusivity in advance of the scientific review is that BPCA 
requires to us to render a decision on exclusivity at 90 days 
after the application is submitted. 90 days. For a priority 
review, scientific review, under our current user fee 
legislation, we have 6 months to complete our review. And 
sometimes the decision about--many times the exclusivity 
determination is relatively easy to make where you can quickly 
get a good sense of the data in the application, but the types 
of--and some of the cases where we denied exclusivity is 
because it is very clear on its face that we asked for a study 
of a certain size and the company came in with a study a 
fraction of the size that we had already made very clear in our 
written request, would never be able to provide us meaningful 
information. That is common.
    The more difficult areas where we struggle with the 90 days 
versus the 6 months is where we are trying to make an 
assessment about the quality in the way the study was 
conducted. It is extremely difficult to do that within 90 days 
in many cases. It may require us to do an inspection of one of 
the clinical trial sites to really delve into more detail or 
obtain more data from the sponsor of the application. We have 
had one situation I can think of where we did deny exclusivity 
for that reason. It was difficult for us to get to that 
determination in 90 days, but we were able to do it because we 
thought that the study was very poorly conducted.
    Mr. Waxman. You describe instances in which you would have 
reversed your decision to avoid exclusivity after having 
conducted the more extensive scientific review of the studies. 
GAO's report describes an instance in which FDA awarded 
exclusivity only to later find the children participating in 
the study had not actually received the treatments as the drug 
sponsor had claimed in the description of the study.
    Dr. Kweder. Yes, I was trying to remember what the drug 
was. There was one asthma drug for example where we did award 
exclusivity. A study appeared to have been conducted well, the 
size was OK, the population was right. They seemed to have done 
all the things that we asked for.
    Mr. Waxman. But rather than talking about one alone because 
I see my time is running out, are there instances in which you 
would have reversed your decision----
    Dr. Kweder. Yes, this is one. Yes, this is definitely one, 
yes, because when we got into the data in more detail we found 
significant problems with the findings of the data that 
indicated the study had been not conducted well.
    Mr. Waxman. OK. I want to ask Dr. Mattison, the GAO report 
lists some of the studies that NIH is currently conducting and 
the spending NIH anticipates on those studies. Most of the 
studies listed were under $10 million, and several were in the 
$1 to $2 million range. Is it fair to say that those amounts 
are typical costs for pediatric studies both for NIH and 
companies that undertake this research?
    Dr. Mattison. Those are the costs that we have been able to 
negotiate with the various investigators, depending upon the 
nature of the study. I can't comment on how companies would 
negotiate with investigators to conduct their studies.
    Mr. Waxman. They wouldn't do anything all that much 
different, would they?
    Dr. Mattison. They would be doing similar ones, that is 
correct.
    Mr. Waxman. OK. Thank you. Thank you, Mr. Chairman. I see 
my time is expired.
    Mr. Pallone. Mr. Burgess.
    Mr. Burgess. Thank you. Dr. Mattison, in your written and 
your oral testimony, you state that some of what we learned was 
unexpected, information on a number of drugs which we initially 
thought would require only phase III or phase IV proved to be 
completely inadequate. We were forced to revise our plans and 
add a few more preliminary studies. So in some instances you 
would have to go back and essentially recreate the entire phase 
I, phase II, phase III, phase IV study for a particular drug? 
How does the NIH fund that?
    Dr. Mattison. The funding for all of the studies that we 
have conducted under BPCA has come from a series of 
contributions from the 19 institutes and centers that partner 
with us in the BPCA-related activity. Their partnership was 
determined based on the size of their pediatric research 
portfolios. So it is a group of contributions that have come 
from the various institutes and centers.
    Mr. Burgess. Are there examples from what you provided in 
table 1 of some of those compounds where you had to literally 
go back to the beginning and recapitulate the entire study?
    Dr. Mattison. That is correct, and I can give you several 
examples. In one instance, we have had extensive meetings with 
pediatric cardiologists, both in the United States and around 
the world about two commonly used drugs used in the neonatal 
intensive care unit, dopamine and dobutamine, drugs that are 
used variously to increase blood pressure or increase profusion 
through organs; and based on extensive discussions with these 
pediatric cardiologists, we have been unable to arrive at a 
scientifically credible clinical trial design. So we have 
decided that we needed to go back and better understand how 
those drugs work in the newborn. We do have a pretty good 
understanding of how those drugs work in adults, but that 
understanding hasn't translated to an improved understanding.
    Another example is morphine, a drug that has been used 
extensively and is off-patent, 30, 40, 50, 75 years, very, very 
extensively used. We have data suggesting that morphine alters 
the way the children's brains respond to trauma during 
development, and so we have elected to try to understand better 
the expression of receptors for that drug, rather than to 
embark on the clinical trials.
    Mr. Burgess. Is any of the body of evidence that has been 
collected over the last say 70 years in the instance of 
morphine, is any of that useful to you or do you simply have to 
start anew?
    Dr. Mattison. Well, it is very useful because we are 
beginning to understand the receptors that morphine interacts 
with in terms of producing its effect. What it doesn't help us 
with is understanding how those receptors are expressed across 
the course of development in children and whether they are 
expressed the same way centrally in the brain or in the central 
part of the body or peripherally.
    Mr. Burgess. That is a fascinating subject. I would 
actually like to talk to you about that in greater detail, but 
I don't have time.
    Dr. Kweder, in your testimony, you talked about the PREA 
process. You mentioned just almost in passing that some of 
these things would apply to biologics also. Now, it is not 
really part of this hearing but we are at some point going to 
be asked to issue guidelines on what are so-called biosimilar 
products or follow-on biologics and is it your feeling that 
these two would have to, these follow-on or biosimilar 
products, would need to be exposed to the same types of 
rigorous study, in some instances even going back to the 
beginning for biologists in use in children?
    Dr. Kweder. You are asking me several things. Let me just 
say it is a bit of a frustration for us that we can't utilize 
BPCA and biologic therapeutics. As clinicians, doctors don't 
make a distinction in their treatment needs based on whether it 
is a biological or a small molecule drug. That is an invisible 
distinction in the practice of medicine. And so to the 
practicing clinician, the distinction we have to make is a bit 
artificial. There are many biological products that we regulate 
that have potentially very important uses in children.
    Mr. Burgess. But does the concept of having to approve and 
provide the certification of safety for a follow-on biologic 
for use in the pediatric population, is this of necessity going 
to take you back further in that research timeline?
    Dr. Kweder. I am not sure it necessarily will. I mean, 
these would be basically like generic, what we consider generic 
products. We don't have these requirements necessarily for 
generics. We can utilize BPCA if we elect to but----
    Mr. Burgess. If we go to Dr. Mattison, the list in table 1, 
I mean, it is basically all generics.
    Dr. Kweder. Right, because they are old products, off-
patent.
    Mr. Burgess. Correct.
    Dr. Kweder. Right.
    Mr. Burgess. And he has found that it was necessary to get 
back to step one.
    Dr. Kweder. And we may indeed have to. We may certainly 
have to go back to some very basic science in studying these 
biological products in children simply because of the way that 
they act, their mechanisms of action.
    Mr. Burgess. All right. Thank you, Mr. Chairman.
    Mr. Pallone. Thank you. Ms. Eshoo.
    Ms. Eshoo. Thank you for recognizing me, Mr. Chairman. As 
we are asking questions and reviewing the potential for changes 
to the reauthorizations of this bill, I couldn't help but think 
that elsewhere in the capitol there is a national summit on 
America's children taking place which is I think the first time 
in at least a decade that the intelligencia of our country have 
gathered relative to America's children, and I can't help but 
think that what we are doing here obviously is for them as 
well. So I think that this is a good day here in the Congress.
    Dr. Kweder, I wanted to go back to the exchange that you 
had with Mr. Waxman when you spoke about the 90 days. In your 
view, does that need to be adjusted? Do you need more than 90 
days?
    Dr. Kweder. In some cases we would have been very happy to 
have more than 90 days to make that determination.
    Ms. Eshoo. Is it important enough to change it when you say 
``some''?
    Dr. Kweder. Yes.
    Ms. Eshoo. OK. I think that you both agree that FDA's 
authority to require pediatric studies should be permanent in 
PREA? Do you? I am making that assumption. I don't know whether 
you agree.
    Dr. Kweder. I can't imagine that we would have any 
objection but that is certainly up to you.
    Ms. Eshoo. Well, that sounds kind of medium-rare to me. 
Well, I understand who the legislators are but we have the 
experts here to help guide us in making policy.
    Dr. Kweder. May I add to that? We are as I have said in my 
oral testimony, we are just beginning and it is positive to 
really fully utilize these tools, and we think that they offer 
enormous potential and look forward to their continuation.
    Ms. Eshoo. I think that there were some questions earlier 
on the Senate blockbuster provision or an extension of the 
current 6-month exclusivity. Would you like to comment on that, 
Dr. Mattison?
    Dr. Mattison. Not from the NIH's perspective, no.
    Ms. Eshoo. Not from the NIH's? And Dr. Kweder, you don't 
have anything further to comment on?
    Dr. Kweder. My comment is that this program has worked 
extraordinarily well. The opportunity to offer exclusivity in 
exchange for something that we determine, and we are very 
particular about this, will have a meaningful public health 
benefit to pediatrics has been probably what has been the most 
useful tool that we have had to encourage pediatric drug 
development, ever. We have been able to utilize the exclusivity 
provision not just to get information about drug A in a 
particular narrow indication but as Dr. Mattison has implied, 
we have utilized it to build a field of pediatric research and 
answer broader questions that will ultimately apply to more 
than one product.
    Ms. Eshoo. Well, I worked very hard on that part of the 
legislation to motivate the outcomes that we were looking for 
so what you are saying is reinforcing it. On labeling, are 
there any instances where as a result of pediatric studies FDA 
has requested labeling changes be made to a product and where 
the drug sponsor has not complied and if so, how did you handle 
these situations?
    Dr. Kweder. We have been very successful in getting 
pediatric labeling changes. Some of them have taken longer than 
we would have liked. Some cases it is because we need more 
information, but the legislation does provide for us if we are 
having difficulty getting something in labeling to take it to 
the Pediatric Advisory Committee. We have not had to take 
anything.
    Ms. Eshoo. Do you need any additional authority in that----
    Dr. Kweder. We have been successful to date.
    Ms. Eshoo. So you are saying you don't need any additional 
authority? Are there any instances, this is on pediatric 
formulations, where pediatric formulations such as syrup or 
where a chewable tablet has been developed but not marketed?
    Dr. Kweder. One of the big problems that we have is 
sometimes there have been examples where a product has been 
developed for use in a clinical trial, a very small batch that 
you use on a few patients. But the problem has come where when 
you try to scale up manufacturing to make something widely 
available on the market, everything changes. That is a common 
problem in manufacturing and that is why the biggest I would 
say for in pediatric formulations as well as the experiment to 
development.
    Ms. Eshoo. That is the debate on biosimilars but I didn't 
realize that it applied here.
    Dr. Kweder. Yes, it does in formulation development, yes.
    Ms. Eshoo. Do you have any specific suggestions about how 
Congress can improve pediatric labeling?
    Dr. Kweder. Pediatric labeling? I think by some of the 
things in the BPCA that will allow us to link exclusivity to 
the scientific review process will result in better decisions 
on exclusivity and better decisions on labeling. I think 
otherwise we feel like we have most of the tools we need in 
pediatrics.
    Ms. Eshoo. Thank you, Mr. Chairman. Thank you to the 
witnesses for your good work and your testimony.
    Mr. Pallone. Thank you. Mr. Murphy.
    Mr. Murphy. Thank you, Mr. Chairman. I would like to thank 
the panel. This is very enlightening. I want to further delve 
into something here that in terms of--Dr. Kweder, you are 
saying the program is working pretty well. My understanding is 
about 80 percent of the time the labeling of the drugs were 
changed to reflect the pediatric information obtained from this 
research. Does that number sound about correct?
    Dr. Kweder. That sounds about right.
    Mr. Murphy. OK. But among these drugs that show labeling 
changes, what percentage of the overall drugs the FDA has asked 
manufacturers to study does that reflect? So in other words, 
you may come up with 100 drugs. What percentage of those do the 
manufacturers really choose to study, to go into further?
    Dr. Kweder. I am not sure I am really understanding the 
question. I am sorry to be dense.
    Mr. Murphy. Let me explain then.
    Dr. Kweder. Yes.
    Mr. Murphy. Let us say you lay out 100 drugs that you would 
like some pediatric studies done on.
    Dr. Kweder. OK.
    Mr. Murphy. Do they do every one of those or do the 
companies decline sometimes?
    Dr. Kweder. Actually, we usually issue the written 
requests. Under the written requests we may ask for more 
studies than one, in fact, often we do.
    Mr. Murphy. What percent of the time will they do those?
    Dr. Kweder. Most of the time we have had overall, since the 
beginning of exclusivity which was actually 1997, we have had 
41 companies decline to----
    Mr. Murphy. Why? Why did they decline?
    Dr. Kweder. They declined for a variety of reasons, 
sometimes because they are off-patent and they don't see a 
benefit.
    Mr. Murphy. What kind of benefit don't they see?
    Dr. Kweder. They see the pediatric market is too small to 
make it worth their while. They see that in order to address 
the written request, we have to ask for some of the basic 
scientific information that Dr. Mattison is referring to. They 
don't have the tools to address that.
    Mr. Murphy. So let me just continue on this. They say the 
pediatric population may be too small?
    Dr. Kweder. The pediatric population may be too small.
    Mr. Murphy. Too small for them to recover whatever 
investment and make the research based upon the 6-month 
exclusivity?
    Dr. Kweder. Yes, even with the 6-month exclusivity.
    Mr. Murphy. The 6-month thing doesn't give them enough?
    Dr. Kweder. It is not enough. And sometimes I don't have 
any exclusivity to attach to but we will ask them to do the 
study anyway. But there is no incentive. They are not going to 
do it.
    Mr. Murphy. And I want to clarify this because it is 
important. There are different kinds of populations of 
diseases, some are very common, unfortunately common and so 
companies may feel they can recoup their loss.
    Dr. Kweder. Right.
    Mr. Murphy. I am particularly concerned about some of the 
rare diseases of some children that I have treated myself and 
saw that no one was investing in some of these orphan diseases.
    Dr. Kweder. Right.
    Mr. Murphy. And are those the kind of things sometimes the 
companies say is just not worth their----
    Dr. Kweder. Yes.
    Mr. Murphy. I am really interested in any recommendations 
you have on how we correct this. Does the 6-month number work, 
and I don't know if all diseases should be treated equally 
here, and if some are more rare and have some awful tragic 
consequence but if we could somehow encourage companies to do 
some of the pediatric research on these, should we have 
different levels here? Some have 6 months, some have longer, so 
that they can look in terms of making the investments in some 
of these rarer diseases?
    Dr. Kweder. That is an interesting question. I am trying to 
remember. BPCA does apply to orphan products, but whether or 
not additional exclusivity would give companies the incentive 
to further their exploration of some of those even more 
orphaned pediatric indications as we do--some examples are 
things like juvenile rheumatoid arthritis, very, very rare. 
Doing pediatric studies is extremely difficult for a lot of 
these companies.
    Mr. Murphy. Yes.
    Dr. Kweder. If you are a large company particularly and you 
have some experience in doing trials in children, you have a 
set-up system and you know how to do these, it is a very, very 
different kettle of fish than if you are a company that has 
just done adult studies, it takes an entirely different kind of 
expertise, entirely different network, and they just feel like 
they don't have the resources and the energy to even begin.
    Mr. Murphy. Exactly. Thank you so much for your comments on 
that because in my years of treating patients and 
psychologists, I remember one young man who was diagnosed with 
adrenal leukodystrophy, fairly rare, so much so that as I was 
identifying some of these symptoms, we had to search around for 
people who really knew these and treated these people.
    Dr. Kweder. Right.
    Mr. Murphy. And it was so tragic to watch this boy wither 
away because his body was basically eating away at itself in 
its own proteins and watch what happened as his own 
neurological development eroded. And yet I saw people were not 
really investing in treatments for someone like that. How many 
more diseases are there are like that? I hope that one of the 
things you might be able to provide this committee and send to 
the Chairman might be some ideas of how we deal with some other 
diseases because there are parents out there who feel that no 
one is paying attention to their children and to treat all 
diseases as equal. I don't think it is fair to them, and I hope 
you can--I don't expect you to do it now but I hope that is 
something you can make some recommendations to the Chairman on.
    Dr. Kweder. No. Thank you.
    Mr. Murphy. Thank you, Mr. Chairman.
    Mr. Pallone. And we would certainly welcome those 
recommendations in writing. Thank you. Mrs. Capps.
    Mrs. Capps. I also particularly appreciated this last 
exchange of questioning. It is has been lurking in the back of 
my mind, orphan diseases, adults or children but children in 
general are not a lucrative population for the topic that we 
are discussing today. How we can provide those services so that 
all patients can feel safe and confident that there is somebody 
looking out should something develop. I had two different 
questions to ask you since we have kind of jumped around here, 
Dr. Kweder. One is in the Best Pharmaceuticals for Children 
Act, HHS was required to issue a rule regarding the 
availability of a toll-free number which patients and providers 
could use to report adverse effects, and this rule was supposed 
to be proposed within 1-year of enactment. It is 3 years later, 
and I want to ask about that rule. Has it been released?
    Dr. Kweder. I am looking at my regulatory counsel here who 
is telling me that the answer is no.
    Mrs. Capps. Well, you know what I am going to ask you next. 
When and why not?
    Dr. Kweder. We do have on all product labels, on all 
product labels, and we do require that the FDA MedWatch 1-800 
number and Web site address be listed where anyone, healthcare 
provider or consumer, is encouraged to report any adverse 
effect related to any medicine. When one reports, one of the 
questions that is asked is what is the age of the patient, and 
so we are able to collect extensive amount of adverse event 
information through that system. We worked very hard over the 
years, now independent of this, to try and have one channel for 
communication to FDA so that people don't have to figure out, 
oh, did I call the right number? But that is one of the ways 
that FDA gets its information. One of the things that we have 
had to do in thinking about putting together this rule under 
BPCA is work through some consumer groups and do some testing 
to determine whether or not having a second number or second 
pathway is going to confuse things rather than help. And we are 
in the process of completing some of those studies.
    Mrs. Capps. In this case it would be parents most likely 
who would be reporting because of the----
    Dr. Kweder. That is right. And that is typically how we get 
the information, even through our MedWatch system about 
children from--the children don't report them themselves 
obviously, the parents do.
    Mrs. Capps. And I think again with all the questions that 
have come up with what we are talking about, this is so 
important for us to know, for you all to know, and the public 
to feel confident that this unique population, always changing, 
developing, is going to be acknowledged in terms of any kind of 
effect, good, bad, or----
    Dr. Kweder. Right. And this kind of information is exactly 
the kind of information that we ask our Pediatric Advisory 
Committee to review at the 1-year mark, information about both 
adults and children, after exclusivity is granted.
    Mrs. Capps. Now, a different topic but also based on child 
development. Children, because they are constantly growing and 
developing, it is even more important I believe that ongoing 
clinical studies are part of that process to determine the 
long-term safety and efficacy of either a device or a 
pharmaceutical. But currently there is a 3-year limit on FDA 
mandated post-market studies on medical devices. An Institute 
of Medicine report released in 2005 recommends that this 3-year 
limit be lifted because it restricts the FDA from mandating 
appropriate studies involving devices effects on children 
growth and development. I wonder if you agree with this 
conclusion and the suggestion that this limit should happen, be 
lifted. And Dr. Less? OK.
    Ms. Less. Congresswoman Capps, thank you very much. Before 
I answer your question, let me just say thank you to Chairman 
Pallone and the members of the subcommittee for inviting us 
today to speak with you on this important issue, both post-
market safety of pediatric medical devices as well as 
facilitating the development of new devices. We welcome this 
opportunity and look forward to working with you this very 
important issue.
    With regard to section 522, currently it is limited to 3 
years, and we agree with the IOM that in some cases, especially 
in the cases of implants, it would be important to be able to 
go longer than the 3 years. Right now, if we want to go longer 
we have to work with the manufacturer and get their agreement 
in order to do so. We have not had that problem or we think 
that because manufacturers are paying much more attention and 
recognize the importance of collecting this information, it 
hasn't been an issue. But we would not be opposed to having 
that additional authority.
    Mrs. Capps. Good. I was just thinking of an important or 
some device for a 2-year-old would not--at 3 years, they are 
still very much in the process of developing. So I would hope 
that this advise be taken seriously in the reauthorization.
    Ms. Less. Thank you.
    Mr. Pallone. Thank you. Mr. Green.
    Mr. Green. Dr. Mattison, would you like to explore the 
requirements of NIH and the resources it receives to study the 
drugs both on-patient and off-patient, and can you compare the 
process and resources NIH receives distinguishing between the 
off-patent and on-patent drugs, resources comparison.
    Dr. Mattison. The funding that we use to support the 
studies that we do on the drugs comes from contributions from 
the 19 institutes and centers that are participating with us in 
the BPCA activities, and those cover the studies that we need 
to conduct both on- and off-patent drugs. We also receive 
contributions from the foundation for the NIH to help defray 
the cost of the on-patent drug studies that we are engaged in, 
but those contributions are substantially less than the cost of 
the studies themselves.
    Mr. Green. Do you have any comparison of the process or 
resources it receives? That is the only funding you receive?
    Dr. Mattison. I am sorry. I am not sure I understand it, 
but the funding from the institutes has been a set contribution 
from each of them since 2004. Again, through the foundation for 
the NIH, they have provided us what they felt was appropriate 
based on the resources that they have collected. I am sorry if 
I am not answering you.
    Mr. Green. Are there any private contributions?
    Dr. Mattison. There are private contributions that come to 
the foundation for the NIH. I can't answer the question about 
who has contributed those.
    Mr. Green. OK. Recently a published GAO report on studies 
conducted under the BPCA had noted that the process for 
approving labeling changes is often lengthy for drugs that have 
labeling changes after being granted exclusivity. The report 
states that it took between 238 and 1,055 days for information 
to be reviewed and labeling changes to be approved for 
approximately 40 percent of the drugs granted exclusivity, with 
seven of these taking more than a year. Drug studies under the 
BPCA are used for a number of life-threatening diseases. Would 
you agree that the amount of time consumed for labeling changes 
to occur poses a dangerous public health concern for some 
children and why is it taking so long for labeling changes to 
occur? Is it lack of resources?
    Dr. Mattison. That I think is a question for the FDA.
    Dr. Kweder. I would be happy to answer that question. When 
we make an approval for labeling changes, it is usually based 
on a scientific review which as I mentioned before is on a 
different time clock than the exclusivity determination. So the 
exclusivity determination precedes the ultimate decision on how 
and whether to label a product. Decisions about labeling 
ultimately depend on the scientific data available that 
underlie those changes. For a priority application, we would 
usually render a decision on that scientific application at 6 
months, others are a 10-month clock. It is not unusual for us 
to have to go back and ask for more information and another 
round of review before we can have the confidence that we need 
in the labeling that we want to make. We have become I would 
say since we started these programs a few years ago much better 
at getting those out there more quickly and making cuts on 
labeling changes that we can make early while we wait for 
additional data to supplement the labeling later. But there 
will always be a situation where we are stuck with needing more 
information before we can make a confident change to a label.
    Mr. Green. But it is not from lack of resources?
    Dr. Kweder. No.
    Mr. Green. What about with disagreements with manufacturers 
on labeling?
    Dr. Kweder. Again, that is an area where we have been 
really pushing the envelope to getting these things into the 
label. We feel very strongly that information about pediatric 
use of products needs to be available to practicing clinicians. 
Our best tool for that is the labeling. We do have a provision 
in the statutes that allows us to take a labeling dispute with 
a company to the Pediatric Advisory Committee. We have not had 
to utilize that to date.
    Mr. Green. So you are saying that the numbers I gave, you 
know, the 238 to 1,055 days, it is much better in the last few 
years?
    Dr. Kweder. Yes, yes. Absolutely.
    Mr. Green. OK. Thank you, Mr. Chairman.
    Mr. Pallone. Thank you. The gentlewoman from Illinois?
    Ms. Schakowsky. Thank you, Mr. Chairman. I am picking up a 
little bit on what Mr. Waxman had raised about the cost of 
actually doing the pediatric studies versus the amount of money 
that the pharmaceutical companies make with this exclusivity 
provision. The Wall Street Journal estimated that pediatric 
studies have grown from $200,000 to $3 million each. Does that 
sound right or is that $200,000 maybe a little low?
    Dr. Mattison. $200,000 is awfully low.
    Ms. Schakowsky. OK.
    Dr. Mattison. The studies that we are conducting, depending 
upon the severity of the disease and the children that are 
enrolled in the study, they typically cost in the $10 to $15 
million range.
    Ms. Schakowsky. OK. And yet, 6 months of additional 
exclusivity was worth nearly $8 billion for Prozac and $575 
million for Claritin. So regardless, $10 or $15 million, it is 
a lot of money, potentially a lot of money in exclusivity. My 
staff is telling me that the FDA has estimated that consumers 
will pay nearly $14 billion in higher prescription drug costs 
over the next 20 years if the current pediatric exclusivity 
program is reauthorized. You look quizzical. Is that----
    Dr. Kweder. That is not a statistic I am familiar with.
    Ms. Schakowsky. OK. Maybe my staff will write me a note 
while I am asking the rest of the questions. And I am concerned 
though that these high prices and the differential is so high, 
is virtually borne by senior citizens who are the highest 
consumers of and have a disproportionate share of prescription 
drug use and the uninsured who have to pay the full cost. And I 
am concerned that under the current system of granting 
additional exclusivity, there really is little incentive for 
companies to test drugs other than the blockbusters.
    For example, I have Glucophage, a diabetes medication, 
received an exclusivity period worth about $640 million, yet it 
is barely used for children. Less than one percent of its 
prescriptions are written by pediatricians. And six out of the 
10 drugs most widely used in children without adequate labeling 
are not eligible for pediatric exclusivity because they are 
already off-patent. So should we be considering this 
differential and how much it is worth to the drug companies 
because ultimately the consumers pay the cost and how can we 
incentivize studies in these very important drugs? I mean, if 
the companies can simply decline to do the studies, then as Mr. 
Green was exploring, that money then is entirely borne by the 
taxpayers. Are these issues that we need to deal with? In my 
opinion I think they are. So either or both of you actually----
    Dr. Kweder. I will take a stab. These are really difficult 
issues. One of the things that we do when we have a company 
that declines an initial written request, to go to your last 
point first, sometimes there is a long period of time that 
passes that they have been thinking about that and events occur 
in the interim that make that written request-- for example, we 
look very carefully to make sure that this is something that we 
want the taxpayers to really fund. Sometimes new information 
has come to light while they were thinking about that written 
request that changes the public health value equation. So we 
would make a decision to put that lower on the priority list 
for NIH funding. The struggle that the public has in assessing 
value is looking at the cost of studies, the financial gain 
that companies receive in terms of exclusivity, the cost to the 
public of generic drugs, those are all factors I have to say 
the monetary costs have not really been part of the equation 
for FDA in deciding what to ask for in the way of studies. We 
have really based our decisions on seeking study data on what 
we perceive to be a potentially important public health 
benefit.
    To use the example of the Glucophage that you raised, that 
is one of the oldest oral diabetic agents on the market; and 
while the population of pediatric users today may be small, we 
have an epidemic of obesity in pediatric population that is 
growing in this county. In particular in Type II diabetes, the 
type that is associated with obesity, that is a mainstay of 
therapy among diabetics. So we expect that physicians are going 
to increasingly be seeking to use those kinds of treatments in 
children. So it was very important we felt from a public health 
standpoint to really understand whether that drug was safe in 
children and whether it was effective. We learned that it is 
not effective in children. That is an enormously important 
public health benefit and prevents children from being exposed 
to a drug that is not effective and may only have risks. I 
don't know how we could attach a monetary value to this, and 
that has been our struggle in thinking about how to assign 
different values in terms of----
    Ms. Schakowsky. But clearly the companies are assigning a 
monetary value when they decline to do a study.
    Dr. Kweder. Yes, they are.
    Ms. Schakowsky. I am not trying to put a price tag on the 
life of a child but there certainly is a cost benefit analysis 
and it is pretty easy for the companies to say, well, it is 
off-patent, we decline.
    Dr. Kweder. Yes.
    Ms. Schakowsky. I wondered if you had any comment doctor, 
even though I am out of time, Mr. Chairman. Can I ask him if he 
has any comments?
    Mr. Pallone. We will ask Dr. Mattison and then we will move 
on.
    Dr. Mattison. Again, we focus our attention on the off-
patent drugs because we assume that those will get the least 
attention by any other interested group, and we feel that by 
focusing our attention on that group of drugs and identifying 
those that provide the greatest public health benefit in terms 
of what do we know versus what would we like to know to improve 
those drugs, we at the NIH can make the best impact possible 
under BPCA.
    Ms. Schakowsky. Thank you. Thank you, Mr. Chairman.
    Mr. Pallone. Thank you and I thank all three of you for 
your input in answering our questions, and I think as you know 
you may get additional questions from us within the next 10 
days or so; and please follow through. Thank you.
    Dr. Kweder. We will, and thank you very much.
    Mr. Pallone. And if the next panel could come forward and I 
ask that the panel be seated.
    Let me start by introducing each of you. On my left is Ms. 
Lori Reilly who is vice president for policy and research for 
PhRMA; and then we have Dr. Marcia Crosse who is director of 
health care issues for the GAO; and then we have Dr. Gorman, 
Richard Gorman, who is chair of the AAP section on Clinical 
Pharmacology and Therapeutics for the American Academy of 
Pediatrics; we have Dr. Peter Lurie who is deputy director of 
Public Citizen's Health Research Group; we have Ms. Susan 
Belfiore who is testifying on behalf of Elizabeth Glaser 
Pediatric AIDS Foundation; we have Mr. Ed Rozynski who is vice 
president for Global Government Affairs at Stryker Corporation; 
and last is Mr. Donald Lombardi who is president and CEO of the 
Institute for Pediatric Innovation.
    We are going to give each of you 5 minutes. You can, of 
course, submit additional written statements if you like with 
the committee's permission afterwards; and we will start with 
Ms. Reilly. Thank you.

STATEMENT OF LORI REILLY, VICE PRESIDENT, POLICY AND RESEARCH, 
      PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA

    Ms. Reilly. Thank you Chairman Pallone and members of the 
subcommittee for having me here today. My name is Lori Reilly, 
and I am vice president for policy and research at the 
Pharmaceutical Research and Manufacturers of America, otherwise 
known as PhRMA.
    I have seen firsthand the benefits of this program. While I 
am here today in my capacity representing PhRMA, I am also a 
mother; and I have seen the benefits firsthand of this program. 
When my youngest daughter was born, at about 6 weeks of age my 
husband noticed that she had a strange, wheezing sound when she 
was breathing. Obviously this is alarming as a parent to hear 
that and we were worried about whether she was getting enough 
air and whether she had the ability to breathe correctly. After 
seeing our pediatrician and a pulmonologist and an ear, nose, 
and throat specialist, she was diagnosed with a rare condition 
called laryngomalacia which is a fancy term for a floppy voice 
box which thankfully self-corrects itself in about 18 months. 
One of the other symptoms in addition to having trouble 
breathing is significant reflux or vomiting and this was 
causing a problem because she was having an inability to gain 
weight. Thankfully there was a drug available that was approved 
under BPCA that allowed my pediatrician to prescribe the drug 
to her that controlled that symptom and also allowed her to 
gain weight. So I thank Congress personally for enacting these 
very important provisions because I am not unlike many other 
parents in this country and families that have seen firsthand 
the benefits of this program.
    As the FDA has said, the current pediatric exclusivity 
program has done more to further research and generate clinical 
information for pediatric populations, and it is a very 
important program. By the end of 2006 alone, FDA had issued 
nearly 400 written requests for almost 800 studies to be done 
on pediatric patients. In comparison, when you look back prior 
to the enactment of this program, from 1990 to 1997, only 11 
drugs had been studied in children. So clearly we have made a 
lot of progress in a short period of time.
    Companies are responding to written requests from FDA in 
very high numbers. Back in 2001, FDA had estimated that about 
80 percent of the time companies would respond proactively to a 
written request; and in fact, they are doing that anywhere from 
81 to 84 percent of the time depending on the data that you 
look at. And not only are companies responding in high amounts, 
they are also responding to broad categories of disease. 
According to the GAO, about 17 broad categories of disease 
including cancer, which is obviously a very significant 
condition, was the most studied condition under the pediatric 
exclusivity program.
    In less than 10 years since the program began, over 120 
drugs and conditions have had new labeling changes as a result 
of this program, and in fact nearly 90 percent of all drugs 
that have been granted exclusivity under BPCA have received 
important labeling changes. And this is important because when 
we look at, for example, a study that was done in JAMA and you 
look at the time period between 2002 and 2004, there were 59 
drug products that received exclusivity under BPCA. And prior 
to 2002, about 34 percent of those drugs had been used and 
physicians were prescribing these drugs, either making a dosing 
error or placing a child at risk of serious adverse events. So 
having this critical information available to patients and 
doctors is vitally important.
    While the benefit of this program has continued to grow 
over time since its inception, also growing are the cost, time, 
and complexity to do these studies. Companies have continued, 
however, in engaging in this research despite the increase in 
time and costs. From 2000 to 2006, the average number of 
patients per written request increased 178 percent while the 
average number of studies requested by the FDA in a written 
request increased by 60 percent. Sponsors have also been 
increasing the proportion of the safety and efficacy tests, 
often the most expensive and time-consuming of all tests done 
by companies from 25 percent in 2000 to 40 percent in 2006. The 
time required to complete pediatric studies has also increased 
significantly. It has doubled in fact in the last 6 years. And 
the average cost to complete a written request has increased 
eight-fold. Given these significant increases we have seen in 
the cost, time, scope, and complexity of studies, it is PhRMA's 
position that Congress should not adopt significant 
modifications to these programs that may inevitably reduce 
incentives for companies to engage in this kind of research. As 
we know, these provisions have had a tremendously positive 
impact on the lives of children, but there is much more to be 
accomplished. The program is working well, and its basic 
features should not be altered. Changes in the current program 
have the potential to reduce incentives that exist for 
companies to engage in this very important research.
    As mentioned above, the cost, time, and complexity of these 
studies is increasing. Given these factors, Congress should not 
increase the hurdle that companies must go through to qualify 
for pediatric exclusivity. As I mentioned earlier in my 
testimony, companies have pursued pediatric studies for a broad 
range of conditions, about 17 in total; but the majority of 
drugs studied under these programs were not high-selling drugs, 
nor were they blockbuster drugs. In fact, 60 percent of the 
drugs studied were not even in the top 200 selling drugs. Some 
of these drugs included medicines for HIV/AIDS, leukemia, anti-
infectives and others. Again, only about 10 percent of the 
drugs studied under this program are what you would consider 
blockbuster drugs.
    As with drug development in general, blockbuster drugs and 
higher-revenue drugs, support the ability of pharmaceutical 
companies to invest in research for lower-selling, lower-volume 
drugs. And in the case of pediatrics, not only have 
blockbusters allowed companies to invest in research for lower 
volume or lower-selling drugs and clearly companies are, it has 
also given the companies the ability to build needed 
infrastructure for pediatric programs. This infrastructure 
includes hiring researchers that have particular expertise in 
pediatric populations and building the kind of in-house 
infrastructure needed. Unique expertise is required to develop 
drugs for use in children, and thanks to the pediatric 
incentive, companies have made significant investments in 
building capabilities in this area.
    We must preserve the pediatric exclusivity as it is 
currently structured to ensure that pediatric drug development 
is not hindered. Diminishing or reducing the value of 
incentives, for instance, by reducing the exclusivity period or 
tiering it for certain products could also create unintended 
consequences throughout the program. In addition, BPCA and PREA 
are complimentary programs and should remain connected as they 
have to date. Together these two programs have worked extremely 
well to generate new information on pediatric use.
    In conclusion, PhRMA strongly urges Congress to reauthorize 
BPCA and PREA without modification. The increasing rate of 
industry study proposals and FDA written requests shows 
continuing progress which could be significantly undermined of 
these two programs were allowed to expire. In addition, we urge 
Congress to proceed with caution when considering changes to 
the incentive that could have unintended consequences to 
pediatric research. Thank you.
    [The prepared statement of Ms. Reilly follows:]

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    Mr. Pallone. Dr. Crosse.

STATEMENT OF MARCIA CROSSE, DIRECTOR, HEALTH CARE ISSUES, U.S. 
                GOVERNMENT ACCOUNTABILITY OFFICE

    Ms. Crosse. Mr. Chairman and members of the subcommittee, I 
am pleased to be here today as you examine pediatric therapies. 
My remarks are based on GAO's recent report on the Best 
Pharmaceuticals for Children Act, BPCA. I will focus on studies 
conducted under BPCA for on-patent drugs, for off-patent drugs, 
and the impact of the statute on the labeling of drugs for 
pediatric use. As we have heard here today, when FDA determines 
that a drug may provide health benefits to children, it may 
issue a written request of the drug sponsor to conduct 
pediatric drug studies. A drug sponsor can also propose to FDA 
that a written request be issued for a particular drug, but FDA 
makes the determination of whether this is warranted. Only a 
minority of the studies that sponsors proposed resulted in FDA 
issuing a written request.
    BPCA has been relatively successful in promoting the study 
of on-patent drugs. Drug sponsors agreed to study over 80 
percent of the on-patent drugs for which FDA issued written 
requests. Studies have been completed for about one-third of 
these drugs. Of those drug studies completed and submitted to 
FDA, over 90 percent have resulted in FDA granting pediatric 
exclusivity. A total of 73 drugs to date under BPCA and 136 
drugs under BPCA and its predecessor, FDAMA. FDA grants 
exclusivity regardless of whether the studies show the drug 
should be used to treat children. Indeed a finding that a drug 
should not be used in children can be just as valuable as a 
finding that shows positive results.
    In contrast to the relative success of the process when 
drug sponsors agree to conduct the requested studies, the 
picture is much less positive when the drug sponsor declines. 
To date, the study of only one on-patent drug has been 
initiated when the drug sponsor declined the written request. 
BPCA allows FDA to refer declined written requests for on-
patent drugs to the Foundation for the National Institutes of 
Health, FNIH, an independent, non-profit corporation that 
raises private sector funds for research including for BPCA 
studies. Through 2005, drug sponsors declined 41 written 
requests for on-patent drugs and FDA chose to refer nine of 
these to FNIH for funding. FNIH subsequently agreed to fund the 
study of one of these drugs, even though all its available 
funding for BPCA studies could only provide partial support for 
this research. As of June 2006, FNIH had only raised about $4 
million to fund BPCA studies, and the study of this one drug 
was estimated to cost about $8 million. Similarly, few off-
patent drugs have been studied under BPCA. Through 2005, NIH 
had identified 40 off-patent drugs it recommended for study and 
FDA issued written requests for 16 of these drugs. However, 
drug sponsors declined 15 of these 16 written requests. NIH 
subsequently used its appropriations to fund studies for half 
of these off-patent drugs. Under BPCA the most frequently 
studied drugs were those used to treat cancer, neurological and 
psychiatric disorders, metabolic diseases, cardiovascular 
disease, and viral infections. In addition, about half of the 
10 drugs most frequently prescribed for children have been 
studied under BPCA. Moreover, almost 90 percent of the drugs 
that have been granted pediatric exclusivity have had important 
labeling changes, but the process for reviewing the study 
results and making these changes can be lengthy. The labeling 
of drugs was often changed because pediatric drug studies 
revealed that children may have been exposed to ineffective 
drugs, ineffective dosing, overdosing, or previously unknown 
side-effects. For the drugs we examined, they took between 238 
and 1,055 days or almost 3 years for FDA to approve the 
labeling changes when the agency required additional 
information to support the proposed changes.
    In conclusion, BPCA has made important contributions to 
increasing the knowledge of appropriate usage of drugs in 
children. The drugs studied under the statute are used to treat 
children for a broad range of diseases and many serious or 
life-threatening conditions. However, the provisions to promote 
the study of a drug when the sponsor declines the written 
request or when a drug is off-patent have worked less well. 
Funding has not been sufficient to ensure that in these 
situations studies of the drugs are undertaken.
    Mr. Chairman, this concludes my prepared remarks. I would 
be happy to respond to question that you or other members of 
the subcommittee may have.
    [The prepared statement of Ms. Crosse follows:]

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    Mr. Pallone. Thank you, Dr. Crosse. Dr. Gorman.

  STATEMENT OF RICHARD L. GORMAN, M.D., F.A.A.P., CHAIR, AAP 
  SECTION OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, AMERICAN 
                     ACADEMY OF PEDIATRICS

    Dr. Gorman. Mr. Chairman and members of the committee, I am 
Richard Gorman, a pediatrician and member of the American 
Academy of Pediatrics, and I have practiced pediatrics for over 
25 years taking care of infants, children, and adolescents in 
my private practice. I thank the committee for having this 
hearing on the need for safe and effective medicines.
    It is through my practice, Pediatric Partners in Ellicott 
City that I see firsthand the therapeutic benefits of increased 
information on drugs used in children. With over 80,000 
pediatric visits annually in our four clinical sites in three 
counties in Maryland, my partners and I can attest to the 
importance of pediatric drug studies and the legislation that 
supports them.
    I am here today on behalf of the American Academy of 
Pediatrics to discuss the BPCA and the Pediatric Research 
Equity Act which represent critical public policy successes for 
children.
    I begin my testimony today by saying without reservation 
that in the last decade we have gained more useful information 
on drugs through BPCA and PREA than we have had in the previous 
70 years. These two pieces of legislation have advanced medical 
therapies for infants, children, and adolescents by generating 
substantial new information on the safety and efficacy of these 
drugs where previously there was none. Since the passage of 
FDAMA over a decade ago, FDA has requested nearly 800 studies 
involving more than 45,000 children in pediatric trials. The 
information gained from these studies have resulted in label 
changes for 128 drugs. Medical and clinical pharmacology review 
summaries of over 76 drugs are now publicly available on the 
FDA's Web site. It is vitally important that these laws be 
reauthorized.
    In previous testimony before Congress, I have described 
children as the canaries in the mine shaft, acting as early 
warnings of unknown dangers in therapeutics. BPCA and PREA 
working together have changed this by creating an effective, 
two-pronged approach to generating new pediatric studies. PREA 
provides FDA the authority to require pediatric studies of 
drugs when their uses for children would be the same as adults. 
BPCA provides voluntary incentives to drug manufacturers for an 
additional 6 months of marketing exclusivity for conducting 
pediatric studies of drugs that FDA determines may be useful 
for children.
    Despite these important advances, there is much more we 
still need to do. Children remain second-class citizens when it 
comes to drug safety and efficacy information. Currently two-
thirds of the drugs used in children are not labeled for them. 
Almost 80 percent of hospitalized children receive at least one 
drug prescribed for them for an off-label use. For children, 
off-label use remains the rule and not the exception. Both BPCA 
and PREA are crucially important and must be reauthorized this 
year, including needed improvements.
    The FDA bill recently passed in the Senate reauthorizes 
BCPA and PREA, and we applaud the Senate's work. The studies 
generated under BPCA provide information beyond safety and 
produce information on dosing, efficacy, and importantly the 
lack of efficacy and off-label use.
    PREA created a new presumption that all drugs would, in 
fact, be studied in children at the time of the application, 
thus preventing the need for a safety program to trigger drug 
studies after the drug is on the market. Mr. Chairman, in my 
written testimony I have elaborated on recommendations for 
improvement to BPCA and PREA in several areas. The American 
Academy of Pediatrics urges this committee to pass a 
reauthorized bill which increases the dissemination, the 
transparency, and the tracking of pediatric drug information; 
streamlines and integrates the Food and Drug Administration's 
administration of BPCA and PREA to improve the uniformity, 
consistency, and quality of pediatric studies; expands the 
study of off-patent drugs and generic drugs and addresses the 
gaps in understandings of pediatric therapeutics; and crafts a 
balanced compromise that will preserve both the quality and the 
number of pediatric studies gained through BPCA's exclusivity 
extension and also addresses the concerns regarding excessive 
revenues for blockbuster drugs. And lastly, the AAP wants PREA 
to become a permanent part of the Food and Drug Act and allow 
for the periodic re-evaluation of BPCA to ensure that 
incentives remain fair and continue to yield pediatric 
information.
    In conclusion, I would like to thank the committee again 
for allowing me the opportunity to share with you the strong 
support of the American Academy of Pediatrics for 
reauthorization of Best Pharmaceuticals for Children and the 
Pediatric Research Equity Act. We urge their improvement and 
renewal for the sake of all children throughout the United 
States. I will be glad to answer any questions you may have.
    [The prepared statement of Dr. Gorman follows:]

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    Mr. Pallone. Thank you. Dr. Lurie.

STATEMENT OF PETER LURIE, M.D., M.P.H., DEPUTY DIRECTOR, PUBLIC 
                CITIZEN'S HEALTH RESEARCH GROUP

    Mr. Lurie. Good morning, and thank you for the opportunity 
to testify before the committee. You have already heard a lot 
about the successes of the Act, and I think that they are clear 
and don't merit challenge exactly, but those aren't the right 
questions. The right questions are firstly whether or not the 
system could be more successful and second, whether or not 
these successes or perhaps even greater ones could have been 
obtained through an alternative method, and I will address 
those two questions in turn.
    First, are there gaps, and I think there are three. We have 
heard some of them from Dr. Crosse on off-patent, on-patent, 
and I will talk especially about the diseases that have been 
studied.
    The biggest deficiency is in off-patent drug studies, and I 
don't think that is a surprise to anybody given the way the 
BPCA is structured. As Dr. Crosse testified, very few of the 
off-patent drugs for which studies have been requested have in 
fact been done. In 83 percent of the studies requested by the 
NIH, no study has been done. So I think we are looking at a 
significant problem there. In part this is because the NIH has 
received no appropriations specifically for these pediatric 
studies. And even with respect to on-patent drugs, there are 
problems as well. According to the GAO, 19 percent of written 
requests from the FDA were turned down, presumably because 
there wasn't enough money to be made from conducting studies; 
and the BPCA does provide a mechanism for the study of those 
written requests that have been declined, but as we have heard 
in the end not one of those studies has in fact been funded. So 
those are the first two points.
    The third is that the kinds of diseases being studied are, 
not surprisingly, those diseases that are likely to have large 
sales in adults because that is where the great majority of the 
pharmaceutical market is. So market-based solutions result in 
these kinds of market-based distortions. Using two different 
data sources, GAO determined that only four or five, depending 
on which data source you looked at, of the 10 most commonly 
prescribed pediatric drugs had in fact been studied under the 
BPCA. And a group of researchers in the Netherlands which has 
just implemented a BPCA-like solution of its own has studied 
the United States experience, and what they found was that the 
profile of drugs being studied much more closely mirrored in 
the adult population prescribing habits than it did in the 
pediatric. For example, the top three drug categories that were 
granted pediatric exclusivity matched precisely in both 
category and sequence the top three prescribing categories for 
adults and none of the three top-prescribing categories for 
children appeared in the top three for which pediatric 
exclusivity was granted. So we have a clear distortion there.
    So, first, it is not really working as well as some people 
have said, and second, my point is that there are other ways of 
receiving these exact benefits without the kinds of handouts to 
industry that have so far characterized this initiative. And of 
course, the obvious model here is the PREA which has already 
produced 55 labeling changes, all of these of course without 
any need to resort to a patent extension. Recent published 
research shows the exclusivity provisions under the BPCA can be 
absurdly generous. Nine drugs were studied, and for the current 
6-month patent extension, the net economic returns on 
individual drugs were as high as $508 million with a median of 
$134 million. For one drug product with $3.8 billion in sales, 
the economic benefit to the sponsor was 74 times as high as its 
expenses, a 7,400 percent profit margin, and the median was a 
12.4 times net gain for the companies.
    And the costs of this are substantial. As mentioned earlier 
by Ms. Schakowsky, the FDA estimated in 2001 that the total 
value of the 6-month patent extension would be on the order of 
$13.9 billion. Much of this will come out of the pockets of 
consumers but now with Medicare Part D, the Government will be 
footing the bill for its own generosity as well. Unless there 
is a strong reason to believe that pediatric use will be 
minimal, conducting pediatric studies should be seen as the 
responsibility of all companies seeking to market or to 
continue marketing a drug, not an undertaking for which 
companies should be rewarded, let alone as generously as they 
currently are. The FDA should have the authority to compel such 
studies by expanding the provisions of PREA no matter what the 
stage in the drug's lifespan without having to resort to patent 
extensions.
    I mentioned in my written testimony that the pediatric 
testing process is not transparent, and I shan't go into that 
in detail, just to mention briefly that the FDA does not make 
clear when the studies are actually being conducted and when 
they might be completed. There are delays in label changes of 
the order of time that we have heard, and in addition, if you 
think that doctors can instead rely upon published medical 
literature as a substitute while they are waiting for the label 
change to actually take place, that is not the case because in 
many cases, particularly if the result is negative, the 
companies don't bother to publish.
    Let me just make a couple of brief comments on medical 
devices which are general comments but apply in the pediatric 
situation as well. First, the medical device approval standard 
is too low. To receive permission for a device to be approved, 
the standard is that there must be, quote, ``reasonable 
assurance that the device is safe and effective'', a much lower 
standard than for drugs where the standard is ``substantial 
evidence of effectiveness for the claimed conditions.'' So the 
result is we can see, with otherwise equal data, a device being 
approved where a drug would not, and that is potentially 
diverting people from effective drugs to less effective or 
ineffective devices. The vagus nerve stimulator is a good 
example of this, and in that particular case the people from 
the drug division of the FDA told the Senate finance committee 
that had data of that quality been submitted to them, they 
would not even have permitted the filing of a new drug 
application, instead, the device wound up being approved.
    A second problem involves the 510(k) process which in 
effect is a less-than-full pre-market review for most devices 
including most class 3 devices which are the most invasive of 
those class 3 devices. Intended at the time of the enactment of 
the amendments to be the exception rather than the rule, a 
510(k) is now the route to approval for 99 percent of new class 
3 devices. Moreover, a device can be considered substantially 
equivalent under the 510(k) through a predicate device, the 
already approved device, even if it does not have the same 
technological characteristics as the predicate device. A recent 
example of this is something called Repetitive Transcranial 
Magnetic Stimulation, rTMS system, in which even though the 
predicate device, electroshock therapy, electricity, this 
device was considered for approval under 510(k) as being 
substantially equivalent, even though it used magnets. This 
makes no sense at all and makes it far too easy for devices to 
get on the market without proper approval.
    In parallel to the situation under drugs, the medical 
device testing process is also not transparent; and the 
Institute of Medicine's report on that makes it quite clear. 
Quote, ``the most obvious deficits in FDA's performance are the 
lack of effective procedures for monitoring the status of 
required post-market studies and the lack of public information 
regarding such studies.'' In that respect as well, we need to 
see an improvement in transparency.
    That is the end of my comments.
    [The prepared statement of Dr. Lurie follows:]

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    Mr. Pallone. Thank you. I have been letting some of you go 
beyond 2 minutes only because I am interested in what you are 
saying, but we can't be going too long. Let me go next to Ms. 
Belfiore. Thank you.

           STATEMENT OF SUSAN BELFIORE, PRINCETON, NJ

    Ms. Belfiore. Thank you. Mr. Chairman, Ranking Member Deal, 
and distinguished committee members, thank you so much for 
having me here today. I am Susan Belfiore. I am the mother of 
five children. Four of those five children, my husband and I 
adopted from Romania, and they are HIV-positive.
    I am honored to be here today to let you know the 
difference that the pediatric drug legislation has made in our 
lives and why it is so important to continue to test drugs 
specifically for children. This issue is not settled by any 
means, but the progress we are making is because of you. You 
are all true champions for children. I would like to give a 
special thanks to Ms. Eshoo and Mr. Waxman for their 
longstanding leadership on this issue. My children would like 
to be here today. They have lobbied hard to be here today to 
thank you personally, but alas, they have finals.
    I would last like to thank the Elizabeth Glaser Pediatric 
AIDS Foundation for the work they do for children and families. 
Our children are living healthier, better lives because of 
their work.
    I am here today because our family, like so many families 
throughout the country, are dependent on medications to keep 
their children strong and healthy. As you just heard, four of 
our five children have the AIDS virus. Our daughters, Mihaela 
and Loredana, are taking live-sustaining drugs. So clearly this 
is an issue that is close to my heart. As a parent, there is 
nothing more difficult than knowing that your child is sick. 
You can often feel scared and helpless, yet our family believes 
in miracles but miracles cannot happen without the correct 
dosing. Both of these can be achieved only through pediatric 
testing.
    I still remember the first time we put our then 8-year-old 
Mihaela on a cocktail of drugs that was used by many adult AIDS 
patients. We took the medications out of the pill boxes, put it 
in a special box that was decorated with horses. Mihaela loves 
horses, and we had a silly hat party that night at the dining 
table. We wanted to turn the whole event into something that 
was positive instead of focusing on the fact that for the rest 
of her life, Mihaela will be dependent on the latest 
medications to keep her healthy. But the truth is that Loredana 
and thousands of children like them are dependent on the latest 
medications to keep them strong, healthy, and alive. That is 
why the Best Pharmaceuticals for Children Act and the Pediatric 
Research Equity Act are so important. Unless these laws are 
continued, our children won't have a chance. They cannot rely 
on guesswork. We tried that, and I can tell you, it does not 
work.
    This binder here contains my children's medical life for 
the last 14 years. I have cataloged all aspects of their 
health, every 3 months, blood work being done, medications that 
they were taking, any adverse effects to the medication, and 
illnesses.
    Ten years ago we thought Mihaela was taking an effective 
drug regime for HIV. She was not. It turns out she had been 
under medicated because the drug she was taking had not been 
studied sufficiently for use in children. Mihaela's health 
suffered. Her virus increased, and once again, she started to 
pick up opportunistic infections.
    Mihaela had only used this medication for a few years 
before forming a resistance. As a mother, I can tell you 
resistance is a scary word. It means that your child has lost 
access to one drug regime in a very limited supply of options, 
and when options run out, children suffer.
    I recently looked at a picture of Mihaela from 5 years ago 
when we first came to Congress to advocate for the Pediatric 
Research Equity Act. I was shocked when I saw the picture of 
her standing there that day. She was underweight, she had a 
look about her that you might know as being very familiar with 
the AIDS virus, more advanced stages of the AIDS virus. She had 
failure to thrive. When I was in that moment, I didn't realize 
it. I didn't realize it until I went back and I looked at that 
photo.
    In the last 5 years, though, things are very different. For 
the first time, Mihaela is taking medication that was tested 
specifically for use in children. The results have been 
dramatic. Mihaela has grown, she has put on weight, and she is 
free of infections. And for the last 4 years, Mihaela has had 
undetectable virus in her system. She now rides horses more 
than ever before.
    My family's personal struggle is with HIV, but I have to 
point out that the value of these laws goes beyond HIV and my 
individual family. My family and I are here for all parents 
today. You have heard the statistics, about three-quarters of 
all medication has not been tested for use in children. The 
drugs are from everything from asthma, cancer, to HIV and AIDS.
    Now, I understand that testing for drugs for use in 
children is an additional expense for the drug companies. I 
also understand it can be difficult to conduct studies for a 
variety of enrollment issues. That is why BPCA includes an 
incentive for companies to do pediatric studies. The law is 
working well and it should be continued.
    But this issue is not just about profits and bottom line. 
It must be about the value of a child's life. To be honest, I 
wonder why the idea that all medications should be studied for 
use in children should even be a question. As a adults we 
wouldn't take medication that is not tested for us, so why 
would we give it to our children. That is why I strongly 
believe the Pediatric Research Equity Act should be made 
permanent.
    I appeal to you on behalf of my children and millions of 
children like them. Surely we can agree that our children 
deserve nothing less than the same information about safety and 
dosing that we require of ourselves.
    Thank you again for inviting me here today, and on behalf 
of all parents, thank you so much for what you are doing for 
our children. I can tell you personally, it really is making a 
difference.
    [The prepared statement of Ms. Belfiore follows:]

                      Statement of Susan Belfiore

    Mr. Chairman, Ranking Member Deal and distinguished 
committee members. Thank you so much for having me here today. 
I am Susan Belfiore, mother of 5 children, 4 of whom are HIV 
positive. I'm honored to be here today to let you know the 
difference pediatric drug legislation has made in our lives and 
why it's so important that medications continue to be 
specifically tested for use in children.
    This issue is not settled, by any means, but the progress 
we have made is because of you. You are all true champions for 
children.
    I'd also like to thank the Elizabeth Glaser Pediatric AIDS 
Foundation for everything they do for children and families. 
Our children are living healthier lives because of their work.
    I am here today because our family--like so may other 
families throughout the country--is dependent on medications to 
keep our children healthy. As you just heard, four of our five 
children are living with the AIDS virus. Mihaela and Loredana 
are taking life-sustaining medications.
    So clearly, this is an issue that I hold close to my heart. 
As a parent, there is nothing more difficult than knowing your 
child is sick. You can often feel scared and helpless. Our 
family believes in miracles. But miracles won't happen without 
the correct medication and their correct dosing. Both of these 
can be achieved only through pediatric testing.
    I still remember the first time we put our then eight-year-
old daughter Mihaela on a cocktail of drugs used by many AIDS 
patients. We took the medications out of the pill boxes and put 
them into a container decorated with horses. Mihaela loves 
horses. We had a silly hat party at the dining room table. We 
wanted to turn the whole event into something that was 
positive, instead of focusing on the fact that for the rest of 
her life, Mihaela would be dependent on the latest medications 
to keep her healthy.
    But the truth is that Mihaela and Loredana and thousands of 
children like them ARE dependent on the latest medication to 
keep them healthy and strong and alive. And that is why the 
Best Pharmaceuticals for Children Act and the Pediatric 
Research Equity Act are so important. Unless these laws are 
continued, many kids won't have a chance. They cannot afford to 
rely on guesswork. We've tried that, and I can tell you 
personally that it just doesn't work.
    This binder is the story of my children's medical life. For 
the last 14 years, I have cataloged all aspects of their 
health. Charting their blood work every three months, their 
medications, and their reactions to these medications.
    Ten years ago, we thought Mihaela was taking an effective 
drug regime for HIV. She was not. It turns out she had been 
undermedicated because the drug she was taking had not been 
studied sufficiently for use in children. Mihaela's health 
suffered. Her virus increased. Once again, she started to pick 
up opportunistic infections.
    Mihaela had only used this medication for a few years 
before forming a resistance. As a mother, resistance is a very 
scary word because it means your child has lost access to one 
more drug regime, one in a very limited supply of options. And 
when the options run out, children suffer.
    Recently I looked at a picture of Mihaela from 5 years ago 
when we first came to Congress to advocate for the Pediatric 
Research Equity Act to become law. I was shocked when I saw 
Mihaela. She was underweight. She looked sick. When you're in 
the moment, you don't realize it, until you go back.
    In the last five years, though, things have been different. 
For the first time, Mihaela has taken medication that WAS 
tested specifically for use in children. The results have been 
dramatic. Mihaela has grown, put on weight, and has been free 
of infections. And for the last 4 years she has had 
undetectable virus. She now rides horses more than ever.
    My family's personal struggle is with HIV. But I have to 
point out that the value of these laws goes beyond HIV, beyond 
my individual family. My family and I are here for all parents 
and children, not just those living with HIV and AIDS. We've 
all heard the statistic: About three-quarters of prescription 
medications have not been tested for use in children. These are 
drugs for everything from asthma to cancer to HIV and AIDS.
    Now, I understand that testing drugs for use in children is 
an additional expense for drug companies. And I also understand 
that it can be difficult to conduct the studies because of a 
variety of enrollment issues. That's why BPCA includes an 
incentive for companies to do pediatric studies. That law is 
working well and should be continued.
    But this issue cannot just be about profits and the bottom 
line. It must be about the value of a child's life. To be 
honest, I wonder why the idea that all medications should be 
studied for children is even a question. As adults, we wouldn't 
take medications that were not tested for us. So why would we 
give them to our children? And that is why I strongly believe 
that the Pediatric Research Equity Act should be made 
permanent.
    I appeal to you on behalf of my children, and millions of 
other children just as precious and important as they are, to 
reauthorize these laws as soon as possible. Surely we can agree 
that our children deserve nothing less than the same 
information about the safety and dosing of drugs that we demand 
for ourselves as adults.
    Thank you again for inviting me here today. And on behalf 
of all parents, thank you so much for all you do for our 
children. I can tell you personally, you are making a real 
difference.
                              ----------                              

    Mr. Pallone. Thank you so much, and thank you for being 
here today to tell the story. I appreciate it. Mr. Rozynski.

  STATEMENT OF ED ROZYNSKI, VICE PRESIDENT, GLOBAL GOVERNMENT 
                  AFFAIRS, STRYKER CORPORATION

    Mr. Rozynski. Good afternoon, Chairman Pallone, Ranking 
Member Deal, and other members of the subcommittee. Mr. 
Burgess, thank you for your comments.
    Again, my name is Ed Rozynski from the Stryker Corporation. 
As an early supporter of the bill, we sincerely appreciate 
Congressmen Markey and Rogers' leadership role on children's 
issues and this landmark legislation. Like you and your 
colleagues, we want children to have access to the fullest and 
best medical treatments, even if that means doing or inventing 
something new just for them. Stryker is one of the world's 
leading medical technology companies, and is headquartered in 
Kalamazoo, MI. Stryker also has facilities in New Jersey, 
Massachusetts, California, Texas, New Hampshire, and Tennessee. 
Stryker's products are used in over 80 percent of the hip and 
knee replacement procedures performed in the United States. 
Currently our bone healing and bone regeneration technology is 
being used for humanitarian purposes to save the limbs and to 
repair the backs of soldiers at Walter Reed Hospital.
    Stryker's commitment to children is not new. We are the 
leading manufacturer of orthopedic oncology prostheses and 
pediatric-related devices used to treat cranial facial 
deformities such as cleft lip and palate. Soft tissue sarcomas 
and bone cancers represent less than one percent of all adult 
malignancies. However, they represent 15 percent of all 
malignancies in children. Twenty years ago the standard 
treatment for primary malignant bone and soft tissue sarcoma 
was amputation. Since that time, Stryker has developed limb-
sparing solutions including a growing prosthesis that can be 
elongated to account for a child's growth. With respect to 
cranial facial deformities, Stryker partners with medical 
organizations such as Operation Smile, a non-profit 
organization which last year was able to provide free cleft lip 
surgeries to more than 8,000 children in 23 countries, on 
average taking 45 minutes and costing just $242 per child. 
These surgeries have a positive, lasting impact on the lives of 
children and their families.
    It is our sincere hope that this pediatric device 
legislation will encourage the evolution of novel healthcare 
solutions for children. First, the bill authorizes new money to 
create a grant program to promote pediatric device development 
including matchmaking between inventors and manufacturers. 
Second, the bill improves incentives to develop devices for the 
pediatric device market which is very small, and I would want 
to underscore very small with respect to pediatric devices. 
These incentives at least directionally should entice companies 
to think about developing pediatric products that they might 
otherwise have neglected in favor of profitable products 
developed for use in the much larger adult population.
    Third, the bill facilitates the pooling and collection of 
more information about pediatric devices so that information 
and solutions can be easily shared and analyzed within the 
community.
    We are aware of ongoing discussions related to the post-
market surveillance provisions of the bill and hope successful 
resolution will be reached on this issue. This bill has twin 
goals which together must be achieved, number one, bringing 
more pediatric devices to market and number two, improving 
information about pediatric devices. All stakeholders should 
work together to ensure that both goals are achieved.
    In conclusion, Chairman Pallone and members of the 
committee, we applaud you for considering this legislation. We 
look forward to continuing to work with you on refining the 
bill and advocating for its passage into law this year. As 
parents, we say that we give our children the very best. We 
protect them, we try to send them to the best schools, we buy 
them nice clothes and give them the latest gadgets. Therefore, 
we should not allow children's healthcare products to become 
the residual of products that we develop for the big people 
that they look up to. Children deserve our special attention, 
children deserve our very best efforts. At Stryker, we see the 
hope and the benefit that our latest bone implants provide to 
children with cancerous tumors. Unfortunately, many families, 
even those with health insurance, cannot afford to frequently 
take off work or pay the cost to travel with their children, 
their sick child to a faraway hospital. Stryker will soon 
announce a plan to provide charitable assistance to families 
and patients to cover their expenses associated with travel to 
NIH Cancer Care Centers, expenses not covered by health 
insurance. These uncovered expenses often pose a serious 
impediment to a family's ability to provide for their child's 
care and recovery. We believe that Stryker's charitable 
initiative will compliment the advanced technologies for 
children that Stryker already develops. It is our hope that we 
and other medical technologies will be further encouraged to 
develop more pediatric devices as a result of this legislation.
    Again, thank you, Mr. Chairman. I would be pleased to 
answer any questions the committee may have.
    [The prepared statement of Mr. Rozynski follows:]

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    Mr. Pallone. Thank you, Mr. Rozynski. Mr. Lombardi.

 STATEMENT OF DONALD P. LOMBARDI, PRESIDENT AND CEO, INSTITUTE 
                    FOR PEDIATRIC INNOVATION

    Mr. Lombardi. Thank you, Mr. Chairman and committee 
members. While a lot of the testimony has focused on how to 
research, test, and regulate pediatric products, I would like 
also to ask that Congress think about what it can do to 
stimulate the invention and development of products that have 
the special requirements needed for treating children.
    My name is Don Lombardi. I am president and CEO of the 
Institute for Pediatric Innovation, a non-profit organization 
located in Cambridge Massachusetts.
    The challenges that industry faces in getting products 
developed for children are also faced by pediatric hospitals in 
their attempts to commercialize discoveries they make. I was 
the chief intellectual property officer for Children's Hospital 
Boston for 15 years, responsible for managing that 
organization's compliance with the Bayh-Dole Act which focuses 
on the translation of research discoveries to commercial 
products for the benefit of the public. The program was very 
successful. Six products got onto the market, 10 more into 
clinical development through our licensee companies. Twenty-
five new companies were started around our technologies. The 
program brought in tens of millions of dollars of license 
revenues to Children's Hospital.
    The paradox? Very little of these products benefited 
children. Most were based on very early stage biology research, 
and the investors and companies who took on these ideas to 
develop them naturally focused on the largest and easiest to 
access adult markets. My experience at Children's Hospital 
Boston is reflected as well in the experience of the major 
pediatric hospitals everywhere.
    You have heard a lot about the issues of the small market 
size and the challenging regulatory pathways and the fact that 
children aren't small adults. I won't reiterate those issues. I 
would like to add another perspective based on the experience 
in the tech transfer program at an academic institution such as 
these pediatric hospitals. The innovation process focuses on 
researchers, not on clinicians. Clinicians are the ones who 
know what is needed, not the researchers. On the other hand, 
the clinicians generally lack the time and the ability to 
create inventions and develop products. This problem is a 
national-scale problem that needs novel approaches to 
collaborations between the hospitals and industry and between 
these parties and others who can provide pieces of the puzzle 
to develop products.
    I left my job at Children's Hospital Boston a year ago to 
create the Institute for Pediatric Innovation to focus 
exclusively on the practical translation of ideas into products 
for pediatric care.
    Our plan is to form a small consortium of leading pediatric 
centers, and using this consortium as a microcosm of the 
market, carry out a very careful needs analysis to determine 
what products are needed to save lives, improve outcomes, 
reduce costs, increase satisfaction of patients, parents, and 
caregivers. We will then evaluate and set priorities on the 
products based on three criteria, first, which ones will have 
the highest impact; second, of these, which are commercially 
feasible; and third, of these, which can our specific 
consortium members add value both in the product design and the 
clinical testing phase. From these we will select six or seven 
products and develop detailed opportunity analyses of these 
products. We are going to focus initially on three categories 
of products. The first is reformulated drugs. You have heard 
from other testimony about the off-label use of drugs. I have 
learned in an informal survey of five or six pediatric 
hospitals that some 60 percent of the prescriptions written in 
institutions such as these are actually formulated off label by 
the pharmacies in the hospital, which is an enormous of risk 
for patients and institutions themselves. And I know from my 
conversations with these parties that there are somewhere 
between 30 and 50 pharmaceuticals that pediatricians either do 
use or wish to use that are not available in the proper dosage 
and delivery forms.
    The second area is in the re-engineering of medical 
devices. Again, as you have been told, this is not just 
downsizing devices. There are a variety of specific pediatric 
bioengineering issues that need to be addressed in the redesign 
and the re-engineering of these products. These products need 
to adapt to the very different physiology, material 
interactions with the body, impact on the patient's skin and of 
course the very challenging issue of the dynamic nature of both 
the anatomy and the physiology of the child.
    Following this we will undertake what we call product 
imagination, brainstorming sessions that will bring together 
nurses, doctors, engineers and marketing people to imagine and 
develop product concepts for new products. For the new products 
as opposed to the re-engineered and reformulated projects we 
are focusing initially on the needs of neonatal care. This is 
because we have a company which has agreed to fund this 
program. We expect that the practices that we develop for 
developing new products we can also apply in other areas with 
other companies in general pediatric surgery, cardiology, GI, 
and neurosurgery. Finally, I congratulate the committee for its 
work in this area, and my recommendations about legislation are 
included in my handout. Thank you very much.
    [The prepared statement of Mr. Lombardi follows:]

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    Mr. Pallone. Thank you. I know it is an unusually large 
panel today. You can barely sit through it. But thank you for 
your testimony. I appreciate it. We are going to take some 
questions, and I will start with my own questions for 5 
minutes.
    I wanted to ask Dr. Crosse, you noted that drug 
manufacturers accepted 81 percent of FDA's written request to 
complete pediatric studies, and this is with regard to the on-
patent drugs.
    Ms. Crosse. Yes.
    Mr. Pallone. And I am concerned about what happened to the 
other 19 percent of those. As I understand the process, they 
are referred to the Foundation for the National Institutes of 
Health for funding. Would you say that the process of sending 
them to FNIH is working or do you have any recommendations on 
how Congress might improve that part of the process?
    Ms. Crosse. It hasn't been working well because FNIH has 
not been able to raise sufficient private funds to cover the 
expenses of conducting these studies. In the first 4 years that 
this arrangement was underway, they were raising approximately 
$1 million a year. During the 1-year course of our conducting 
our work they raised no additional funds. They had raised a 
total of about $4 million which was insufficient to fund even 
one study. It only covered the cost of about half of the study 
expenses, and NIH stepped in with its own appropriations to 
pick up the remaining expenses for this drug because they felt 
it was so important to be studied.
    We don't have specific recommendations for how this could 
be covered. The arrangement seemed a logical one at the time. 
It still called for private sector funding of the research, 
just as when the companies, the drug sponsors, paid for the 
studies but contributions have not been sufficient to FNIH to 
come anywhere close to filling the gap for these on-patent 
drugs when the drug sponsor declines.
    Mr. Pallone. OK. I am going to ask another money question, 
but I don't want everybody to answer this. But if someone wants 
to volunteer, we have been told by CBO that a continuation of 
the pediatric exclusivity program would score under the budget 
rules and as such a bill of this kind needs to have an 
offsetting tax increase or spending cut. Any of you want to 
recommend how to pay for the extension of the pediatric 
exclusivity program? You don't have to, but if anyone has an 
idea, I would like to hear it. Any volunteers here? Somebody is 
pondering. Dr. Lurie?
    Mr. Lurie. Sure, don't reauthorize it in that sense. I 
mean, don't do it through patent extensions, do it instead 
through mandatory requirements as under PREA. That will save 
them money.
    Mr. Pallone. Well, that was easy, I guess. All right. 
Anyone else? Otherwise I will move on.
    Ms. Belfiore, I really appreciate your being here today 
because your story about your family is truly compelling, and I 
wanted to thank you for sharing that for not only what you said 
and your family but for all the work that you do with the 
Elizabeth Glaser Pediatric AIDS Foundation. I am a parent. I 
have three children, and even as someone who is involved in 
developing these policies I don't think that it occurs to me to 
ask a physician when our children are sick as to whether or not 
the medicines they prescribe have been tested in children. In 
fact, almost three-quarters of the drugs prescribed to kids 
have not been tested as you have said, and I think that is a 
startling statistic; and it is even more startling for children 
who suffer from life-threatening illnesses. Do you know how 
many drugs used for treating HIV/AIDS have currently been 
studied for pediatric use and just comment if you will on that 
because I am concerned in particular with the life-threatening 
illnesses and whether or not BPCA or PREA could have an impact.
    Ms. Belfiore. I do not know the number as to how many have 
been tested, but I do know that through BPCA that six new AIDS 
drugs have been approved for children. I was saddened and also 
happy to see that one of the drugs was the one that my daughter 
Mihaela formed a resistance to because she had not been given 
enough, saddened because she didn't get the use out of that 
drug. It is a very good drug in the adult population. People 
get a long time out of it, and my daughter did not get that 
time out of it.
    But only because of this legislation is it now available 
for use in children. So I compliment what is being done here. 
It really makes a difference.
    Mr. Pallone. Thank you. I wanted to ask Mr. Rozynski. You 
speak of the lifting of the HDE which I guess is Humanitarian 
Device Exemption profit restriction in the Markey-Rogers 
legislation. Is this the most effective or is there any other 
incentives that you would suggest?
    Mr. Rozynski. Well, first, we appreciate the lifting of the 
restrictions so that way you in effect balance the incentives 
that you have in the adult population with those in the 
children's population. We don't have and we are not even 
seeking the concept of extended exclusivity for devices like 
you have for drugs. I am not sure that there is really an easy 
additional incentive that you could provide.
    So therefore, I would say instead to just make sure the 
regulatory hurdles do not change in such a way that there is a 
disincentive to go into the market. Right now I think that 
there is balance in terms of how the FDA regulates this area. 
If the regulatory hurdles go too high, and as I say, we are not 
seeking any significant incentives, what you may end up doing 
is not reaching those twin goals of encouraging more devices, 
while at the same time having adequate information on these 
devices. Now, with regard to information, I would like to say 
that Stryker and other companies are prepared to give away in 
effect the knowledge that we have, the studies that we have, 
and to put them in a public database so that way if we can't 
figure out something in terms of ways to make this better or to 
address areas where perhaps we had some shortcomings, we are 
opening up this information to the public so that others can 
then perhaps use it to develop a better device. So we are 
prepared to open up as part of this legislation the studies 
that we do have and to share them in a public database as a way 
to stimulate more activity in the area of pediatric devices.
    Mr. Pallone. All right. Thank you. Thank you very much, all 
of you. Mr. Deal?
    Mr. Deal. Thank you. We have a variety of opinions here, 
some that say the present system is working OK, others who say 
it needs to be changed. But I think there is one thing that 
most everybody seems to agree with and that is the off-patent 
drugs is an area that we don't have any way to incentivize 
under the current system.
    Dr. Crosse, do you have any suggestions as to how to deal 
with that particular issue? Obviously NIH is having difficulty 
coming up with the funding to do that.
    Ms. Crosse. No, sir, other than providing funds that are 
specifically available for undertaking these studies. I cannot 
see any way to incentivize the generic drug manufacturers to 
undertake the costs of conducting these studies.
    Mr. Deal. OK. We have a smaller market obviously for 
pediatric type applications of medicines. But I assume there 
are some drugs that are exclusively developed and marketed just 
for pediatric patients. Ms. Reilly, do you have any idea of how 
large that is compared with the overall approval of drugs?
    Ms. Reilly. Well, what I can tell you is that there are 
about 200 medicines in development today specifically for 
pediatric populations. So while this pales in comparison to the 
overall number of drugs in development which is somewhere 
around 2,000 drugs in development, there is significant 
progress underway in our companies in terms of looking at 
research for pediatric populations.
    Mr. Deal. And I assume that there are some drugs that from 
the outset there is general acknowledgment that probably would 
never be appropriate for pediatric patients.
    Ms. Reilly. That is true. I mean, obviously there are a 
number of drugs for which young children just don't happen to 
get those diseases. Osteoporosis is one example. But I think 
one thing that we have learned through the BPCA process is that 
for drugs, one drug for example, Tamoxifen, which is a drug to 
treat breast cancer was studied under the pediatric exclusivity 
program and was found to be effective for treatment of a rare 
disease affecting young girls. So I think even in the instances 
where we have drugs that one would assume are only for an adult 
population, oftentimes our companies have done research and 
found that that use is effective for different populations, in 
this case, a rare condition. And that was made available under 
BPCA.
    Mr. Deal. Mr. Lombardi, in your testimony I gathered that 
you were trying to figure out ways to develop this partnership 
between the industry and the pediatric hospitals which 
obviously are a very good incubator in which to either test 
devices or provide further research. You mentioned 
reformulation of drugs.
    Mr. Lombardi. Yes.
    Mr. Deal. Now, I assume you were talking about off-patent 
drugs that are reformulated for more specific purposes. Would 
you elaborate on that and what obstacles do you encounter in 
that environment?
    Mr. Lombardi. Thanks. Yes, we are focusing specifically, 
since we wish to get near-term products available to the 
clinicians, we are focusing specifically on off-patent drugs 
for which a better formulation or delivery method is needed. I 
will give an example. While still at Children's Hospital, we 
had a clinician who treated lead poisoning for 30 years with a 
product that had never been approved for children or for lead 
poisoning, but was long ago approved by the FDA in adults for a 
different use. It comes in a pill this size. It smelled of 
rotten eggs. It is a sulfur compound, and so we needed to find 
a company that would take this compound and reformulate it into 
something palatable, unsmelly, and digestible for children. We 
made an arrangement, what I call a risk sharing arrangement in 
which they would risk and we would share to put the research 
into developing this formulation. They used formulation 
technology that has been used in many other drugs. So we had a 
compound that has a long experience in the clinic with adults 
and 30 years with children, and a formulation technology that 
has been previously used. So the question was how would we 
finance the clinical development of this, and we found an angel 
investor who studied this and realized that he could get the 
product through the clinical stage if things went well for 
between $1 million and $1.5 million. So he formed a small 
virtual company to take the product rights, and he has got his 
first investment now and the project will be developed in the 
clinic; and at the end of this process, he will sell this 
product off to a company that has got a sales force in 
pediatrics.
    Mr. Deal. Would that reformulated product be a patentable 
item in and of itself?
    Mr. Lombardi. Well, the composition is not patentable, but 
the formulation is patentable. It is not a strong patent 
because people can come up with an alternative formulation that 
may accomplish similar results. But it will give this party a 
degree of exclusivity.
    Mr. Deal. Is there anything we can do in that arena that 
would incentivize these reformulations? Is there anything there 
you see either through the patent process or through some 
degree of exclusivity or something because it appears to me 
that more than likely that is where the off-patent is going to 
produce results is in reformulation of some type.
    Mr. Lombardi. I don't have a specific proposal, but I think 
if there is a way of broadening the concept of the orphan 
exclusivity to cover pediatrics for pediatric-specific 
formulations, that would be helpful. Second, another area that 
we worked on was with a different formulation company on a 
different product, and that company applied for, and I 
understand recently was awarded, an SBIR grant from the NIH for 
the development and clinical testing of that product. So 
funding always helps because if the product development phase 
can be accomplished on monies that do not require a return on 
investment, then the calculus for having the product be able to 
sustain itself in the market changes significantly. Thank you.
    Mr. Deal. Thank you.
    Mr. Pallone. Dr. Burgess.
    Mr. Burgess. Thank you, Mr. Lombardi. Mr. Rozynski, it 
seems I guess fortuitous that you are sitting there together at 
the end of the table because Mr. Rozynski, you talked about 
having the ability for having someone to be a matchmaker 
between inventors and manufacturers, and Mr. Lombardi, you are 
talking about stimulating research and development; and I hope 
you two will at least exchange business cards before the 
hearing is over because that does seem like an enormously 
worthwhile activity. But Mr. Rozynski, I wonder if you could 
tell us, from your perspective, are there concerns about the 
legislation we are working on or are there things that we can 
do that will be injurious to going forward with new devices and 
new procedures, and what concerns would those be?
    Mr. Rozynski. Thank you for the question. It is a very 
interesting question which we have thought about quite a bit. I 
would first like to say that we support the legislation. We are 
here to support it, and we want to see its passage. We believe 
that this is an important step forward. So we are not really 
looking to nitpick. But I think about how devices are developed 
in the small populations, I mean, we even have situations where 
we work with one doctor on one child to develop one custom 
device. And so when you look at some of the additional 
regulatory issues that are raised within the bill which would 
require multi-year long studies, we agree with a lot of that, 
but at the same time, we are trying to scratch our heads and 
say what will this do to people who today serve that market and 
want to continue to serve that market, that individual patient, 
that doctor, that small population. Is there is a potential 
regulatory hammer hanging over their head that they may end up 
having all sorts of additional costs and additional studies 
that they are going to have to do? So we are not against it, we 
are just saying this is really a difficult question. But in the 
end, we want to make sure that the net effect of the 
legislation is to get more devices to market and to get more 
information developed. And as I said, we are prepared with 
other companies to open up all of our studies to share the 
information to do the match-making. But we want to make sure 
when we change FDA's current authority, we do not create such 
an imbalance that people are further encouraged to go serve 
those adult populations as opposed to serving those much 
smaller children's populations where the incentives in the end 
really in the area of medical devices are not highly financial. 
You are not going to make a lot of money doing these custom 
devices, doing these small developments. So that is really the 
challenge, tomake sure we address those questions and we get 
the balance right.
    Mr. Burgess. And yet, I mean again, your compelling 
testimony about the treatment of childhood sarcomas, I mean I 
can remember a University of Texas football player at age 18 
played a football game, had a pathologic fracture, and 2 weeks 
later his leg was amputated to save his life. I mean, you have 
now changed that equation forever for the better. And I for one 
am grateful that those things are available as there may indeed 
have been one doctor and one manufacturer working together to 
try to come up with, hey, can we do something better for this 
patient and now we can extrapolate it to still a small but a 
much wider population. So I guess if we can build in the 
flexibility for the most unique situations into the 
legislation, that is certainly something that I am interested 
in trying to do.
    Dr. Gorman, I think you and Dr. Crosse both discussed how 
because of the lack of the data and the research on pediatric 
indications, a lot of the things that you did during your 
practice life are essentially off-label uses of medication; and 
I was an OB/GYN by trade before I came to Congress, so I can 
promise you, I can think of one or two compounds that actually 
stayed approved for use during pregnancy. No one wants that 
liability. We saw what happened to Bendictin 30 years ago, and 
no one is going to take that chance unless it is something 
exclusive to pregnancy like treating premature labor. And yet, 
we hear testimony from Dr. Zerhouni and others at NIH that we 
are embarking on an age of personalized medicine. How do you 
see these studies on the pediatric side working in that 
environment? Will we just develop systems where because we are 
working on personalized medicine, just by its nature we take 
into account the pediatric population and the obstetric 
population, the prenatal population as well as the adult 
population?
    Mr. Gorman. Pediatricians, maybe more than any other group, 
are awaiting the world of personalized medicine where we can 
treat the person with the disease, rather than the disease and 
the person. We have laid the ethical and legislative structure 
for the eventual advancement into all the populations that you 
talked about. Today, NIH is studying vaccines in mothers to 
protect children. So hopefully in your future or your 
children's future as a practicing OB/GYN, there will be more 
and more medications----
    Mr. Burgess. No, they are not going to do that. My 
liability will fix that for us.
    Mr. Gorman. Well, whatever career path they take, they will 
have the ability to have drugs that are studied in their 
population and personalized medicines that are studied in their 
populations. But the framework that these particular pieces of 
legislation have formulated, with all of their small warts but 
major successes at the same time allows other groups of 
specialized populations to see the path to their own successful 
futures.
    Mr. Pallone. I am sorry. We started voting, and there is 
only about 8 minutes left.
    Mr. Burgess. I beg your pardon.
    Mr. Pallone. So I am going to just ask Markey to ask a few 
questions, and then we are going to go over and finish up. 
Thanks.
    Mr. Markey. I thank you, Mr. Chairman, and by the way, I 
thank you for your leadership on this issue and the focused way 
in which you are bringing all of these issues to the attention 
of the Congress and I thank Chairman Dingell as well for his 
comments yesterday on Avandia and the need for FDA reform. I 
agree with him 100 percent that this is one more example why we 
need legislation to reform the drug safety system at the FDA, 
and I was extremely pleased that Chairman Dingell said that he 
plans to address FDA's shortcomings and safety while writing 
legislation to reauthorize PDUFA. I think that is the right 
context for us to do it.
    I have just two quick questions. Dr. Gorman, what has 
happened since 2004 to convince the American Academy of 
Pediatrics that it is important to act now to get the 
legislative changes that is in the Markey-Rogers bill?
    Mr. Gorman. One of the wonderful things about being a 
pediatrician in practice is that you get to see what works and 
doesn't work and then get to modify what doesn't work, 
hopefully with things that are more effective. For 10 years we 
have watched FDAMA and BPCA, but now for 5 years we have 
watched PREA work; and we have seen some things that it does 
very well, and we have seen some things that it doesn't do as 
well as we would like. Some of the BPCA and PREA use slightly 
different standards and slightly different formulations of 
thought on how they approach pediatric labeling. And we think 
they should be unified. We think that the results that are 
generated from studies, both the positive and the negative, 
should be reflected on the labels that the American consumer 
uses when deciding and their practitioners on the safety of the 
drugs.
    Mr. Markey. And why is expanded post-market monitoring 
authority important?
    Mr. Gorman. We think that expanded post-marketing authority 
is important for at least three separate reasons. One is that 
we think that you get more safety data when a drug is being 
used by 2 million people than when it is being used by 300 
people in a clinical trial. So the majority of data is 
presented after a drug is approved. So the safety data is there 
for being mined.
    Mr. Markey. OK.
    Mr. Gorman. Second, there is the possibility that 
pharmaceutical companies promise post-marketing studies that 
then don't get done. And the track record for those being done 
is outlined in the GAO report about how many were promised and 
how many were performed. And third, we think that pediatric 
patients, because they are a clean system, in other words, 
generally they have very few other diseases, that they are a 
system in which you can see safety signals more clearly.
    Mr. Markey. OK. So, Mr. Rozynski, could you tell me why you 
now believe that this Markey-Rogers Pediatric Devices bill 
should pass as well?
    Mr. Rozynski. We are a very early and a very big supporter 
of this bill. We think this bill is a step forward to focus 
attention on the need for more pediatric devices. We do believe 
that there are really twin goals here, of course, which are 
encouraging more pediatric devices and also encouraging the 
development and sharing of pediatric device information. We 
want to make sure that both of those goals work together. I 
know there have been a few questions raised about when and 
where do you collect this additional information. We want to 
provide more information. We also want to make sure that we do 
not request information in a way that we continue to have 
companies migrate towards developing devices for the adult 
population at the expense of the pediatric population. We think 
this bill is a big step in that direction and at the same time, 
we want to make sure that in the end, those twin goals are 
achieved, which is more devices.
    Mr. Markey. I thank you and I also want to clarify that the 
post-marketing provisions in our legislation will give the FDA 
more authority to require monitoring of pediatric devices at 
the Secretary's discretion. It does not require clinical trials 
in the post-market setting. This was a recommendation of the 
Institute of Medicine, and we don't have much time left on the 
roll call.
    Mr. Chairman, again, I thank you for your leadership. I 
thank Mr. Dingell for his comment, and I thank you for your 
indulgence.
    Mr. Pallone. Thank you, Mr. Markey, and thank you all. We 
only have 3 minutes left, but I really do want to thank you all 
for spending the time. As I always say, within the next 10 
days, you may get additional questions from some of us that we 
would ask you to respond to in writing; and obviously, we are 
going to use your testimony as we move forward with 
reauthorizing some of these initiatives. So thank you again, 
and this hearing is now adjourned.
    [Whereupon, at 1:15 p.m., the subcommittee was adjourned.]

                                 
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