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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

COMMITTEE ON ENERGY AND COMMERCE

JOHN D. DINGELL, Michigan, Chairman

HENRY A. WAXMAN, California

EDWARD J. MARKEY, Massachusetts

RICK BOUCHER, Virginia

EDOLPHUS TOWNS, New York

FRANK PALLONE, JR., New Jersey

BART GORDON, Tennessee

BOBBY L. RUSH, Illinois

ANNA G. ESHOO, California

BART STUPAK, Michigan

ELIOT L. ENGEL, New York

ALBERT R. WYNN, Maryland

GENE GREEN, Texas

DIANA DEGETTE, Colorado

Vice Chairman

LOIS CAPPS, California

MIKE DOYLE, Pennsylvania

JANE HARMAN, California

TOM ALLEN, Maine

JAN SCHAKOWSKY, Illinois

HILDA L. SOLIS, California

CHARLES A. GONZALEZ, Texas

JAY INSLEE, Washington

TAMMY BALDWIN, Wisconsin

MIKE ROSS, Arkansas

DARLENE HOOLEY, Oregon

ANTHONY D. WEINER, New York

JIM MATHESON, Utah

G.K. BUTTERFIELD, North Carolina

CHARLIE MELANCON, Louisiana

JOHN BARROW, Georgia

BARON P. HILL, Indiana

JOE BARTON, Texas

Ranking Member

RALPH M. HALL, Texas

J. DENNIS HASTERT, Illinois

FRED UPTON, Michigan

CLIFF STEARNS, Florida

NATHAN DEAL, Georgia

ED WHITFIELD, Kentucky

BARBARA CUBIN, Wyoming

JOHN SHIMKUS, Illinois

HEATHER WILSON, New Mexico

JOHN B. SHADEGG, Arizona

CHARLES W. ‘‘CHIP’’ PICKERING,

Mississippi

VITO FOSSELLA, New York

STEVE BUYER, Indiana

GEORGE RADANOVICH, California

JOSEPH R. PITTS, Pennsylvania

MARY BONO, California

GREG WALDEN, Oregon

LEE TERRY, Nebraska

MIKE FERGUSON, New Jersey

MIKE ROGERS, Michigan

SUE WILKINS MYRICK, North Carolina

JOHN SULLIVAN, Oklahoma

TIM MURPHY, Pennsylvania

MICHAEL C. BURGESS, Texas

MARSHA BLACKBURN, Tennessee

PROFESSIONAL STAFF

DENNIS B. FITZGIBBONS, Chief of Staff

GREGG A. ROTHSCHILD, Chief Counsel

SHARON E. DAVIS, Chief Clerk

BUD ALBRIGHT, Minority Staff Director

(II)

(III)

SUBCOMMITTEE ON HEALTH

FRANK PALLONE, JR., New Jersey, Chairman

HENRY A. WAXMAN, California

EDOLPHUS TOWNS, New York

BART GORDON, Tennessee

ANNA G. ESHOO, California

GENE GREEN, Texas

Vice Chairman

DIANA DEGETTE, Colorado

LOIS CAPPS, California

TOM ALLEN, Maine

TAMMY BALDWIN, Wisconsin

ELIOT L. ENGEL, New York

JAN SCHAKOWSKY, Illinois

HILDA L. SOLIS, California

MIKE ROSS, Arkansas

DARLENE HOOLEY, Oregon

ANTHONY D. WEINER, New York

JIM MATHESON, Utah

JOHN D. DINGELL, Michigan (ex officio)

NATHAN DEAL, Georgia,

Ranking Member

RALPH M. HALL, Texas

BARBARA CUBIN, Wyoming

HEATHER WILSON, New Mexico

JOHN B. SHADEGG, Arizona

STEVE BUYER, Indiana

JOSEPH R. PITTS, Pennsylvania

MIKE FERGUSON, New Jersey

MIKE ROGERS, Michigan

SUE WILKINS MYRICK, North Carolina

JOHN SULLIVAN, Oklahoma

TIM MURPHY, Pennsylvania

MICHAEL C. BURGESS, Texas

MARSHA BLACKBURN, Tennessee

JOE BARTON, Texas (ex officio)

(V)

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

(1)

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

2

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.

3

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

4

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 bigselling 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

5

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

6

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

7

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 offlabel 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 excluVerDate 11-SEP-98 15:17 Oct 06, 2008 Jkt 000000 PO 00000 Frm 00012 Fmt 6633 Sfmt 6633 Q:\DOCS\110-49 SCOM1 PsN: SCOM1
8

sivity, 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

9

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

10

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

11

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 offpatent 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:]

12

13

14

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

15

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.

16

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

17

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:]

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

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

35

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.

36

[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.

37

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

38

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

39

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

40

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.

41

Mr. DEAL. Dr. Mattison, let me ask you with regard to your offpatent 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 offpatent; 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?

42

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.

43

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,

44

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

45

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.

46

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?

47

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?

48

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 setup 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

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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

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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 onpatent 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,

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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.

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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

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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

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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.

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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 eightfold. 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

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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

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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 genVerDate 11-SEP-98 15:17 Oct 06, 2008 Jkt 000000 PO 00000 Frm 00096 Fmt 6633 Sfmt 6633 Q:\DOCS\110-49 SCOM1 PsN: SCOM1
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erated 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

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ent 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

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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

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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 chilVerDate 11-SEP-98 15:17 Oct 06, 2008 Jkt 000000 PO 00000 Frm 00134 Fmt 6633 Sfmt 6633 Q:\DOCS\110-49 SCOM1 PsN: SCOM1
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dren, 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.

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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

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ucts 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 BayhDole 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

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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

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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.

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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

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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?

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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

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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

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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 postmarketing 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.

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[Whereupon, at 1:15 p.m., the subcommittee was adjourned.]

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