99–010

Calendar No. 184

107TH CONGRESS REPORT

1st Session " ! SENATE 107–79

BEST PHARMACEUTICALS FOR CHILDREN ACT

OCTOBER 4, 2001.—Ordered to be printed

Mr. KENNEDY, from the Committee on Health, Education, Labor,

and Pensions, submitted the following

REPORT

[To accompany S. 838]

The Committee on Health, Education, Labor, and Pensions, to

which was referred the bill (S. 838) to amend the Federal Food,

Drug, and Cosmetic Act to improve the safety and efficacy of pharmaceuticals for children, having considered the same, reports favorably thereon with an amendment and recommends that the bill (as

amended) do pass.

CONTENTS

Page

I. Purpose and summary of the bill ................................................................. 1

II. Background and need for the legislation ..................................................... 3

III. Legislative history and committee action .................................................... 5

IV. Explanation of legislation and committee views ......................................... 7

V. Cost estimate .................................................................................................. 11

VI. Application of law to the legislative branch ................................................ 11

VII. Regulatory impact statement ........................................................................ 11

VIII. Section-by-section analysis ............................................................................ 12

IX. Changes in existing law ................................................................................ 14

I. PURPOSE AND SUMMARY OF THE BILL

To address a longstanding concern that only 20 percent of prescription medications on the market have been tested and approved

for use in children, Congress enacted a market incentive law, commonly referred to as the ‘‘pediatric exclusivity’’ or ‘‘pediatric testing’’ incentive, as part of the Food and Drug Administration Modernization Act of 1997 (FDAMA Pub. L. 105–115). By providing 6

months of additional market exclusivity on a drug for a holder of

an approved application under section 505(b)(1) of the Federal

Food, Drug, and Cosmetic Act (FFDCA) that has completed pediatric studies of the drug when requested by the Food and Drug AdVerDate 11-MAY-2000 06:36 Oct 06, 2001 Jkt 099010 PO 00000 Frm 00001 Fmt 6659 Sfmt 6602 E:\HR\OC\SR079.XXX pfrm11 PsN: SR079
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ministration (FDA), Congress sought to find an approach that

would be more successful than previous efforts to have the pharmaceutical industry study the safety and effectiveness in children of

drugs that, without such studies, would be prescribed ‘‘off-label’’ to

children.

The Best Pharmaceuticals for Children Act, S. 838, is designed

to continue the successes of and improve upon the current pediatric

exclusivity law in generating studies of medicines for children.

Drug companies have studied several drugs in children and those

drugs now carry appropriate pediatric labeling because of the

FDAMA pediatric exclusivity provision. It remains the case, however, that drug manufacturers have tested only 25 percent of medicines in children, and so FDA has approved only that small percentage of today’s drugs for use in children. The FDA, the General

Accounting office (GAO), and others have issued reports describing

how highly effective the pediatric exclusivity law has been in generating pediatric studies and useful new labeling information. They

have also, however, expressed concerns about areas that need to be

improved. This legislation seeks to stimulate additional pediatric

testing and to provide for the testing of off-patent medicines for

children, for timely labeling changes, and for testing in neonates so

that they also benefit from additional studies and labeling information.

1. THE LEGISLATION AUTHORIZES THE TESTING OF DRUGS LACKING

PATENT OR OTHER EXCLUSIVITY PROTECTIONS

The current pediatric testing incentive was not designed to stimulate pediatric studies for medicines that lack patent terms or

other market exclusivities because there is no patent or other exclusivity on the drug to which to attach a 6-month period of additional market exclusivity. An FDA analysis of 1994 data found that

6 of 10 drugs most commonly prescribed for children were off-patent. This legislation creates an off-patent research fund to provide

for studies of such drugs by pediatric pharmacology research units

(PPRUs) or other entities, after the manufacturers of the drug have

declined a right of first refusal to conduct the studies of the drug.

2. THE LEGISLATION PROVIDES FOR TIMELY LABELING CHANGES FOR

DRUGS THAT ARE GRANTED EXCLUSIVITY AND THAT ARE STUDIED

THROUGH THE OFF-PATENT RESEARCH FUND

The Prescription Drug User Fee Act (PDUFA), as amended by

FDAMA, exempts supplements for a new indication for use in pediatric populations from the user fee that must ordinarily accompany

filings with FDA. This provision has meant that manufacturers

have not paid user fees when they submit their reports of studies

in response to a request from FDA for pediatric studies, as such reports are submitted in the form of supplements to their new drug

applications. This legislation removes this exemption by requiring

companies to pay PDUFA fees at the time they submit pediatric

supplements with reports of their completed studies to the FDA. It

thereby helps ensure that FDA will have sufficient resources to review pediatric labeling supplements as ‘‘priority supplements.’’ The legislation also provides a procedure for timely labeling of

branded drugs granted pediatric exclusivity and for drugs tested

under the off-patent research fund. If a manufacturer refuses to

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make labeling changes requested by FDA, the agency must refer

the issue to its Pediatric Advisory subcommittee of the Anti-Infective Drugs Advisory Committee, which then makes a recommendation to the agency about a labeling change. After considering this

recommendation, FDA may request an appropriate labeling change

and, if the company refuses to make the requested change, the

FDA may deem the company’s drug to be misbranded.

3. THE LEGISLATION CLARIFIES THAT WRITTEN REQUESTS FOR

PEDIATRIC STUDIES MAY INCLUDE NEONATES WHEN APPROPRIATE

The legislation clarifies that written requests for pediatric testing my include neonates (newborns to 1 month old) in all appropriate cases.

4. THE LEGISLATION PROVIDES FOR THE PUBLIC DISSEMINATION OF

PEDIATRIC TEST INFORMATION BEFORE LABELING CHANGES ARE MADE

The legislation requires the FDA to make public a summary of

the medical and clinical pharmacology reviews of the pediatric

studies, except that confidential commercial information or trade

secrets contained in the pediatric supplement would not be disclosed.

5. THE LEGISLATION PROVIDES FOR THE INSTITUTE OF MEDICINE TO

REVIEW FEDERAL REGULATIONS, REPORTS AND RESEARCH INVOLV- ING CHILDREN

The legislation recognizes the need to review current legal and

ethical safeguards for children involved in clinical research and

provides for a study of this matter by the Institute of Medicine

(IOM). The IOM, with the involvement of pediatric experts, must

complete its review and report to Congress with recommendations

in 2 years.

II. BACKGROUND AND NEED FOR THE LEGISLATION

Although children suffer from many of the same diseases as

adults and are often treated with the same medicines, the pharmaceutical industry has studied and labeled for use in children only

about 25 percent of today’s medicines. Dosing children based merely on their lower weight is often imprecise, since their bodies can

metabolize medicines differently than adults. Some drugs may have

different adverse side effects or toxicities in children than in

adults, so estimating dosages for children from dosages found to be

safe and effective in adults may not be appropriate. The lack of pediatric studies and labeling information may lead to unintended

medical errors and place children at risk of being under-dosed or

over-dosed with medication. The lack of age-appropriate formulations (e.g., liquid form) can also make it difficult to give children

and infants prescribed amounts of a needed medication.

Before 1997, regulatory efforts to address the lack of pediatric

studies and insufficient labeling information had been largely unsuccessful. In 1979, the FDA first issued a rule requiring specific

pediatric indications, if any, to be described under the ‘‘Indications

and Usage’’ section of the label, with pediatric dose information included in the ‘‘Dosage and Administration’’ section. The rule also

required that recommendations for pediatric use must be based on

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data from adequate and well-controlled studies in the pediatric

population. The 1979 rule did not successfully encourage the pharmaceutical industry to conduct pediatric studies and appropriately

label their products for children. Accordingly, in 1994, the FDA

published a final rule requiring drug manufacturers to survey existing data and to determine whether it would support pediatric labeling, and if it did, to file a supplemental new drug application.

FDA’s December 1994 Pediatric Plan sought to encourage the pharmaceutical industry to develop voluntarily pediatric data both during the drug development process and after marketing. Neither of

these 1994 initiatives increased substantially the number of drugs

with adequate pediatric labeling.

Senators Dodd and Kassebaum first introduced the Better Pharmaceuticals for Children Act in the 102nd Congress, and it was reintroduced in each subsequent Congress until it was enacted in

1997 as part of FDAMA. In the 1997 report on the legislation, the

committee stated, ‘‘there is little incentive for drug sponsors to perform studies for medications which they intend to market primarily

for adults and whose use in children is expected to generate little

additional revenue. Pediatric studies pose ethical and moral issues

relating to using new unapproved drugs in young patients. Second,

there are substantial produce liability and medical malpractice

issues. Third, pediatric patients are more difficult to attract into

studies. Fourth, the some drugs, pediatric use represents more difficult issues of drug administration and patient compliance than

adult use.’’

Accordingly, the pediatric exclusivity provision enacted by congress in 1997 provides a market incentive of 6 months of additional

exclusive sales to drug companies for studies of medicines in children. Also in 1997, FDA proposed its Pediatric rule, which it finalized in 1998, and which became effective only 1999. That rule requires the manufacturers of certain new and marketed drugs and

biological products to provide adequate labeling for the use of the

products in children. The rule is both broader and narrower than

the pediatric exclusivity provision enacted by congress in 1997.

When their scopes overlap, Congress provided that pediatric studies required under the rule could also satisfy the requirements for

market exclusivity.

The incentive provided by 6 months of market exclusivity has

successfully encouraged drug companies to respond affirmatively to

most of FDA’s requests for pediatric studies. Yet the incentive varies widely from drug to drug. For example, nearly three quarters,

or 27, of the first 37 drugs granted exclusivity would have sales in

6 months of less than $150 million, based on 2000 sales data. The

remaining 10 of those 37 drugs, by contrast, had sales in 6 months

over $200 million, and 1 of those had sales in 6 months exceeding

$2 billion, a second had sales exceeding $1.2 billion, and 2 had

sales exceeding $800 million.

Because of pediatric exclusivity, FDA had granted 37 drugs pediatric exclusivity as of September 7, 2001. The results of the pediatric studies have provided new and useful information for use of

these medicines in children, 19 of which have been relabeled to include pediatric information. As of August 6, 2001, FDA had issued

196 written requests for more than 422 studies of drugs for antiVerDate 11-MAY-2000 06:36 Oct 06, 2001 Jkt 099010 PO 00000 Frm 00004 Fmt 6659 Sfmt 6602 E:\HR\OC\SR079.XXX pfrm11 PsN: SR079
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inflammatory, cardiovascular, anti-viral, oncology, neurology, and

endocrine, among other, diseases and conditions.

In its January 2001 Status Report to Congress on the pediatric

exclusivity provision, the FDA wrote:

The pediatric exclusivity provision has done more to generate clinical studies and useful prescribing information

for the pediatric population than any other regulatory or

legislative process to date. * * * As a result of the pediatric exclusivity provision and FDA’s filing requirement

that study reports be submitted in a manner which will result in labeling information for children, critical drugs

used to treat a variety of conditions (e.g., gastro intestinal

reflux disease, diabetes mellitus, pain, asthma, hypertension) have or soon will have pediatric use information

in their labeling.

The GAO Director for Health Care, Janet Heinrich, testified at

the committee’s May 8, 2001, hearing that, ‘‘[s]ince enactment of

the pediatric exclusivity provision, both the numbers of drugs studied in children and the therapeutic classes they represent have

substantially increased. Hundreds of studies are being done on

drugs that are important to pediatric patients.’’ The pediatric exclusivity law has provided for pediatric research on different medicines in the same therapeutic class because it is important that

children have a choice of medicines, as do adults, because some

children may only tolerate 1 drug in a therapeutic class.

At a time when the infrastructure is now in place to accommodate the increasing pediatric studies, many pediatric experts are

concerned about the January 1, 2002, sunset date in the current

law. During the May 8, 2001, committee hearing, the GAO stated

that, ‘‘Experts agree that, since FDAMA, there also has been significant growth in the infrastructure necessary to conduct pediatric

studies. For example, NICHD [National Institute of Child Health

and Development] has expanded the number of PPRUs from 7 to

13. * * * Prior to FDAMA, the PPRU Network had conducted 17

studies for drug sponsors. By 2000, the PPRUs were conducting 73

pediatric drug studies for drug sponsors. The pharmaceutical industry also has increased its capacity to conduct pediatric studies

since enactment of FDAMA.’’ This strong infrastructure for conducting pediatric studies will help to ensure the continuing success

of this law, which has seen the study of a wide range of drugs in

many therapeutic areas.

III. LEGISLATIVE HISTORY AND COMMITTEE ACTION

On May 7, 2001, Senators Dodd and DeWine introduced S. 838,

the ‘‘Best Pharmaceuticals for Children Act.’’ On May 8, 2001, the

committee held a hearing entitled ‘‘Better Pharmaceuticals for

Children: Assessment and Opportunities.’’ In the hearing, the committee examined how the 1997 pediatric exclusivity law has worked

and how it could be improved, so as to determine whether and how

the provision should be reauthorized.

On August 1, 2001, the committee held an executive session to

consider S. 838. Senators Dodd and DeWine offered an amendment

in the nature of a substitute that the committee considered as

original text for purposes of further amendment. Senators Dodd,

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Kennedy, and DeWine offered an amendment that the committee

accepted without objection. Also without objection, the committee

directed that technical and conforming changes be made. The committee approved S. 838, as amended, by voice vote.

A. Amendment Adopted Without Objection During Executive Session

The committee adopted 1 amendment without objection.

1. Senator Dodd offered an amendment for himself, Senators

Kennedy and DeWine that clarifies the interaction of pediatric

market exclusivity under this provision and the market exclusivity

awarded to an applicant for approval of a drug under section 505(j)

of the FFDCA. Under the 1997 pediatric exclusivity law, Congress

created a 6-month market incentive for a holder of an approved application under section 505(b)(1) of the FFDCA to conduct pediatric

studies of a drug FDA’s request, thereby rewarding companies that

invest resources to test medicines for children. Under the 1984

Waxman-Hatch Act, Congress created a 6-month period of market

exclusivity (‘‘ANDA exclusivity’’) for the first applicant for approval

of a drug under section 505(j) of the FFDCA to challenge a patent

on that drug, during which FDA may not approve subsequent abbreviated applications for the drug; this incentive rewards the first

filer of an abbreviated application that pursues the risk and expense of challenging a patent.

When Congress passed the pediatric exclusivity provision in

1997, it had not meant to change the incentives for challenging

patents under the Waxman-Hatch Act by reducing periods of

ANDA exclusivity. The committee has since learned, however, that

in some instances, pediatric exclusivity on a drug may run over all

or a portion of the 180 days of ANDA exclusivity for the first applicant to challenge a patent on that drug.

The amendment clarifies how a period of ANDA exclusivity on a

drug is to be extended when a pediatric exclusivity period on the

drug overlaps with it. When there is overlap and the period of

ANDA exclusivity expires after the period of pediatric exclusivity,

the period of ANDA exclusivity is extended by the length of the

overlap. When there is overlap and the period of ANDA exclusivity

expires during the period of pediatric exclusivity, the period of

ANDA exclusivity is extended by six months. The amendment gives

the filer of an abbreviated drug application who challenges a patent no more and no less time to market his drug exclusively before

subsequent abbreviated applications for the drug may be approved

then it would have received but for the intervening period of pediatric exclusivity.

For example, the committee understands there may be instances

in which 2 patents on a drug are challenged in an abbreviated new

drug application, and that, in subsequent litigation, a court holds

the first patent to expire to be valid and infringed, and the second

patent to expire to be invalid. If the section 505(b)(1) drug is granted a period of pediatric exclusivity with respect to the first patent,

and if the court decision, which triggers the beginning of the ANDA

exclusivity, falls 60 days before that period of pediatric exclusivity

begins (that is, 60 days before the first patent will expire), the

ANDA exclusivity will overlap with the pediatric exclusivity for 120

days. In the absence of pediatric exclusivity, the holder of the abVerDate 11-MAY-2000 06:36 Oct 06, 2001 Jkt 099010 PO 00000 Frm 00006 Fmt 6659 Sfmt 6602 E:\HR\OC\SR079.XXX pfrm11 PsN: SR079
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breviated drug application would enjoy at most 120 days to market

its drug before a subsequent abbreviated application for the drug

could be approved. But for the amendment, because of pediatric exclusivity, the holder of the abbreviated drug application would

enjoy no ANDA exclusivity, because the first 120 days of the pediatric exclusivity period would run over the last 120 days of its

ANDA exclusivity. The amendment adds 6 months to the ANDA

exclusivity period, so that the manufacturer of the section 505(j)

drug would enjoy 120 days of ANDA exclusivity after the period of

pediatric exclusivity expires.

B. Five Amendments Offered and Subsequently Withdrawn

1. Senator Clinton offered and then withdrew an amendment to

establish a council on pediatric cancer therapeutics to identify,

evaluate, and prioritize new and promising oncology drugs for use

in children, and to require manufacturers to include in an application for study of a new drug their intent for pediatric studies of the

drug and their procedures for individual access to the drug.

2. Senator Bond offered and then withdrew an amendment to

provide an additional 3 months of exclusivity when a company does

studies of a drug in a pediatric population not studied under the

first request for pediatric studies.

3. Senator Clinton offered and then withdrew an amendment to

provide that, when a manufacturer does not accept a written request from FDA to study a drug, the drug could be studied under

the process for studying off-patent drugs provided for in S. 838.

4. Senator Clinton offered and then withdrew an amendment to

provide that drugs that have annual sales of $800 million or more

would receive 3 months rather than 6 months of pediatric exclusivity.

5. Senator Kennedy offered and then withdrew an amendment to

require pediatric testing of new drugs for their approved uses in

adults.

IV. EXPLANATION OF THE LEGISLATION AND COMMITTEE VIEWS

Priority lists of drugs to be studied

The FDA recommended that the requirement that the Secretary

create and maintain a priority list of drugs to be studied for their

pediatric use in children be eliminated. Development of the list was

resource intensive, and diverted resources from other needed work

on pediatric drugs. The list also did little to prioritize effectively

which drugs should be studied in children. Finally, the priority list

created the mistaken impression on the part of some drug manufacturers that only those drugs on the list could qualify for the pediatric incentive. Accordingly, the legislation has eliminated the

list.

At the same time, the legislation establishes a process and standard by which the National Institutes of Health (NIH) and FDA are

to prioritize the study of drugs that lack patents or other market

exclusivity protections. The committee expects that this process

and standard for the prioritization of drugs will produce a useful

priority list for the study of such drugs. These drugs will be studied

using limited Federal funds, and the committee believes that these

funds can be used most efficiently to study drugs that will provide

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significant benefit to significant numbers of children. The committee intends the standards in the legislation to guide the

prioritization process, so that a rational plan for the study of offpatent drugs will emerge.

Fund and process for study of drugs lacking patents and other market exclusivities

The 1997 pediatric exclusivity law makes no provision for the

study of drugs lacking patent and other market exclusivity protections, as such drugs lack any market exclusivity to which the 6-

month period of pediatric exclusivity may attach. This legislation

therefore addresses concerns raised by the FDA, GAO, and pediatric groups about the urgent need for pediatric studies of such

drugs. Data from 1994 showed that 6 of 10 drugs most commonly

prescribed for children lacked patent terms. By creating an off-patent research fund, this legislation creates a mechanism for the Secretary to contract with PPRUs and other entities that have expertise to conduct pediatric clinical trials (universities, hospitals, and,

other public or private institutions) for studies of an off-patent

drug. Under this provision, the companies that market the drug

would be offered the right of first refusal to conduct and fund the

studies and, if the companies do not respond within 30 days, they

would not be eligible to receive funds from the off-patent research

fund to conduct the study. Only the entity awarded a contract by

the Secretary to perform the study of the off-patent drug would

have access to public funds in the off-patent research fund.

Under sections 505(c)(3)(D)(iii) and (iv) and 505(j)(5)(D)(iii) and

(iv) of the FFDCA, a company is eligible for three-year WaxmanHatch exclusivity only if it submits a new drug application (NDA)

to FDA containing reports of new clinical investigations that are

essential to approval of the application and that are conducted or

sponsored by the applicant. By regulation, FDA has required that

a study is ‘‘conducted or sponsored by’’ a company if (1) the company is the sponsor named in the IND for the study submitted to

FDA (i.e., the company conducts the study), or (2) the company provides 50 percent or more of the cost of conducting the study. 21

CFR 314.50(j)(4)(iii). Accordingly, if a company declines to conduct

or sponsor studies of an off-patent drug and another entity (such

as a PPRU) conducts the studies, it is the committee’s understanding that the company would not be able to benefit from an additional 3 years of Hatch-Waxman exclusivity. If the Secretary

agrees with an off-patent study that shows that a formulation

change is necessary, the legislation requires that the Secretary

send a nonbinding letter recommending such formulation change to

each holder of an approved application for the drug.

Timely labeling of drugs granted exclusivity and of off-patent drugs

The committee understands that some drug companies have been

reluctant to relabel their products once pediatric studies are complete when the information from the study is adverse. The committee believes that all useful and appropriate information on the

safety and effectiveness of a drug in children should appear in drug

labeling, and that this information should appear in the drug label

as soon as possible. Pediatricians and parents must have timely acVerDate 11-MAY-2000 06:36 Oct 06, 2001 Jkt 099010 PO 00000 Frm 00008 Fmt 6659 Sfmt 6602 E:\HR\OC\SR079.XXX pfrm11 PsN: SR079
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cess to all appropriate information when they are deciding whether

and how to give a drug to a child.

Accordingly, the legislation provides a process by which FDA can

seek labeling changes to drugs granted pediatric exclusivity and to

of off-patient drugs studied under the off-patent research fund. The

committee intends the process to be a reasonably quick and open

process, after which the government could initiate an enforcement

action to require relabeling of the drug. The process requires referral to the Pediatric Advisory Subcommittee of the Anti-Infective

Drugs Advisory Committee after a company has refused an FDA

request to relabel a product. The FDA then makes a second request

for a labeling change after considering the recommendation of the

Pediatric Advisory Subcommittee and, if the company refuses to

relabel its drug, the FDA can deem the drug to be misbranded.

The committee expects that, generally, the government would

rely on the injunction provisions of the FFDCA to seek an order

from the court for the company to label its product with appropriate pediatric labeling, not seizure or criminal provisions. The

committee does not believe that the government should routinely

seek an order enjoining the company from marketing what is a safe

and effective drug for use in adults merely because it may lack appropriate pediatric labeling.

The committee believes that the government would make its case

that a company’s drug is misbranded before the court by showing

that FDA made an initial request for relabeling that the company

refuse, that FDA referred the issue of the Pediatric Advisory Subcommittee, which reviewed the matter and made a recommendation about a labeling change to FDA, that FDA made a second request for a labeling change, which the company refused, and that

FDA’s second requested labeling change was appropriate because

without the change the drug would lack adequate directions for use

in children.

The committee expects this Pediatric Advisory process to be an

open one, in that, in accordance with existing law and FDA policies

and procedures, materials provided to the Pediatric Advisory Subcommittee will be made available to the public, including by posting the material on the FDA’s website. All disclosures of information are subject to the Freedom of Information Act and the Trade

Secrets Act. The committee understands that current FDA guidance on the disclosure of information provided to an advisory committee can be found in the following FDA Guidance Documents:

‘‘Disclosure of Materials Provided to Advisory Committee in Connection with Open Advisory Committees Convened by the Center

for Drug Evaluation and Research Beginning on January 1, 2000’’

(Nov. 1999), and ‘‘Disclosing Information Provided to Advisory

Committees in Connection with Open Advisory Committee Meetings Related to the Testing or Approval of New Drugs and Convened by the Center for Drug Evaluation and Research, Beginning

on January 1, 2000’’ (Dec. 1999).

As an additional means to provide for timely pediatric labeling

changes on drugs, the legislation removes the exemption for pediatric indication supplements in PDUFA that excludes companies

that perform pediatric drug studies at FDA’s request from paying

a user fee. By requiring that drug companies pay PDUFA fees

when they submit their completed studies as supplements to the

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FDA, the committee expects that FDA will have sufficient resources to review pediatric labeling supplements quickly as ‘‘priority supplements,’’ and that pediatric labeling changes can be

made as quickly as possible.

Pediatric expertise at FDA

The committee is aware that the incentives created by the pediatric exclusivity provision have encouraged the drug industry to develop and expand its infrastructure and expertise in the study of

drugs in pediatrics. The committee intends that both the payment

of user fees for the review of pediatric labeling supplements and

the establishment of an Office of Pediatric Therapeutics at FDA

will facilities similar gains in coordinated expertise and infrastructure at FDA.

Pediatric studies in neonates

The committee understands that, at times, FDA has awarded pediatric exclusivity without requesting studies in neonates

(newborns less than a month old), often because study in neonates

must follow studies in older children for scientific, medical, or ethical reasons. This practice recognizes that neonates are an especially vulnerable population and should be tested only with the

highest regard for their safe and ethical treatment. For the same

reasons, however, it is important that drugs be studied in neonates

whenever appropriate; otherwise, any use in neonates will be

unguided by the knowledge that could be appropriately gained in

high quality clinical trials using neonates. The legislation therefore

emphasizes that neonate testing should be included in a written request by FDA in appropriate cases.

The committee is not mandating that neonate studies be done.

Nor does the committee intend this change to mean that neonate

testing should be performed prematurely. However, it does intend

that FDA will have broad discretion to structure its requests for

pediatric trials so as to protect children and enhance the value of

the information obtained through pediatric studies. For example,

the committee intends that, if FDA concludes that it would be appropriate to conduct neonatal studies after it has had the opportunity to examine data from studies in older children, FDA may,

in 1 written request for pediatric studies, request the submission

of a report from studies in older children, to be followed by studies

in younger children and neonates if the data from the earlier studies may allow appropriate studies in the younger children.

Dissemination of pediatric information

The committee believes that public dissemination of information

about pediatric drug studies will facilitate improved understanding

and use of drugs in children. The legislation accomplishes this goal

by requiring that, subject to the Freedom of Information Act and

the Trade Secrets Act, the FDA make public a summary of the

medical and clinical pharmacology reviews of the pediatric studies,

including by publication in the Federal Register. Confidential commercial information or trade secrets contained in the pediatric supplement could not be disclosed and would have to be redacted from

any information released to the public.

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Study of research involving children

The pediatric exclusivity provision has increased significantly the

number of drug studies conducted in children. This increase, coupled with reports of unrelated incidents that have raised concern

about human subject protection, has led some to request a thorough examination of safety and ethical controls on pediatric studies. The committee shares the concern that the ethical conduct of

pediatric research and the safety of children be paramount. The

legislation therefore requires that the IOM conduct a 2-year study

of Federal regulations and reports to assess the adequacy of current legal and ethical safeguards. The committee expects the IOM

to conduct an independent review and to consider a number of options to improve current legal and ethical safeguards, including

those proposed in the May 2001 review by the Department of

Health and Human Services mandated in the Children’s Health

Act of 2000 (P.L. 106–310).

V. COST ESTIMATE

Due to time constraints the Congressional Budget Office estimate

was not included in the report. When received by the committee,

it will appear in the Congressional Record at a later time.

VI. APPLICATION OF LAW TO THE LEGISLATIVE BRANCH

The Best Pharmaceuticals for Children Act reauthorizes and

amends the section 505A of the Federal Food, Drug, and Cosmetic

Act to further improve the safety and efficacy of pharmaceuticals

for children. It also provides for the study of off-patent drugs by

amending the Public Health Service Act. As such, it has no application to the legislative branch.

VII. REGULATORY IMPACT STATEMENT

By granting drug manufacturers a 6-month extension of market

exclusivity for a drug upon satisfactory completion of requested pediatric studies of the product and delaying the availability of lower

cost generic alternatives, the bill will make those prescription

drugs, when provided under Medicaid, more expensive. This provision would not constitute a mandate under the Unfunded Mandates Reform Act because prescription drugs under Medicaid are

provided at a State’s option. In addition, there would be cost savings to the Medicaid program because, for example, safe and effective use of drugs in children is expected to reduce the need to hospitalize many children and to reduce errors in dosing and medicating children. The private sector is affected by the bill because

it increases the nation’s annual pharmaceutical bill by one half of

one percent. There would also be cost savings to the private sector

by, for example, the reduced need for hospitalization of children

and reduced errors in medicating children. FDA calculated the aggregate increased cost of drugs from pediatric exclusivity to be

$695 million per year in undiscounted dollars and it estimated the

direct medical cost savings from reduced hospitalizations of children for just 5 illnesses to be $228 million annually.

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VIII. SECTION-BY-SECTION ANALYSIS

Sec. 1. Short title

Sec. 2. Pediatric studies of already-marketed drugs

Section 2 deletes the requirement that the Secretary develop a

priority list of on-patent drugs for which additional pediatric information may be beneficial. It provides that a drug may qualify for

a written request for pediatric studies if the Secretary determines

that information relating to the use of an approved drug in the pediatric population may produce health benefits in that population.

Sec. 3. Research fund for the study of drugs lacking exclusivity

Section 3 creates a research fund for the pediatric studies of offpatent drugs, authorized at $200 million for FY 2002 (and such

sums for each of the next 5 years), to be administered by the National Institutes of Health (NIH). The Secretary, acting through the

Director of NIH in consultation with the Commissioner of Food ad

Drugs, would establish a prioritized list of off-patent drugs that

need to be tested for children. Drugs would be prioritized considering the availability of information on safe and effective use of the

drug in children, whether additional information is needed, whether new pediatric studies of the drug may produce health benefits

for children, and whether a reformulation of the drug is necessary.

Section 3 specifies the process for contracts for the studies and

labeling of drugs lacking patent and other market exclusivity protection. The Commissioner of Food and Drugs, in consultation with

the Director of NIH, would issue a written request for pediatric

studies of such a drug to all companies that produce the drug. If

a company accepts, then that company would pay for the study and

perform the study pursuant to the requirements stated in the

FDA’s written request. If no company responds within 30 days to

the written request (or if companies decline to perform the study),

the Secretary must publish a request for contract proposals to conduct the pediatric studies described in the written request. If the

Secretary is able to enter into a satisfactory contract for the studies, and once the contractor completes the study, the contractor

must submit a report, including all data generated by the study,

to the Director and the Commissioner, and the report must then

be made available to the public.

Within 180 days of submission of the report, the Commissioner

must review the data and negotiate labeling changes with the

drug’s manufacturer indicating the labeling change sought by the

Commissioner. The Commissioner must place a copy of the report

and any requested labeling changes sought in a public docket file,

and must publish a summary of the report and the requested labeling changes in the Federal Register. If a company refuses to make

the labeling changes sought by the Commissioner with 180 days of

submission of the report, the Commissioner must immediately refer

the report, data, and labeling change request to the Pediatric Advisory Subcommittee of the Anti-Infective Drug Advisory Committee.

The Pediatric Advisory Subcommittee then has 90 days to review

the report, data, and labeling change request and recommend to

the Commissioner appropriate labeling changes. The Commissioner

would then have 30 days to consider the Subcommittee’s recVerDate 11-MAY-2000 06:36 Oct 06, 2001 Jkt 099010 PO 00000 Frm 00012 Fmt 6659 Sfmt 6602 E:\HR\OC\SR079.XXX pfrm11 PsN: SR079
13

ommendation, and then make a final request to the drug company

regarding a labeling change. If the drug company fails to agree to

the labeling changes within 30 days, the Commissioner may deem

the drug to be misbranded under the FEDCA. If the pediatric studies indicate that formulation change is necessary (from a pill to a

liquid form, for example), the Secretary must send a nonbinding

letter of recommendation for such a formulation change to all drug

companies that market the drug.

Sec. 4. Timely labeling changes for drugs granted exclusivity; drug

fees

Section 4 requires drug companies to pay user fees at the time

they submit their completed studies to the FDA. Payment of user

fees would then trigger the PDUFA ‘‘priority supplement’’ goal of

6 months for FDA to review pediatric labeling supplements submitted by the company. Within 180 days of submission of the report, the Commissioner of Food and Drugs must request whatever

labeling changes he deems appropriate. If the drug company does

not agree within that 180-day period to make the changes sought

by the FDA, then the Commissioner must immediately refer the

matter to the agency’s Pediatric Advisory Subcommittee. Within 90

days, the Pediatric Advisory Subcommittee must review the pediatric study reports and make a recommendation to the Commissioner as to appropriate labeling changes. Within 30 days, the

Commissioner must consider the recommendations of the Subcommittee and make a final request to the drug company for a labeling change. If the drug company does not agree with 30 days to

this labeling change request from the Commissioner, the Commissioner may deem the drug misbranded.

Sec. 5. Office of Pediatric Therapeutics

Section 5 requires the Secretary to establish an Office of Pediatric Therapeutics within the FDA. This office would oversee and

coordinate RDA activities that could have an effect on pediatrics.

The office would include 1 or more people with expertise in pediatric ethics and 1 or more people with pediatric expertise to consult

on FDA activities that might have an effect on pediatrics.

Sec. 6. Neonates

Section 6 clarifies that the pediatric age groups in which pediatric studies are to be performed in response to requests for such

studies by FDA should include neonates when their inclusion is appropriate.

Sec. 7. Sunset

Section 7 sunsets the billion October 1, 2007, and provides that

a drug may receive pediatric exclusivity if, before that date, the

Secretary makes a written request for pediatric studies of the drug

and an approvable application for the drug has been submitted,

and all requirements of section 505A of the FFDCA are met.

Sec. 8. Dissemination of pediatric information

Section 8 requires that, within 6 months after a drug manufacturer has submitted a pediatric labeling change supplement to the

FDA, the FDA must make public a summary of the medical and

14

clinical pharmacology reviews of the pediatric studies, including by

publication in the Federal Register. All disclosures of information

are subject to the Freedom of Information Act and the Trade Secrets Act.

Sec. 9. Clarification of interaction of market exclusivity under section 505 of the Federal Food, Drug, and Cosmetic Act and market exclusivity awarded to an applicant for approval of a drug

under section 505(j) of that act

Section 9 clarifies the interaction of pediatric exclusivity provided

under this legislation with ANDA exclusivity awarded under the

Waxman-Hatch Law. It specifies that, when the pediatric exclusivity period for a drug overlaps with a period of ANDA exclusivity

for the drug, the period of ANDA exclusivity is extended by an

amount necessary to ensure that the holder of ANDA exclusivity

enjoys the same possibility of exclusive commercial marketing that

the holder would have enjoyed in the absence of pediatric exclusivity, no more and no less.

Sec. 10. Study concerning research involving children

Section 10 requires the Secretary to contract with the IOM to

conduct a 2-year study of Federal regulations involving children in

research; the written and oral processes for obtaining ‘‘assent, permission,and informed consent’’ of children in research from parents, guardians, and legal representatives; the definition of ‘‘minimal risk’’ with respect to children with illnesses or health children;

the appropriateness of regulations applicable to children of differing ages and maturity; financial (or other) incentives that are or

may be offered; the monitoring and enforcement of violations of existing regulations; the roles and responsibilities of institutional review boards (IRBs) in reviewing research involving children; and

the composition of membership of such IRBs.

Sec. 11. Technical and conforming amendments

IX. CHANGES IN EXISTING LAW

In compliance with rule XXVI paragraph 12 of the Standing

Rules of the Senate, the following provides a print of the statute

or the part or section thereof to be amended or replaced (existing

law proposed to be omitted is enclosed in black brackets, new matter is printed in italic, existing law in which no change is proposed

is shown in roman):

PUBLIC HEALTH SERVICE ACT

* * * * * * *

TITLE IV—NATIONAL RESEARCH INSTITUTES

PART A—NATIONAL INSTITUTES OF HEALTH

ORGANIZATION OF THE NATIONAL INSTITUTES OF HEALTH

SEC. 401. ø281¿ (a) * * *

* * * * * * *

15

SEC. ø409C.¿ 409G. CLINICAL RESEARCH.

(a) IN GENERAL.—The director of National Institutes of Health

shall undertake activities to support and expand the involvement

of the National Institutes of Health in clinical research.

(b) REQUIREMENTS.—In carrying out subsection (a), the Director

of National Institutes of Health Shall—

(1) consider the recommendations of the Division of Research

Grants Clinical Research Study Group and other recommendations for enhancing clinical research; and

(2) establish intramural and extramural clinical research fellowship programs directed specifically at medical and dental

students and a continuing education clinical research training

program at the National Institutes of Health.

(c) SUPPORT FOR THE DIVERSE NEEDS OF CLINICAL RESEARCH.—

The Director of National Institutes of health, in cooperation with

the Directors of the Institutes, Centers, and Divisions of the National Institutes of Health, shall support and expand the resources

available for the diverse needs of the clinical research community,

including inpatient, outpatient, and critical care clinical research.

(d) PEER REVIEW.—The Director of National Institutes of Health

shall establish peer review mechanisms to evaluate applications for

the awards and fellowships provided for in subsection (b)(2) and

section 409D. Such review mechanisms shall include individuals

who are exceptionally qualified to appraise the merits of potential

clinical research training and research grant proposals.

SEC. ø409D.¿ 409H. ENHANCEMENT AWARDS.

(a) MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARDS.—

(1) GRANTS.—

(A) IN GENERAL.—The Director of the National Institutes

of Health shall make grants (to be referred to as

‘‘Mentored Patient-Oriented Research Career Development

Awards’’) to support individual careers in clinical research

at general clinical research centers or at other institutions

that have the infrastructure and resources deemed appropriate for conducting patient-oriented clinical research.

(B) USE.—Grants under subparagraph (A) shall be used

to support clinical investigators in the early phases of their

independent careers by providing salary and such other

support for a period of supervised study.

(2) APPLICATIONS.—An application for a grant under this

subsection shall be submitted by an individual scientist at such

time as the Director may require.

(3) AUTHORIZATION OF APPROPRIATIONS.—For the purpose of

carrying out this subsection, there are authorized to be appropriated such sums as may be necessary for each fiscal year.

(b) MID-CAREER INVESTIGATOR AWARDS IN PATIENT-ORIENTED RESEARCH.—

(1) GRANTS.—

(A) IN GENERAL.—The Director of the National Institutes

of Health shall make grants (to be referred to as ‘‘Mid-Career Investigator Awards in Patient-Oriented Research’’) to

support individual clinical research projects at general

clinical research centers or at other institutions that have

16

the infrastructure and resources deemed appropriate for

conducting patient-oriented clinical research.

(B) USE.—Grants under subparagraph (A) shall be used

to provide support for mid-career level clinicians to allow

such clinicians to devote time to clinical research and to

act as mentors for beginning clinical investigators.

(2) APPLICATIONS.—An application for a grant under this

subsection shall be submitted by an individual scientists at

such time as the Director requires.

(3) AUTHORIZATION OF APPROPRIATIONS.—For the purpose of

carrying out this subsection, there are authorized to be appropriated such sums as may be necessary for each fiscal year.

(c) GRADUATE TRAINING IN CLINICAL INVESTIGATION AWARD.— (1) IN GENERAL.—The Director of the National Institutes of

Health shall make grants (to be referred to as ‘‘Graduate

Training in Clinical Investigation Awards’’) to support individuals pursuing master’s or doctoral degrees in clinical investigation.

(2) APPLICATIONS.—An application for a grant under this

subsection shall be submitted by an individual scientist at such

time as the Director may require.

(3) LIMITATIONS.—Grants under this subsection shall be for

terms of 2 years or more and shall provide stipend, tuition, and

institutional support for individual advanced degree programs

in clinical investigation.

(4) DEFINITION.—As used in this subsection, the term ‘‘advanced degree programs in clinical investigation’’ means programs that award a master’s or Ph.D degree in clinical investigation after 2 years of training in areas such as the following:

(A) Analytical methods, biostatistics, and study design.

(B) Principles of clinical pharmacology and pharmacokinetics.

(C) Clinical epidemiology.

(D) Computer data management and medical

informatics.

(E) Ethical and regulatory issues.

(F) Biomedical writing.

(5) AUTHORIZATION OF APPROPRIATIONS.—For the purpose of

carrying out this subsection, there are authorized to be appropriated such sums as may be necessary for each fiscal year.

(d) CLINICAL RESEARCH CURRICULUM AWARDS.—

(1) IN GENERAL.—The Director of the National Institutes of

Health shall make grants (to be referred to as ‘‘Clinical Research Curriculum Awards’’) to institutions for the development and support of programs of core curricula for training

clinical investigators, including medical students. Such core

curricula may include training in areas such as the following:

(A) Analytical methods, biostatistics, and study design.

(B) Principles of clinical pharmacology and pharmacokinetics.

(C) Clinical epidemiology.

(D) Computer data management and medical

informatics.

(E) Ethical and regulatory issues.

(F) Biomedical writing.

17

(2) APPLICATIONS.—An application for a grant under this

subsection shall be submitted by an individual institution or a

consortium of institutions at such time as the Director may require. An institution may submit only one such application.

(3) LIMITATIONS.—Grants under this subsection shall be for

terms of up to 5 years and may be renewable.

(4) AUTHORIZATION OF APPROPRIATIONS.—For the purpose of

carrying out this subsection, there are authorized to be appropriated such sums as may be necessary for each fiscal year.

SEC. 409I. PROGRAM FOR PEDIATRIC STUDIES OF DRUGS LACKING EXCLUSIVITY.

(a) LIST OF DRUGS LACKING EXCLUSIVITY FOR WHICH PEDIATRIC

STUDIES ARE NEEDED.— (1) IN GENERAL.—Not later than 1 year after the date of enactment of this section, the Secretary, acting through the Director of the National Institutes of Health and in consultation with

the Commissioner of Food and Drugs and experts in pediatric

research, shall develop, prioritize, and publish an annual list of

approved drugs for which—

(A)(i) there is an approved application under section

505(j) of the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 355(j));

(ii) there is a submitted application that could be approved under the criteria of section 505(j) of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)); or

(iii) there is no patent protection or market exclusivity

protection under the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 301 et seq.); and

(B) additional studies are needed to assess the safety and

effectiveness of the use of the drug in the pediatric population.

(2) CONSIDERATION OF AVAILABLE INFORMATION.—In developing the list under paragraph (1), the Secretary shall consider,

for each drug on the list—

(A) the availability of information concerning the safe

and effective use of the drug in the pediatric population;

(B) whether additional information is needed;

(C) whether new pediatric studies concerning the drug

may produce health benefits in the pediatric population;

and

(D) whether reformulation of the drug is necessary;

(b) CONTRACTS FOR PEDIATRIC STUDIES.—The Secretary shall

award contracts to entities that have the expertise to conduct pediatric clinical trials (including qualified universities, hospitals, laboratories, contract research organizations, federally funded programs such as pediatric pharmacology research units, other public

or private institutions, or individuals) to enable the entities to conduct pediatric studies concerning one or more drugs identified in

the list described in subsection (a).

(c) PROCESS FOR CONTRACTS AND LABELING CHANGES.—

(1) WRITTEN REQUEST TO HOLDERS OF APPROVED APPLICATIONS FOR DRUGS LACKING EXCLUSIVITY.—

(A) IN GENERAL.—The Commissioner of Food and Drugs,

in consultation with the Director of National Institutes of

Health, may issue a written request (which shall include a

18

timeframe for negotiations for an agreement) for pediatric

studies concerning a drug identified in the list described in

subsection (a) to all holders of an approved application for

the drug under section 505 of the Federal Food, Drug, and

Cosmetic Act. Such a request shall be made in accordance

with section 505A of the Federal Food, Drug, and Cosmetic

Act.

(B) PUBLICATION OF REQUEST.—If the Commissioner of

Food and Drugs does not receive a response to a written request issued under subparagraph (A) within 30 days of the

date on which a request was issued, the Secretary, acting

through the Director of National Institutes of Health and

in consultation with the Commissioner of Food and Drugs,

shall publish a request for contract proposals to conduct

the pediatric studies described in the written request.

(C) DISQUALIFICATION.—A holder that receives a first

right of refusal shall not be entitled to respond to a request

for contract proposals under subparagraph (B).

(D) GUIDANCE.—Not later than 270 days after the date of

enactment of this section, the Commissioner of Food and

Drugs shall promulgate guidance to establish the process

for the submission of responses to written requests under

subparagraph (A).

(2) CONTRACTS.—A contract under this section may be awarded only if a proposal for the contract is submitted to the Secretary in such form and manner, and containing such agreements, assurances, and information as the Secretary determines

to be necessary to carry out this section.

(3) REPORTING OF STUDIES.— (A) Upon completion of a pediatric study in accordance

with a contract awarded under this section, a report concerning the study shall be submitted to the Director of National Institutes of Health and the Commissioner of Food

and Drugs. The report shall include all data generated in

connection with the study.

(B) AVAILABILITY OF REPORTS.—Each report submitted

under subparagraph (a) shall be considered to be in the

public domain, and shall be assigned a docket number by

the Commissioner of Food and Drugs. An interested person

may submit written comments concerning such pediatric

studies to the Commissioner of Food and Drugs, and the

written comments shall become part of the docket file with

respect to each of the drugs.

(C) ACTION BY COMMISSIONER.—The Commissioner of

Food and Drugs shall take appropriate action in response

to the reports submitted under subparagraph (A) in accordance with paragraph (4).

(4) REQUEST FOR LABELING CHANGES.—During the 180-day

period after the date on which a report is submitted under

paragraph (3)(A), the Commissioner of Food and Drugs shall—

(A) review the report and such other data as are available concerning the safe and effective use in the pediatric

population of the drug studied; and

(B) negotiate with the holders of approved applications

for the drug studied for any labeling changes that the ComVerDate 11-MAY-2000 06:36 Oct 06, 2001 Jkt 099010 PO 00000 Frm 00018 Fmt 6659 Sfmt 6603 E:\HR\OC\SR079.XXX pfrm11 PsN: SR079
19

missioner of Food and Drugs determines to be appropriate

and requests the holders to make; and

(C)(i) place in the public docket file a copy of the report

and of any requested labeling changes; and

(ii) publish in the Federal Register a summary of the report and a copy of any requested labeling changes.

(5) DISPUTE RESOLUTION.—If, not later than the end of the

180-day period specified in paragraph (4), the holder of an approved application for the drug involved does not agree to any

labeling change requested by the Commissioner of Food and

Drugs under that paragraph— (A) the Commissioner of Food and Drugs shall immediately refer the request to the Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee;

and

(B) not later than 90 days after receiving the referral, the

Subcommittee shall— (i) review the available information on the safe and

effective use of the drug in the pediatric population, including study reports submitted under this section; and

(ii) make a recommendation to the Commissioner of

Food and Drugs as to appropriate labeling changes, if

any.

(6) FDA DETERMINATION.—Not later than 30 days after receiving a recommendation from the Sub-committee under paragraph (5)B(ii) with respect to a drug, the Commissioner of Food

and Drugs shall consider the recommendation and, if appropriate, make a request to the holders of approved applications

for the drug to make any labeling change that the Commissioner of Food and Drugs determines to be appropriate.

(7) FAILURE TO AGREE.—If a holder of an approved application for a drug, within 30 days after receiving a request to make

a labeling change under paragraph (6), does not agree to make

a requested labeling change, the Commissioner may deem the

drug to be misbranded under the Federal Food, Drug, and Cosmetic Act.

(8) RECOMMENDATION FOR FORMULATION CHANGES.—If a pediatric study completed under public contract indicates that a

formulation change is necessary and the Secretary agrees, the

Secretary shall send a nonbinding letter of recommendation regarding that change to each holder of an approved application.

(d) AUTHORIZATION OF APPROPRIATIONS.—

(1) IN GENERAL.—There are authorized to be appropriated to

carry out this section—

(A) $200,000,000 for fiscal year 2002; and

(B) such sums as are necessary for each of the 5 succeeding fiscal years.

(2) AVAILABILITY.—Any amount appropriated under paragraph (1) shall remain available to carry out this section until

expended.

* * * * * * *

FEDERAL FOOD, DRUG, AND COSMETIC ACT

* * * * * * *

20

CHAPTER II—DEFINITIONS

SEC. 201 ø21 U.S.C. 321¿ For the purposes of this Act— (a)(1) * * *

* * * * * * *

(kk) PRIORITY SUPPLEMENT.—The term ‘‘priority supplement’’ means a drug application referred to in section 101(4) of the Food

and Drug Administration Modernization Act of 1997 (111 Stat.

2298).

* * * * * * *

SEC. 505A. ø21 U.S.C. 355a¿ PEDIATRIC STUDIES OF DRUGS.

ø(g)¿ (a) DEFINITIONS.—As used in this section, the term ‘‘pediatric studies’’ or ‘‘studies’’ means at least one clinical investigation

(that, at the Secretary’s discretion, may include pharmacokinetic

studies) in pediatric age groups (including neonates in appropriate

cases) in which a drug is anticipated to be used.

ø(a)¿ (b) MARKET EXCLUSIVITY FOR NEW DRUGS.—If, prior to approval of an application that is submitted under section 505(b)(1),

the Secretary determines that information relating to the use of a

new drug in the pediatric population may produce health benefits

in that population, the Secretary makes a written request for pediatric studies (which shall include a timeframe for completing such

studies), and such studies are completed within any such timeframe and the reports thereof submitted in accordance with subsection (d)(2) or accepted in accordance with subsection (d)(3)— (1)(A)(i) the period referred to in subsection (c)(3)(D)(ii) of

section 505, and in subsection ø(j)(4)(D)(ii)¿ (j)(5)(D)(ii) of such

section, is deemed to be five years and six months rather than

five years, and the references in subsections (c)(3)(D)(ii) and

ø(j)(4)(D)(ii)¿ (j)(5)(D)(ii) of such section to four years, to fortyeight months, and to seven and one-half years are deemed to

be four and one-half years, fifty-four months, and eight years,

respectively; or

(ii) the period referred to in clauses (iii) and (iv) of subsection

(c)(3)(D) of such section, and in clauses (iii) and (iv) of subsection ø(j)(4)(D)¿ (j)(5)(D) of such section, is deemed to be

three years and six months rather than three years; and

(B) if the drug is designated under section 526 for a rare disease or condition, the period referred to in section 527(a) is

deemed to be seven years and six months rather than seven

years; and

(2)(A) if the drug is the subject of—

(i) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of

section 505 and for which pediatric studies were submitted

prior to the expiration of the patent (including any patent

extensions); or

(ii) a listed patent for which a certification has been submitted under subsections (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of

section 505,

the period during which an application may not be approved

under section 505(c)(3) or section ø505(j)(4)(B)¿ shall be extended by a period of six months after the date the patent expires (including any patent extensions); or

21

(B) if the drug is the subject of a listed patent for which a

certification has been submitted under subsection (b)(2)(A)(iv)

or (j)(2)(A)(vii)(IV) of section 505, and in the patent infringement litigation resulting from the certification the court determines that the patent is valid and would be infringed, the period during which an application may not be approved under

section 505(c)(3) or section 505(j)(4)(B) shall be extended by a

period of six months after the date the patent expires (including any patent extensions).

ø(b) SECRETARY TO DEVELOP LIST OF DRUGS FOR WHICH ADDI- TIONAL PEDIATRIC INFORMATION MAY BE BENEFICIAL.—Not later

than 180 days after the date of enactment of the Food and Drug

Administration Modernization Act of 1997, the Secretary, after consultation with experts in pediatric research shall develop,

prioritize, and publish an initial list of approved drugs for which

additional pediatric information may produce health benefits in the

pediatric population. The Secretary shall annually update the list.¿

(c) MARKET EXCLUSIVITY FOR ALREADY-MARKETED DRUGS.—If the

Secretary determines that information relating to the use of an approved drug in the pediatric population may produce health benefits

in that population and makes a written request to the holder of an

approved application under section 505(b)(1) for pediatric studies

(which shall include a timeframe for completing such studies) øconcerning a drug identified in the list described in subsection (b)¿, the holder agrees to the request, the studies are completed within

any such timeframe, and the reports thereof are submitted in accordance with subsection (d)(2) or accepted in accordance with subsection (d)(3)— (1)(A)(i) the period referred to in the subsection (c)(3)(D)(ii)

of section 505, and in subsection ø(j)(4)(D)(ii)¿ (j)(5)(D)(ii) of

such section, is deemed to be five years and six months rather

than five years, and the references in subsections (c)(3)(D)(ii)

and ø(j)(4)(D)(ii)¿ (j)(5)(D)(ii) of such section for four years, to

forty-eight months, and to seven and one-half years are

deemed to be four and one-half years, fifty-four months, and

eight years, respectively; or

(ii) the period referred to the clauses (iii) and (iv) of subsection (c)(3)(D) of such section, and in clauses (iii) and (iv) of

subsection ø(j)(4)(D)¿ (j)(5)(D) of such section, is deemed to be

three years and six months rather than three years; and

(B) if the drug is designated under section 526 for a rare disease or condition, the period referred to in section 527(a) is

deemed to be seven years and six months rather than seven

years; and

(2)(A) if the drug is the subject of—

(i) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of

section 505 and for which pediatric studies were submitted

prior to the expiration of the patent (including any patent

extensions); or

(ii) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of

section 505,

the period during which an application may not be approved

under section 505(c)(3) or section 505(j)(4)(B) shall be extended

22

by a period of six months after the date the patent expires (including any patent extensions); or

(B) if the drug is the subject of a listed patent for which a

certification has been submitted under subsection (b)(2)(A)(iv)

or (j)(2)(A)(vii)(IV) of section 505, and in the patent infringement litigation resulting from the certification the court determines that the patent is valid and would be infringed, the period during an application may not be approved under section

505(c)(3) or section 505(j)(4)(B) shall be extended by a period

of six months after the date the patent expires (including any

patent extensions).

(d) CONDUCT OF PEDIATRIC STUDIES.— (1) AGREEMENT FOR STUDIES.—The Secretary may, pursuant

to a written request from the Secretary under subsection ø(a)

or (c)¿ (b) or (c), after consultation with— (A) the sponsor of an application for an investigational

new drug under section 505(i);

(B) the sponsor of an application for a new drug under

section 505(b)(1); or

(C) the holder of an approved application for a drug

under section 505(b)(1),

agree with the sponsor or holder for the conduct of pediatric

studies for such drug. Such agreement shall be in writing and

shall include a timeframe for such studies.

(2) WRITTEN PROTOCOLS TO MEET THE STUDIES REQUIRE- MENT.—If the sponsor or holder and the Secretary agree upon

written protocols for the studies, the studies requirement of

subsection ø(a) or (c)¿ (b) or (c) is satisfied upon the completion

of the studies and submission of the reports thereof in accordance with the original written request and the written agreement referred to in paragraph (1). Not later than 60 days after

the submission of the report of the studies, the Secretary shall

determine if such studies were or were not conducted in accordance with the original written request and the written

agreement and reported in accordance with the requirements

of the Secretary for filing and so notify the sponsor or holder.

(3) OTHER METHODS TO MEET THE STUDIES REQUIREMENT.— If the sponsor or holder and the Secretary have not agreed in

writing on the protocols for the studies, the studies requirement of subsection ø(a) or (c)¿ (b) or (c) is satisfied when such

studies have been completed and the reports accepted by the

Secretary. Not later than 90 days after the submission of the

reports of the studies, the Secretary shall accept or reject such

reports and so notify the sponsor or holder. The Secretary’s

only responsibility in accepting or rejecting the reports shall be

to determine, within the 90 days, whether the studies fairly respond to the written request, have been conducted in accordance with commonly accepted scientific principles and protocols, and have been reported in accordance with the requirements of the Secretary for filing.

(e) DELAY OF EFFECTIVE DATE FOR CERTAIN APPLICATION.—If the

Secretary determines that the acceptance or approval of an application under section 505(b)(2) or 505(j) for a new drug may occur

after submission of reports of pediatric studies under this section,

which were submitted prior to the expiration of the patent (includVerDate 11-MAY-2000 06:36 Oct 06, 2001 Jkt 099010 PO 00000 Frm 00022 Fmt 6659 Sfmt 6602 E:\HR\OC\SR079.XXX pfrm11 PsN: SR079
23

ing any patent extension) or the applicable period under clauses (ii)

through (iv) of section 505(c)(3)(D) or clauses (ii) through (iv) of section, ø505(j)(4)(D)¿ 505(j)(5)(D), but before the Secretary has determined whether the requirements of subsection (d) have been satisfied, the Secretary shall delay the acceptance or approval under

section 505(b)(2) or 505(j) until the determination under subsection

(d) is made, but any such delay shall not exceed 90 days. In the

event that requirements of this section are satisfied, the applicable

six-month period under subsection ø(a) or (c)¿ (b) or (c) shall be

deemed to have been running during the period of delay.

(f) NOTICE OF DETERMINATIONS ON STUDIES REQUIREMENT.—The

Secretary shall publish a notice of any determination that the requirements of subsection (d) have been met and that submissions

and approvals under subsection (b)(2) or (j) of section 505 for a

drug will be subject to the provisions of this section.

ø(h)¿ (g) LIMITATIONS.—A drug to which the six-month period

under subsection ø(a) or (b)¿ (b) or (c) has already been applied— (1) may receive an additional six-month period under subsection (c)(1)(A)(ii) for a supplemental application if all other

requirements under this section are satisfied, except that such

a drug may not receive any additional such period under subsection (c)(2); and

(2) may not receive any additional such period under subsection (c)(1)(B).

ø(i)¿ (h) RELATIONSHIP TO REGULATIONS.—Notwithstanding any

other provision of law, if any pediatric study is required pursuant

to regulations promulgated by the Secretary and such study meets

the completeness, timeliness, and other requirements of this section, such study shall be deemed to satisfy the requirement for

market exclusivity pursuant to this section.

ø(j) SUNSET.—A drug may not receive any six-month period

under subsection ø(a) or (c)¿ (b) or (c) unless the application for the

drug under section 505(b)(1) is submitted on or before January 1,

2002. After January 1, 2002, a drug shall receive a six-month period under subsection (c) if—

ø(1) the drug was in commercial distribution as of the date

of enactment of the Food and Drug Administration Modernization Act of 1997;

ø(2) the drug was included by the Secretary on the list under

subsection (b) as of January 1, 2002;

ø(3) the Secretary determines that there is a continuing need

for information relating to the use of the drug in the pediatric

population and that the drug may provide health benefits in

that population; and

ø(4) All requirements of this section are met.¿

ø(l)¿ (i) LABELING SUPPLEMENTS.—

(1) PRIORITY STATUS FOR PEDIATRIC SUPPLEMENTS.—Any supplement to an application under section 505 proposing a labeling change pursuant to a report on a pediatric study under this

section—

(A) shall be considered to be a priority supplement; and

(B) shall be subject to the performance goals established

by the Commissioner for priority drugs.

(2) DISPUTE RESOLUTION.—If the Commissioner determines

that an application with respect to which a pediatric study is

24

conducted under this section is approvable and that the only

open issue for final action on the application is the reaching of

an agreement between the sponsor of the application and the

Commissioner on appropriate changes to the labeling for the

drug that is the subject of the application— (A) not later than 180 days after the date of submission

of the application— (i) the Commissioner shall request that the sponsor

of the application make any labeling change that the

Commissioner determines to be appropriate; and

(ii) if the sponsor of the application does not agree to

make a labeling change requested by the Commissioner

by that date, the Commissioner shall immediately refer

the matter to the Pediatric Advisory Subcommittee of

the Anti-Infective Drugs Advisory Committee;

(B) not later than 90 days after receiving the referral, the

Pediatric Advisory Subcommittee of the Anti-Infective

Drugs Advisory Committee shall— (i) review the pediatric study reports; and

(ii) make a recommendation to the Commissioner

concerning appropriate labeling changes, if any;

(C) the Commissioner shall consider the recommendations of the Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee and, if appropriate, not

later than 30 days after receiving the recommendation,

make a request to the sponsor of the application to make

any labeling change that the Commissioner determines to

be appropriate; and

(D) if the sponsor of the application, within 30 days after

receiving a request under subparagraph (C), does not agree

to make a labeling change requested by the Commissioner,

the Commissioner may deem the drug that is the subject of

the application to be misbranded.

ø(m)¿ (j) DISSEMINATION OF PEDIATRIC INFORMATION.—

(1) IN GENERAL.—Not later than 180 days after the date of

submission of a report on a pediatric study under this section,

the Commissioner shall make available to the public a summary of the medical and clinical pharmacology reviews of pediatric studies conducted for the supplement, including by publication in the Federal Register.

(2) EFFECT OF SUBSECTION.—Nothing in this subsection alters or amends in any way section 552 of title 5 or section 1905

of title 18, United States Code.

ø(n)¿ (k) CLARIFICATION OF INTERACTION OF MARKET EXCLUSIVITY AWARDED TO AN APPLICANT FOR APPROVAL OF A DRUG

UNDER SECTION 505(J).—

(1) IN GENERAL.—If a 180-day period under section

505(j)(5)(B)(iv) overlaps with a 6-month extension under this

section, so that the applicant for approval of a drug under section 505(j) entitled to the 180-day period under that section

loses a portion of the 180-day period to which the applicant is

entitled for the drug, the 180-day period shall be extended— (A) if the 180-day period would, but for this subsection,

expire after the 6-month extension, by the number of days

of the overlap; or

25

(B) if the 180-day period would, but for this subsection,

expire during the 6-month extension, by 6 months.

(2) EFFECT OF SUBSECTION.—Under no circumstances shall

application of this section result in enabling an applicant for

approval of a new drug under section 505(j) to commercially

market the drug to the exclusion of a subsequent applicant for

approval of a new drug under section 505(j) for more than 180

days.

ø(k)¿ (l) REPORT.—The Secretary shall conduct a study and report to Congress not later than January 1, 2001, based on the experience under the program established under this section. The study

and report shall examine all relevant issues, including—

(1) the effectiveness of the program in improving information

about important pediatric uses for approved drugs;

(2) the adequacy of the inventive provided under this section;

(3) the economic impact of the program on taxpayers and

consumers, including the impact of the lack of lower cost generic drugs on patients, including on lower income patients;

and

(4) any suggestions for modification that the Secretary determines to be appropriate.

ø(j)¿ (m) SUNSET.—A drug may not receive any 6-month period

under subsection (b) or (c) unless—

(1) on or before October 1, 2007, the Secretary makes a written request for pediatric studies of the drug;

(2) on or before October 1, 2007, an approvable application

for the drug is submitted under section 505(b)(1); and

(3) all requirements of this section are met.

* * * * * * *

SEC. 736. ø21 U.S.C. 379h¿ AUTHORITY TO ASSESS AND USE DRUG FEES.

(a) TYPES OF FEES.—Beginning in fiscal year 1998, the Secretary

shall assess and collect fees in accordance with this section as follows:

(1) HUMAN DRUG APPLICATION AND SUPPLEMENT FEE.—

(A) * * *

* * * * * * *

ø(F) EXCEPTION FOR SUPPLEMENTS FOR PEDIATRIC INDICATIONS.—A supplement to a human drug application proposing to include a new indication for use in pediatric populations shall not be assessed a fee under subparagraph

(A).¿

ø(G)¿ (F) REFUND OF FEE IF APPLICATION WITHDRAWN.—

If an application or supplement is withdrawn after the application or supplement was filed, the Secretary may refund the fee or a portion of the fee if no substantial work

was performed on the application or supplement after the

application or supplement was filed. The Secretary shall

have the sole discretion to refund a fee or a portion of the

fee under this subparagraph. A determination by the SecVerDate 11-MAY-2000 06:36 Oct 06, 2001 Jkt 099010 PO 00000 Frm 00025 Fmt 6659 Sfmt 6602 E:\HR\OC\SR079.XXX pfrm11 PsN: SR079
26

retary concerning a refund under this paragraph shall not

be reviewable.

* * * * * * *

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