[Federal Register: December 2, 1998 (Volume 63, Number 231)]

[Rules and Regulations]

[Page 66631-66672]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr02de98-24]

[[Page 66631]]

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Part II

Department of Health and Human Services

_______________________________________________________________________

Food and Drug Administration

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21 CFR Parts 201, 312, 314 and 601

Regulations Requiring Manufacturers to Assess the Safety and

Effectiveness of New Drugs and Biological Products in Pediatric

Patients; Final Rule

[[Page 66632]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 312, 314, and 601

[Docket No. 97N-0165]

RIN 0910-AB20

 

Regulations Requiring Manufacturers to Assess the Safety and

Effectiveness of New Drugs and Biological Products in Pediatric

Patients

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing new

regulations requiring pediatric studies of certain new and marketed

drug and biological products. Most drugs and biologics have not been

adequately tested in the pediatric subpopulation. As a result, product

labeling frequently fails to provide directions for safe and effective

use in pediatric patients. This rule will partially address the lack of

pediatric use information by requiring that manufacturers of certain

products provide sufficient data and information to support directions

for pediatric use for the claimed indications.

DATES: Effective date. The regulation is effective April 1, 1999.

Compliance dates. Manufacturers must submit any required

assessments of pediatric safety and effectiveness 20 months after the

effective date of the rule, unless the assessments are waived or

deferred by FDA.

FOR FURTHER INFORMATION CONTACT: Khyati N. Roberts, Center for Drug

Evaluation and Research (HFD-103), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-6779, or Karen D. Weiss,

Center for Biologics Evaluation and Research (HFM-570), Food and Drug

Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-5093.

SUPPLEMENTARY INFORMATION:

I. Introduction

In the Federal Register of August 15, 1997 (62 FR 43900)

(hereinafter referred to as the proposal), FDA proposed to require that

manufacturers of certain new and marketed drugs and biologics conduct

studies to provide adequate labeling for the use of these products in

children. As described in the proposal, children are subject to many of

the same diseases as adults, and are, by necessity, often treated with

the same drugs and biological products as adults. However, many drugs

and biological products marketed in the United States that are or could

be used in children are inadequately labeled for use in pediatric

patients or for use in specific pediatric subgroups (Refs. 1 and 2).

Indeed, many of the drugs and biological products that are widely used

in pediatric patients carry disclaimers stating that safety and

effectiveness in pediatric patients have not been established (Refs. 2

and 3). Safety and effectiveness information for some pediatric age

groups is particularly difficult to find. For example, there is almost

no information on use in patients under 2 years of age for most drug

classes (Ref. 1).

As described in more detail in the proposal, the absence of

pediatric labeling information poses significant risks for children.

Inadequate dosing information exposes pediatric patients to the risk of

adverse reactions that could be avoided with an appropriate pediatric

dose. The lack of pediatric safety information in product labeling

exposes pediatric patients to the risk of age-specific adverse

reactions unexpected from adult experience. The proposal cited reports

of injuries and deaths in children resulting from use of drugs that had

not been adequately tested in the pediatric population. The absence of

pediatric testing and labeling may also expose pediatric patients to

ineffective treatment through underdosing, or may deny pediatric

patients therapeutic advances because physicians choose to prescribe

existing, less effective medications in the face of insufficient

pediatric information about a new medication. Failure to develop a

pediatric formulation of a drug or biological product, where younger

pediatric populations cannot take the adult formulation, may also deny

pediatric patients access to important new therapies, or may require

pediatric patients to take the drug in extemporaneous formulations that

may be poorly or inconsistently bioavailable.

The proposed rule described previous steps taken by FDA in recent

years to address the problem of inadequate pediatric testing and

inadequate pediatric use information in drug and biological product

labeling. FDA's Center for Drug Evaluation and Research (CDER) and

Center for Biologics Evaluation and Research have implemented a

``Pediatric Plan'' designed to focus attention on, and encourage

voluntary development of, pediatric data both during the drug

development process and after marketing. In addition, in the Federal

Register of December 13, 1994 (59 FR 64240) (hereinafter referred to as

the 1994 rule), FDA issued a regulation requiring manufacturers of

marketed drugs to survey existing data and determine whether those data

were sufficient to support additional pediatric use information in the

drug's labeling. Under the 1994 rule, if a manufacturer determines that

existing data permit modification of the label's pediatric use

information, the manufacturer must submit a supplemental new drug

application (NDA) to FDA seeking approval of the labeling change.

Although the preamble to the 1994 rule recognizes FDA's authority

to require drug and biological product manufacturers to conduct

pediatric studies on a case-by-case basis, the rule does not impose a

general requirement that manufacturers carry out studies when existing

information is not sufficient to support pediatric use information.

Instead, if there is insufficient information to support a pediatric

indication or pediatric use statement, the rule requires the

manufacturer to include in the product's labeling the statement:

``Safety and effectiveness in pediatric patients have not been

established.''

The response to the 1994 rule has not substantially addressed the

lack of adequate pediatric use information for marketed drugs and

biological products. Pediatric labeling supplements were submitted for

approximately 430 drugs and biologics, a small fraction of the

thousands of prescription drug and biological products on the market.

Of the supplements submitted, approximately 75 percent did not

significantly improve pediatric use information. Over half of the total

supplements submitted simply requested the addition of the statement

``Safety and effectiveness in pediatric patients have not been

established.'' Others requested minor wording changes or submitted

unorganized, unanalyzed collections of possibly relevant data.

Approximately 15 percent (approximately 65) of the supplements provided

adequate pediatric information for all relevant pediatric age groups,

and another 8 percent (approximately 35) provided adequate pediatric

information for some but not all relevant age groups.

The absence of adequate pediatric use information remains a problem

for new drugs and biologics as well as for marketed products. The

proposal presented data from 1988 through the 1990's showing that the

percentage of new products entering the marketplace with adequate

pediatric safety and effectiveness information has not increased in the

last decade.

For example, FDA compared the number of new molecular entities

(NME's) approved in 1991 and 1996

[[Page 66633]]

with potential usefulness in pediatric patients and looked at the

adequacy of pediatric labeling for those drugs. Fifty-six percent (9/

17) of the NME's approved in 1991 with potential usefulness in

pediatric patients had some pediatric labeling at the time of approval.

In 1996, only 37 percent (15/40) of the NME's with potential usefulness

in pediatric patients had some pediatric labeling at the time of

approval. For both 1991 and 1996, those drugs counted as having

pediatric labeling may not have been studied in all age groups in which

the drug was potentially useful. The manufacturers of an additional 7

of the 1991 drugs and 17 of the 1996 drugs promised to conduct

pediatric studies after approval. Since publication of the proposal,

figures for 1997 NME's have become available. In 1997, 39 NME's were

approved. Twenty-seven had potential usefulness in pediatric patients,

and 33 percent of these (9/27) had some pediatric labeling at the time

of approval. Postapproval studies were requested or promised for an

additional six. It is uncertain how many of the commitments made for

postapproval studies of the 1996 and 1997 drugs will result in

pediatric labeling. Of the seven NME's approved in 1991 for which

sponsors made commitments to conduct postapproval pediatric studies,

pediatric labeling has been added to only one. This figure reflects

both studies that resulted in positive labeling, i.e., safety and

dosing information, and studies that resulted in warnings against

pediatric use. It does not reflect studies that failed to provide any

useful information about pediatric use or studies that were completed

but the sponsor failed to seek a change in its pediatric use labeling.

These data indicate that voluntary efforts have, thus far, not

substantially increased the number of products entering the marketplace

with adequate pediatric labeling. FDA has therefore concluded that

additional steps are necessary to ensure the safety and effectiveness

of drug and biological products for pediatric patients. This rule

requires the manufacturers of new and marketed drugs and biological

products to evaluate the safety and effectiveness of the products in

pediatric patients, if the product is likely to be used in a

substantial number of pediatric patients or would provide a meaningful

therapeutic benefit to pediatric patients over existing treatments.

In addition to issuing this rule, FDA has initiated other actions

that it hopes will encourage the development of adequate pediatric use

information. FDA has issued a draft guidance document entitled

``General Considerations for Pediatric Pharmacokinetic Studies for

Drugs and Biological Products'' (November 30, 1998). FDA also plans to

develop additional guidance on how to develop effectiveness, safety,

and dosing information to support pediatric labeling. The agency also

supported a provision in the reauthorized Prescription Drug User Fee

Act (PDUFA) eliminating user fees for pediatric supplements to

encourage the submission of these supplements.

Finally, FDA has issued a guidance document entitled ``Providing

Clinical Evidence of Effectiveness for Human Drug and Biological

Products,'' describing the kinds of studies that can support

effectiveness in supplemental or original applications. In that

document, FDA provides guidance to manufacturers on the circumstances

in which FDA may approve an initial or supplemental claim in which

substantiation of the results of an adequate and well-controlled trial

is provided by information other than a second adequate and well-

controlled trial precisely replicating the first trial, or the

circumstances in which studies without the extensive documentation

ordinarily required could be utilized. This guidance will often be

relevant to the data needed to support claims in a pediatric

population.

Since the issuance of the proposal, Congress has enacted a bill

that has an impact on pediatric studies of certain drugs. The Food and

Drug Administration Modernization Act of 1997 (FDAMA) (Pub. L. 105-115)

contains provisions that establish economic incentives for conducting

pediatric studies on drugs for which exclusivity or patent protection

is available under the Drug Price Competition and Patent Term

Restoration Act (Pub. L. 98-417) and the Orphan Drug Act (Pub. L. 97-

414). These provisions extend by 6 months any existing exclusivity or

patent protection on a drug for which FDA has requested pediatric

studies and the manufacturer has conducted such studies in accordance

with the requirements of FDAMA. FDAMA also specifically recognizes

FDA's intention to require pediatric studies by regulation and extends

by 6 months any existing exclusivity or patent protection on a drug

whose manufacturer submits pediatric studies in compliance with this

rule, if the studies meet the completeness, timeliness, and other

requirements of section 505A. Under FDAMA, a manufacturer who submits

pediatric studies required under this rule may receive a 6-month

extension of exclusivity or patent protection granted to the

manufacturer for that drug.

Although FDA expects the exclusivity offered by FDAMA to provide a

substantial incentive for sponsors to conduct some pediatric studies,

the agency nonetheless believes that this final rule is necessary to

significantly increase the number of drug and biological products that

have adequate labeling. Certain limitations on the scope and effect of

the exclusivity offered by FDAMA are likely to leave significant gaps

in pediatric labeling. For example, because FDAMA exclusivity applies

only to products that have exclusivity or patent protection under the

Drug Price Competition and Patent Term Restoration Act and the Orphan

Drug Act, it provides no incentive to conduct studies on certain

categories of products, including most antibiotics, biologics, and off-

patent products.

In addition, the voluntary nature of the incentive provided by

FDAMA is likely to leave many drugs, age groups, and indications

unstudied. Given limited resources to conduct pediatric studies, it is

probable that manufacturers will elect to conduct pediatric studies

preferentially on those drugs for which the incentives are most

valuable, i.e., on drugs with the largest sales. This may leave

unstudied drugs that are greatly needed to treat pediatric patients,

but that have smaller markets. For similar reasons, manufacturers are

less likely to seek FDAMA exclusivity by conducting studies on drugs

that require studies in neonates, infants, or young children. The

youngest pediatric populations are more difficult to study and may

require pediatric formulations, making pediatric studies of these

groups more expensive, thereby reducing the value of the incentives

provided by FDAMA. Thus, where there is a great medical need for data

on drugs with relatively small markets or for studies on neonates,

infants, or young children, it may be necessary to require the

collection of such data, rather than rely on incentives.

Finally, manufacturers are eligible for FDAMA exclusivity when they

submit a study to FDA that is consistent with FDA's written request for

such a study. The study results are not required to provide useful

information on pediatric use (e.g., the results may be inconclusive),

and the sponsor is not required to obtain approval of a supplement

adding the information gained in the study to the drug's label. Thus,

FDAMA provides no guarantee that the studies conducted under the

statute will result in improved pediatric labeling.

[[Page 66634]]

For these reasons, FDA believes that there remains an important

need for this rule. FDA has concluded, however, that with respect to

already marketed drugs eligible for exclusivity under FDAMA, the

publication of the list required by section 505A(b) and the

availability of pediatric exclusivity may diminish the need to exercise

the agency's authority to require studies. Under the rule, FDA has

discretion whether to require studies of marketed drugs (see

Sec. 201.23 (21 CFR 201.23)). FDA believes that, in exercising its

discretion under Sec. 201.23, it is appropriate to determine whether

manufacturers will undertake the needed studies voluntarily. FDA will

therefore allow an adequate opportunity for manufacturers voluntarily

to submit studies for drugs listed by FDA as having a high priority.

If, following such an opportunity, there remain marketed drugs for

which studies are needed and the compelling circumstances described in

the rule are met, the agency will consider exercising its authority to

require studies. With respect to marketed drugs and biologics that are

not eligible for exclusivity under FDAMA, FDA intends to exercise its

authority to require studies as of the effective date of the rule in

the circumstances described in the regulation. FDA emphasizes that the

appearance of a drug or biologic on the list published under section

505A(b) carries no implication that FDA will require studies on that

drug or biologic under this rule. FDA intends to reserve its authority

to require studies of marketed drugs and biologics to situations in

which the compelling circumstances described in the regulation are

present.

FDA intends to issue further regulations and guidance implementing

the pediatric exclusivity provisions of FDAMA, which will, among other

things, provide guidance on the interaction of this rule and FDAMA

exclusivity.

II. Highlights of the Final Rule

This final rule is designed to ensure that new drugs and biological

products contain adequate pediatric labeling for the approved

indications at the time of, or soon after, approval. The final rule

establishes a presumption that all new drugs and biologics will be

studied in pediatric patients, but allows manufacturers to obtain a

waiver of the requirement if the product does not represent a

meaningful therapeutic benefit over existing treatments for pediatric

patients and is not likely to be used in a substantial number of

pediatric patients. The rule also authorizes FDA to require pediatric

studies of those marketed drugs and biological products that: (1) Are

used in a substantial number of pediatric patients for the claimed

indications, and where the absence of adequate labeling could pose

significant risks; or (2) would provide a meaningful therapeutic

benefit over existing treatments for pediatric patients, and the

absence of adequate labeling could pose significant risks to pediatric

patients.

A. Scope of Rule

The proposed rule would have required an application for a drug

classified as a ``new chemical entity'' or a new (never-before-

approved) biological product to contain safety and effectiveness

information on relevant pediatric age groups for the claimed

indications. Based upon comments observing that changes in already

marketed chemical entities, such as new indications or dosage forms,

can have as much or more therapeutic significance for pediatric

patients than the original product, the final rule expands the scope of

the rule to include new active ingredients, new indications, new dosage

forms, new dosing regimens, and new routes of administration for which

an applicant seeks approval. The final rule does not, however, require

the submission of pediatric data for a drug for an indication or

indications for which orphan designation has been granted under section

526 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.

360bb).

B. Types of Studies Needed

As described in the 1994 final rule, gathering adequate data to

establish pediatric safety and effectiveness may not require controlled

clinical trials in pediatric patients. Where the course of the disease

and the product's effects are similar in adults and pediatric patients,

FDA may conclude that pediatric safety and effectiveness can be

supported by effectiveness data in adults together with additional

data, such as dosing, pharmacokinetic, and safety data in pediatric

patients. The rule also does not necessarily require separate studies

in pediatric patients. In appropriate cases, adequate data may be

gathered by including pediatric patients as well as adults in the

original studies conducted on the product.

The specific pediatric information needed in each case will depend

on the nature of the application, what is already known about the

product in pediatric populations, and the underlying disease or

condition being treated. The final rule requires an assessment of

safety and effectiveness in pediatric patients only for the indications

claimed by the manufacturer. It does not require a manufacturer to

study its product for unapproved or unclaimed indications, even if the

product is widely used in pediatric patients for those indications. In

the proposed rule, the pediatric study requirement for drugs was

contained in Sec. 314.50(g) (21 CFR 314.50(g)). In the final rule, the

requirement is located in new Sec. 314.55, because Sec. 314.50 does not

contain other specific study requirements. The location of the

requirement for biological products (Sec. 601.27 (21 CFR 601.27))

remains unchanged in the final rule.

C. Age Groups

The final rule requires pediatric studies in each age group in

which the drug or biological product will provide a meaningful

therapeutic benefit or will be used in a substantial number of

pediatric patients for the indications claimed by the manufacturer. The

relevant age groups will, however, be defined flexibly, depending on

the pharmacology of the drug or biological product, rather than

following the fixed age categories defined in the 1994 rule and

identified in the preamble to the proposed rule. For drugs and

biological products that offer a meaningful therapeutic benefit, the

rule requires manufacturers to develop pediatric formulations, if

needed, for those age groups in which studies are required.

Manufacturers may, however, avoid this requirement if they demonstrate

that reasonable attempts to develop a pediatric formulation have

failed.

D. Not-Yet-Approved Products

1. Deferral of Studies Until After Approval

The final rule permits the submission of pediatric information to

be deferred until after approval if there is an adequate justification

for deferral, e.g., because pediatric studies should not begin until

some safety and/or effectiveness information on adults has been

collected, or awaiting the completion of pediatric studies would delay

the availability of a product to adults. When trials should begin in

particular cases, and whether deferral will be necessary, will depend

upon the seriousness of the disease for which the drug or biological

product is indicated, the need for the product, the amount of safety

and effectiveness data available, and what types of pediatric studies

are needed.

In general, FDA expects that studies of drugs or biological

products for diseases that are life threatening in pediatric patients

and that lack adequate

[[Page 66635]]

therapy could begin earlier than studies of drugs that are less

urgently needed, ordinarily as early as the availability of preliminary

safety data in adults (frequently referred to as phase 1 data), even if

data from well-controlled studies are not yet available. For less

critical drugs and biologics, pediatric studies could ordinarily begin

when additional safety and/or effectiveness data from the initial well-

controlled trials in adults (frequently referred to as phase 2 data)

became available. Of course, studies of products for exclusively

pediatric diseases ordinarily need not await the development of adult

data. The timing of individual pediatric studies will, however,

necessarily depend on the specific information available about the

product in question. For example, a study of a noncritical drug in

adolescents might begin after the initial safety studies in adults, if

all the parties involved agreed that initiation was appropriate in

light of the results of the adult and animal safety studies.

In other cases, studies should not begin in pediatric patients

until significantly more adult data are collected. For example, FDA

does not believe that early study or use in pediatric patients is

appropriate for some so-called ``me-too'' drugs that are expected to be

widely used but are members of a drug class that already contains an

adequate number of approved products with pediatric labeling. Such

drugs may not have been shown to provide any benefit over other

products in the same class, and may introduce new risks that are not

apparent until the drug has been in wide use after marketing. Studies

of such drugs will therefore usually be deferred until the safety

profiles of the drugs are well established through marketing

experience. To encourage use of properly labeled drugs in pediatric

patients, FDA may require the pediatric use section of the approved

labeling of such a me-too drug to contain a statement recommending

preferential use of other drugs that are adequately labeled for

pediatric use.

2. Waiver of the Study Requirement

The pediatric study requirement applies to all applications for new

active ingredients, new indications, new dosage forms, new dosing

regimens, and new routes of administration, unless FDA waives the

requirement. Under criteria established in the rule, FDA may waive the

study requirement for some or all pediatric age groups. The burden is

on the sponsor to justify a waiver. A waiver will be granted if the

waiver request demonstrates that the product meets both of the

following conditions: (1) The product does not represent a meaningful

therapeutic benefit for pediatric patients over existing treatments,

and (2) the product is not likely to be used in a substantial number of

pediatric patients. There was some confusion in the comments on the

proposed rule over these waiver criteria. FDA emphasizes that the study

requirement applies to a product that offers a meaningful therapeutic

benefit even if it is not used in a substantial number of pediatric

patients, and vice versa.

In response to comments, FDA has refined its definitions of

``meaningful therapeutic benefit'' and ``substantial number of

pediatric patients.'' To define meaningful therapeutic benefit for both

drugs and biologics covered by this rule, FDA has relied, in part, on

CDER's current administrative definition of a ``Priority'' drug,

applied to pediatric populations. The administrative definition of

``Priority'' products for biologics relies on different criteria (Ref.

2). Use of CDER's Priority drug definition to help define ``meaningful

therapeutic benefit'' is not intended to affect the administrative

definition of a Priority biologic. The Priority classification for

drugs is determined based on CDER's estimate, at the time of NDA

submission, of a drug's therapeutic, preventive, or diagnostic value. A

Priority drug is defined as one that, if approved, would be a

significant improvement in the treatment, diagnosis, or prevention of a

disease, compared to marketed products approved for that use. In

establishing meaningful therapeutic benefit for pediatric use, the

comparison will be to other products adequately labeled for use in the

relevant pediatric population. If there are no such products, a new

product would usually be considered to have a meaningful therapeutic

benefit. Improvement over existing products labeled for pediatric use

can be demonstrated by, for example: (1) Evidence of increased

effectiveness in treatment, prevention, or diagnosis of disease; (2)

elimination or substantial reduction of a treatment-limiting drug

reaction; (3) documented enhancement of patient compliance; or (4)

evidence of safety and effectiveness in a new subpopulation. Evidence

of improvement over existing therapies need not in all cases come from

head-to-head trials.

To help ensure that pediatric patients have a sufficient range of

treatments available, a product will also be considered to provide a

meaningful therapeutic benefit if it is in a class of products or for

an indication for which there is a need for additional therapeutic

options, notwithstanding the fact that it might not be a priority drug.

In contrast to the range of therapies for a given indication often

available to adults, there are relatively few instances in which

therapeutic alternatives are studied and labeled for pediatric

patients. For some diseases, however, it is therapeutically important

to have a range of available treatment options, e.g., because there are

frequent treatment failures. The Priority definition would cover the

first product labeled for pediatric use, but might not cover the second

or third product for a given indication or in a given class, if the

subsequent product did not offer an advantage over existing therapies.

The specific number of products needed will depend upon such factors as

the severity of the disease being treated and the adverse reaction

profile of existing therapies. FDA will seek further guidance on

applying this criterion from a panel of pediatric experts.

Thus, new products will meet the definition of a meaningful

therapeutic benefit if: (1) They provide a significant improvement over

existing adequately labeled therapies; or (2) if they are indicated for

diseases or conditions, or are in product classes, in which there are

currently few products labeled for pediatric use and more therapeutic

options are needed. FDA expects that over time, as the number of

products adequately labeled for pediatric patients grows, the number of

new products meeting the second criterion will diminish. FDA emphasizes

that the addition of the second criterion for defining meaningful

therapeutic benefit under this final rule is not intended to alter the

definition of a Priority drug, and that products meeting the second

criterion will not thereby be eligible for Priority status. FDA also

notes that the rule's definition of meaningful therapeutic benefit is

intended to apply only in the pediatric study context.

FDA has also revised the proposed definition of ``a substantial

number of pediatric patients.'' Many comments argued that the number

chosen by FDA in the proposal (100,000 prescriptions per year or

100,000 pediatric patients with the disease) was arbitrary. Physician

mention data from the IMS National Disease and Therapeutic Index (Ref.

38), which tracks the use of drugs by measuring the number of times

physicians mention drugs during outpatient visits, shows that pediatric

use of drugs is generally grouped in two distinct ranges. Physician

mentions of drugs for pediatric use generally fall either below 15,000

per year or above 100,000 per year. Few drugs fall within the two

ranges. Thus, selecting a cut-off

[[Page 66636]]

for ``substantial number of pediatric patients'' in the middle of the

two ranges will provide a reasonable discrimination between products

that are widely used and those that are less commonly used, and the

specific number chosen will not arbitrarily include or exclude a

significant number of drugs. FDA has therefore chosen 50,000 as the

cut-off for a substantial number of pediatric patients. Because the

number of pediatric patients with the disease or condition is easier to

determine than the number of prescriptions per year, a substantial

number of pediatric patients will be defined as 50,000 pediatric

patients with the disease or condition for which the drug or biological

product is indicated. Although physician mentions per year does not

correspond exactly to the number of patients with the disease or

condition, they provide a rough approximation and the IMS data show

that the number of products included or excluded is relatively

insensitive to changes in the cut-off chosen. As proposed, a partial

waiver for a particular pediatric age group would be available under

this method if 15,000 patients in that age group were affected by the

disease or condition. This definition of ``a substantial number of

pediatric patients'' has not been codified, however, and FDA may modify

it, after consulting with a panel of pediatric experts. Any

modification will be issued in a guidance document with an opportunity

for comment.

FDA will also waive the pediatric study requirement where: (1) The

applicant shows that the required studies on the product are impossible

or highly impractical because, for example, the population is too small

or geographically dispersed; (2) the product is likely to be unsafe or

ineffective in pediatric patients; or (3) reasonable efforts to develop

a pediatric formulation (if one is needed) have failed.

To reduce the burden on manufacturers in applying for waivers and

deferrals, FDA intends to issue a guidance document providing a format

for a request for waiver or deferral.

E. Marketed Products

The final rule is also intended to improve pediatric use

information for already marketed drugs and biological products. The

rule codifies FDA's authority, discussed in the 1994 rule, to require,

in the compelling circumstances described in the regulation, that

manufacturers of already marketed drugs and biological products conduct

studies to support pediatric-use labeling for the claimed indications.

The criteria for requiring studies of marketed products have been

revised slightly in response to comments.

F. Early Discussions and Pre- and Postmarket Reports

The final rule contains provisions designed to encourage

discussions of the need for pediatric studies early in the drug

development process, as well as pre- and postmarketing reporting

requirements designed to assist FDA in determining whether pediatric

studies are needed for particular products and whether required studies

are being carried out with due diligence.

G. Pediatric Committee

Many comments on the proposed rule urged FDA to form a committee of

outside experts to assist in various aspects of the implementation of

the rule. FDA has concluded that such a panel could provide useful

advice and experience. FDA will convene a panel of pediatric experts,

including at least one industry representative, and seek its advice on

a range of issues related to implementation of the rule, including: (1)

The agency's implementation of all aspects of the final rule, including

its waiver and deferral decisions; (2) which marketed drugs and

biological products meet the criteria for requiring studies; (3) when

additional therapeutic options are needed for a given disease or

condition occurring in pediatric patients; (4) ethical issues raised by

clinical trials in pediatric patients; (5) the design of trials and

analysis of data for specific products or classes of products; and (6)

issues related to the progress of individual studies.

H. Remedies for Violation of the Rule

For violations of this rule, FDA would ordinarily expect to file an

enforcement action for an injunction, asking a Federal court to find

that the product is misbranded under section 502 of the act (21 U.S.C.

352) or is an unapproved new drug under section 505(a) of the act (21

U.S.C. 355) or an unlicensed biologic under section 351 of the Public

Health Service Act, and to require the company to submit an assessment

of pediatric safety and effectiveness for the product. Violation of the

injunction would result in a contempt proceeding or such other

penalties as the court ordered, e.g., fines. FDA does not intend,

except possibly in rare circumstances, to disapprove or withdraw

approval of a drug or biological product whose manufacturer violates

requirements imposed under this rule.

III. Comments on the Proposed Rule

FDA received 54 written comments on the proposed rule from

pediatricians, professional societies, parents, members of the

pharmaceutical industry, organizations devoted to specific diseases,

and patient groups. A significant majority of the comments, primarily

those from pediatricians, professional societies, parents,

organizations devoted to specific diseases, and patient groups,

supported regulations requiring that drugs and biologics be studied in

children. Many of these comments described the problems faced by the

pediatric community and parents resulting from inadequate pediatric

labeling and the absence of pediatric formulations, and argued that a

pediatric study requirement was long overdue. Some comments, primarily

those from the pharmaceutical industry, opposed a pediatric study

requirement, arguing that existing voluntary measures and incentives

were sufficient to ensure adequate pediatric labeling. Finally, a

number of comments addressed FDA's legal authority to require pediatric

testing of drugs and biologics.

FDA also held a day-long public hearing on October 27, 1997, in

Washington, DC, at which recognized experts in the field, members of

the pharmaceutical industry, and other interested parties were given an

opportunity to discuss the issues raised by the proposed rule. There

were three panels, each of which comprised representatives from

industry, the pediatric community, organizations devoted to specific

diseases, patient groups, and a bioethicist. The panels considered the

following three issues: (1) When pediatric studies are needed, (2) what

types of studies are needed, and (3) special challenges in testing

pediatric patients. Those who spoke were nearly unanimous in their

support for some kind of regulation requiring pediatric studies of some

drugs and biologics. There was, however, a wide range of views on which

drugs and biologics should be the subject of required studies and on

how the requirement should be implemented.

Many written and oral comments raised specific issues for

consideration by the agency. These comments are addressed below.

A. Purpose of Rule

1. FDA received many comments arguing that this rule is needed to

ensure adequate medical care for children. Many comments from

pediatricians stated that they regularly must prescribe to young

children drugs

[[Page 66637]]

that are not labeled for children under 6 or even 12, and for which

pediatric dosage forms do not exist. One comment stated that, without

adequate testing and labeling, physicians must estimate appropriate

pediatric doses, and that even at ``appropriate'' doses, it is not

known whether use in children is as safe as use in adults. One comment

argued that the absence of pediatric labeling puts children at greater

risk for adverse drug reactions (ADR's) and therapeutic failures than

adults. According to another comment, most common and severe ADR's in

pediatric patients would be eliminated by adequate testing, and that

perhaps 2 percent of all pediatric hospitalizations are due to ADR's.

One comment concluded that the failure to conduct pediatric studies

results in a different standard of care for children and adults in this

country.

A comment from a pharmaceutical trade association argued, however,

that most of the toxicity problems identified by FDA as caused by

inadequate pediatric labeling were from the 1950's and that these

``dated'' examples are not relevant to current practice. As an example,

the comment cited chloramphenicol, a drug referred to by FDA in the

proposed rule because, when it was used in the 1950's in neonates

without adequate testing, it was responsible for many infant deaths

(Ref. 4). According to the comment, it is now known that

chloramphenicol can be used in neonates if the dose is correct. The

comment also stated that practicing physicians have access to adequate

dosing information from case reports in the medical literature.

FDA agrees that the absence of adequate pediatric labeling puts

pediatric patients at risk for adverse drug reactions and ineffective

dosing. FDA believes that the reference to new dosing information that

permits use of chloramphenicol in infants illustrates the need for this

final rule. Had adequate safety and dosing information been available

earlier, many babies' lives could have been saved. Instead, adequately

supported dosing information was not available until after the drug had

been used in a large number of babies, with tragic consequences. FDA

also disagrees with the comment that the remaining reports cited in the

proposal of unexpected toxicity in pediatric patients from inadequately

tested drugs are ``dated.'' Contrary to the assertion in the comment, a

majority of these reports are from the 1980's and 1990's (Refs. 5

through 14).

FDA also does not believe that case reports scattered through the

medical literature are an adequate substitute for organized and

complete pediatric labeling information. To the extent that published

experience is informative and credible, it should be used to improve

labeling. The comments received from pediatricians reflect their view

that there is often no adequately supported dosing and safety

information for the drugs they use routinely in their patients. Even

where case reports are available, they describe a limited number of

pediatric patients and cannot provide sufficient information to

establish the safety profile of a drug in pediatric patients.

2. Some comments argued that pediatric studies are needed because

differences between children and adults can make extrapolation from

adult data treacherous. One comment pointed out that research on

antiarrhythmics in pediatric patients has revealed many surprises in

dosing and side effects. For example, drugs that bind to milk may cause

safety or effectiveness problems in pediatric patients not detected in

adults.

FDA agrees that pediatric dosing cannot necessarily be extrapolated

from adult dosing information using an equivalence based either on

weight milligram/kilogram (mg/kg) or body surface area (mg/m \2\).

There are potentially significant differences in pharmacokinetics, or

unique drug-food interactions, that may alter a drug's blood levels in

pediatric patients. Moreover, there can be pharmacodynamic differences

between adults and pediatric patients.

3. Several comments argued that voluntary measures have not

resulted in a significant increase in pediatric labeling, and that new

products continue to enter the market without adequate, or any,

pediatric labeling. Pediatricians, professional societies, parents,

organizations devoted to specific diseases, and patient groups provided

many examples of diseases and drug classes for which pediatric labeling

was long-delayed, inadequate, or nonexistent. Acquired immune

deficiency syndrome (AIDS) drugs were frequently cited as an example of

the industry's failure to obtain adequate pediatric labeling at or near

the time of approval. One comment pointed to protease inhibitors, which

are theoretically most effective in newborns but have not been tested

or approved for use in this group. Even for older children, the comment

observed that it has taken over a year after adult approval to obtain

pediatric labeling for these life-saving drugs. Another comment stated

that the absence of drugs for human immunodeficiency virus (HIV)

infection that are appropriately labeled and formulated for pediatric

patients causes parents to give children inappropriate doses, sometimes

giving up part of their own dose if the child's physician will not

prescribe it.

Other comments pointed out that epilepsy is considered a pediatric

disease but claimed that many new epilepsy drugs are approved without

information for use in pediatric patients. These comments urged that

anti-epileptic drugs be added to the list of drug classes with

inadequate labeling. A comment from a specialist in pulmonary medicine

stated that although asthma is a common disease in pediatric patients,

adult formulations are often released first, leaving pediatric patients

without effective treatments. Other comments observed that not one of

the standard immunosuppressive medications used in pediatric patients

has been tested in pediatric patients. One comment contended that poor

information about the pharmacokinetics of these drugs in pediatric

patients has led to inadequate dosing to achieve effectiveness and

possibly unnecessary toxicity.

The American Psychiatric Association commented that significant

psychiatric diseases are increasingly diagnosed in pediatric patients,

who may be treated with drugs despite the lack of pediatric labeling.

According to this comment, most psychoactive medications are

underutilized in pediatric patients due to the lack of pediatric

labeling and to fear of overdosing. In the case of anti-hyperactivity

drugs, however, the comment states that as many children are

overtreated as undertreated, especially among pre-school age children.

A comment from the National Institute of Mental Health (NIMH) stated

that the rule was much needed to provide essential data on the safety

and effectiveness of psychiatric medications in pediatric patients.

This comment attached seven NIMH reviews of the existing data on

psychotropic medications for pediatric patients, identifying many

critical knowledge gaps that remain to be addressed by pediatric

research.

One comment stated that pediatric nephrologists frequently

prescribe drugs to pediatric patients for life-threatening conditions,

including antihypertensive medications, diuretics, lipid-lowering

agents, and immunosuppressive agents, even for pediatric patients less

than 2 years of age, without benefit of formal studies. This comment

further stated that drug therapy for chronic conditions like kidney

failure is currently based only on experience gained from drug usage in

children after approval for the indication in adults, and that

[[Page 66638]]

discovering ``inadequate dosing or severe side effects by empiric use

of these drugs is not desirable or safe.'' Another comment provided the

results of a survey of 4,898 pediatric patients with end-stage renal

disease on the medications they receive. Ninety-seven percent received

prednisone or prednisolone, 91 percent received cyclosporine, and 84

percent received azathioprine. According to the comment, none of these

drugs was studied in pediatric patients and no information on the

pharmacokinetics of these drugs in pediatric patients is available.

In contrast, several comments from the pharmaceutical industry

argued that voluntary measures, the 1994 rule, and the incentives

provided by FDAMA are adequate to assure adequate pediatric labeling

and that FDA has not given these steps sufficient time to work. Several

comments argued that to obtain pediatric studies, FDA should use

encouragement and early discussion with sponsors, together with

incentives, rather than imposing new requirements. These comments

contended that sponsors should make ``phase 4 commitments''

(commitments to conduct pediatric studies after approval) and FDA

should track these commitments. According to one comment, these methods

have not been systematically used by FDA. According to another comment,

FDA did not describe its present experience in getting manufacturers to

conduct pediatric studies. Other comments argued that FDA has not

allowed the 1994 rule sufficient time to produce results and that the

agency should wait until it has reviewed and acted upon all supplements

submitted under that rule before imposing new requirements. One comment

contended that if the 1994 rule was successful in producing pediatric

labeling for marketed drugs, the new rule should apply only to new

drugs. One comment argued that incentives, including exclusivity,

waiver of user fees, tax credits, and expedited reviews of pediatric

supplements, and liability protection for research physicians,

Institutional Review Boards (IRB's), universities, pharmaceutical

firms, and parents, are the best means of obtaining pediatric labeling.

A few comments argued that excessive litigation will follow imposition

of this rule.

Two comments argued that the 53 NME's approved in 1996 demonstrate

that pediatric labeling efforts by the industry are adequate, and that

new requirements are not needed. Although the figures used in the 2

comments do not agree exactly, these comments stated that 20 or 21 of

the 53 have potential for pediatric use. According to these comments,

of these, 4 have approved pediatric labeling, 14 have planned or

ongoing studies, 1 is switching to over-the-counter (OTC) use, and 1 or

2 have no immediate plans for pediatric labeling activities. One

comment contended that, between 1990 and 1997, a 28 percent increase

occurred in the number of new drugs in development for pediatric uses,

but provided no data to support this claim.

FDA believes that the current state of pediatric labeling for drugs

and biologics in the United States, as amply illustrated by comments

from the pediatric community, is unsatisfactory. The agency's failure

to obtain a significant increase in labeling for either new or marketed

drugs or biologics through other measures implemented over the last

several years demonstrates the need for a requirement that sponsors

conduct pediatric studies of drugs and biologics that represent a

meaningful therapeutic benefit to pediatric patients or that will be

widely used in pediatric patients. As described in section I of this

document, the response to the 1994 rule has not produced a significant

improvement in pediatric labeling for marketed drugs. FDA received

labeling supplements only for a small fraction of the drugs and

biologics on the market. Of those supplements it did receive, over half

of the submissions merely sought to add a statement to the product's

labeling that ``safety and effectiveness in pediatric patients have not

been demonstrated,'' and less than a quarter provided adequate

pediatric information for some or all relevant age groups.

The agency's experience in attempting to obtain pediatric labeling

for new drugs entering the marketplace through voluntary measures has

also been disappointing. As described in the proposal, the percentage

of NME's with adequate pediatric labeling has not increased since 1991,

when the agency began systematic efforts to obtain better pediatric

labeling. Although the number of requests by the agency and commitments

by sponsors to conduct phase 4 (postapproval) pediatric studies may

have increased, these requests and commitments have so far infrequently

resulted in pediatric labeling. Table 1 of this document displays the

results of commitments or requests to conduct pediatric studies

postapproval between 1991 and 1996. FDA notes that the table does not

reflect any labeling supplements under review. There are a total of six

pediatric labeling supplements currently under review for NME's

approved between 1991 and 1996. These supplements may or may not add

significant new labeling information; but, in any case, would not

substantially increase the number of successfully conducted

postapproval studies.

Table 1.--Pediatric Labeling

----------------------------------------------------------------------------------------------------------------

Status of pediatric labeling 1991 1992 1993 1994 1995 1996 Totals

----------------------------------------------------------------------------------------------------------------

NME's approved.......................................... 30 25 25 22 28 53 183

Pediatric studies not needed............................ 14 11 11 7 14 13 70

Label includes some pediatric use information or

pediatric studies complete at time of approval......... 9 4 \1\ 5 \1\ 6 5 15 44

Postapproval pediatric studies promised or requested.... 7 10 \2\ 10 \2\<SUP>,\3

\ 10 \2\ 10 17 64

Pediatric labeling added after approval................. 1 0 2 4 2 2 11

----------------------------------------------------------------------------------------------------------------

\1\ In one case, pediatric use information provided for one of two approved indications.

\2\ In one case, pediatric data requested for second of two approved indications.

\3\ In one case, pediatric data requested for additional age groups.

As Table 1 of this document reflects, FDA's figures disagree with

those of the comments for the number of 1996 NME's with potential for

pediatric use, the number with some pediatric labeling at the time of

approval and the number for which commitments or requests for

postapproval studies have been made. The comments did not identify

specific drugs, so it is not possible to determine why the two sets of

figures conflict. Nevertheless, the historical experience reflected in

the table suggests that most of the postapproval pediatric studies for

which commitments were made for the

[[Page 66639]]

1996 NME's will not result in pediatric labeling. Of the 17 commitments

to conduct pediatric studies in 1996, there have thus far been only 2

additions of pediatric labeling. Although some additional studies

supporting labeling changes may be submitted in the future, the

experience reflected in Table 1 of this document suggests that this

will not be a large number. For example, the 27 promised or requested

studies for the 1991 through 1993 cohorts have resulted in just 3

additions of pediatric labeling 5 to 7 years after approval. Thus, FDA

does not agree that the experience with 1996 NME's demonstrates the

adequacy of current efforts to obtain pediatric labeling.

None of the comments claiming that the rule will result in

excessive litigation provided any evidence suggesting a relationship

between pediatric testing and increased litigation or liability. As

shown in the number of NME's with pediatric labeling at the time of

approval, a significant minority of drug and biologic manufacturers

already conducts pediatric testing. FDA is aware of no evidence that

excessive litigation has been associated with this testing.

With respect to the argument that the incentives provided by FDAMA

will be sufficient to ensure adequate pediatric labeling, FDA believes

that a mixture of incentives and requirements is most likely to result

in real improvements in pediatric labeling. FDA is hopeful, e.g., that

the FDAMA incentives will make more resources available for pediatric

studies. As described earlier, FDA does not believe, however, that

incentives alone will result in pediatric studies on some of the drugs

and biologics where the need is greatest. The incentives provided by

FDAMA are available only for drugs already covered by the exclusivity

or patent protection provided by sections 505 and 526 of the act. Thus,

the FDAMA incentives are not available for many already marketed drugs,

or for many antibiotics or biologics. In addition, limited resources

available to conduct pediatric studies and fiduciary obligations to

shareholders may cause manufacturers to conduct pediatric studies

preferentially on those drugs where the incentives are most valuable,

rather than on those drugs or biological products where studies are

most needed.

4. Two comments argued that the rule is inconsistent with a 1977

FDA document entitled ``General Considerations for the Clinical

Evaluation of Drugs in Infants and Children,'' which recommended, among

other things, that ``reasonable evidence of efficacy generally * * * be

known before infants and children are exposed to [a drug].''

As described in more detail in section III.D of this document under

``Deferral,'' FDA expects that for drugs and biologics other than those

for life-threatening diseases without adequate treatment, clinical

trials in pediatric patients will ordinarily begin no earlier than when

initial data from well-controlled trials in adults (frequently referred

to as phase 2 data) become available to ensure that reasonable

preliminary evidence of safety and/or effectiveness is available before

pediatric patients are exposed to the drug or biological product. How

much evidence of safety or effectiveness is ``reasonable evidence''

that should be available before pediatric trials may begin will be

determined on a case-by-case basis. Thus, FDA believes that this rule

is substantially consistent with the 1977 document.

FDA notes that the 1977 document was based upon a report prepared

for FDA under a contract with the American Academy of Pediatrics (AAP).

The AAP is currently developing proposed revisions to this document

concerning the types of data needed to support pediatric labeling. The

1977 document, which falls under the general category of guidance

documents, does not bind FDA or the public, but represents the agency's

current thinking on a particular issue. Alternative approaches may be

used if the alternative satisfies the requirements of the applicable

statute and regulations (62 FR 8961, February 27, 1997) (Good Guidance

Practices document). Until such time as an updated guidance on the

clinical evaluation of drugs in infants and children is published,

sponsors are encouraged to confer with the agency before initiating

pediatric studies.

5. Several comments challenged FDA's use of the 1994 IMS National

Disease and Therapeutic Index (NDTI) data on the 10 drugs used most

frequently in pediatric patients without adequate labeling, arguing

that the data incorrectly imply that physicians have no labeling

information, when in fact prescribing information is now, or will be,

available for most of the 10 drugs listed.

These comments misunderstand the purpose for which FDA cited the

1994 data. Those data provided a snapshot of the labeling information

available to physicians for 10 widely used drugs at a given point in

time. Even if additional information had been added to the labels of

these drugs in the 4 years since the survey was conducted, there was

none available during a year in which the drugs, together, were

prescribed to pediatric patients over 5 million times. FDA notes,

moreover, that, contrary to the suggestion in the comments, adequate

labeling has been added for only 1 of the 10 drugs for the age group

described in the proposal.

6. Two comments disputed the estimated number of times their

products were prescribed to pediatric patients. One manufacturer argued

that the total units sold of Auralgan were less than the listed number

of prescriptions. Another manufacturer disputed the estimates of

Ritalin usage. This manufacturer also complained that it was not

contacted by FDA about use of Ritalin despite the statement in the

proposal that FDA had contacted the manufacturers of the top 10 drugs

used without adequate labeling in pediatric patients.

Limitations on the data used to estimate number of prescriptions

may have resulted in the discrepancy noted by the manufacturers of

Auralgan or Ritalin. The number of prescriptions is estimated from data

provided by IMS America, Ltd. IMS NDTI surveys a sample of physicians

(more than 2,940 physicians representing 27 specialities) to determine

the number of times that, during patient contacts, physicians mentioned

specific drugs for particular age groups. Physician mentions may not

correlate exactly with actual usage. In addition, the NDTI numbers

taken from the sample of physicians are extrapolated to the nation as a

whole, using a given formula. With respect to the claim that FDA has

not contacted the manufacturer of Ritalin, FDA notes that it has

scheduled meetings with the manufacturer to discuss use of the drug in

children, which have been canceled at the manufacturer's request.

7. One comment challenged FDA's use of quinolones as an example of

a class of drug that does not need to be studied in pediatric patients.

The comment claimed quinolones do need to be studied in pediatric

patients because of their important use in cystic fibrosis patients.

FDA agrees that fluoroquinolones may provide important therapeutic

benefits to patients with cystic fibrosis. At present, all approved

fluoroquinolones are labeled with the following statement: ``Safety and

effectiveness in children and adolescents less than 18 years of age

have not been established.'' In addition, the label includes a

statement advising that the fluoroquinolones cause arthropathy in

juvenile animals. Historically, the agency has recognized a potential

therapeutic role for the fluoroquinolones in children with cystic

fibrosis and hematology/oncology

[[Page 66640]]

disorders. Indeed, FDA recently approved ciprofloxacin labeling

containing a discussion of cystic fibrosis experience in the pediatric

use subsection. These actions show that the agency recognizes that

there may be a need to study fluoroquinolones in some pediatric

patients.

8. One comment from a pharmaceutical company argued that serious

ethical, legal, medical, and technical difficulties often prevent

conducting pediatric studies. The comment cited difficulties in

enrolling pediatric patients in sufficient numbers, unwillingness of

parents to enroll children, and the absence of pediatric patients with

the disease near convenient and qualified study centers. According to

the comment, studies have been successfully conducted in pediatric

patients in the past where there was a medical need for the drug in

pediatric patients, but this rule will require pediatric studies of

drugs intended for adults that may or may not be administered to

pediatric patients. The comment also contended that the rule will

necessitate a massive infusion of resources for industry, FDA, and

medical speciality organizations, and that the agency should start with

a small list of diseases with similar pathophysiology in adults and

children, and a small list of drug classes known to have similar

metabolism, and plan a graduated approach.

Contrary to the suggestion in the comment, this rule is designed to

require studies only in those settings in which there is a significant

medical need or where usage among pediatric patients is likely to be

substantial. FDA acknowledges the difficulties encountered in some

cases, but agrees that where there is a need for studies these

difficulties have been overcome and that pediatric studies have been

successfully conducted in many situations. FDA believes that the number

of such studies already conducted each year, for example of

antibiotics, vaccines, and roughly 25 percent of NME's, support the

view that such studies are not medically, ethically, or technically

impossible. FDA also emphasizes that this rule will not require studies

in settings where ethical or medical concerns militate against studies.

As with all studies regulated by FDA, no pediatric study may go forward

without the approval of an IRB, which is responsible for ensuring that

the study is ethical and adequately protects the safety of the

subjects. In addition, the deferral provisions of the rule are

specifically designed to ensure that no pediatric study begins until

there are sufficient safety and effectiveness data to conclude that the

study is ethically and medically appropriate.

B. Scope

The proposal would have covered only original applications for

those drugs classified as ``new chemical entities,'' including

antibiotics, and new biological products that had never been approved

for any indication. A ``new chemical entity,'' defined in 21 CFR

314.108(a), is a drug that contains no previously approved active

moiety. Under the proposal, chemical modifications that did not change

the active moiety, such as the formation of a different salt or ester

of the moiety, would not have required further study. New indications

or dosage forms of a previously approved moiety also would not have

required further studies. FDA sought comment on whether the requirement

should apply more broadly, e.g., to applications for minor chemical

variations of approved products, new indications, new dosage forms or

new routes of administration.

9. A majority of those who commented on the scope of the rule

recommended that the final rule cover all new drugs and biologics,

including new dosage forms and indications, because modifications in

existing drugs may be as therapeutically significant to pediatric

patients as the original drug or biologic. These comments included

pediatricians, medical societies, one pharmaceutical company, and one

disease-specific organization. Several comments, including two

companies, an IRB, the AAP, a disease-specific organization, and a

professional society recommended including new indications and dosage

forms on a case-by-case basis, generally if their inclusion were

recommended by an expert panel. Several comments supported the narrow

scope of the proposal, including a pharmaceutical trade association, a

professional society, and several companies. The pharmaceutical trade

association suggested that the rule might also apply to new

formulations uniquely suited to pediatric patients.

FDA has reconsidered the scope of the rule in light of the comments

and has concluded that, in some cases, the need for pediatric studies

is as great for modifications of existing products and new claims as

for the original products. A new indication or dosage form for a

previously approved drug, e.g., could be far more relevant to pediatric

patients than the originally approved product. From a public health

standpoint, FDA cannot justify the distinction in the proposal between

new chemical entities and never-before approved biologics, on one hand,

and significant modifications of those products, on the other hand.

Therefore, FDA has revised proposed Secs. 314.55 (proposed 314.50(g))

and 601.27(a) to cover applications for new active ingredients, new

indications, new dosage forms, new dosing regimens, and new routes of

administration. The final rule exempts from its coverage any drug for

an indication or indications for which orphan designation has been

granted under the Orphan Drug Act (21 U.S.C. 360bb). FDA believes this

exemption is appropriate because the purpose of the Orphan Drug Act is

to encourage the development of drugs for patient populations that are

so small as to make the manufacture and sale of the drug unprofitable

if not for the incentives offered by the Orphan Drug Act. Imposition of

a pediatric study requirement on an orphan drug could conflict with the

balance struck by the Orphan Drug Act, by further raising the cost of

marketing the drug. This exemption does not apply after marketing under

Sec. 201.23 of this final rule.

FDA's decision to expand the scope of the rule does not mean,

however, that pediatric studies would always be needed for a new

product entering the marketplace, or for a new claim. The waiver

criteria will apply equally to modifications of existing drugs and

biological products. Thus, FDA will require studies only of those new

drugs and biologics that offer a meaningful therapeutic benefit to

pediatric patients or that are expected to be used in a substantial

number of pediatric patients. In many cases, moreover, new dosage forms

might need relatively little pediatric data, such as pharmacokinetic

data alone.

10. One comment sought clarification of the applicability of the

rule to generic drugs. The comment argued that the collection of

pediatric data was unwarranted where a generic manufacturer was copying

a drug with an adult dose, and that FDA should require a pediatric

bioequivalence study only where the innovator submits a supplement for

a new dose or regimen in the pediatric population. Another comment from

a generic drug trade association argued that bioequivalence studies in

children should never be required to support approval of a generic

drug.

This rule does not impose any requirements on studies submitted in

support of applications for generic copies of approved drugs that meet

the requirements of section 505(j) of the act. FDA also does not

currently require bioequivalence studies to be conducted

[[Page 66641]]

in children for generic drugs. FDA notes that petitions submitted under

section 505(j)(2)(C) for a change in active ingredient, dosage form, or

route of administration may be denied if ``investigations must be

conducted to show the safety and effectiveness of'' the change. Thus,

if a petition is submitted for a change that would require a pediatric

study under this rule, the petition may be denied.

C. Required Studies

FDA proposed to amend its regulations related to the content of NDA

and biologic license applications (BLA's) to include required

information on pediatric studies for certain applications. Under the

proposal, an application for a new chemical entity or never before

approved biologic would have been required to contain data adequate to

assess the safety and effectiveness of the product for all pediatric

age groups for the claimed indications, unless FDA granted a deferral

or full or partial waiver of the requirement. As described in section

III.B of this document under ``Scope'', FDA has revised Sec. 314.55(a)

(proposed Sec. 314.50(g)(1)) and Sec. 601.27(a)) to cover applications

for new active ingredients, new indications, new dosage forms, new

dosing regimens, and new routes of administration. Under the final

rule, all covered applications will be required to contain data

adequate to assess the safety and effectiveness of the product, unless

FDA has granted a waiver or deferral of the requirement (see ``Waiver''

and ``Deferred Submission'' in section III.D and E of this document).

Assessments required under this section for a product that

represents a meaningful therapeutic benefit over existing treatments

must be carried out using appropriate formulations for the age group(s)

for which the assessment is required, unless reasonable efforts to

produce a pediatric formulation had failed (see ``Waiver'' in section

III.E of this document). Comments on issues related to formulation are

addressed under ``Pediatric Formulations'' in section III.I of this

document.

The proposal did not mandate particular types of studies. The

proposal recommended that the sponsor consult with FDA on the types of

data that would be considered adequate to assess pediatric safety and

effectiveness in particular cases.

FDA received several comments on the design and conduct of clinical

trials in pediatric patients.

11. One comment asked for clarification of what is meant by

``adequate evidence'' to demonstrate safety and effectiveness. The

comment argued that FDA should not require two adequate and well-

controlled trials for pediatric studies, and that the amount of

evidence required should depend on the ability of the data to be

extrapolated from adult to pediatric patients, the seriousness of the

illness to be treated, the ability to assess meaningful measures of

efficacy in pediatric patients, and the feasibility of conducting

adequate trials in relatively uncommon pediatric disease states.

Another comment claimed that the ability to extrapolate from adult

efficacy data is limited and argued that well-controlled trials in

pediatric patients should be the norm. This comment also stated that

safety cannot be extrapolated from adult data and recommended studying

300 pediatric patients for an adequate period to identify frequent

ADR's. Other comments questioned the appropriateness of extrapolating

from adult effectiveness data in a variety of settings. One comment

argued that in the area of blood products, in addition to extrapolating

from pharmacokinetic data, it may be appropriate to extrapolate from

adult data using relative blood volume replacement. Several comments

urged reliance on a variety of other sources of data, including

published studies and reports, and actual use information. One comment

urged FDA to rely on advanced scientific and statistical methods that

optimize safety, convenience, and informativeness, while minimizing

unnecessary or uninformative clinical trials.

FDA agrees that ``adequate evidence'' of safety and effectiveness

for pediatric patients does not necessarily require two adequate and

well-controlled trials. One of two central purposes of the 1994 rule

was to make it clear that pediatric effectiveness may, in appropriate

circumstances, be based on adequate and well-controlled studies in

adults with supporting data in pediatric patients that permit

extrapolation from the adult data. FDA agrees, however, that

extrapolation from adult effectiveness data would not always be

appropriate and that it may not be appropriate to extrapolate pediatric

safety from adult safety data. FDA has specifically noted, in the FDA

guidance document entitled ``Providing Clinical Evidence of

Effectiveness for Human Drug and Biological Products,'' that if further

controlled trial data were needed in a population subset, it would

usually be sufficient to conduct a single additional controlled trial.

FDA also agrees that useful information can come from data other than

adequate and well-controlled trials, and encourages the submission of

valid and reliable data from a variety of sources. The type and amount

of data required in any particular case will depend upon many factors,

including those cited in the comments.

12. One comment urged FDA, in the final rule, to encourage sponsors

to use Computer-Assisted Trial Design (CATD), allowing them to reduce

number of actual trials in pediatric patients.

FDA encourages the use of any validated scientific method for

designing, conducting, or analyzing clinical trials.

13. One comment questioned whether there will be a sufficient pool

of pediatric subjects to complete trials, in light of the increase in

the number of trials occasioned by the rule.

FDA believes that with appropriate organization, the pool of

pediatric patients available for studies should be adequate. The

Pediatric Pharmacology Research Units (PPRU's), a network of groups

instituted to conduct pediatric research, some of which are located

outside of major population centers, have an established record of

recruiting pediatric patients and completing valid studies. Even where

the number of pediatric patients affected by a disease is small, valid

studies have sometimes been successfully conducted. It should also be

reemphasized that many of the studies contemplated under the rule are

pharmacokinetic studies, dose-response studies with short-term

endpoints (pharmacodynamic studies) and safety studies that are likely

to impose relatively little burden on individual patients. Where,

however, patient recruitment is so difficult as to make the study

impossible or highly impractical, the rule permits a waiver of the

study requirement (Secs. 314.55(c) and 601.27(c)).

14. One comment urged that the final rule include a broader

research requirement, and sought to have drug interactions and drug

metabolism taken into consideration. Another comment sought to have the

final rule codify minimal requirements for studies, such as toxic

overdose and pharmacokinetic data. One comment urged FDA not to codify

specific requirements for clinical trials, but to establish these

requirements in consultation with an expert pediatric committee.

FDA declines to codify specific requirements for pediatric studies.

Flexibility is necessary to assure that required studies are

appropriate for each product. FDA will, however, consult with a

pediatric committee on specific pediatric study issues.

[[Page 66642]]

15. One comment from a professional pharmacy organization urged

that all protocols for pediatric studies be reviewed by pediatric

experts, including a pharmacist knowledgeable about pharmacodynamic

factors in each age group.

FDA reviews protocols for pediatric studies submitted in

investigational new drug applications (IND's), and its reviewers

include experts in pediatrics and pharmacology.

D. Deferred Submission

The proposal recognized that there would be circumstances in which

it would be appropriate to permit the submission of pediatric data

after approval. Two such circumstances were described in the preamble

to the proposal: (1) Where adult safety or effectiveness data need to

be collected before the product could be appropriately studied in

pediatric patients, and (2) where the product was ready for approval in

adults before studies in pediatric patients were completed. Although

not included in the text of the proposal, these examples have been

added to the final rule. Under the proposal, FDA would have the

authority to defer the submission of some or all of the required

pediatric data until after approval of the product for adult use, on

its own initiative or at the request of the applicant. Under the

proposed provisions, if the applicant requested deferral, the request

would be required to contain an adequate justification for delaying

pediatric studies. If FDA concluded that there were adequate

justification for deferring the submission of pediatric use studies,

the agency could approve the product for use in adults subject to a

requirement that the applicant submit the required pediatric studies

within a specified time after approval. It is important to appreciate

that deferred submission of pediatric data refers to the date on which

the data are submitted, not when the studies are initiated. Thus,

deferred studies will generally be initiated before approval, unless it

is concluded that the full adult data base or marketing experience are

needed before pediatric studies may appropriately begin.

FDA stated in the proposal that it would consult with the sponsor

in determining a deadline for the deferred submission, but tentatively

concluded that it would require the submission not more than 2 years

after the date of the initial approval. To ensure that deferral would

not unnecessarily delay the submission of pediatric use information,

FDA proposed that a request for deferred submission include a

description of the planned or ongoing pediatric studies, and evidence

that the studies were being, or would be, conducted: (1) With due

diligence, and (2) at the earliest possible time. FDA sought comment on

the circumstances in which FDA should permit deferral, and on the

factors that should be considered in determining whether a given

product was one that should be studied in adults before pediatric

patients. FDA received many comments on the deferral provisions in the

proposal.

16. A few comments stated that the deferral provisions are an

appropriate means of assuring that pediatric patients are not studied

before adequate safety data have been gathered. A number of comments

from the pharmaceutical industry asserted, however, that the proposal

would require concurrent testing in adults and pediatric patients

despite medical and ethical reasons for delaying testing pediatric

testing. For example, a comment from a pharmaceutical trade association

claimed that the rule:

* * * would require testing of new medical compounds in children

before safety in adults has been studied adequately, before

effectiveness in adults has been established, and in young children and

neonates without adequate information about the effects of the drug in

older pediatric patients.

These industry comments appear to have misunderstood the explicit

deferral provisions of the rule and perceived them as rare exceptions

to a usual requirement that adults and children be studied at the same

time. Nothing in the rule requires concurrent testing in adults and

pediatric patients, nor testing in infants and neonates before testing

in older children. As stated previously and in the proposal, the

deferral provisions were specifically included to, among other things,

ensure that pediatric studies could be delayed when necessary to assure

that appropriate safety and/or effectiveness data were available to

support pediatric testing.

17. Most of the comments on deferral focused on whether the need

for safety and/or effectiveness data in adults before initiating

pediatric studies should be a basis for deferral. Comments from

disease-specific organizations, medical societies, including the AAP,

and pediatricians argued that deferrals should be granted rarely if at

all on this basis. One comment argued that delaying availability of

life-saving drugs to children cannot be rationalized scientifically,

legally, or ethically, and contended that deferral should not be

permitted for serious and life-threatening diseases where there is no

substantial difference between the disease or the anticipated effect of

the drug in children or adults. Another comment argued that deferral

should be used sparingly in all age groups, including infants and

neonates, and that its use should be evaluated in the context of the

seriousness of the condition to be treated, the therapeutic advance the

drug represents, and the likelihood that the drug will be given to

children as soon as it is approved. According to this comment, the

risks of research in pediatric patients may be outweighed by the risks

that the drug will be given to them without data.

One comment argued that pediatric studies of important drugs should

be conducted in parallel to adult studies, especially in children under

12. Several comments from the pediatric community, however, supported

the development of some adult safety and/or effectiveness data before

initiation of pediatric studies. One comment from an organization

devoted to pediatric AIDS stated that while the general assumption

should be that pediatric studies will be submitted at the same time as

adult studies, it may be appropriate to have some testing in adults

before children. The AAP stated that it is appropriate to begin studies

in pediatric patients after phase 1 and phase 2 studies in adults have

defined routes of clearance and metabolic pathways. Thus, the comment

urged that pediatric studies be conducted during phases 2 and 3, not 4.

A comment from a nephrology organization argued that drugs for organ-

specific diseases should be studied in phase 3, as soon as phase 1 and

2 trials have shown safety in adults. This and another comment stated

that deferring studies until after approval compromises clinical trial

enrollment, citing the experience with recombinant erythropoietin.

According to these comments, erythropoietin was not studied in

pediatric patients until after its approval for adults, and enrollment

was so difficult that pediatric studies were not completed for 5 years.

Several comments from the pediatric community also cited limited

circumstances in which they believed deferral to be appropriate. A

medical society argued that data should be collected after adult

studies only for drugs with narrow therapeutic indices, unusual

accumulation in the body, where the drug study requires extensive blood

sampling, or where the study design places young patients at risk for

limited information gain.

Many comments from the pharmaceutical industry argued, in contrast,

that deferral should be the

[[Page 66643]]

rule, rather than the exception. Most of these comments contended that

it was unethical to begin studying drugs in pediatric patients, other

than those that are intended primarily for pediatric patients, until

the drugs are shown to be reasonably safe and effective in adult

patients. All argued that pediatric studies must not be initiated until

substantial data in adults are available, but cited different

initiation points, e.g., after phase 2, after safety and effectiveness

is established in adults and an approvable letter is received, after

approval, after 1 year of marketing.

Although many of these industry comments argued that pediatric

studies should be conducted exclusively as phase 4 (postapproval)

commitments, a significant number of industry comments acknowledged

that pediatric studies could begin before approval, generally after

phase 2, and that there were circumstances in which deferral was not

appropriate. One comment argued that because early pediatric studies

often require pediatric formulations and because up to 50 percent of

drugs are abandoned before phase 3, it is wasteful to require companies

to manufacture a pediatric formulation and begin studies before the end

of phase 2. Another comment argued that no pediatric studies should

begin before the decision to proceed to phase 3, except where: (1) The

disease affects only pediatric patients; (2) the disease mainly affects

pediatric patients, or the natural history or severity of the disease

is different in pediatric patients and adults; or (3) the disease

affects both pediatric patients and adults and lacks adequate treatment

options. One comment urged that the final rule state that ``in most

cases, pediatric testing should not begin with any drug or biological

product until certain adult safety and/or effectiveness information has

been collected.'' According to this comment, there could be exceptions

where no other therapy was available and there was a potential for the

drug to be lifesaving. A pharmaceutical trade association argued for a

presumption that pediatric studies not begin until the end of phase 2

or 3, but listed circumstances in which deferral should not occur: (1)

Where the disease is life threatening and there is no alternative

therapy, (2) where the drug is intended for a pediatric indication, (3)

where the drug presents no major safety issues, (4) where the drug

class is well studied in pediatric patients, or (5) where a large

amount of ``off-label'' use in pediatric patients is anticipated.

In general, FDA expects that some data on adults will be available

before pediatric studies begin, but that less data will usually be

required to initiate studies of drugs and biologics for life-

threatening diseases without adequate treatment than for less serious

diseases. Pediatric studies of drugs and biologics for life-threatening

diseases may in some cases be appropriately begun as early as the

initial safety data in adults become available, because the urgency of

the need for such products may justify early trials despite the

relative lack of safety and effectiveness information. In such cases,

deferral of submission of pediatric studies until after approval will

be unnecessary, unless drug development is unusually rapid and the

product is ready for approval in adults before completion of the

pediatric studies.

Pediatric studies on products for less serious diseases should

generally not begin until more adult data have been collected,

ordinarily no earlier than the availability of data from the initial

well-controlled studies in adults. As noted earlier in this document,

there may occasionally be exceptions to this principle where all

parties agree that earlier initiation is appropriate. Whether deferral

of submission of the data until after approval will be necessary for

such products will depend upon when pediatric studies can

scientifically and ethically begin in each case and how difficult the

studies are to complete.

In some cases, FDA expects that scientific and ethical

considerations will dictate that studies not begin until after approval

of the drug or biological product. For example, pediatric studies of

``me-too'' drugs that do not offer a meaningful therapeutic benefit and

that are members of a drug class that already contains an adequate

number of approved products with pediatric labeling may be deferred

until well after approval. In cases where a drug has not been shown to

have any benefit over other adequately labeled drugs in the class, the

therapeutic need is likely to be low and the risks of exposing

pediatric patients to the new product may not be justified until its

safety profile is well established in adults through marketing

experience. Because the basis for the deferral in such cases will be

concern that the drug presents risks to pediatric patients that will

not be known until there is widespread marketing experience, without

offsetting benefit, FDA may require, in appropriate cases, that such

drugs carry labeling statements recommending preferential use in

pediatric patients of products that are already adequately labeled.

Such a statement might read:

The safety and effectiveness of this product have not been

established in children. There are alternative therapies that have

been shown to be safe and effective for use in children with

[indicated condition]. Ordinarily, products already labeled for use

in children should be used in preference to [name of this product].

FDA labeling regulations at 21 CFR 201.57 express the agency's

authority to ensure that drugs are safe for use under the conditions

prescribed, recommended, or suggested in their labeling, and to require

labeling identifying safety considerations that limit the use of drugs

to certain situations. Some drugs with no demonstrated advantage over

available therapy can nonetheless be expected to have wide use in

pediatric patients. Pediatric studies of such drugs should be initiated

relatively early, even if they are not completed at the time of

approval.

18. A comment from a pharmaceutical company listed several

circumstances in which it argued FDA should permit deferral: (1) The

pediatric population is so small that enrollment and completion of

trials cannot be accomplished in parallel with adult trials, (2) the

natural course of the disease is different in adults and children, (3)

analytic tools and clinical methodologies cannot be easily adapted to

the pediatric population, (4) the drug has complex pharmacokinetic

properties in adults making it hard to extrapolate a pediatric dosage

range, (5) the scope and nature of nonclinical studies support only

adult clinical studies, (6) two or more attempts to develop a pediatric

formulation have failed, or (7) unique drug-drug or drug-food

interactions in children confound drug development. Another comment

added to this list: (1) Where fewer than 200,000 pediatric patients are

affected by the disease being treated, and (2) drugs with a low

therapeutic index.

FDA agrees that some of these circumstances could make completion

of studies prior to approval in adults difficult, but does not agree

that they would make studies impossible or impractical in all cases.

The need for deferral must be considered case-by-case. A small

pediatric population, e.g., might make completion of controlled trials

very slow, but might not prevent obtaining pharmacokinetic data. Simply

citing a pediatric population under 200,000 will not be sufficient to

justify deferral; a small fraction of this number participating in

trials may be sufficient to support timely pediatric studies, depending

on the nature of the studies. As an example, over 70 percent of the

estimated 6,000 pediatric patients with cancer each year are enrolled

in clinical trials (Ref. 15). There does not seem to

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be any reason to conclude that deferral is warranted solely because the

natural course of the disease is different in adults and children. FDA

also disagrees that deferral is necessarily warranted where analytic

tools and clinical methodologies cannot be easily adapted to pediatric

patients. Deferral may be necessary in some cases where the infants and

toddlers are unable to provide subjective outcome data, but it may also

be possible to utilize alternative endpoints or to extrapolate

effectiveness data from older pediatric age groups, obtaining

pharmacokinetic data from the younger age groups to determine an

appropriate dose. Drugs with a low therapeutic index that do not

fulfill an urgent need should, in general, be studied in pediatric

patients later in drug development.

With respect to complex pharmacokinetic properties that prevent

extrapolation of adult data to pediatric patients, low-therapeutic

index drugs, and unique drug-drug or drug-food interactions in

pediatric patients, FDA believes that the need for pediatric studies

before approval is even greater where these conditions are present;

moreover, none of them represents a significant impediment to studies.

Recognizing that drugs and biologics approved for adults are regularly

prescribed to pediatric patients despite the absence of adequate dosing

and safety data, information positively suggesting that dosing and

safety cannot be extrapolated from adult data increases the importance

of conducting pediatric studies before the product is widely used in

pediatric patients. The absence of supporting nonclinical studies

(e.g., studies in young animals) should not usually be a basis for

deferral. These studies, if needed, are readily conducted. Moreover, a

full adult data base provides pertinent safety information that might

make further preclinical data unnecessary. Difficulties in developing

an adequate pediatric formulation may, in some cases, justify deferral

of studies in young pediatric patients. In other cases, however, it may

be appropriate to study a less-than-optimal formulation, e.g., an

injection, if one is available, in pediatric patients while awaiting

the development of a more desirable pediatric formulation.

19. One comment argued that it was ``unacceptable'' to defer

pediatric studies to avoid delaying approval for adult use. Instead,

the comment urged FDA to provide a ``limited approval'' for adult use

until pediatric data are available and impose a monetary penalty for

failure to comply. Another comment argued that permitting deferral to

avoid delay in adult marketing could be applied to most applications,

creating a de facto situation in which pediatric data were understood

to be not required until 2 years after approval. One comment stated

that while pediatric dosing schedules are essential, pediatric studies

should not delay approval of drugs for a major population, adults.

FDA continues to believe that deferral is appropriate where

awaiting the completion of pediatric studies would delay the

availability of a safe and effective drug or biological product for

adults. Granting a deferral does not automatically mean, however, that

pediatric studies need not be submitted for 2 years or that initiating

them should be long delayed. The proposal suggested 2 years as the

maximum period for a deferral. Where pediatric studies are supposed to

be nearing completion at the time a product is ready for approval in

adults, FDA expects that the period of deferral would be significantly

shorter than 2 years. Where some useful pediatric information, e.g.,

safety information, is available at the time of approval, even if some

required studies are not complete, FDA may require that the pediatric

use section of the product's labeling include that information, to the

extent consistent with 21 CFR 201.57(f)(9). FDA also notes that it has

no authority to impose a monetary penalty for failure to submit a

required study of a drug or biological product. FDA must ask a court to

impose such a penalty in a contempt proceeding.

20. Several comments argued that pediatric trials should be

conducted sequentially, beginning with the oldest pediatric age group,

and ending with the youngest. One comment stated that IRB's would

question testing a drug in younger children before older children. The

AAP argued that there is little defense for studying pediatric patients

sequentially from oldest to youngest, and that such a policy will

result in approvals without data in neonates. This comment argued that

the timing of studies should give consideration to safety, but without

consideration of sequence. Another comment argued that FDA should not

routinely require that drugs for serious and life-threatening diseases

be studied sequentially. In HIV, according to this comment, drug

testing should be ``as simultaneous as possible'' because safety and

dosing may be initiated in each age group in a dose escalating manner

regardless of the results in previously tested groups.

FDA agrees that age-dependent sequential studies are not

necessarily appropriate. Particularly were there is urgent need for a

product, there may be good reason to study older and younger children

at the same time.

21. A few comments objected to FDA's tentative decision to require

the submission of studies ordinarily no later than 2 years after the

initial approval. One comment stated that deferral of up to 2 years was

excessive, citing the ``critical'' need to ensure timely performance of

pediatric studies in populations where the drug is likely to be used.

Another comment stated that 2 years may be adequate for collecting

pharmacokinetic data, but not necessarily for collecting safety data.

According to this comment, the size of the clinical data base will be

the principal determinant of when data should be submitted. A comment

from the American Red Cross stated that the extensive IRB review of

studies of blood products involving pediatric patients, and the

difficulty in enrolling such patients, makes the 2-year deferral

deadline unrealistic for this category of product.

FDA agrees with the comments that the 2-year deadline suggested by

the proposal may not be appropriate, and that the length of the

deferral should be decided on a case-by-case basis. The timing of the

deferred submission will depend upon such factors as the need for the

drug or biologic in pediatric patients, when sufficient safety data

become available to initiate pediatric trials, the nature and extent of

pediatric data required to support pediatric labeling, and

substantiated difficulties encountered in enrolling patients and in

developing pediatric formulations. FDA may also extend the date for

submission of studies at the time of approval, e.g., where other drugs

in the class have been approved during the pendency of the NDA and the

new drug is no longer needed as a therapeutic option.

E. Waivers

FDA does not intend to require pediatric assessments unless the

product represents a meaningful therapeutic benefit over existing

treatments or is expected to be used in a substantial number of

pediatric patients. FDA also does not intend to require pediatric

assessments in other situations where the study or studies necessary to

carry out the assessment are impossible or highly impractical or would

pose undue risks to pediatric patients. Thus, FDA proposed to add

Sec. 314.50(g)(3) (now Sec. 314.55(c)) and Sec. 601.27(c) to authorize

FDA to grant a waiver of the pediatric study requirement on its own

initiative or at the request of the applicant unless the product

represented a meaningful therapeutic benefit over existing

[[Page 66645]]

treatments, or was likely to be used in a substantial number of

pediatric patients. These provisions also require FDA to grant a waiver

if necessary studies were impossible or highly impractical, because,

e.g., the number of pediatric patients was very small or patients were

geographically dispersed, or there was evidence strongly suggesting

that the product would be ineffective or unsafe in some or all

pediatric populations. If a waiver were granted because there was

evidence that the product would be ineffective or unsafe in pediatric

patients, this information would be included in the product's labeling.

An applicant could request a full waiver of all pediatric studies

if one or more of the grounds for waiver applied to the pediatric

population as a whole. A partial waiver permitting the applicant to

avoid studies in particular pediatric age groups could be requested if

one or more of the grounds for waiver applied to one or more pediatric

age groups. In addition to the other grounds for waiver, the proposal

would authorize FDA to grant a partial waiver for those age groups for

which a pediatric formulation was required (see ``Pediatric

Formulations'' in section III.I of this document), if reasonable

attempts to produce a pediatric formulation had failed.

The proposal would require the applicant to include in the request

for a waiver an adequate justification for not providing pediatric use

information for one or more pediatric populations.

FDA would grant the waiver request if the agency found that there

was a reasonable basis on which to conclude that any of the grounds for

a waiver had been met. If a waiver were granted on the ground that it

was not possible to develop a pediatric formulation, the waiver would

cover only those pediatric age groups requiring a pediatric

formulation.

The agency also proposed two possible methods of determining a

``substantial number of patients.'' The first method would focus on the

number of times the drug or biologic was expected to be used in

pediatric patients, annually. Under this method, FDA tentatively

concluded that 100,000 or more prescriptions or uses per year in all

pediatric age groups would be considered a substantial number.

The second proposed method for establishing whether there was a

substantial number of pediatric patients would focus on the number of

pediatric patients affected by the disease or condition for which the

product is intended. Under this method, FDA tentatively concluded that

100,000 pediatric patients affected by the disease or condition for

which a product was indicated would be considered a ``substantial

number'' of pediatric patients. FDA sought comment on the waiver

criteria and on these methods of calculating a substantial number of

pediatric patients. FDA also sought comment on whether cost to the

manufacturer should justify a waiver.

FDA received many comments on the waiver provisions of the

proposal, and has made certain changes in response to the comments, as

described below.

22. As proposed, new drugs and biologics are presumptively required

to be studied in pediatric patients, unless a waiver is granted. The

presumption in the proposal was supported by comments from

pediatricians, a pharmacy organization, disease specific organizations,

and medical societies, including the AAP. Several industry comments

argued, however, that new drugs and biologics should presumptively not

be covered by the rule, unless they were specifically identified by FDA

as needing to be studied. One of these comments stated that companies

should not have to waste the effort of applying for waiver for drugs of

no potential benefit to pediatric patients, which the comment estimated

as a majority of those developed.

FDA continues to believe that it is appropriate to presume that

drugs and biologics should be studied in pediatric patients, and that

this presumption should be overcome only if there are clear grounds for

concluding that such studies are unnecessary. Pediatric patients are a

significant subpopulation, affected by many of the same diseases as

adults, and are foreseeable users of new drugs and biologics. The

agency has stated, in the context of pediatric studies and other

subpopulations, that an application for marketing approval should

contain data on a reasonable sample of the patients likely to be given

a drug or biological product once it is marketed (59 FR 64240 at 64243;

58 FR 39406 at 39409, July 22, 1993). FDA does not believe that the

cost of drafting a waiver request will be great, particularly where the

basis for the waiver is that the product has no potential use in

pediatric patients. To assist sponsors in preparing such waivers, FDA

has included in this document a partial list of diseases that are

unlikely to occur in pediatric patients and for which waiver requests

need include only reference to this document.

23. FDA received many comments on the proposed criteria for waiving

pediatric studies. A few comments supported the proposed criteria. Many

comments from pediatricians, medical societies, and disease-specific

organizations argued that the proposed grounds for waiver were too

broad. Several of these stated that the rule should apply to drugs for

all conditions that affect pediatric patients unless there is a special

reason not to do so. One comment argued that waivers should be

available only for drugs known to be extremely toxic in pediatric

patients or to have no anticipated use in pediatric patients.

Other comments from the pharmaceutical industry argued that the

waiver provisions were too narrow. One comment from a generic trade

association urged that pediatric studies be required only when there is

a significant public health concern with respect to the safety of a

drug product in pediatric patients or to the availability of adequate

pharmacological intervention for pediatric patients for the indication.

Another comment stated that the criteria in the proposal ``do not begin

to address the complexities associated with moving forward on a

clinical development plan'' and argued that additional criteria should

include: (1) The lack of correlative safety evidence, (2) liability

concerns, and (3) prohibitive cost (but the sponsor, not FDA, should be

allowed to determine the importance of cost).

FDA believes that the criteria for waiver in the final rule strike

a careful balance. On the one hand, requiring studies for all new

products would have potentially severe resource implications for

manufacturers and the agency. On the other hand, obtaining studies only

where the studies impose no burden on the sponsor would continue to

expose millions of pediatric patients to unnecessary risks and

ineffective treatment. Requiring pediatric studies only of those drugs

or biologics that offer a meaningful therapeutic benefit or that are

expected to be used in a substantial number of pediatric patients

focuses limited resources on those products that are most critically

needed for the care of pediatric patients.

24. Several comments addressed the definition of ``meaningful

therapeutic benefit.'' Some comments from the pharmaceutical industry

stated that ``meaningful therapeutic benefit'' should be defined as it

is used in 21 CFR 314.500. (That regulation applies to drugs ``that

provide meaningful therapeutic benefit to patients over existing

treatments (e.g., ability to treat patients unresponsive to, or

intolerant of, available therapy, or improved patient response over

available therapy).'') One of these comments

[[Page 66646]]

suggested that analogous cases in the pediatric context would be: (1)

Where the drug treats a pediatric disease for which no other treatments

exist; (2) where the drug treats patients who are unresponsive to or

intolerant of other drugs; or (3) where the drug produces a superior

response over other treatments. One industry comment argued that the

agency should consult with the sponsor, and the pediatric investigators

involved to assess whether the drug will provide a ``meaningful

therapeutic benefit.'' According to the comment, the assessment should

include the likely use of the product in a specific pediatric

population, the likely benefit without increased risk to patients

versus existing treatments, a ``definitive need'' for a new therapy in

very serious or life-threatening illnesses, and the cost and

feasibility of developing the necessary formulations and of conducting

studies. Another comment from a disease-specific organization argued

that ``meaningful therapeutic benefit'' should be a relative term,

depending on the severity of the illness, the potential risk posed by

the drug, and the availability of alternative treatments. One comment

from a medical society devoted to the treatment of psychiatric

disorders contended that ``meaningful therapeutic benefit'' should mean

that the product enables a child to function better, and participate in

age-appropriate activities, such as playing and going to school,

without undue pain and suffering from the disease or disorder. Another

comment argued that ``meaningful therapeutic benefit'' should mean

better response or ability to treat nonresponsive patients. Another

comment maintained that the presumption should be that a product

represents a meaningful therapeutic benefit in pediatric patients if it

is expected to provide a meaningful therapeutic benefit in adults.

Several comments from the pharmaceutical industry contended that it

is not possible to define meaningful therapeutic benefit before

approval or that FDA should not be responsible for defining it. A

pharmaceutical trade association argued that meaningful therapeutic

benefit is the decision of the sponsor, not FDA, and that it is not

possible to determine meaningful therapeutic benefit until a drug has

been used for some period of time. Another comment maintained that FDA

must first have adult data to reach the conclusion that a drug offers a

meaningful therapeutic benefit. The same comment also argued that a

rigorous determination of meaningful therapeutic benefit would require

randomized, controlled trials in pediatric patients.

FDA disagrees that it is impossible or beyond FDA's expertise to

reach a conclusion before approval about whether a product has the

potential to offer a meaningful therapeutic benefit. FDA routinely

estimates the therapeutic benefit of new drugs and biologics at the

time applications are first submitted, in order to determine whether to

assign ``Priority'' (expedited) status to the review of the

application. In assigning Priority status to new drug applications,

CDER determines whether the product, if approved, ``would be a

significant improvement compared to'' marketed (or approved, if such is

required) products, including nondrug products or therapies.

``Improvement can be demonstrated by, for example: (1) Evidence of

increased effectiveness in treatment, prevention, or diagnosis of

disease; (2) elimination or substantial reduction of a treatment-

limiting drug reaction; (3) documented enhancement of patient

compliance; or (4) evidence of safety and effectiveness in a new

subpopulation'' (Ref. 16). These criteria are similar to many of the

criteria suggested in the comments. FDA notes that demonstration of an

advantage over existing products may come from evidence other than

head-to-head comparisons of the new product and existing products. For

example, in some cases a new product could be shown to lack an adverse

effect associated with an existing product, or to have an effect on a

different outcome or on a different stage of disease than an existing

product, without a direct comparison of the two products.

FDA has concluded that in determining whether a product offers a

meaningful therapeutic benefit, it will use the Priority definition,

with some modifications. First, in determining whether a product is

expected to be an improvement over other products, the comparison will

be made only to other products that are already adequately labeled for

use in the relevant pediatric population. Second, it is often

therapeutically necessary to have two or more therapeutic options

available, because some patients will be unresponsive to a given

therapy. Because the Priority definition would not cover more than the

first or second product for a given indication or in a given class

(unless the product offered an advantage over others for the indication

or in the class), a drug or biologic will also be considered to provide

a meaningful therapeutic benefit if it is in a class of drugs and for

an indication for which there is a need for additional therapeutic

options. The specific number of products needed will depend upon such

factors as the severity of the disease being treated, and the adverse

reaction profile of existing therapies. FDA has added this definition

of meaningful therapeutic benefit to Secs. 314.55(c)(5) and

601.27(c)(5). This rule's definition of meaningful therapeutic benefit

is intended to apply only in the pediatric study context and is not

intended to alter the definition of a Priority drug.

25. Several comments addressed the definition of ``a substantial

number of pediatric patients.'' A few comments argued that it would be

difficult to estimate product use until after marketing. Several

comments argued that FDA should not base waivers on the number of

patients or prescriptions. Many other comments claimed that the

proposed numerical cut-offs are arbitrary. These comments maintained

that waivers should be decided on a case-by-case basis. Several

comments urged that FDA consult with an expert panel in deciding

whether pediatric use was substantial.

Comments from the pediatric community contended that the numerical

cut-offs in the proposal were too high, and would preclude studies of

many serious diseases affecting fewer than 100,000 pediatric patients.

One comment, for example, voiced concern that pediatric patients with

less common seizure types may not benefit from the regulations because

the use is not sufficiently widespread. Another comment argued that

numerical cut-offs should not apply to drugs for serious and life-

threatening diseases, unless the number of pediatric patients was so

low as to make clinical study impossible. Another comment suggested

that studies be required not only for uses greater than 100,000

prescriptions, but for ``drugs used chronically for a defined, though

smaller group of pediatric patients, usually for organ-specific

diseases, such as kidney failure or hypertension.''

Comments from the pharmaceutical industry argued that the numerical

cut-offs proposed by FDA were too low. Some of these comments argued

that 100,000 prescriptions per year translates to fewer than 100,000

patients, and that the resulting population could be so small that it

would be difficult to study. Several of these comments urged that cut-

off for substantial use be 200,000 patients with the disease, the

threshold established by the Orphan Drug Act for identifying rare

diseases.

FDA has decided to revise its proposed method of defining a

substantial number of patients, in light of the comments. Physician

mention

[[Page 66647]]

data from the IMS National Disease and Therapeutic Index (Ref. 38),

which tracks the use of drugs by measuring the number of times

physicians mention drugs during outpatient visits, shows that pediatric

use of drugs is generally grouped in two distinct ranges. Physician

mentions of drugs for pediatric use generally fall either below 15,000

per year or above 100,000 per year. Few drugs fall within the two

ranges. Thus, selecting a cut-off for ``substantial number of pediatric

patients'' in the middle of the two ranges will provide a reasonable

discrimination between products that are widely used and those that are

less commonly used, and the specific number chosen will not arbitrarily

include or exclude a significant number of drugs. FDA has therefore

chosen 50,000 as the cut-off for a substantial number of pediatric

patients. Because the number of pediatric patients with the disease is

easier to determine than the number of prescriptions per year, a

substantial number of pediatric patients will be defined as 50,000

pediatric patients with the disease for which the drug or biological

product is indicated. Although physician mentions per year does not

correspond exactly to the number of patients with the disease, they

provide a rough approximation and the IMS data show that the number of

products included or excluded is relatively insensitive to changes in

the cut-off chosen. As proposed, a partial waiver for a particular

pediatric age group would be available under this method if 15,000

patients in that age group were affected by the disease or condition.

This definition of ``a substantial number of pediatric patients'' has

not been codified, however, and FDA may modify it, after consulting

with the pediatric panel discussed in section III.M of this document

(``Pediatric Committee''). Any modification will be issued as a

guidance document.

In response to those comments that voiced concern that this

definition would exclude a number of serious diseases, FDA emphasizes

that the definition of ``meaningful therapeutic benefit'' assures that

drugs and biologics will be covered by the rule if they are medically

needed as therapeutic options because there are insufficient products

adequately labeled for pediatric patients for that indication or in

that drug class. Until there are enough adequately labeled products

available, many new drugs and biologics for serious and life-

threatening diseases will be considered to offer a meaningful

therapeutic benefit and thus will be required to be studied, even if

the products are not also used in a substantial number of pediatric

patients. This will be particularly true during the first few years

after implementation of this rule when few drugs and biologics will yet

be adequately labeled for use in pediatric patients, and a larger

proportion of new entrants into the marketplace will be considered to

be medically necessary therapeutic options.

In response to the comments arguing that FDA's proposed numerical

cut-off is too low and will result in too many pediatric studies, FDA

expects to defer until after approval many of the studies of products

that will be used in a substantial number of pediatric patients but

that do not offer a meaningful therapeutic benefit. As described

previously in response to comments on the deferral provisions, studies

of new drugs and biologics that do not offer a meaningful therapeutic

benefit and are members of a class that is already adequately labeled

for pediatric patients are likely to be deferred until well after

approval of the product for adults.

26. A few comments addressed the provisions that would permit

waiver if pediatric trials were impossible or impractical. One comment

argued that the provision authorizing waiver if the proposed population

was ``too small or geographically dispersed'' was too broad. This

comment urged that tests should be waived only if ``significant efforts

to recruit patients fail.'' The comment also argued that the

unsupported suggestion that tests are ``impractical'' should not be

accepted, and that evidence of due diligence should be required.

Another comment argued that waivers should never be granted because the

population is too small or dispersed. According to this comment, many

safety and pharmacokinetic studies are already performed in dispersed

populations, and the comment maintained that no experimental drug

should be administered to a child with a serious or life-threatening

disease without requiring that some safety data and pharmacokinetics

data be obtained. Another comment observed that although only 600 renal

transplants are performed each year in pediatric patients, pediatric

academic centers have been creative in forming collaborative efforts to

study these small groups. One comment from an organization devoted to

children with HIV stated that the ``impossible or highly impractical''

standard must be narrowly interpreted, and that a manufacturer should

show that all reasonable efforts to recruit patients have failed.

According to this comment HIV/AIDS drugs should be a benchmark of when

a waiver should not be granted: Any group as big or bigger than the

pediatric AIDS population should be considered big enough to study.

Another comment argued that because of special difficulties

encountered in recruiting pediatric patients into studies of blood

products, such as parental fear of disease transmission, the inability

to obtain a sufficient number of test subjects should be added to the

criteria for waiver or to the definition of ``highly impractical.''

FDA agrees with those comments urging that this ground for waiver

be interpreted narrowly and that unsupported assertions be rejected as

a basis for waiver. Although the number of patients necessary to permit

a study must be decided on a case-by-case basis, FDA agrees that there

are methods available to conduct adequate studies in very small

populations. Moreover, where only safety or pharmacokinetic studies are

required to support pediatric labeling, the size of the population or

geographic dispersion would only rarely be a sufficient basis to

consider trials impossible or highly impractical. Because of the speed

and efficiency of modern communications tools, geographic dispersion

will justify a waiver only in extraordinary circumstances and will

generally have to be coupled with very small population size. FDA is

not persuaded that inability to recruit patients because of parental

fears associated with administration of the drug is an adequate basis

to conclude that studies are impractical where there is also evidence

that similar products are regularly prescribed to pediatric patients

outside of clinical trials.

27. Several comments responded to the request for comment on

whether cost should justify a waiver. Comments from the pediatric

community argued that cost to the manufacturer should never or rarely

justify a waiver. Two of these comments stated that the cost of failure

to study is always higher than the cost of research. Another comment

stated that cost may be a factor, but FDA must be careful not to allow

studies to be waived automatically because they ``cost too much.'' Two

comments from a pharmaceutical company and a pharmaceutical trade

association argued that FDA should not have responsibility for

assessing the costs of a study.

In light of the comments, FDA has concluded that it does not have

an appropriate basis to evaluate and weigh cost in granting or

declining to grant a waiver. Therefore, cost will not ordinarily be a

factor in determining whether a waiver should be granted.

[[Page 66648]]

28. One comment claimed that the proposal lacks adequate regulatory

procedures for timely processing of waiver requests and will result in

a new layer of bureaucracy.

As described previously in response to comments on the deferral

provisions, preliminary decisions on whether to grant waivers will be

provided to the sponsor at the end of phase 1 for drugs and biologics

for life-threatening diseases and at the end of phase 2 for other

products. FDA does not agree that processing of waiver requests will

result in a new layer of bureaucracy. The decisions will be made by the

division responsible for reviewing the NDA or BLA. FDA intends to

ensure that the process is timely and fair. To reduce the burden on

manufacturers in applying for waivers and deferrals, FDA intends to

issue a guidance document providing a format for a request for waiver

or deferral.

29. One comment asked that the rule clarify that the onus is on the

manufacturer to justify waivers. Another comment argued that the

proposed standard for granting a waiver (``reasonable basis'') places

an inadequate burden of proof on manufacturers. According to this

comment, manufacturers should be required to present ``persuasive

proof,'' and FDA should have to find that the grounds for waiver have

``in fact'' been met.

FDA agrees that the burden is on the manufacturer to justify

waivers, but believes that the rule already adequately imposes that

burden. The rule requires both a certification from the manufacturer

that the grounds for waiver have been met and an adequate justification

for the waiver request. FDA believes that it would be inappropriate to

require ``proof'' that the grounds for waiver have ``in fact'' been met

because each ground requires a degree of speculation about the safety

and effectiveness of, or the ability to test, a product, in a

population in which it has not yet been tested.

30. Many comments from pediatricians, disease-specific

organizations, a pharmacists' organization, a medical society, several

companies, a pharmaceutical trade association, and the AAP urged that

the decision to require pediatric studies be reviewed by a panel of

outside pediatric experts. Some of the comments recommended that the

panel include industry representatives. The comments were divided on

whether the panel would review only waiver requests or would be

responsible for identifying, in the first instance, those drugs that

need study. Some of these comments believed that the rule should

include no criteria for granting waivers and that the decision should

be made on a case-by-case basis in consultation with the expert panel.

As described later in this document, FDA intends to convene a panel

of pediatric experts, which will include one or more industry

representatives, to assist the agency in implementing this rule. FDA

will bring before that panel some issues related to waivers. FDA does

not believe, however, that it is reasonable to bring every product

undergoing clinical studies before the panel for a decision on whether

pediatric studies are required. Because many dozens of drugs and

biologics reach the end of phase 1 and phase 2 each year, and the panel

could not realistically meet more than once every few months, insisting

that each product be brought before the panel would introduce

substantial delay into the development and review of drugs and

biologics. Moreover, many waiver decisions will be straightforward and

noncontroversial.

FDA does, however, agree that it would be beneficial to have the

advice of pediatric experts on its administration of the waiver

provisions of the rule. FDA will therefore ask the panel, at least on

an annual basis for the first several years, to review the agency's

waiver decisions and provide advice on whether it believes that the

criteria used in making those decisions were appropriate. FDA will use

the advice it receives to modify future waiver decisions. FDA also

expects to consult with individual members of the panel on difficult

waiver decisions in their fields of expertise.

31. One comment suggested that FDA identify diseases that are not

likely to occur in pediatric patients, such as prostate cancer, and

classes of drugs not likely to be used in pediatric patients, and grant

blanket waivers. Another comment listed the following product classes

as having no applicability to pediatric patients: Alcohol abuse agents,

Alzheimer's agents, Amyotrophic lateral sclerosis agents, antifibrosis

therapy, antiparkinsonian agents, fertility agents, gout preparations,

multiple sclerosis drugs, oral hypoglycemics, osteoporosis agents,

oxytocics, tremor preparations, uterine relaxants, and vasodilators

(including cerebral vasodilators).

FDA agrees that there are some disease and drug classes that have

extremely limited applicability to pediatric patients and that waiver

is appropriate for these. The decision to grant a waiver in such cases

would be based on a conclusion that a disease does not have sufficient

significance in the pediatric population (either because of frequency

or severity) to constitute a meaningful therapeutic benefit for

pediatric patients or to be used in a substantial number of pediatric

patients. FDA emphasizes that this decision would not be intended to

prevent or impede studies of these diseases or drug classes in the

pediatric population, should a sponsor wish to conduct them.

The agency has identified the diseases following for which waivers

will be likely to be granted. Some of the diseases listed in the

comment are included in FDA's list. Others, such as osteoporosis, gout,

multiple sclerosis, and tremors can develop in children, and are not

included in FDA's list. Waiver decisions on products for the listed

diseases are expected to be straightforward and noncontroversial. FDA

may add to or revise this list in the future by issuing guidance

documents. An applicant who wishes to obtain a waiver because the

product is indicated for a disease on the list may refer in the waiver

request to this Federal Register notice, or to any guidance document

modifying this notice. FDA's list follows:

1. Alzheimer's disease.

2. Age-related macular degeneration.

3. Prostate cancer.

4. Breast cancer.

5. Non-germ cell ovarian cancer.

6. Renal cell cancer.

7. Hairy cell Leukemia.

8. Uterine cancer.

9. Lung cancer.

10. Squamous cell cancers of the oropharynx.

11. Pancreatic cancer.

12. Colorectal cancer.

13. Basal cell and squamous cell cancer.

14. Endometrial cancer.

15. Osteoarthritis.

16. Parkinson's disease.

17. Amyotrophic lateral sclerosis.

18. Arteriosclerosis.

19. Infertility.

20. Symptoms of the menopause.

F. Pediatric Use Section of Application

FDA proposed to add Sec. 314.50(d)(7), under which applicants would

be required to include in their applications a section summarizing and

analyzing the data supporting pediatric use information for the

indications being sought. FDA received no comments on this provision.

The new pediatric use section will be required to contain only brief

summaries of the studies together with a reference to the full

description of each provided elsewhere in the application.

[[Page 66649]]

G. Planning and Tracking Pediatric Studies

1. Sections 312.23(a)(3)(v), 312.47 (b)(1)(i), (b)(1)(iv) and (b)(2),

and 312.82--Early Discussion of Plans for Pediatric Studies

In the proposal, FDA identified several critical points in the drug

development process, before submission of an NDA or BLA, during which

the sponsor and FDA should focus on the sponsor's plans to assess

pediatric safety and effectiveness. These time points include: Any pre-

IND meeting or ``end-of-phase 1'' meeting for a drug designated under

subpart E of part 312 (21 CFR part 312), the IND submission, the IND

annual report, any ``end-of-phase 2'' meeting, the presentation of the

IND to an FDA drug advisory committee, and any pre-NDA or pre-BLA

meeting. Of these, the pre-IND meeting, the ``end-of-phase 1'' meeting,

the IND submission, the IND annual report, the ``end-of-phase 2''

meeting, and the pre-NDA/pre-BLA meeting are codified in part 312,

FDA's regulations governing IND's.

In a separate rulemaking, FDA has already amended the IND annual

report requirement to include discussion of pediatric patients entered

in trials (63 FR 6854, February 11, 1998). In the proposal, FDA

proposed to amend Secs. 312.23(a)(3)(v), 312.47 (b)(1)(i) and (b)(2),

and 312.82 (a) and (b) to specify that these meetings and reports

should include discussion of the assessment of pediatric safety and

effectiveness. To assist manufacturers in planning for studies that may

be required under this proposal, FDA also proposed to inform

manufacturers, at the ``end-of-phase 2'' meeting, of the agency's best

judgment, at that time, of whether pediatric studies would be required

for the product and when any such studies should be submitted. The

proposal also stated that, in addition to the discussions of pediatric

testing codified in the proposal, FDA would assist manufacturers by

providing early consultations on chemistry and formulation issues

raised by requirements under this rule.

Because, as described previously, studies of drugs and biologics

for life-threatening diseases may begin as early as the end of phase 1,

FDA will, at the end-of-phase 1 meeting, provide the sponsor of such a

product the agency's best judgment, at that time, whether pediatric

studies will be waived or deferred. Section 312.82(b) has been revised

to include this requirement. Because studies of other products may

begin as early as the end of phase 2, FDA will, at the end-of-phase 2

meeting, provide the agency's best judgment, at that time, whether

waiver or deferral is appropriate. Although a formal request for

deferral or waiver is not required until submission of the NDA or BLA,

FDA has revised Sec. 312.47(b)(1)(iv) to state that a manufacturer who

plans to seek a waiver or deferral should provide information related

to the waiver or deferral in the advance submission required before the

end-of-phase 1 or end-of-phase 2 meeting, as appropriate.

As described earlier, a pediatric study required under this rule

may be eligible for exclusivity under FDAMA, if such study ``meets the

completeness, timeliness, and other requirements of [section 505A].''

(See 21 U.S.C. 355A(i).) Among other requirements, a pediatric study

must, to be eligible for exclusivity, be responsive to a written

request for the study from FDA. To obtain a written request, a

manufacturer may submit a proposed written request to FDA that contains

the information described in a guidance document issued by FDA

entitled, ``Qualifying for Pediatric Exclusivity Under Section 505A of

the Federal Food, Drug, and Cosmetic Act.'' A manufacturer who has been

told in the end-of-phase 1 or end-of-phase 2 meeting that it is FDA's

best judgment at that time that it does not intend to waive the study

requirement may submit a proposed written request at any time

thereafter. FDA will issue a written request for a study required under

this rule promptly after an adequate proposed written request is

submitted.

FDA also sought comment on the types of evidence that FDA should

examine to ensure that deferred pediatric studies are carried out in a

timely fashion. In response to comments, FDA has revised Secs. 312.47

(b)(1)(iv) and (b)(2) to require submission of information about

planned and ongoing pediatric studies.

32. One comment supported the proposed provisions and the need for

early consultation with sponsors, stating that discussions should take

place as early as possible in drug development. The comment urged that

proposed Sec. 312.47(b)(1) be revised to acknowledge the possibility

that studies could already be underway.

FDA agrees with this comment and has revised Sec. 312.47(b)(1) as

suggested in the comment.

33. Several comments provided suggestions on how to assure that

deferred studies are carried out expeditiously. One comment urged that

the criteria to ensure deferred studies are carried out in a timely

fashion be modeled on the AIDS Clinical Trials Group (ACTG) system of

National Institute of Allergy and Infectious Diseases (NIAID). Another

comment recommended that evidence demonstrating that the required

studies were underway be submitted to FDA within 6 months of approval.

This comment suggested that the evidence should include: (1) A

finalized protocol, (2) evidence of sufficient entry of patients to

address the objective of the protocol, and (3) a time line for data

analysis and submission to FDA. Another comment argued that the burden

should be on manufacturers to provide evidence that studies are being

conducted with due diligence through submission of protocols, progress

reports and certifications by researchers. To hold manufacturers

accountable, this comment suggested that nonproprietary information

related to deferrals be made available to the public, including

deferral requests, FDA action, postmarketing status reports, and the

time line for deferred studies. One comment argued that FDA's current

procedures are adequate to track the timeliness of pediatric studies. A

pharmaceutical trade association argued that FDA should institute an

adequate tracking system and meet periodically with the sponsor to

discuss the progress of the studies, but that no new rules are needed.

FDA agrees that an adequate system for ensuring that studies, both

deferred and nondeferred, are carried out in a timely manner requires

the submission of plans and progress reports from the sponsor at

defined intervals. As described previously, FDA will provide sponsors

with a preliminary decision on whether pediatric studies will be

required and their timing at the end-of-phase 1 meeting, for drugs and

biologics for life-threatening diseases, and at the end-of-phase 2

meeting, for other products. FDA has revised Sec. 312.47(b)(1)(iv) to

state that sponsors should submit, in the advance submission for the

end-of-Phase 2 meeting, a proposed time line for protocol finalization,

enrollment, completion, data analysis, and submission of pediatric

studies, or, in the alternative, information to support a planned

request for waiver or deferral. For drugs and biologics for life-

threatening diseases, the submission should be made in advance of the

end-of-Phase 1 meeting. FDA has also revised Sec. 312.47(b)(2)(iii) to

state that sponsors should submit, in the submission in advance of the

pre-NDA or pre-BLA meeting, information on the status of needed and

ongoing pediatric studies. The proposed language of Sec. 312.47 has

been slightly modified to

[[Page 66650]]

seek information on ``needed'' and ongoing studies rather than

``planned'' and ongoing studies. This change has been made because not

every sponsor elects to have an end-of-phase 1 or end-of-phase 2

meeting. In those cases, the need for a pediatric study may be

discussed for the first time at the pre-NDA or pre-BLA meeting. FDA has

also revised the title of Sec. 312.47(b)(2) from `` `Pre-NDA'

meetings'' to `` `Pre-NDA' and `pre-BLA' meetings.'' This is merely a

clarification, because part 312 is expressly applicable to products

subject to the licensing provisions of the Public Health Service Act,

as well to products subject to section 505 of the act and 21 CFR

312.2(a).

2. Sections 314.81(b)(2) and 601.37--Postmarketing Reports

To permit FDA to monitor the conduct of postapproval studies to

ensure that they are carried out with due diligence, FDA proposed to

amend Sec. 314.81(b)(2) of the postmarketing report requirements to

require applicants to include in their annual reports: (1) A summary

briefly stating whether labeling supplements for pediatric use have

been submitted and whether new studies in the pediatric population to

support appropriate labeling for the pediatric population have been

initiated; (2) where possible, an estimate of patient exposure to the

drug product, with special reference to the pediatric population; (3)

an analysis of available safety and efficacy data in the pediatric

population and changes proposed in the label based on this information;

(4) an assessment of data needed to ensure appropriate labeling for the

pediatric population; and (5) whether the sponsor has been required to

conduct postmarket pediatric studies and, if so, a report on the status

of those studies. (Additional postmarketing reporting requirements are

described under ``Remedies'' in section III.L of this document.)

Although the proposal was intended to cover both drugs and biological

products, the proposal inadvertently omitted a postmarketing reports

requirement specifically applicable to biological products. In the

final rule, FDA has corrected this oversight and included an identical

postmarketing reports requirement in Sec. 601.37.

FDA notes that FDAMA includes a provision requiring reports of

postmarketing studies in a form prescribed by the Secretary of Health

and Human Services (the Secretary) in regulations. (Section 506 of the

act (21 U.S.C. 356B).) At such time as regulations implementing this

provision are issued, FDA may modify or withdraw Secs. 314.81(b)(2) and

601.37 for consistency with the implementing regulations.

34. Three comments from the pharmaceutical industry agreed that it

was appropriate to require postmarketing reports on the progress of

postapproval pediatric studies. One comment argued, however, that

collection of this information along with an adequate system to track

pediatric studies could preclude the need to finalize the rule. Another

comment argued that the required analyses of pediatric data ``may lead

to exposure of a larger number of children to an unapproved product.''

This comment also contended that estimates of patient exposure are

difficult to obtain and unreliable.

FDA disagrees that postmarket reports and a tracking system are an

adequate means of assuring that drugs and biologics are appropriately

labeled for pediatric use. As shown above, even postmarket commitments

to conduct pediatric studies have infrequently resulted in pediatric

labeling submissions. FDA also disagrees that the analyses required

under Sec. 314.81(b)(2) require exposure of any new patients. The

analyses referred to in the provision are of already collected data.

Finally, the rule requires estimates of patient exposure ``where

possible.'' If there are no data on which to make such estimates, the

estimates are not required. FDA notes, however, that there are

commercial data bases designed to estimate use of marketed drugs.

35. One comment argued that FDA should require postmarket

surveillance of approved drugs that do not have pediatric labeling, to

generate helpful comparative information and provide additional

information useful for analysis of adverse event profiles.

The provisions of the final rule require manufacturers of approved

drugs without pediatric labeling to conduct postmarket surveillance on

their products and provide an analysis of available safety and efficacy

data in the pediatric population.

H. Studies in Different Pediatric Age Groups

Because the pharmacokinetics and pharmacodynamics of a drug or

biological product may be different in different pediatric age groups

or stages of development, FDA proposed to require an assessment of

safety and effectiveness in each pediatric age group for which a waiver

was not granted. The following age categories for the pediatric

population were distinguished in the proposal: (1) Neonates (birth to 1

month); (2) infants (1 month to 2 years); (3) children (2 years to 12

years), and (4) adolescents (12 years to 16 years). The proposal stated

that the need for studies in more than one age group would depend on

whether the drug or biological product was likely to be used or offered

meaningful therapeutic benefit in each age group (see ``Waivers''

section III.E of this document), the metabolism and elimination of the

drug, and whether safety and effectiveness in one age group could be

extrapolated to other age groups. The proposal further stated that it

would not ordinarily be necessary to establish effectiveness in each

age group, but there would generally need to be pharmacokinetic data in

each group to allow dosing adjustments. The proposal recognized that

studies in neonates and young infants present special problems, and

sought comment on whether it is appropriate to require the assessment

of safety and effectiveness in this age group.

36. Several comments addressed the requirement that all relevant

age groups be studied. Some comments opposed studies in more than one

age group. One comment contended that requiring safety data in each

pediatric group may place an unnecessary burden on the sponsor, and

that FDA should require safety data only in one group, presumably that

with the highest potential use. Another comment claimed that requiring

studies in all four age groups would almost never be justified. In most

cases, according to this comment, it should be possible to study a

single subgroup and extrapolate. Other comments argued that studies in

more than one age group could be necessary depending on the

pharmacokinetics of the drug, the disease, and expected use of the

drug. Most of these comments stated that the type and extent of studies

in different age groups must be decided on a case-by-case basis.

Several comments contended that drugs should be studied in each age

group in which they are expected to be used. One comment stated that

studies in toddlers are especially needed. A comment from an

organization devoted to pediatric AIDS argued that all age groups

should be studied unless the manufacturer provides compelling evidence

that it would be impossible or virtually impossible to study that

group.

FDA continues to believe that studies in more than one age group

may be necessary, depending on expected therapeutic benefit and use in

each age group, and on whether data from one age group can be

extrapolated to other age groups.

[[Page 66651]]

37. Many comments argued that the pediatric subgroups identified in

the proposal were arbitrary and that FDA should be flexible in

determining which age ranges or stages of development need to be

studied. A comment from a pharmaceutical trade association contended

that rigid age divisions for required studies were inappropriate, and

that the method by which the compound is cleared from the body must be

considered in light of what is known about physical development. The

AAP stated that the groups identified in the proposal provide

acceptable guidelines, but should not be adhered to rigidly. One

comment argued that the definition of pediatric patients should include

all subgroups of growth and development from 0 to 21 years.

FDA agrees that the age ranges identified in the proposal may be

inappropriate in some instances and that it will be reasonable in some

cases to define subgroups for study using other methods, such as stage

of development. FDA has deleted the references in the rule to specific

age ranges.

38. Several comments addressed inclusion of neonates in studies.

One comment maintained that because neonates are a special challenge,

they should not ordinarily be included in studies under this rule.

Another comment described the difficulties in conducting studies in

infants and neonates and recommended that before studies in this group

there be an assessment of ``the expected extent of use and potential

benefit in this patient population'' and an evaluation of safety data

in adults and older pediatric patients. One comment contended that

there are not many instances in which the benefit will outweigh the

risk of exposing neonates and young infants to drugs. This and another

comment also argued that it is not always possible to extrapolate from

data in older pediatric patients. A pharmaceutical trade association

maintained that validated end-points and ability to assess these by age

should determine which age groups to include, and that it may not be

possible to study certain end-points in very young pediatric patients.

One comment argued that early research on neonates raises special

ethical issues. Citing the 1977 FDA guideline, this comment asserted

that testing in neonates should occur only when substantial evidence of

benefit or superiority over accepted agents has been demonstrated in

older pediatric patients and adults.

Other comments argued that neonates should not be excluded from

studies. According to one comment, study designs will be appropriate

and necessary ethical issues will be addressed if neonatologists are

included in the review of studies. Another comment stated that neonates

represent the greatest disparity in drug disposition compared to

adults, and that, on a scientific and ethical basis, they must

therefore be included in drug studies. The AAP stated that premature

infants, newborns, and infants are more difficult to study, but that

the difficulties do not outweigh the importance of studying them.

According to this comment, inadequate study of neonates has led to

frequent and severe toxicity. This comment agreed that it is

inappropriate to extrapolate from older pediatric patients to the

youngest age group.

FDA agrees that the benefits and risks to premature infants,

neonates, and infants must be carefully weighed before these pediatric

patients are included in pediatric studies. Although the agency

believes that studies in these groups may be frequently waived or

deferred until adequate safety data have been collected, there will be

cases in which the drug or biologic is important and expected to be

used in these groups. In such cases, it will be appropriate to require

studies in these groups. To exclude them from study would be to subject

the most vulnerable patients to the risks of the drugs in clinical use

without adequate information about safety or dosing. FDA agrees that

studies in neonates and young infants raise special ethical issues, but

once these issues are addressed in each case, the studies should

proceed.

I. Pediatric Formulations

As described in the proposal, testing of a product in pediatric

patients could require the development of a pediatric formulation. Many

young children are unable to swallow pills and may require a liquid,

chewable or injectable form of the product. A standardized pediatric

formulation also ensures bioavailability and consistency of dosing,

compared to alternatives such as mixing ground-up tablets with food,

and permits meaningful testing of safety and effectiveness. FDA

proposed in Secs. 201.23, 314.50(g)(1) (now 314.55(a)) and 601.27(a) to

require a manufacturer to produce a pediatric formulation, if one were

necessary, only in those cases where a new drug or new biological

product provided a meaningful therapeutic benefit over existing

treatments, and where the study requirement had not been waived in the

age group requiring the pediatric formulation. The proposal recognized

that the difficulty and cost of producing a pediatric formulation may

vary greatly depending upon such factors as solubility of the compound

and taste. FDA proposed to waive the requirement for pediatric studies

(see ``Waivers'' in section III.E of this document) in age groups

requiring a pediatric formulation, if the manufacturer provided

evidence that reasonable attempts to produce a pediatric formulation

had failed.

FDA sought comment on whether it is appropriate to require a

manufacturer to develop a pediatric formulation, on whether the cost of

developing a pediatric formulation should ever justify a waiver of the

pediatric study requirement, and on how to define ``reasonable

attempts'' to develop a pediatric formulation.

39. Many comments from the pediatric community argued that it is

appropriate to require manufacturers to produce pediatric formulations.

Several comments from pediatricians and parents described the

difficulties and uncertainties in attempting to administer adult

formulations to pediatric patients, and argued that pediatric

formulations are essential to assure bioavailability, accurate dosing,

and patient compliance, and to avoid wasting medications. The AAP

argued that FDA should require development of an appropriate

formulation for each age group for which the drug will be used, taking

into account ease of administration and ability to dose accurately.

Comments from the pharmaceutical industry described technical

problems in producing pediatric formulations, including stability,

taste and palatability, and claimed that FDA underestimated these

difficulties. Some of these comments maintained that requiring

development of pediatric formulations during the investigational phase

will necessitate diversion of resources, increase the cost of the adult

formulation, and create a disincentive to produce drugs with pediatric

uses. One comment argued that it would be wasteful to require

development of a pediatric formulation before some evidence of

effectiveness has been collected and dose selection has been achieved,

because before that time the drug could be abandoned because of lack of

safety or effectiveness. A pharmaceutical trade association opposed a

pediatric formulation requirement, arguing that the government has no

right to tell manufacturers what products to market. This comment

stated that only if FDA successfully demonstrated that ``all attempts

to develop a voluntary solution have failed'' might the industry

consider other options. One comment stated that

[[Page 66652]]

a single drug could require more than one pediatric formulation for

different pediatric age group, such as a chewable tablet, a nonalcohol

containing liquid, and sprinkles. Counting failed attempts, this

comment claimed that producing a pediatric formulations may cost

millions of dollars.

FDA believes that for drugs and biologics that offer a meaningful

therapeutic benefit to pediatric patients, it is essential to provide

pediatric formulations that ensure bioavailability and accurate dosing.

FDA disagrees that it is inappropriate for the government to require

manufacturers to produce pediatric formulations. As many comments

demonstrated, adult formulations of these drugs are frequently used in

pediatric patients because there is no other choice. Drug manufacturers

profit from these uses, but do not take responsibility for them. Where

a product is commonly being used in a subpopulation for an indication

recommended by the manufacturer, it is appropriate to require the

manufacturer to take steps to ensure that the use is safe and

effective.

FDA agrees that producing a pediatric formulation can be difficult

or, rarely, impossible and has attempted to account for this problem by

permitting waiver of the pediatric study requirement where reasonable

attempts to produce a pediatric formulation have failed. FDA notes that

the pharmaceutical industry did not respond to FDA's request to help

define what should constitute such ``reasonable attempts.''

To permit pediatric studies that may begin, for products for life-

threatening diseases, at the end of phase 1, or, for other products, at

the end of phase 2, it may be necessary to begin development of a

pediatric formulation before initiation of clinical trials. FDA does

not agree that it is wasteful to begin development of a pediatric

formulation at this stage. This rule is premised on the view that for

drugs and biologics that will have important use in pediatric patients,

it is the responsibility of the manufacturer to ensure that use is safe

and effective. Although some such products may ultimately prove to be

unsafe or ineffective, work on pediatric formulations of such products

is not necessarily more wasteful than work on adult formulations. FDA

does not agree that manufacturers will be required to develop several

pediatric formulations for different age groups. Even for a drug that

was to be used in all pediatric age groups, a liquid formulation, e.g.,

might be usable in all age groups.

FDA has no basis to conclude that producing pediatric formulations

will increase the cost of adult formulations or create disincentives

for producing drugs and biologics with pediatric uses. No evidence was

submitted to support either of these assertions.

40. Several comments discussed how to define ``reasonable

attempts'' to produce a pediatric formulation. The AAP argued that

difficulty in producing a pediatric formulation should be a basis for

waiver only if the sponsor provides data showing that formulation

experts encountered insurmountable problems of solubility, stability,

compatibility, or palatability using accepted methods, and that cost be

given only limited consideration. The AAP urged that such an assertion

be corroborated by a panel of pediatric experts and FDA as well as

formulation experts. Another comment agreed that formulations

appropriate for younger age groups should be developed unless the

manufacturer shows it would be virtually impossible. This comment

argued that if a manufacturer wants to show that the cost is

prohibitive, it should provide information allowing the financial and

other costs of development to be seen in terms of the entire drug

development process. Another comment argued that waivers should not be

based on whether reasonable efforts to develop a pediatric formulation

have failed because this ground for a waiver would permit small

companies to avoid producing pediatric formulations on cost grounds.

This comment urged that waivers be allowed only if a pediatric

formulation cannot be produced for scientific or technological reasons.

One comment argued that even if producing a pediatric formulation is

impossible, the manufacturer should be required to study the adult

formulation in pediatric patients, because it will be used in pediatric

patients.

One industry comment urged that the decision to require a pediatric

formulation be made on a case-by-case basis. Another comment argued

that pediatric formulations should be required only if a panel of

pediatric experts concludes that there is a genuine pediatric need and

substantial benefit.

FDA agrees that the burden should be on the manufacturer to provide

evidence that experts in formulation chemistry had encountered

unusually difficult technological problems in the development of a

pediatric formulation. In determining whether those problems were

sufficiently severe to warrant a waiver of pediatric studies, FDA will

consider the potential importance of the product for pediatric

patients. The more important the product, the more efforts should be

made to develop a pediatric formulation. FDA will also, at its

discretion, take to the Advisory Committee for Pharmaceutical Sciences

questions about whether ``reasonable attempts'' have been made to

produce pediatric formulations in particular cases. Although FDA

believes that it is appropriate to consider the cost to the

manufacturer in determining whether attempts to produce a pediatric

formulation have been reasonable, the agency received no helpful

guidance on how to assess whether the costs of producing a pediatric

formulation were unreasonable. In addition to any informative cost

information provided by the manufacturer, FDA will take into account

whether a product is still under patent or exclusivity protection. FDA

will assume that manufacturers can incur greater costs for products

that have significant patent life or exclusivity remaining.

41. One comment contended that FDA chemistry requirements have

increased over the last 10 years. Another comment urged that FDA be

more flexible in its review of formulations, e.g., by permitting

generally recognized as safe (GRAS) substances in pediatric

formulations.

FDA recently held a conference on pediatric formulations at which

the agency sought input from industry on identifying the regulatory

issues that affect the development of pediatric formulations for both

new and approved marketed drugs. At this meeting, FDA also requested

proposals for solutions to facilitate the development and approval of

pediatric formulations. FDA is committed to removing unnecessary

burdens on the review and approval of pediatric formulations.

42. Two comments urged manufacturers to provide formulas in product

labeling for extemporaneous pediatric formulations made by pharmacists.

These comments stated that the current practice among hospital

pharmacies is to use unvalidated formulas, resulting in a lack of

consistency from one hospital to another, no stability testing, and, in

some cases, reluctance to produce pediatric formulations at all because

of the lack of guidance. One comment stated that information on

extemporaneous formulations should be provided only where: (1) A

commercial formulation is not possible or (2) the drug has extremely

limited use in pediatric patients.

FDA is concerned that the availability of this approach may

undermine efforts to produce standardized pediatric formulations. There

are, however, one or two examples in which approved labeling carries

directions for producing

[[Page 66653]]

extemporaneous pediatric formulations. FDA will consider, on a case-by-

case basis whether such an approach is appropriate, e.g., where it has

not been possible to develop a stable commercial formulation.

J. Marketed Drug and Biological Products

FDA proposed in Sec. 201.23 to codify its authority to require, in

certain circumstances, a manufacturer of a marketed drug or biological

product to submit an application containing data evaluating the safety

and effectiveness of the product in pediatric populations. FDA proposed

to impose such a requirement only where the agency made one of two

findings: (1) That the product was widely used in pediatric populations

and the absence of adequate labeling could pose significant risks to

pediatric patients; or (2) the product was indicated for a very

significant or life-threatening illness, but additional dosing or

safety information was needed to permit its safe and effective use in

pediatric patients.

Before requiring a study under this section, FDA proposed to

consult with the manufacturer on the type of studies needed and on the

length of time necessary to complete them, and would notify the

manufacturer, by letter, of the agency's tentative conclusion that such

a study was needed and provide the manufacturer an opportunity to

provide a written response and to have a meeting with the agency. At

the agency's discretion, such a meeting could be an advisory committee

meeting. If, after reviewing any written response and conducting any

requested meeting, FDA determined that additional pediatric use

information was necessary, FDA proposed to issue an order requiring the

manufacturer to submit a supplemental application containing pediatric

safety and effectiveness data within a specified time. The proposal

referred to the order in one place as a letter. FDA has clarified the

final rule by stating that the manufacturer will receive ``an order, in

the form of a letter.'' A few other minor clarifying revisions have

also been made in this section.

FDA sought comment on whether it should codify its authority to

require the manufacturers of marketed drugs and biologics to conduct

pediatric studies, and, if so, on the circumstances in which the agency

should exercise that authority.

43. Many comments from the pediatric community agreed that FDA

should codify its authority to require pediatric studies on marketed

drugs. Several comments from the pharmaceutical industry argued that

FDA lacked authority to require studies of marketed drugs and that the

1994 rule sufficiently addressed pediatric labeling for marketed drugs.

Some comments argued that adding pediatric labeling for indications

applicable to pediatric patients should be at the sponsor's discretion.

Others claimed that incentives are better than requirements. One

comment contended that the proposed requirement forces manufacturers

``to take on unwanted liabilities in order to maintain an asset which

was created and earned under a different set of rules.'' Other comments

maintained that companies should not be required to conduct new

studies, and that pediatric labeling should be based on existing data,

such as marketing experience and dosing regimens generally accepted by

experts. A comment from a pharmaceutical trade association argued that

studies should not be required but that FDA should work with industry

and others to ``develop creative ways to obtain the needed labeling

information'' for marketed drugs.

FDA believes that it has ample authority to require pediatric

studies of marketed drugs and biologics, as described in the preamble

to the 1994 rule (59 FR 64240 at 64243) and in ``Legal Authority''

section IV of this document. FDA has also concluded, as described

previously, that the response to the 1994 rule and other voluntary

measures have not produced a significant improvement in pediatric

labeling for many marketed drugs and biologics. In addition, as one

pharmaceutical company conceded, manufacturers are unlikely to initiate

clinical research on marketed drugs whose patents have expired, or are

about to expire. FDA has therefore concluded that where pediatric

information is critical to patient care, it is necessary to require

that pediatric studies be carried out. FDA notes that new requirements

are sometimes imposed on already marketed consumer products when such

requirements are necessary to protect the public health. FDA

emphasizes, however, that it will require studies of marketed products

only in the compelling circumstances described in the regulation.

44. FDA received many comments on the grounds for requiring studies

of marketed products. Comments from medical societies, pediatricians,

and disease-specific organizations argued that the proposed grounds

were too narrow. One comment stated that pediatric studies should be

required of any marketed drug that is likely to be used in pediatric

patients. Several comments argued that the phrase ``very significant

illness'' was ill-defined. One comment stated that it was ``so open-

ended and subjective as to be impossible for use as a regulatory

standard.'' Another comment suggested that any definition of ``very

significant illness'' would be arbitrary and overbroad. Several

comments urged that the same criteria that are applied to not-yet-

approved drugs be applied to marketed drugs. One of these comments

argued that even if the criteria remain as proposed, ``widely used''

and ``significant risk'' should be defined in terms of the severity of

the illness. According to this comment, if the consequences of no

treatment are serious, the absence of labeling should be more readily

found to present a significant risk. One industry comment maintained

that the requirement should apply to marketed drugs only where there is

a ``compelling need'' for pediatric data. One comment argued that the

requirement should apply to all marketed drugs unless an expert panel

concluded that studies were not required, while other comments urged

that FDA utilize an expert panel to affirmatively identify and

prioritize marketed drugs that should be studied in pediatric patients.

Some of these comments suggested that there be no criteria and that the

panel should determine which drugs should be studied on a case-by-case

basis. One comment suggested that the list should be prioritized using

the number of pediatric prescriptions.

FDA believes that criteria are necessary to assure consistency and

fairness in deciding which marketed drugs and biologics are studied.

FDA has reviewed the grounds for requiring pediatric studies of

marketed drugs and biologics and has revised them in light of the

comments. FDA has concluded that the phrase ``very significant

illness'' is not sufficiently defined and agrees that it would be less

confusing to use the same concepts that are used in defining which new

products will be subject to the pediatric study requirement. FDA has

therefore replaced the concept of ``very significant illness'' and

replaced it with ``meaningful therapeutic benefit.'' However, to ensure

that this authority is reserved for cases in which there is a

compelling need for studies, FDA has added the requirement (already

present in the first criterion) that FDA also find that the absence of

adequate labeling could pose significant risks for pediatric patients.

The second criterion will now read:

[[Page 66654]]

* * * there is reason to believe that the drug product would

represent a meaningful therapeutic benefit over existing treatments

for pediatric patients for one or more of the claimed indications,

and the absence of adequate labeling could pose significant risks to

pediatric patients.

FDA has also revised the first criterion to conform more closely to

the criteria for requiring studies in not-yet-approved drugs and

biologics, replacing ``widely used'' with ``used in a substantial

number of pediatric patients.'' FDA will use the same definition of

``substantial number'' for both marketed and not-yet-approved drugs and

biologics. The first criterion will, however, continue to include the

requirement that ``the absence of adequate labeling could pose

significant risks to patients.'' FDA believes that the pediatric study

requirement may impose greater burdens on the manufacturers of marketed

drugs and biologics than the manufacturers of not-yet-approved

products, and that it is appropriate to require such studies only in

the compelling circumstances described in the regulation. In

determining which marketed products ``could pose significant risks to

patients,'' FDA will consider such factors as the severity of the

illness and the consequences of inadequate treatment, the number of

pediatric prescriptions, and any available information on adverse

events associated with use of the product.

FDA emphasizes that it intends to exercise its authority under

Sec. 201.23 only in compelling circumstances. FDA has estimated that it

will require studies of approximately two marketed drugs per year.

FDA agrees that an expert panel can provide useful experience and

guidance in developing a prioritized list of marketed drugs and

biologics that meet the criteria for required studies. FDA intends to

seek advice on developing such a list from a pediatric panel, as

described in section III.M of this document (``Pediatric Committee'').

FDA also notes that FDAMA requires the agency to publish a list of

marketed drugs for which ``additional pediatric information may produce

health benefits in the pediatric population.'' FDA published this list

within 180 days of the enactment of FDAMA, as required by that statute.

Although the products on the list designated as high priority may be

appropriate candidates for required studies under this rule, the list

of high priority products is not necessarily exhaustive. Other products

that might be subject to a requirement under this rule might not appear

on the list. FDA also emphasizes that there is no implication that the

agency will require studies of any particular product on the list. As

noted in the Introduction to this preamble, before imposing any

requirements under Sec. 201.23, FDA intends to allow manufacturers

eligible for FDAMA incentives an adequate opportunity to voluntarily

conduct studies of marketed drugs in response to those incentives. If,

following such an opportunity, there remain marketed drugs for which

studies are needed and the compelling circumstances described in the

rule are met, the agency will consider exercising its authority to

require studies.

45. One comment claimed that the proposal requires studies only

from manufacturers of innovator drugs (sponsors of the original

application for the drug), while the major market share for many of

these drugs is now held by generic manufacturers. This comment argued

that a waiver should be granted if ANDA holders fail to share the costs

of required studies. Another comment argued that the pediatric study

requirement should apply only to the sponsor of the original

application.

Where the agency requires pediatric studies on a multi-source

marketed drug, each manufacturer of that drug, whether innovator or

generic, will be responsible for satisfying the study requirement. To

avoid duplication of research, FDA will encourage all the manufacturers

to jointly fund an appropriate study. If, however, a joint study is not

agreed to, each manufacturer will be responsible for submitting

adequate studies.

K. Ethical Issues

In the proposal, FDA noted that because pediatric patients

represent a vulnerable population, special protections are needed to

protect their rights and to shield them from undue risk. To address

ethical concerns in research on pediatric patients, both the AAP (Ref.

17) and the Department of Health and Human Services (DHHS), 45 CFR part

46, subpart D, have developed guidelines for the ethical conduct of

clinical studies in pediatric patients. FDA advised in the proposal

that sponsors should adhere to these guidelines for pediatric studies

conducted under this rule. The agency also sought comment on ethical

issues raised by the proposal.

46. A few comments addressed appropriate ethical guidelines for

pediatric studies. Several comments said that existing ethical

guidelines provide an adequate framework for pediatric studies. A

comment from the AAP stated that ethical conduct should be guided by

the DHHS and AAP guidelines, and that IRB approval that explicitly

ensures protection of vulnerable subjects should be obtained. This

comment also stated that the AAP guidelines provide a means to ensure

ethical conduct of studies without impeding pediatric research. One

comment said that DHHS ethics regulations may not provide sufficient

protection for pediatric patients and suggested incorporating AAP

guidelines for ethical conduct of pediatric studies into FDA's human

subjects protections regulations. Another comment contended that

pediatric studies should strictly adhere to regulations currently in

effect for studies of human subjects who are unable to give consent,

and urged FDA to further define requirements for investigation in

vulnerable populations.

FDA believes that adherence to the DHHS and AAP guidelines will

provide sufficient protection to pediatric patients from the risks of

research. FDA will, however, seek advice from a panel of pediatric

experts on whether additional protections are necessary.

47. Several comments addressed the ethics of requiring pediatric

studies as described in the proposal. Two comments asserted that

children are overmedicated and that administering drugs to children is

unacceptable and ``ungodly.'' Comments from the pharmaceutical industry

claimed that the rule as drafted would result in unethical testing of

pediatric patients. One comment maintained that the regulations do not

adequately protect pediatric patients from the risks of research

because they impose a ``general rule that a deferral of testing in

pediatrics will only be granted in narrow and limited circumstances.''

In contrast, comments from the pediatric community maintained that

far more serious ethical concerns are raised by using untested drugs in

pediatric patients than by conducting pediatric research. A comment

from the AAP stated that there is no greater ethical dilemma than

whether to give a drug with insufficient safety and effectiveness data

to a child, or to withhold treatment and let the disease progress

unabated.

Some comments suggested specific points in drug development at

which pediatric testing becomes ethical. One comment argued that

testing in pediatric patients before efficacy is demonstrated in adults

may unnecessarily expose pediatric patients to a product's risks before

its benefits are established. Another comment contended that it is

unethical to begin studying drugs in pediatric patients that are not

intended primarily for pediatric patients until the drug is adequately

characterized in

[[Page 66655]]

adult patients, including choice of appropriate adult dose and

establishment of reasonable evidence of safety and efficacy with an

acceptable therapeutic margin. A pharmaceutical trade association

argued that it is unethical to begin trials in pediatric patients until

enough adult safety and effectiveness data have been gathered to

conclude that the drug ``is likely to be approved for use in adults.''

FDA believes that some of the comments from the pharmaceutical

industry misstate the application of the rule. As described fully

previously, deferral of pediatric studies is specifically permitted in

those cases where data should be collected in adults before exposing

pediatric patients to the agent. There is no suggestion in either the

proposed or final rule that deferral will be granted only in ``narrow

and limited circumstances.'' FDA believes that, as drafted, the

deferral provisions of the rule permit ethical pediatric testing that

does not expose pediatric patients to inappropriate risks.

48. A few comments urged that placebo-controlled trials in

pediatric patients be used rarely if at all. The AAP stated that

placebo controls should not be used where that design would impose a

substantial increase in risk to the child or would impede the ability

to perform useful clinical trials. This comment urged that alternatives

to placebo controls be used wherever possible and that where placebo

controls are used, the study design should incorporate safeguards to

avoid undue risk.

The question of appropriate control group arises only when there is

a need for controlled trials to establish efficacy in the pediatric

population. FDA agrees that alternatives to placebo-controlled trials

should be used wherever they can provide sufficient information to

establish effectiveness. FDA often accepts data from active control

studies for certain therapeutic classes, such as anti-infectives and

oncologic drugs. (See 21 CFR 314.126.) In some cases, new treatments

can also be studied against a placebo together with a background of

existing therapy, i.e., studied in ``add-on'' trials.

49. One comment argued that parents should not be given money or

equivalent compensation for participation in drug studies. This comment

suggested that any compensation could be put in the child's IRA.

The IRB overseeing a research study, rather than FDA, is

responsible for determining whether compensation offered to the

subjects of the study is ethically appropriate.

L. Remedies

If a manufacturer failed, in the time allowed, to submit adequate

studies to evaluate pediatric safety and effectiveness required under

proposed Sec. 201.23(c) or Sec. 314.55 (proposed Sec. 314.50(g)), FDA

proposed to consider the product misbranded under section 502 of the

act or an unapproved new drug under section 505(a) of the act (see

``Legal Authority,'' in section IV of this document). Although proposed

Sec. 201.23 expressly covered both drugs and biologics, FDA

inadvertently omitted in that section a reference to actions against

biologics that have not obtained a license under section 351 of the

Public Health Service Act. Such a reference has been added in the final

rule. When a product is misbranded or an unapproved new drug, sections

302, 303, and 304 of the act (21 U.S.C. 332, 333, 334) authorize

injunction, prosecution or seizure. FDA may also seek an injunction or

bring a prosecution under the Public Health Service Act. In the

proposal, FDA advised that it would bring an enforcement action for

injunctive relief for failure to submit a required assessment of

pediatric safety or effectiveness. Violation of the injunction would

result in a contempt proceeding or such other penalties as the court

ordered, e.g., fines. As noted in the proposal, FDA does not intend to

deny or withdraw approval of a product for failure to conduct pediatric

studies, except possibly in rare circumstances, because removal of a

product from the marketplace could deprive other patients of the

benefits of a useful medical product. Such circumstances might arise

where the predominant use of the product was in pediatric patients

rather than adults, and there were life-threatening risks associated

with use of the product in pediatric patients when used without proper

dosing and safety information in the labeling.

To assist FDA in determining whether pediatric assessments are

needed or are being carried out with due diligence, FDA proposed to

amend Sec. 314.81(b)(2) (21 CFR 314.81(b)(2)) (annual postmarketing

reports) to require that annual reports filed by the manufacturer

contain information on labeling changes that have been initiated in

response to new pediatric data, analysis of clinical data that have

been gathered on pediatric use, assessment of data needed to ensure

appropriate labeling for the pediatric population, and information on

the status of ongoing pediatric studies. FDA also proposed to require

that, where possible, the annual report contain an estimate of patient

exposure to the drug product, with special reference to the pediatric

population.

50. Several comments agreed with the agency that withdrawal or

denial of approval is infeasible and supported the use of injunctive

remedies. One comment argued that if FDA provides no incentives,

disincentives to avoid pediatric trials must be strong, and that

withdrawal and denial of approval must therefore be used as a remedy.

FDA continues to believe that refusal to approve or removal from

the market is generally an unsatisfactory remedy from a public health

perspective because it denies adequately studied populations access to

safe and effective medicines.

51. Several comments supported the imposition of monetary fines.

One comment urged that fines be imposed in the amount of a percentage

of the profits to ensure that large and small companies had an equal

disincentive. Several comments argued that fines should be used by FDA

to fund pediatric studies carried out by government or private

agencies. One comment contended that monetary penalties, such as fines

or shortening of exclusivity, are the only practical remedy because

industry and government are economically driven, but that injunctions

are too costly.

Although FDA continues to believe that court-imposed fines are an

appropriate remedy for failure to submit pediatric assessments, the

agency has no authority itself to impose fines for violation of this

rule, to set the amount of such fines, or to take the fines and direct

them to specific activities.

52. Two comments opposed treating violative products as

``misbranded'' because this could limit access to the drugs or could

delay availability of the products for adult use. According to one

comment, FDA should consider a misbranding charge only if the sponsor

failed to meet a phase 4 commitment. Another comment argued that

injunction or prosecution are appropriate only as a final response, and

that other, unspecified means are more efficient to elicit compliance.

This comment also argued that seizure would serve only to deprive

patients of safe and effective drugs.

The comments arguing that a misbranding charge could limit access

or delay approval provided no basis for concluding that these results

would occur, and FDA is aware of none. FDA agrees that injunction and

prosecution are appropriate remedies only after the sponsor has been

given an adequate opportunity to meet its obligations under the rule.

FDA emphasizes, however, that providing adequate

[[Page 66656]]

pediatric labeling cannot be long-delayed without putting the health of

pediatric patients at risk and that the agency will not accept

unwarranted delays in submitting required studies. FDA also notes that

it does not intend ordinarily to use seizure as a remedy for failure to

conduct required studies.

53. Some comments offered additional or alternative remedies for

failure to conduct required studies. One comment urged that failure to

provide information to support pediatric labeling result in highly

visible warnings on prescription and OTC labels that the drug has not

been approved by FDA for pediatric use. Two comments argued that the

label should disclose the status of pediatric studies, whether waivers

or deferrals had been requested or granted, and the timetable for full

compliance. Another comment contended that incentives are more

effective than penalties, and that FDA discussions with sponsors during

drug development will achieve the results sought in the proposal.

FDA agrees that publicity can sometimes be a useful tool for

encouraging compliance. FDA does not believe, however, that it is

feasible to include in labeling detailed information on the status of

pediatric trials, because that information could change frequently. As

described in section III.M of this document, FDA will, in appropriate

cases, bring issues related to the progress of pediatric studies before

a panel of pediatric experts, and may utilize other forms of publicity

to provide the public with information about the status of required

pediatric studies. FDA notes, e.g., that FDAMA contains provisions

concerning disclosure of information on the status of postmarketing

studies. FDA may also consider the use of prominent warnings about the

absence of data on pediatric use, if necessary in particular cases.

M. Pediatric Committee

A large number of comments recommended that FDA form a panel of

pediatric experts to provide advice on a range of topics related to

implementation of this rule. Two comments recommended that an expert

panel give advice on all facets of the rule. Several comments suggested

more specific roles for the panel. For example, the AAP recommended

that the panel provide advice on waiver requests, which marketed drugs

require study, whether a drug is ``widely used,'' whether to accept a

manufacturer's failure to develop a pediatric formulation, relevant age

groups for study, the appropriateness of deferral, and appropriate

timetables for completion of deferred studies. A disease-specific

organization urged that a pediatric committee assist in establishing

``pediatric guidelines and practice,'' including a list of drugs for

which studies would be required, protocol design, formulations, and age

ranges. Two industry comments recommended that the panel review which

drugs require testing and labeling, at what phase of drug development

pediatric patients should be exposed, when waivers should be granted,

what methods should be used to evaluate safety and effectiveness, the

economic burdens on industry, and liability issues. Several comments,

including comments from a pharmaceutical trade association, a disease-

specific organization, a medical society, and pediatricians,

recommended that the panel give advice on which drugs should be studied

in pediatric patients. One comment suggested that FDA appoint a

pediatric pharmacology expert to each of the existing drug advisory

committees, except possibly the Fertility and Maternal Health Advisory

Committee.

FDA has concluded that a panel of pediatric experts could provide

useful advice and experience on several aspects of the implementation

of the rule. FDA will therefore convene a panel of pediatric experts,

including at least one industry representative, and seek its advice on

a range of issues. Such a panel may be composed of pediatric experts

appointed to each of FDA's existing drug advisory committees. As

described in section III.E of this document under ``Waivers,'' FDA does

not believe that it would be practical to ask such a committee to

review every waiver or deferral request. However, the agency will ask

the panel to provide annual oversight of the agency's implementation of

the final rule, including the agency's record of granting or refusing

waivers and deferrals. FDA will also seek the advice of the panel in

identifying specific marketed drugs and biological products that should

be studied in pediatric patients, and the age groups in which they

should be studied. FDA will also ask for advice on assessing when

additional therapeutic options are needed in treating specific diseases

and conditions occurring in pediatric patients. As described

previously, FDA will seek the panel's advice on ethical issues raised

by clinical trials in pediatric patients, and whether additional rules

should be implemented in this area. Where a manufacturer is not

carrying out required studies according to the agreed upon timetable,

FDA may seek the advice of the panel on whether the manufacturer is

acting with due diligence. In addition, FDA may bring before the panel

other issues that arise in the implementation of the rule, including

the design of trials and analysis of data for specific products and

classes of products.

N. Other Comments

54. Several comments suggested various forms of oversight for the

implementation of the rule. One comment suggested that FDA establish a

plan to prospectively evaluate these regulations, including their

effect on the cost of drug development and on the time to new drug

approval, and the number and success of pediatric studies actually

performed. Another comment urged FDA to appoint a ``Children's Studies

Ombudsman.'' One comment asked that the rule include an appeals

mechanism to resolve disputes between sponsors and agency reviewers.

As described previously, FDA intends to convene a panel of

pediatric experts, including at least one representative of the

pharmaceutical industry, to, among other things, review the agency's

implementation of the rule. FDA notes that it already has procedures

for resolution of disputes between sponsors and FDA reviewing

divisions, 21 CFR 312.48 and 314.103, and that these procedures will be

available for disputes that arise under this rule.

55. Several comments contended that the rule is inconsistent with

requirements in Canada, Europe, and Japan for pediatric studies. These

comments argued that the rule was at odds with harmonization efforts

and urged FDA to harmonize its requirements with those of other

countries. One comment recommended that the United States, the European

Union (EU), and Japan adopt pediatric drug development as a topic for

global discussion and harmonization.

Although FDA is not required to harmonize its labeling regulations

and enforcement with those of our International Conference on

Harmonization (ICH) partners, harmonization is a goal that the agency

strives to achieve. FDA intends to work through the ICH process to

harmonize methods for conducting pediatric studies.

56. A few comments sought additional incentives for pediatric

studies. One industry comment suggested that FDA should provide: (1)

Priority reviews for applications containing pediatric data or ongoing

studies; (2) waiver of user fees for pediatric effectiveness

supplements; and (3) application of the subpart E

[[Page 66657]]

regulations (21 CFR part 312, subpart E) to pediatric development of

new drugs and biological products, to address the issues associated

with small sample size and therapeutic need.

Since the publication of the proposal, two significant new

incentives have become available for pediatric research. First, as

described elsewhere in this document, FDAMA provides 6 months of

exclusive marketing to certain applicants who conduct pediatric

studies. Second, as a result of changes made during the reauthorization

of the PDUFA, user fees are no longer required for supplements that are

solely for the purpose of adding a new indication for use in pediatric

populations.

IV. Legal Authority

In the proposal, FDA cited as authority for the requirements in the

rule sections 502(a), 502(f), 505(d)(7) of the act, and Sec. 201.5 (21

CFR 201.5), which require adequate directions for use and prohibit

false or misleading labeling; section 201(n) of the act, which defines

as misleading labeling that fails to reveal material facts related to

consequences of the customary or usual use of a drug; sections 201(p),

301(a) and (d) (21 U.S.C. 331(a) and (d)), and 505(a) of the act, which

subject a drug to enforcement action if it is not recognized as safe

and effective or approved for the conditions prescribed, recommended,

or suggested in the labeling; section 502(j) of the act, which

prohibits drugs that are dangerous to health when used in the manner

suggested in their labeling; sections 505(i) and 505(k) of the act,

which authorize FDA to impose conditions on the investigation of new

drugs, including conditions related to the ethics of an investigation,

and to require postmarketing reports; section 701(a) of the act, which

authorizes FDA to issue regulations for the efficient enforcement of

the act; and section 351 of the Public Health Service Act, which

formerly required biological products to meet standards designed to

insure their ``continued safety, purity, and potency.'' FDA notes that

section 351 was amended by FDAMA, and now requires biological products

to be ``safe, pure, and potent.''

FDA has authority under section 302 of the act and under the Public

Health Service Act to seek an injunction requiring studies of certain

marketed drugs on the grounds that the absence of pediatric safety and

effectiveness information in the labeling renders the product

misbranded or an unapproved new drug. The act also authorizes seizures

of misbranded or unapproved drugs under section 304 of the act.

Misbranding drugs and introducing unapproved new drugs into interstate

commerce are prohibited acts under sections 301(a), (d), and (k) of the

act. The statutory definition of ``drug'' is set out at section 201(g)

of the act.

57. Several comments agreed that FDA has authority to require

pediatric testing of drugs and biological products. One comment argued

that the act already gives FDA the authority to require that all drugs

be tested in pediatric patients, and that the rule, which permits

waivers and deferred testing in some cases, weakens the agency's

existing statutory authority. One comment contended a provision of

FDAMA granting exclusivity to ``any pediatric study [that] is required

pursuant to regulations promulgated by the Secretary [and that meets

certain other requirements]'' shows that Congress agrees that FDA has

authority to require pediatric studies. This comment also argued that,

to the extent that FDA's position on its authority to require pediatric

studies has changed, the change in position is justified because the

proposal articulates a reasoned basis for the change.

FDA agrees that it has the authority to require pediatric testing

of drugs and biologics. For the reasons cited in the preamble to the

proposed and final rules, FDA has concluded that the requirements in

the rule appropriately balance the need for adequate pediatric labeling

and the limitations on resources available for pediatric testing and

agency review. FDA also agrees that the reference in FDAMA, which was

enacted after the proposal was issued, to pediatric studies required by

FDA, demonstrate that Congress is aware of FDA's position that it has

the authority to issue this rule and agrees that the agency has such

authority. Finally, FDA agrees that it has articulated a reasoned basis

for its position that the agency has authority to require pediatric

studies, but notes that FDA previously stated its position that it has

the authority to require pediatric studies in 1994 (59 FR 64240 at

64243).

58. Several comments argued that FDA lacks authority to require

pediatric studies of drugs. A few comments cited remarks by former

Commissioner David Kessler during a 1992 speech. In that speech, David

Kessler stated his opinion that FDA does not have ``the authority to

require manufacturers to seek approval for indications which they have

not studied.'' Other comments argued that FDA has no authority to

require the study of any indications or populations other than those

proposed by the manufacturer. One comment challenged FDA's reliance on

section 201(n) of the act for not-yet-approved drugs, claiming that the

agency cannot know what will be the ``customary or usual uses'' of an

unmarketed drug. A few comments argued that the agency's legal theory

would authorize the agency to require studies of all off-label

indications.

FDA disagrees that any of these arguments show that FDA lacks

authority to issue this rule. Under FDA's longstanding policy,

statements made in speeches, even by Commissioners, are informal

expressions of opinion and do not constitute a formal agency position

on a matter. As such they are not binding on the agency. (See, e.g., 21

CFR 10.85(k).)

FDA also disagrees that it has no authority to require a drug or

biologic to be studied in a population that is expected to use the

product for the claimed indication, or that this is a new position. The

agency has repeatedly stated that an application for marketing approval

should contain data on a reasonable sample of the patients likely to be

given the product once it is marketed (59 FR 64240 at 64243; 58 FR

39406 at 39409). The agency has also previously asserted its authority

to require studies in pediatric patients and in other subpopulations

for both not-yet-approved products and marketed products. In the

preamble to the 1994 rule, FDA made the following statement:

If FDA concludes that a particular drug is widely used,

represents a safety hazard, or is therapeutically important in the

pediatric populations, and the drug sponsor has not submitted any

pediatric use information, then the agency may require that the

sponsor develop and/or submit pediatric use information.

If FDA has made a specific request for the submission of

pediatric use information because of expected or identified

pediatric use, and the sponsor fails to provide such information,

the agency may consider the product to be a misbranded drug under

section 502 of the act, or a falsely labeled biological product

under section 351 of the PHS Act, as an unapproved new drug or

unlicensed biological product. (See 21 U.S.C. 355 and 42 U.S.C.

262.)

(59 FR 64240 at 64248; see also 58 FR 39406 at 39409)

The act and implementing regulations require drugs to be adequately

labeled for their intended uses. See sections 502(f) of the act and

Sec. 201.5. ``Intended uses'' encompass more than the uses explicitly

included in the manufacturer's proposed labeling. Id., 21 CFR 201.128.

In determining the intended uses of a drug for which it must be

adequately labeled, FDA may consider both the uses for which it is

expressly labeled and those for which the drug is commonly used,

Sec. 201.5.

[[Page 66658]]

FDA may also consider the actual uses of the drug of which the

manufacturer has, or should have, notice, even if those uses are not

promoted by the manufacturer, 21 CFR 201.128. Section 201(n) of the act

defines labeling as misleading if it fails to include material facts

about the consequences of ``use of the [drug] * * * under such

conditions of use as are customary or usual.'' Sections 201(p) and

505(d) of the act authorize FDA to require evidence establishing the

safety and effectiveness of uses ``suggested'' by the manufacturer's

labeling as well as those expressly recommended in the labeling. Thus,

the agency has authority to require a manufacturer to establish the

safety and effectiveness of, and adequately label its product for, use

of the product in a subpopulation for which the product is not labeled

if that use is common or suggested in the labeling.

As described in the proposal, there is extensive evidence that

drugs and biologics indicated for diseases that affect both adults and

pediatric patients are routinely used in pediatric patients despite the

absence of pediatric labeling, and even in the face of disclaimers

stating that safety and effectiveness have not been established in

pediatric patients. FDA may therefore consider pediatric use to be

``customary or usual'' or ``commonly used'' where the drug is indicated

for a disease or condition that affects both adults and children, and

the drug is not contraindicated in pediatric patients. FDA may also

consider pediatric use to be ``suggested'' in a drug's labeling even

where such use is not expressly recommended or is even disclaimed. The

medical community generally expects that drugs and biological products

will behave similarly in demographic subgroups, including age and

gender subgroups, even though there may be variations among the

subgroups, based on, e.g., differences in pharmacokinetics. Thus, where

a drug or biological product is indicated for a disease suffered

equally by men, women, and children, and is not contraindicated in

women or pediatric patients, the product will be widely prescribed for

all three subgroups even if it were studied only in, or labeled only

for, men.

FDA disagrees that it can know nothing, in advance of marketing,

about whether a drug or biological product will be used in pediatric

patients. The evidence cited in the proposal and confirmed by comments

from the pediatric community is overwhelming that products indicated

for diseases that affect both adults and children are and will be

commonly used in pediatric patients. Indeed, pediatricians often have

no choice but to use these products in pediatric patients. A drug

product that provides a meaningful therapeutic benefit either because

it represents a significant improvement in therapy or because it is a

necessary therapeutic option can be expected to be routinely used in

the treatment of pediatric patients. Under the rule, the decision that

a product will provide a meaningful therapeutic benefit or will be used

in a substantial number of pediatric patients is made on a case-by-case

basis, depending upon such factors as the number of pediatric patients

affected by the disease for which the product is indicated, the

availability and adequacy of other therapeutic options to treat

pediatric patients for the disease, and whether similar products, e.g.,

products in the same drug class, have been widely used in pediatric

patients.

Finally, FDA emphasizes that this rule applies only where a product

is expected to have clinically significant use in pediatric populations

for the indications already claimed by the manufacturer. The record

before the agency documents widespread evidence of actual use of

products in the pediatric population for indications labeled for

adults. This record supports FDA's conclusion that it has authority to

require pediatric studies of drugs and biologics that have or are

expected to have clinically significant use among pediatric patients

for the claimed indications. The agency has not examined evidence

concerning the use of approved products for diseases or conditions not

in the label, and the rule does not apply in those situations.

59. Two comments addressed the agency's reliance on section 701(a)

of the act. One comment argued that 701(a) of the act, in combination

with the substantive statutory provisions cited by FDA, authorizes this

rule because the agency has demonstrated that the rule is reasonably

related to the purposes of the act. Another comment argued that 701(a)

of the act does not authorize the agency to enforce requirements beyond

those imposed by the act.

Section 701(a) of the act gives the Secretary authority to issue

regulations for the efficient enforcement of the act. Consonant with

the Supreme Court's determination that the language of the act should

not be read restrictively, but in a manner consistent with the act's

purpose of protecting the public health, a regulation issued under

section 701(a) of the act will be sustained so long as it is reasonably

related to the purposes of the act. United States v. Nova Scotia Food

Products Corp., 568 F.2d 240, 246 (2nd Cir. 1977). FDA believes that it

has demonstrated that this regulation is reasonably related to the

purposes of the act.

V. Implementation Plan

FDA proposed that the rule would become effective 90 days after the

date of its publication in the Federal Register. For new drug and

biologic product applications submitted before the effective date of

the final rule, the agency proposed a compliance date of 21 months

after the effective date of the final rule (for a total of 2 years

after issuance of the final rule). For new drug and biologic product

applications submitted on or after the effective date of the final

rule, the agency proposed a compliance date of 15 months after the

effective date of the final rule (for a total of 18 months after

issuance of the final rule). FDA has revised the final rule to become

effective 120 days after publication in the Federal Register, to allow

additional time for comment on the revised information collection

requirements. FDA has also revised the compliance dates. All

applications will have a compliance date of 20 months after the

effective date of the rule (for a total of 2 years after publication of

the final rule).

60. Two industry comments argued that the proposed effective dates

were too short. One of these suggested that 15 and 21 months were too

short to develop a pediatric program and formulation, conduct trials,

analyze data, and submit an application. Two comments asked that FDA

clarify what ``compliance'' means. According to one of these comments,

15 months would be adequate for initiation of discussions with a

sponsor about plans, but inadequate for completion of studies. This

comment also argued that it is not in children's interest to rush

through pediatric studies to meet an arbitrary deadline. Another

comment offered the example of Ritonavir, a drug to treat HIV

infection, for which pediatric studies reportedly took 21 months even

after development of a pediatric formulation. According to the comment,

it took 15 months to agree on a protocol, 3 months to recruit patients,

and 3 months to the first interim analysis of data. One disease-

specific organization argued that the effective dates were too long.

This comment proposed 12 months from the effective date of final rule,

which could be extended by 6 months if genuine difficulties occurred.

This comment also urged that compliance with the early discussion

requirements be immediate. One comment argued that pending applications

should be granted a full

[[Page 66659]]

waiver and treated as marketed products.

``Compliance,'' as referred to in the proposal, means the

submission of an assessment of pediatric safety and effectiveness under

Sec. 314.55(a) (proposed Sec. 314.50(g)(1) or 601.27(a)), unless a

waiver or deferral for all relevant age groups has been granted. FDA

has reconsidered the compliance dates and has concluded that

applications submitted on or after the effective date of the final rule

should be given 20 months from the effective date of the final rule to

achieve compliance. Although FDA does not believe that development of,

and agreement on, a protocol should take 15 months, protocol

development, recruitment, enrollment, and data analysis may together

take up to 2 years. There is no reasonable basis on which to

distinguish between an application submitted 1 day before the effective

date of the final rule, and one submitted a day later.

All other provisions of the rule will become effective on the

effective date of the rule. One hundred twenty days from the date of

publication in the Federal Register is sufficient time to meet these

new requirements.

VI. Paperwork Reduction Act of 1995

This final rule contains information collection requirements that

are subject to review by the Office of Management and Budget (OMB)

under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-

3520). The title, description, and respondent description of the

information collection requirements are shown below with an estimate of

the annual reporting burden. Included in the estimate is the time for

reviewing instructions, searching existing data sources, gathering and

maintaining the data needed, and completing and reviewing each

collection of information.

With respect to the following collection of information, FDA

invited comment on: (1) Whether the proposed collection of information

is necessary for proper performance of FDA's functions, including

whether the information will have practical utility; (2) the accuracy

of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the

information to be collected; and (4) ways to minimize the burden of the

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

OMB filed a Notice of Action, not approving the proposed collection

of information. OMB requested that, as part of the final rule, FDA

address all comments received on the information collection

requirements contained in the rule, particularly with respect to the

reporting burden imposed by the rule. FDA received one comment

concerning the proposed burden estimates of this rulemaking under the

PRA. The comment contended that FDA underestimated the time required to

comply with the annual reporting requirements of the proposed

rulemaking.

The agency received several comments that questioned the accuracy

of FDA's estimate of the burden of the proposed collection of

information as being too low and requested changes. For example, one

comment requested changes in the burden estimate for manufacturers

requesting deferrals of submission of pediatric data as well as the

estimate for manufacturers to submit pediatric information in their

annual report. In addition, the estimate for manufacturers to submit in

their annual reports the analysis of available safety and efficacy data

conducted or obtained in the pediatric population as well as proposed

labeling was questioned. Based on these comments the agency increased

the proposed burden estimates. These issues are discussed in more

detail in the preamble to the final rule.

Concerning Sec. 314.50(d)(7), the comment stated that in order to

comply with this requirement, ``one company'' estimated that, for one

pediatric reporting project, medical staff had spent at least 118

hours, rather than the 8 hours that FDA had estimated, reviewing the

medical literature and summarizing the findings. FDA does not believe

that this comparison is fully appropriate because Sec. 314.50(d)(7)

does not require an applicant to review the medical literature, or

other studies, de novo. It simply requires an applicant to provide a

brief summary of data that have already been fully reported and

analyzed elsewhere in the same application. However, because the data

to be summarized may be more extensive than originally estimated, FDA

has, in response to the comment, increased its estimate of the

reporting burden for this requirement from 8 hours to 50 hours.

Concerning Sec. 314.55(a), the comment contended that FDA's

estimate of 10 companies submitting NDA's annually for NME's is too

low. The comment implied that, based on data for 1996, 50 companies

would be a more realistic estimate. The comment also contended that

FDA's estimate of 16 hours for a manufacturer to prepare the report of

the data supporting the safety and effectiveness of the drug for the

indication for the pediatric population is too low. In response to this

comment, FDA has revised its burden estimate from 16 to 48 hours. FDA

has also made a corresponding change in the estimate for

Sec. 601.27(a). FDA has revised the estimate of the number of companies

affected from 10 to 51 to reflect the broader scope of the rule.

Concerning Sec. 314.55(b), the comment stated that FDA's estimate

of 9 manufacturers requesting deferrals of the submission of pediatric

study data and the estimate that this would take 8 hours to complete

are too low. In response to this comment, FDA has revised its burden

estimate from 8 hours to 24 hours. FDA has also made a corresponding

change in the estimate for Sec. 601.27(b). FDA has revised the estimate

of the number of companies affected from 8 to 51 to respond to the

comment and to reflect the broader scope of the rule.

Concerning Sec. 314.81(b)(2)(i), the comment contended that FDA's

estimate of 1.5 hours for manufacturers to submit pediatric information

in their annual reports is too low. In response to this comment, FDA

has revised its burden estimate from 1.5 hours to 8 hours and has made

a corresponding change in its estimate for Sec. 601.27(c).

Concerning Sec. 314.81(b)(2)(vi)(c), the comment contended that

FDA's estimate of 1.5 hours for manufacturers to submit in their annual

reports the analysis of available safety and efficacy data conducted or

obtained in the pediatric population as well as proposed labeling

changes is too low. The comment stated that even an estimate of 15

hours would be too low. Although the comment did not provide an

estimate of the hours required to satisfy Sec. 314.81(b)(2)(i) and

(b)(2)(vi)(c), FDA has increased its estimates to 8 and 24 hours,

respectively.

Based upon these comments, FDA has decided to increase the agency's

proposed burden estimates. These revisions are reflected in the Table 2

of this document. In addition, the burden estimates for

Secs. 314.55(a), (b), and (c), and 601.27(a), (b), and (c), have

increased because of the new requirements in the final rule to include,

in addition to applications for new chemical entities and never-before-

approved biologics, applications for new active ingredients, new

indications, new dosage forms, new dosing regimens, and new routes of

administration. These estimates are based upon FDA's analysis of all

marketing applications and efficacy

[[Page 66660]]

supplements approved over the 5-year period of 1993 to 1997 and those

that would likely have needed additional pediatric data had this rule

been in effect by 1993 (see ``Analysis of Impacts,'' in section VIII of

this document). In addition, burden estimates have been added in Table

2 of this document for the new requirements in the final rule

concerning submissions for end-of-phase 1 and end-of-phase 2 meetings

under Sec. 312.47(b)(1)(iv) and submissions for pre-NDA meetings under

Sec. 312.47(b)(2). These estimates are based on FDA's records of the

number of these meetings held during 1997. Finally, burden estimates

have been added for new postmarket report requirements added for

biological products under Sec. 601.37 (a), (b), and (c), corresponding

to Sec. 314.81 (b)(2)(i), (b)(2)(vi)(c), and (b)(2)(vii). These

estimates are based upon FDA's records of the number of licensed

biological products.

Title: Regulations Requiring Manufacturers to Assess the Safety and

Effectiveness of New Drugs and Biological Products in Pediatric

Patients.

Description: This final rule includes the following reporting

requirements: (1) Reports on planned pediatric studies in IND's

(Sec. 312.23(a)(10)(iii)); (2) Reports for end-of-phase 1 and end-of-

phase 2 meetings (Sec. 312.47(b)(1)(iv)) and reports for pre-NDA

meetings (Sec. 312.47(b)(2)); (3) Summaries of data on pediatric safety

and effectiveness in NDA's (Sec. 314.50(d)(7)); (4) Reports assessing

the safety and effectiveness of certain drugs and biological products

for pediatric use in NDA's and BLA's or in supplemental applications

(Secs. 314.55(a) and 601.27(a)); (5) Requests seeking deferral of

required pediatric studies (Secs. 314.55(b) and 601.27(b)); (6)

Requests seeking waiver of required pediatric studies (Secs. 314.55(c)

and 601.27(c)); (7) Postmarketing reports of analyses of data on

pediatric safety and effectiveness (Secs. 314.81(b)(2)(vi)(c) and

601.37(a)(1)); (8) Postmarketing reports on patient exposure to certain

marketed drug products (Secs. 314.81(b)(2)(i) and 601.37(a)(2)); (9)

Postmarketing reports on labeling changes initiated in response to new

pediatric data (Secs. 314.81(b)(2)(vi)(c) and 601.37(a)(3)); and (10)

Postmarketing reports on the status of required postapproval studies in

pediatric patients (Secs. 314.81(b)(2)(vii) and 601.37). The purpose of

these reporting requirements is to address the lack of adequate

pediatric labeling of drugs and biological products by requiring the

submission of evidence on pediatric safety and effectiveness for

products with clinically significant use in children.

Description of Respondents: Sponsors and manufacturers of drugs and

biological products.

Table 2.--Estimated Annual Reporting Burden \1\

----------------------------------------------------------------------------------------------------------------

Annual Total

21 CFR section No. of frequency annual Hours per Total hours

respondents per response responses response

----------------------------------------------------------------------------------------------------------------

201.23...................................... 2 1 2 48 96

312.47(b)(1)(iv)............................ 27 1.2 32 16 512

312.47(b)(2)................................ 36 1.3 46 16 736

314.50(d)(7)................................ 213 1 213 50 10,650

314.55(a)................................... 51 1 51 48 2,448

314.55(b)................................... 51 1 51 24 1,224

314.55(c)................................... 176 1 176 8 1,408

314.81(b)(2)(i)............................. 625 1 625 8 5,000

314.81(b)(2)(vi)(c)......................... 625 1 625 24 15,000

314.81(b)(2)(vii)........................... 625 1 625 1.5 937.5

601.27(a)................................... 2 1 3 48 144

601.27(b)................................... 2 1 3 24 72

601.27(c)................................... 3 1 4 8 32

601.37(a)................................... 69 1 69 8 552

601.37(b)................................... 69 1 69 24 1,656

601.37(c)................................... 69 1 69 1.5 103.5

-------------------------------------------------------------------

Total................................... ........... ............ ........... ............ 40,571

----------------------------------------------------------------------------------------------------------------

\1\There are no capital or operating and maintenance costs associated with this collection of information.

The information collection provisions of this final rule have been

submitted to OMB for review. Prior to the effective date of this final

rule, FDA will publish a notice in the Federal Register announcing

OMB's decision to approve, modify, or disapprove the information

collection provisions in this final rule. An agency may not conduct or

sponsor, and a person is not required to respond to, a collection of

information unless it displays a currently valid OMB control number.

VII. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

VIII. Analysis of Impacts

A. Introduction and Summary

FDA has examined the impacts of the final rule under Executive

Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the

Unfunded Mandates Reform Act (Pub. L. 104-4). Executive Order 12866

directs agencies to assess all costs and benefits of available

regulatory alternatives and, when regulation is necessary, to select

regulatory approaches that maximize net benefits (including potential

economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). Under the Regulatory

Flexibility Act, unless an agency certifies that a rule will not have a

significant economic impact on a substantial number of small entities,

the agency must analyze regulatory options that would minimize the

impact of the rule on small entities. The Unfunded Mandates Reform Act

(Pub. L. 104-4) (in section 202) requires that agencies prepare an

assessment of anticipated costs and benefits before proposing any rule

that may result in an expenditure by State, local, and tribal

governments,

[[Page 66661]]

in the aggregate, or by the private sector, of $100 million or more in

any one year (adjusted annually for inflation).

The agency has reviewed this final rule and has determined that the

rule is consistent with the regulatory philosophy and principles

identified in Executive Order 12866, and in these two statutes. This

rule is an economically significant regulatory action, because of its

substantial benefits. It is also a significant regulatory action as

defined by the Executive Order due to the novel policy issues it

raises. With respect to the Regulatory Flexibility Act, the agency

certifies that the rule will not have a significant economic impact on

a substantial number of small entities. Since the rule does not impose

any mandates on State, local, or tribal governments, or the private

sector that will result in an expenditure of $100 million or more in

any one year, FDA is not required to perform a cost-benefit analysis

according to the Unfunded Mandates Reform Act.

FDA is requiring that a limited class of important new drugs and

biologicals that are likely to be used in pediatric patients contain

sufficient data and information to support directions for this use. As

the approved labeling for many of these new products lacks adequate

pediatric information, their use in children greatly increases the risk

of inappropriate dosing, unexpected adverse effects, and suboptimal

therapeutic outcomes. This rule is designed to ensure that new drugs,

including biological drugs, that are therapeutically important and/or

likely to be used in a substantial number of children contain adequate

pediatric labeling at the time of, or soon after, approval.

The agency estimated the costs to industry of the required new

pediatric studies by first determining what the annual costs would have

been in 1993 to 1997, had the rule become effective in 1993. The

methodology included: (1) Constructing a data base of all 583 NDA's and

efficacy supplements approved by the agency over that 5-year period for

drugs and biologicals likely to produce health benefits in the

pediatric population, (2) determining which of those applications would

have been required to conduct additional pediatric studies, (3)

calculating how many unapproved and already marketed drugs and

biologicals would have needed additional pediatric studies, and (4)

estimating the size and cost of the additional studies. The analysis

indicated that, on average, this regulation would have required an

estimated 378 additional pediatric studies on about 82 drugs and

biologicals per year. These studies would have involved a total of

10,860 pediatric patients, 7,408 in efficacy studies, and 3,452 in PK

studies. In addition, an estimated 33 of the 82 drugs and biologicals

needing new pediatric data each year may have needed new pediatric

dosage forms. FDA judges that the additional studies would have cost

about $45 million and the new dosage formulations about $33 million

annually, for a total annual cost of almost $80 million. The agency

found, however, that roughly 42 percent of the costs of the studies

would have been spent voluntarily had the extended pediatric

exclusivity provisions of the recent FDAMA statute been in place.

Adjusting for this effect lowers the agency's final cost estimate for

this rule to about $46.7 million per year.

FDA could not develop a quantifiable estimate of the benefits of

this regulation, although numerous anecdotal examples illustrate the

current health problem. To consider some of the potential benefits, the

agency examined hospitalization rates for five serious illness (asthma,

HIV/AIDS, cancer, pneumonia, and kidney infections) and found

significantly higher rates for children than for middle-aged adults.

Although FDA can not estimate the extent to which these differentials

reflect the relative lack of pharmaceutical safety and efficacy

information for pediatric compared to adult use, the agency calculated

that a 25 percent reduction in these differentials would lead to direct

medical cost savings of $228 million per year. FDA also estimates that

about two-thirds of the approved applications needing pediatric studies

will be addressed by the incentives established by FDAMA. If the

estimated medical cost savings were adjusted by a similar ratio, the

analysis suggests that a 25 percent reduction in the pediatric/adult

hospitalization rate differentials would yield annual savings of $76

million for these five illnesses.

B. Number of Affected Products and Required Studies

In the preamble to its proposal, FDA explained that neither the

precise number of drugs that would require additional pediatric studies

nor the cost of these studies could be predicted with certainty. To

develop plausible estimates of the number of new drugs and biologicals

that would be affected, the agency had examined the pediatric labeling

status at time of approval for each NME and important biological

approved from 1991 to 1995, and used these estimates to project the

number of drugs that would have required additional pediatric data had

the proposal been in place over that period.

Several industry comments declared that FDA's analysis of the

proposal substantially underestimated the economic impact by

understating both the number and size of the studies that would be

required. Only two of the comments, however, included alternative

estimates. One suggested that each new drug could require the testing

of 300 or more pediatric patients for safety data alone. The other

comment estimated that, ``each new drug studied would probably require

a minimum of six clinical trials (two each in Phases I, II, and III),

for one indication and one formulation.'' This comment explained that

Phase I trials would include 20 patients, Phase II trials 50 patients,

and Phase III trials 100 patients. Assuming two trials for each phase,

the comment projected that 34,000 pediatric patients would need to be

studied each year (170 patients x 2 trials x 100 drugs).

FDA agrees that some applications will require data from a

substantial number of pediatric patients. The agency believes, however,

that most studies will not include large numbers of pediatric patients.

For example, FDA does not necessarily require two pediatric studies for

each trial phase. Moreover, FDA's 1994 final rule (59 FR 64240)

explains that extrapolations from adult effectiveness data based on PK

studies and other safety data can be sufficient to provide the

necessary pediatric dosing information for those drugs and biologicals

that work by similar mechanisms in adults and children. The agency

expects that the majority of the studies will rely, to some extent, on

such extrapolations.

On the other hand, the proposal primarily addressed drugs and

biologicals that contained no previously approved active moiety. The

final rule requires pediatric data for new active ingredients, new

indications, new dosage forms, new dosing regimens, and new routes of

administration that represent a meaningful clinical benefit over

existing treatments for children, or that are likely to be widely used

in children. The rule also requires pediatric studies for marketed

drugs and biologicals that are already widely used among children for

the claimed indications, if the absence of adequate labeling could pose

significant risks; or if the drug would provide a meaningful clinical

benefit over existing treatments for pediatric patients, but additional

dosing or safety information is needed to permit their safe and

effective use in children.

To develop a revised estimate of the number of drugs and

biologicals that

[[Page 66662]]

would require additional pediatric data, FDA constructed a data base of

all 583 applications and efficacy supplements approved over the 5-year

period from 1993 to 1997 for drugs and biologicals for which pediatric

labeling would be likely to provide a significant health benefit. The

selected drugs and biologicals included all those for which the active

moiety was listed in the priority section in the Federal Register of

May 20, 1998 (63 FR 27733), document entitled ``List of Drugs For Which

Additional Pediatric Information May Produce Health Benefits in the

Pediatric Population'' (``List''). Mandated by FDAMA, this publication

includes the agency's priority list of drugs and biologicals that would

likely provide a significant benefit to the pediatric population. The

selection criteria used to prepare this priority list were almost

identical to those set forth in this final rule, i.e.,

<bullet> The drug product, if approved for use in the pediatric

population, would be a significant improvement compared to marketed

products labeled for use in the treatment, diagnosis, or prevention of

a disease in the relevant pediatric population (i.e., a pediatric

priority drug); or,

<bullet> The drug is widely used in the pediatric population, as

measured by at least 50,000 prescription mentions per year; or,

<bullet> The drug is in a class or for an indication for which

additional therapeutic options for the pediatric population are needed.

FDA then identified each of the 583 applications that would likely

have needed additional pediatric studies had this rule been in effect.

The number and type of studies needed were projected based on specific

decision rules derived from agency experience in reviewing drug

applications and developed strictly for the purpose of estimating the

regulatory costs of this rule. Although in practice, these rules would

have been subject to numerous exceptions, in the aggregate, FDA

believes that they provide plausible estimates of the total number and

type of pediatric studies that would have been required. The decision

rules were as follows:

1. All New Chemical Entities (NCE's) and biologicals were assumed

to need both an efficacy study and a PK study for each age group

identified in the priority section of the ``List'' as needing pediatric

information, although FDA believes that this assumption overstates the

true number of efficacy studies that will be needed.

2. For the following categories of applications, both an efficacy

and a PK study were assumed for each designated age group. Again, FDA

believes that this assumption may overstate the true number of efficacy

studies that will be needed:

Neurological drugs;

Oncology drugs;

Nausea agents;

Pulmonary agents;

NSAIDs--arthritis/pain;

AIDS/HIV agents;

Asthma drugs;

Anesthesia drugs;

Hormones;

Dermatological agents;

Acne agents

3. A PK study alone was assumed sufficient for each relevant age

group for the following types of non-NCE applications:

Allergies;

Infectious diseases;

Cardiovascular diseases;

Imaging agents;

Hematology agents;

GI disorders;

Urologic drugs

4. If pediatric labeling was already adequate as the result of an

approved application, additional applications for new dosage forms were

assumed to be exempt.

5. If a second applicant sought approval for the same indication of

the same drug as a previous applicant that had already satisfied the

pediatric labeling requirements, the second applicant was considered

exempt from the pediatric labeling requirement.

6. Because the regulation imposes requirements only on new NDA's or

efficacy supplements that specifically address an indication needing

pediatric data, no pediatric requirements were assumed for an NDA

supplement submitted for a new indication not identified as needing

pediatric data.

7. Orphan drugs were excluded from additional research

requirements.

The results of this analysis (see Table 3 of this document) show

that about 44 percent, or an estimated 255, of the total 583 drug and

biological applications for the products on the priority section of the

``List'' drugs approved over the 5-year period would have required

additional pediatric studies, had the rule been in effect starting in

1993. Assuming separate studies for each pediatric age group specified

in the ``List,'' indicates that an estimated 459 efficacy studies and

713 PK studies would have been required for these applications.

These estimates understate the required research effort, however,

because they omit pediatric studies for drugs that fail to gain

approval. It is difficult to judge how much additional pediatric

research would be directed towards nonapprovable products. The agency

notes, however, that because only about 63.5 percent of all NME's that

enter phase III trials are eventually approved (Ref. 18), the number of

drugs entering phase III trials is about 58 percent greater than the

number of actual approvals (100/63.5 = 1.58). Moreover, there are two

additional complications. First, under the rule, FDA expects to defer

for several years the conduct of pediatric studies of ``me-too'' drugs

that do not offer a meaningful therapeutic benefit and that are members

of a drug class that already contains an adequate number of approved

products with pediatric labeling. No additional pediatric studies would

be expected for this group of never approved drugs. On the other hand,

applications for ``lifesaving'' drugs may need to begin pediatric

trials by the start of Phase II. On the assumption that these two

factors would roughly offset, FDA has retained the 58 percent figure as

a reasonable adjustment factor to account for the number of studies

conducted for drugs that fail to gain approval. Finally, each year, the

agency expects to identify about two ``already marketed'' drugs that

require additional pediatric efficacy data.

As shown in Table 4 of this document, adjusting for the ``never

approved'' and the ``already marketed'' applications implies that, had

this rule become effective in 1993, about 1,892 new pediatric studies

would have been required over the 1993 to 1997 period. About 740 of the

studies would have been efficacy studies and 1,151 PK studies. Thus, on

average, each year, the rule would have required about 378 new

pediatric studies for about 82 NDA's and or NDA supplements--148

efficacy studies and 230 PK studies.

[[Page 66663]]

Table 3.--Approved New Drug Applications and Their Supplements From 1993 to 1997

----------------------------------------------------------------------------------------------------------------

Applications

Applications needing Efficacy PK studies Total New dosage

Approval year for ``List'' pediatric studies required studies forms

Drugs studies required required

----------------------------------------------------------------------------------------------------------------

1993............................ 77 43 63 122 185 12

1994............................ 76 42 74 118 192 17

1995............................ 107 38 69 107 176 13

1996............................ 177 74 147 213 360 29

1997............................ 146 58 106 153 259 19

-------------------------------------------------------------------------------

Total....................... 583 255 459 713 1,172 90

-------------------------------------------------------------------------------

Average..................... 117 51 92 143 234 18

----------------------------------------------------------------------------------------------------------------

Table 4.--All New Drug Applications and Their Supplements From 1993 to 1997 \1\

----------------------------------------------------------------------------------------------------------------

Applications

Applications needing Efficacy PK studies Total New dosage

Approval year for ``List'' pediatric studies required studies forms

Drugs \2\ studies required required

----------------------------------------------------------------------------------------------------------------

1993............................ 124 69 102 197 299 22

1994............................ 123 68 119 190 310 32

1995............................ 173 61 111 173 284 24

1996............................ 286 119 237 344 581 54

1997............................ 236 94 171 247 418 35

-------------------------------------------------------------------------------

Total....................... 942 411 740 1,151 1,892 167

-------------------------------------------------------------------------------

Average..................... 188 82 148 230 378 33

----------------------------------------------------------------------------------------------------------------

\1\ Includes estimates for ``unapproved'' and ``already marketed'' drugs.

\2\ Adjusted for ``unapproved'' and ``already marketed'' drugs.

C. Number of Pediatric Patients

The number of pediatric patients needed varies with the particular

type of drug studied. However, based on agency experience, FDA

estimates that, for each pediatric age group studied, typical pediatric

PK studies may involve about 15 patients and typical efficacy studies

about 50 patients. For example, if 2 of the 4 age groups lack PK

studies, FDA assumed that a total of 30 subjects would be needed for

the studies. If 3 of the 4 age groups lack efficacy studies, a total of

150 subjects were assumed to be needed in all 3 age groups. These

assumptions indicate that, had this rule become effective in 1993, each

year, about 82 NDA's would have required additional pediatric studies;

7,408 pediatric patients in efficacy studies and 3,452 pediatric

patients in PK studies, for an annual total of about 10,860 pediatric

patients.

D. Costs of Compliance

1. Cost of Pediatric Studies

FDA's analysis of the proposal assumed that new studies would cost

pharmaceutical firms from $5,000 to $9,000 per pediatric patient. Only

one comment, that of a large U.S. pharmaceutical company, submitted

actual estimates of the cost of conducting pediatric trials. This

comment stated that a PK or bioavailability/bioeqivalency study of 20

patients would cost at least $100,000, a Phase II trial of 50 patients

would cost a minimum of $150,000, and a Phase III trial of 100 patients

would cost $200,000. For its revised analysis, therefore, FDA assumes

that a PK study of 15 patients will cost $100,000 per affected age

group and that an efficacy study of 50 patients will cost $150,000 per

affected age group. Although a few trials may need to be larger and,

thus more expensive; others will require substantially fewer pediatric

patients. Thus, FDA believes these figures reasonably project the

average added costs.

As FDA estimates that the regulation would have required

pharmaceutical companies to annually conduct an estimated 378

additional pediatric studies for 82 NDA's, 148 efficacy studies, and

230 PK studies; the above unit cost estimates imply total industry

costs of $45 million annually. Although the industry comment that

included the cost data projected clinical trial costs totaling over

$100 million per year, this estimate assumed the need for 34,000

additional pediatric patients. FDA found that had this rule been in

place over the 1993 to 1997 period, it would have required additional

data from about 10,860 patients per year.

2. Cost of New Formulations

In its earlier analysis of the proposal, FDA calculated that about

30 percent of all NME's were available only in tablets or hard capsules

at the time of approval. Acknowledging the potential difficulties of

developing new formulations for certain drugs, FDA estimated that the

overall costs could average $1 million for each new formulation

developed. Several comments questioned the agency's estimates. Based on

an informal survey of its members, a major industry trade association

reported that the development of a pediatric formulation could take

from 5 months to 4 years and cost from $500,000 to $3.5 million. It

also objected to the agency's estimate of the number of drugs that

would require reformulation. The association, however, apparently

misunderstood FDA's methodology. The agency had found that 10 of 14

drugs per year would not need reformulation because a potentially

adequate dosage form (liquid, an injectable, a solution, a

dermatological, etc.) was already available. The association believed

that FDA has assumed that only tablets and/or capsules were available

for the ten drugs. None of these comments,

[[Page 66664]]

however, offered an alternative methodology for projecting the

aggregate value of these costs.

To develop reasonable estimates of the number of new dosage forms

that would be needed, FDA again reviewed all of the 255 approved drug

applications that would likely have required new pediatric studies

during the 1993 to 1997 period, had this rule been in place. The agency

generally assumed that those drugs identified as having a meaningful

clinical pediatric benefit for the youngest three age groups, but

available only in tablets or hard capsules at the time of approval,

would have needed to develop an alternative dosage form. The agency

also assumed that a new pediatric formulation would not be counted if a

more appropriate pediatric dosage form was subsequently approved for

the same drug. FDA is aware that these estimates can not be considered

precise. For example, not all liquids are adequate for pediatric

populations. On the other hand, new formulations may not be needed if a

drug is used primarily for children between the ages of 8 and 12 years.

Nevertheless, as shown in Table 3 of this document, the results of this

methodology show that about 35 percent of the approved applications

needing studies, or about 18 per year, would have needed new dosage

forms. Table 4 of this document raises this estimate by 83 percent, or

to 33 per year, to account for the number of new dosage forms developed

for drugs not subsequently approved. While FDA cannot confidently

predict a typical initiation time for this effort, the 83 percent

adjustment calculation assumes that work on about 25 percent of all new

formulations would be initiated at the start of Phase 2 trials and 75

percent by the start of Phase 3 trials. (The probability of approval

was assumed to be .635 for a drug entering phase 3 trials and .31 for a

drug entering phase 2 trials (Ref. 18).)

The development of some pediatric formulations will be difficult,

the development of others relatively straightforward and achieved

without substantial problem. The rule requires only that sponsors take

all reasonable steps to develop needed new formulations. Thus, while

acknowledging that the cost for particularly difficult formulations may

be higher, FDA has retained its average cost estimate of $1 million to

develop each new dosage form and projects this total industry cost at

nearly $33 million per year.

3. Cost of Added Paperwork Requirements

The rule also requires additional industry effort for new or

expanded paperwork reporting. Section VI of this document describes

these reporting tasks, discusses the industry comment that questioned

the agency's estimate of the paperwork burden for the proposal, and

presents the agencies revised estimate for this final rule. As shown in

that section, FDA projects an annual burden of about 40,000 hours per

year. On the assumption that 25 percent of these hours will be for

upper management staff, 50 percent for middle management staff, and 25

percent for administrative and clerical support, at respective labor

costs of $52, $34, and $17 per hour, FDA estimates these total

paperwork costs at about $1.4 million per year.

4. Total Costs

Table 5 of this document summarizes the agency's estimates of costs

for efficacy studies, PK studies, new dosage forms, and paperwork.

Because the expense of pediatric trials and dosage form development

will be spread over 2 or 3 years for any given drug, the total costs to

industry in any given year are unlikely to vary as much as shown in

Table 5. Most importantly, however, the average $80.1 million annual

cost figure reflects only what the rule would have cost had the rule

been in effect from 1993 to 1997. The incentives generated by the

additional 6-month marketing exclusivity offered by FDAMA will reduce

the future costs of the regulation.

Table 5.--Estimated Industry Costs--Compliance With Pediatric Labeling

[in millions]

----------------------------------------------------------------------------------------------------------------

New dosage

Year Efficacy PK studies form Paperwork Total

studies developed

----------------------------------------------------------------------------------------------------------------

1993........................................... $15.3 19.7 22.3 1.4 58.6

1994........................................... 17.9 19.0 31.6 1.4 69.9

1995........................................... 16.7 17.3 24.1 1.4 59.5

1996........................................... 35.6 34.4 53.9 1.4 125.2

1997........................................... 25.7 24.7 35.3 1.4 87.0

----------------------------------------------------------------

Average Per Year........................... $22.2 $23.0 $33.4 $1.4 $80.0

----------------------------------------------------------------------------------------------------------------

FDA cannot develop precise adjustments for the forthcoming effects

of FDAMA, due to the complexity of the economic forecasting that would

be needed. Nevertheless, the agency developed rough projections of the

potential impact of this statute by comparing the estimated present

value of the 6-month exclusivity gain with the estimated cost of the

new pediatric studies, for each of the 85 drugs with applications

approved in 1993 and 1994 that would have needed new pediatric

labeling. (More recent years were not used, because the revenues of

newer drugs are far below their peak values.) Where the estimated

exclusivity gain exceeded the cost of all required studies, including

the development of new dosage forms, FDA concluded that the studies for

that drug would have been initiated voluntarily and their cost

attributable to FDAMA rather than to this regulation.

The methodology assumed that a 6-month gain of marketing

exclusivity would be worth about 25 percent of a drug's annual sales

revenue during the year the exclusivity is needed, less 60 percent for

production, administrative, and marketing costs (Ref. 19). Costs of

conducting the required studies for each of the 85 drugs were based on

the cost estimates described previously ($150,000 for each efficacy

study, $100,000 for each PK study, and $1 million for each new dosage

form. The present value of the additional revenues (at a 7 percent

discount rate) were calculated from 1997 sales data published by IMS

America (Ref. 20). Because 1997 sales revenues probably underestimate

the sales revenues that will be realized at the time that the added

exclusivity is used, this methodology likely underestimates the effects

of FDAMA, hence overestimating the costs of the rule. In general,

[[Page 66665]]

however, this analysis was insensitive to the precise assumptions used.

For example, using an 11 percent rather than 7 percent discount rate

raises the cost totals by only $1.2 million per year.

The analysis found that the necessary studies would have been

conducted voluntarily for 56 out of the 85 affected applications (66

percent). Adjusting estimates of only the approved applications by this

percentage (FDAMA was not assumed to affect studies for applications

not obtaining approval), FDA projects that the annual costs

attributable to this rule will be approximately $46.7 million, or about

42 percent below the non-FDAMA adjusted figure of $80 million.

Further, although the agency has not yet evaluated the full

economic impact of the FDAMA legislation, it believes that the present

value of the net revenues expected from the 6 months of added

exclusivity granted under the new FDAMA legislation will greatly exceed

the additional costs imposed by this regulation. One industry

publication (MedAdNews, June 1998, p. 10) for example, reports that

products currently valued at $41 billion in annual sales will come off

patent between 1998 and 2008, or an average of $11 billion per year.

Alternatively, FDA estimates that the annual revenues for NCE's coming

off patent may average between $200 and $300 million each. If 25 NCE's

lose exclusivity each year, these annual revenues would range from $5

billion to $7.5 billion. If only 60 percent of these NCE's become

eligible for extended exclusivity, the methodology described above

implies that industry net incomes will increase from $300 to $450

million per year. Thus, FDAMA and this rule, taken together, will

provide critical pediatric information without diverting current

resources from pharmaceutical innovation.

*COM041**COM041*E. Benefits

The rule addresses two major problems associated with the lack of

adequate information on the effects of drugs on pediatric patients: (1)

Adverse drug reactions in children due to inadvertent drug overdoses or

other drug administration problems that could be avoided with better

information on appropriate pediatric use; and (2) under use of safe and

effective drugs for children due to the prescribing of an inadequate

dosage or regimen, a less effective drug, or no drug at all because of

uncertainty over the drug's effect on children or the unavailability of

a pediatric formulation. By developing improved information on whether,

and in what dosage, a drug is safe and effective for use in children,

FDA believes that the regulation will result in fewer adverse drug

reactions and fewer instances of less-than-optimal treatment of

pediatric patients.

Despite numerous reports of children endangered by the absence of

adequate drug labeling, FDA has found no systematic studies in the

literature that evaluate the overall magnitude of the harm that results

from the incomplete labeling of drugs for use in children. In the

preamble to the proposal, the agency specifically requested,

``information on any available studies or data related to the incidence

and costs of either undertreatment or avoidable ADE's in pediatric age

groups due to the lack of information on the effects of

pharmaceuticals.'' The comments received cited case after case of

children who have died or suffered because of the inadequate testing of

drugs in children, but the information was largely anecdotal and

related to particular instances of drug misuse or underuse.

For example, physicians who care for HIV-infected patients

expressed frustration at their inability to treat children with drugs

known to be effective in adults. Pulmonary specialists described the

dearth of information on risks versus benefits of new antimicrobials

for pediatric patients, citing the example of ciprofloxacin, a

quinolone that may be valuable in treating cystic fibrosis, although

the safety and effectiveness of the drug in children has not been

established. Comments received from asthma specialists reaffirmed the

difficulties of administering medications, treating drug side effects,

or withholding treatment for children with asthma, due to the lack of

research on drug safety and effectiveness.

In both written comments and in commentary at the public hearing in

October 1997, concerns were raised about the costs of not implementing

a requirement for pediatric labeling. Avoidable adverse outcomes, cited

in relation to pediatric dosage problems, included opportunistic

infections from too much immunosuppression, and loss of grafts in

pediatric renal transplant patients with too little immunosuppression.

Comments also cited added health care, including increased

hospitalizations, required as a result of less effective treatment for

pediatric patients. One comment estimated the cost of delayed access in

terms of infant deaths, attributing an additional 2,000 unnecessary

infant deaths over a 2-year period to the delay in access to AZT for

HIV-exposed infants. Another suggested using the Vaccine Injury

Compensation program figure of $250,000 per child as the value of an

avoided death resulting from an ADR. Other comments confirmed that many

adverse outcomes develop quickly and would be detected in early

clinical studies (e.g., ``gray syndrome'' in babies treated with

chloramphenicol).

While clearly demonstrating the critical need for improved

pediatric information, these comments do not suggest a practical

methodology for quantifying the aggregate benefits of this rule. FDA,

also, has been unable to develop a precise assessment of the probable

regulatory benefits. The agency's approach to estimating regulatory

benefits therefore is framed in terms of the following two questions:

(1) Are data available to assess current differences in the safety of

drug therapy for adults versus children with the same condition? and

(2) Are data available to assess current differences in the

effectiveness of drug therapy for adults versus children with the same

condition?

FDA first attempted to assess the safety of drug therapy by looking

for differences in the frequency and severity of ADR's for adults

versus children treated for the same condition. The available clinical

and health survey data, however, did not provide a reliable estimate of

the contribution of ADR's to pediatric as compared to adult rates of

mortality and morbidity. ADR-related data are limited by the lack of a

general requirement and a ready mechanism for the comprehensive

reporting of incidents directly attributable to ADR's (Ref. 21).

Moreover, most available studies have not addressed ADR rates and

associated death rates by age group within a treated condition (Refs.

22, 23, and 24). For example, one study of pediatric patients shows an

ADR-related admission rate in the range of only 2.0 to 3.2 percent,

well below the average for adult and pediatric studies combined.

Pediatric cancer patients, however, experienced a 22 percent ADR-

admission rate (Ref. 25), suggesting that pediatric risks may be

significantly greater within condition-defined subpopulations. In

addition, potential concerns about negative public attention (Ref. 26)

or liability inhibit reporting of ADR's. Finally, for many seriously

ill patients, it is very difficult to attribute a specific medical

outcome to a particular medication, as opposed to some other

complication in the patient's condition, or misadventure in the

patient's care. The agency found therefore that it could not rely on

available ADR studies to derive an assessment of the potential benefits

of this rule.

[[Page 66666]]

Data to assess the effectiveness of drug therapy would indicate

differences in clinical outcomes, or in other health care utilization

concomitant with drug therapy. If drug therapies for children were less

effective than that for adults with the same condition, one might see

longer recovery times, or lower recovery rates, together with increased

health services use, assuming a similar prognosis and course of

illness. A limitation to this approach is that the prognosis and course

of illness may not be the same in children and adults with the same

serious health condition, even if the same drugs were included in best-

practice treatment. Moreover, differential patterns of health care

utilization may reflect variations in physician practice patterns,

insurance benefits, or patient and family behavior and preferences,

rather than measures of drug effectiveness. Notwithstanding such

limitations, comparisons of health care resource use for one

therapeutic approach compared to another are commonly used in

evaluations of therapy effectiveness in the field of pharmacoeconomics.

In this instance, FDA finds that health care utilization data may

provide at least an indirect indication of potential benefits.

Hospitalization rates, in particular, are the most extensively studied

measure of morbidity related to adverse drug reactions and of quality

of care for a number of chronic (e.g., asthma) and acute conditions

(e.g., pneumonia) (Refs. 27 and 28). While hospitalizations due to

adverse drug reactions or drug therapy undertreatment are not always

recognized, these admissions are routinely classified with a primary

diagnosis of the underlying disease. FDA therefore has relied on

diagnosis-related hospitalization rates to develop an order-of-

magnitude assessment of the potential benefits of this rule.

For this assessment, the agency compared rates of hospitalization

of pediatric patients to rates of hospitalization of adult patients for

several important disease conditions. Next, the agency examined the

potential direct and indirect cost savings that would be realized by

diminishing any age-related disparities. The pediatric population was

defined to be all persons under the age of 15 and the comparison group

to be those adults between the ages of 15 and 44. (The exclusion of

older adult patients minimizes the confounding effect of the age-

related increased morbidity and mortality.) Comparisons were limited to

asthma, HIV/AIDS, cancer, pneumonia, and kidney infection, as these

conditions are life threatening, occur in both adults and children, and

comparable data are available for adult and pediatric patients.

Moreover, reports received in the FDA Spontaneous Reporting System

(SRS) in 1993 indicated that the therapeutic areas for which the

highest number of ADR's were reported for patients under age 15,

relative to the number reported for patients 15 to 44, included those

for anti-infectives, pulmonary drugs and oncology drugs.

Direct costs were based on the estimated number of cases,

hospitalization rates, and length of stay for each of the selected

conditions. The number of cases reported were based on national health

survey (Ref. 29) and public surveillance data (Refs. 30, 31, and 32).

In 1994, the total number of cases for these 5 conditions, in patients

under age 15, was approximately 6.65 million. The total number of cases

for patients ages 15 to 44 was approximately 8.3 million. The number of

hospitalizations per year for which the selected condition was the

primary diagnosis was obtained from the National Hospital Discharge

Survey (Ref. 33). As shown in Table 6 of this document, the pediatric

hospitalization rate exceeded the adult rate for all five conditions.

Table 6.--Hospitalization Rates per Patient per Year

------------------------------------------------------------------------

Rate

Rate for

Primary diagnosis under ages 15-

age 15 44

------------------------------------------------------------------------

Asthma................................................ .045 .024

HIV/AIDS.............................................. .533 .233

Cancer................................................ 4.247 3.903

Pneumonia............................................. .147 .129

Kidney Infection...................................... .191 .073

------------------------------------------------------------------------

The average length of hospital stay (ALOS) for patients with the

selected condition as the primary diagnosis (based on ICD-9 code) was

obtained from recent hospital survey data (Ref. 34), the average cost

per day of inpatient hospital care for each of the selected conditions

was based on hospital charge data reported in the survey (Ref. 35), and

the cost of physician services associated with each episode of

hospitalization was based on physician charge data (Ref. 36). Each

episode of care was assumed to include physician charges for emergency

room service, daily inpatient visits, and a postdischarge office visit.

For cancer hospitalizations, daily inpatient visits and a followup

office visit were included. The calculation of indirect costs assumed 8

hours of parental time away from work for each episode of

hospitalization and income and productivity losses based on average

employee compensation, as reported in the 1997 U.S. Statistical

Abstract. A detailed description of all assumptions, calculations, and

data sources is included in the full agency report (Ref. 37).

The assumed hypothesis is that a substantial fraction of the

difference between pediatric and adult hospitalization rates for like

disease conditions are attributable to the greater range of drug

therapies and better information on drug dosages for adults. FDA cannot

estimate the precise magnitude of the relevant fraction. Nevertheless,

if the differentials between pediatric and adult hospitalization rates

were reduced by 25 percent, the resulting direct cost savings would be

$228 million, with indirect cost savings of $5.3 million per year. If

the differentials were reduced by as much as 50 percent, the direct

cost savings would be $456 million per year, with indirect savings of

$10.6 million. Even if the differentials were as low as 10 percent, the

resulting reductions in hospitalization would lead to direct cost

savings of $91.2 million, with indirect savings of $2.1 million per

year.

The timing of the benefit after the rule's implementation is

uncertain. The previous values represent the potential benefit over

time as the safety and effectiveness of drugs are more extensively

tested, new and already marketed drugs become labeled for use in

children, and new formulations and dosage forms are developed to

facilitate therapy for children. The figures may overestimate the

impact for the selected conditions over the next few years, but may

underestimate the potential benefits for these patients in the longer

term if there is an increasing prevalence of asthma, cancer, and

respiratory and other infectious diseases in the pediatric population.

Thus, the lower reduction estimate may be more realistic in the near-

term, with the higher reduction estimates offering a better indication

of longer-term benefit.

As discussed previously, FDA believes that the new FDAMA statute

will cause some of these pediatric studies to be conducted voluntarily.

In its assessment of costs, the agency found that about two-thirds of

the applications for approved drugs needing pediatric studies may be

undertaken voluntarily due to the incentives established by FDAMA.

Adjusting the previous medical cost savings by a similar ratio suggests

that if all of the new pediatric studies achieved a 25 percent

reduction in the pediatric/adult hospitalization differentials, the

additional studies prompted by this rule would yield

[[Page 66667]]

annual savings of $76 million for just those five diseases. This

estimate may represent a lower bound on the benefits to pediatric

patients, however, because a number of other disease conditions are

also common to children and adults, including such life-threatening

conditions as hypertensive disease and renal disease. These pediatric

populations also would experience significant benefits from increased

safety and access to drug treatments currently available only to adult

patients. Moreover, the analysis omits any quantification of benefits

for reduced pain and suffering and reduced pediatric mortality. Thus,

the full benefits of the rule could easily exceed $100 million per

year. Therefore, in accordance with the SBREFA, the Administrator of

the Office of Information and Regulatory Affairs of the Office of

Management and Budget (the Administrator) has determined that this rule

is likely to result in an annual effect on the economy of $100 million

or more and thus is a major rule for the purpose of congressional

review.

F. Small Entities

The rule will impose a burden on relatively few small entities,

because new drug development is typically an activity completed by

large multinational firms. Only one industry comment questioned the

agency's determination that the rule would not have a significant

effect on a substantial number of small entities. That comment

indicated that about 1,500 small entities are conducting diagnostic and

therapeutic R&D in the United States and that ``[c]ontributions to new

drug approvals by the `biotech' and `small pharma' sector are

increasing year by year, and the pace of change will--almost

certainly--continue.''

FDA agrees that small firms contribute substantially to the early

development of many new drugs and biologicals. Nevertheless, because of

the considerable resources needed for clinical testing and marketing,

the agency finds that very few of these small firms retain ownership

and control through the large-scale clinical testing and approval

stages. Moreover, many of the products that are sponsored by small

companies are eligible for orphan designation and therefore exempted

from this rule. To approximate the number of small firms that might be

significantly affected, FDA determined the sponsor company size for all

of the approved applications that may have required additional

pediatric studies had this rule been in place over the years from 1993

to 1997. The agency found that, on average, based on the Small Business

Administration's definition of a small firm, only three approved

applications per year were submitted by small companies. Multiplying by

the previously described 1.58 factor to account for unapproved

applications increases this estimate of the number of small entities

that may have been significantly affected by this rule to just five

small firms per year. Because the agency has certified that the rule

will not impose a significant economic impact on a substantial number

of small entities, the Regulatory Flexibility Act does not require the

agency to prepare a Regulatory Flexibility Analysis. Moreover, the

agency further points out that the required new studies will comprise a

very small part of the total cost of developing new drugs or biologics,

which is generally estimated in the hundreds of millions of dollars for

each new drug.

G. Regulatory Alternatives

The agency carefully examined two major alternatives to the final

rule. The first alternative considered was the initial proposal, which

covered only NCE's. The estimated cost of this alternative, excluding

the FDAMA adjustment, would be about $40 million, or roughly 50 percent

of the cost of the final rule. The agency rejected this alternative

because of the predominant view of the medical community that

additional pediatric data were needed for all of the drugs and

biologicals that may be therapeutically significantly in pediatric

populations, not just for the new chemical entities.

The other major alternative considered was to delay implementation

of the rule until the effects of the new FDAMA statute were reviewed.

FDA fully expects the FDAMA exclusivity provisions to provide a

substantial incentive to conduct large numbers of pediatric studies.

Nevertheless, the agency finds that relying on these incentives, alone,

would leave numerous gaps in many important areas of pediatric

labeling. For example, as described earlier in this preamble, voluntary

research may overlook studies for many important drugs, especially

where such studies require the development of new pediatric dosage

forms. Thus, notwithstanding FDAMA incentives, FDA has determined that

this regulation is necessary to protect the pediatric population and

that further delay is not warranted.

IX. References

The following references have been placed on display in the Dockets

Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers

Lane, rm. 1061, Rockville, MD 20852, and may be seen by interested

persons between 9 a.m. and 4 p.m., Monday through Friday.

1. Pina, L.M., Drugs Widely Used off Label in Pediatrics, Report of

the Pediatric Use Survey Working Group of the Pediatric Subcommittee,

in News Along the Pike, January 1997.

2. Food and Drug Administration, Guidance for Industry: Standards

for the Prompt Review of Efficacy Supplements, Including Priority

Efficacy Supplements, May 1998.

3. Population Division, United States Bureau of the Census, PPL-91,

Appendix a. Resident Population--Estimates by Age, Sex, Race, and

Hispanic Origin, Washington, DC 20233, 1998.

4. Powell, D.A. et al., ``Chloramphenicol: New Perspectives on an

Old Drug,'' Drug Intelligences & Clinical Pharmacy, 16:295-300, 1982.

5. Koren, G. et al., ``Unexpected Alterations in Fentanyl

Pharmacokinetics in Pediatric Patients Undergoing Cardiac Surgery: Age

Related or Disease Related?'' Developmental Pharmacology Therapeutics,

9:183-191, 1986.

6. Gauntlett, I.S. et al., ``Pharmacokinetics of Fentanyl in

Neonatal Humans and Lambs: Effects of Age,'' Anesthesiology, 69:683-

687, 1988.

7. Kauffman, R.E., ``Fentanyl, Fads, and Folly: Who Will Adopt the

Therapeutic Orphans?'' Journal of Pediatrics, 119:588-589, 1991.

8. McCloskey J.J. et al., ``Bupivacaine Toxicity Secondary to

Continuous Caudal Epidural Infusion in Pediatric Patients,'' Anesthesia

Analgesia, 75:287-290, 1992.

9. Fisher, D.M. et al., ``Neuromuscular Effects of Vecuronium (ORG

NC45) in Infants and Pediatric Patients During N<INF>2</INF>O Halothane

Anesthesia,'' Anesthesiology, 58:519-523, 1983.

10. Agarwal, R. et al., ``Seizures Occurring in Pediatric Patients

Receiving Continuous Infusion of Bupivacaine,'' Anesthesia and

Analgesia, 75:284-286, 1992.

11. Mevorach, D.L. et al., ``Bupivacaine Toxicity Secondary to

Continuous Caudal Epidural Infusion in Pediatric Patients,'' Anesthesia

Analgesia, 77:13005-1306, 1993.

12. Editorial: ``Cystic Fibrosis and Colonic Strictures,'' Journal

of Clinical Gastroenterology, 21(1):2-5, 1995.

13. Olkkola, K.T. et al., ``A Potentially Hazardous Interaction

Between Erythromycin and Midazolam,'' Clinical Pharmacology Therapy,

53:298-305, 1993.

[[Page 66668]]

14. Hiller, A. et al., ``Unconsciousness Associated with Midazolam

and Erythromycin,'' British Journal of Anaesthesia, 65:826-828, 1994.

15. Tejeda, H. et al., ``Representation of African-Americans,

Hispanics, and Whites in National Cancer Institute Cancer Treatment

Trials,'' Journal of the National Cancer Institute, 88(12):812-816,

1996.

16. Center for Drug Evaluation and Research, Manual of Policies and

Procedures, Priority Review Policy, MAPP 6020.3, April 22, 1996.

17. Committee on Drugs, American Academy of Pediatrics, Guidelines

for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric

Populations, Pediatrics, 95(2):286-294, 1995.

18. DiMasi et al., ``Cost of Innovation in the Pharmaceutical

Industry,'' Journal of Health Economics, p. 127, 10:1991.

19. Office of Technology Assessment, ``Pharmaceutical R&D: Costs,

Risks and Rewards, Washington, DC: U.S. Government Printing Office,''

Appendix G, February 1993.

20. IMS America, ``1997 Retail Perspective and Provider

Perspective.''

21. Bates, D.W., ``Drugs and Adverse Drug Reactions: How Worried

Should We Be?'' Journal of American Medical Association, vol. 279, No.

15, April 1998.

22. Einarson, T.R. ``Drug-Related Hospital Admission'', The Annals

of Pharmacotherapy, vol. 27, pp. 832-840, July/August 1993.

23. Lazarou, J., B.H. Pomeranz, and P.N. Corey, ``Incidence of

Adverse Drug Reactions in Hospitalized Patients'', Journal of American

Medical Association, vol. 279, No. 15, April 1998.

24. Phillips, D.P., N. Christenfeld, and L.M. Glynn, ``Increase in

U.S. Medication-Error Deaths Between 1983 and 1993'', The Lancet, vol.

351, 643-644, February 1998.

25. Mitchell, A.A., P.G. Lacouture, J.E. Sheehan, R.E. Dauffman,

and S. Shapiro, ``Adverse Drug Reactions in Children Leading to

Hospital Admission,'' Pediatrics, vol. 82, No. 1, July 1988.

26. Bates, D.W., ``Drugs and Adverse Drug Reactions: How Worried

Should We Be?'' Journal of American Medical Association, vol. 279, No.

15, April 1998.

27. National Committee for Quality Assurance (NCQA) HEDIS 2.5,

December 1995.

28. Agency for Health Care Policy Research (AHCPR) Conquest 1.1.

29. Vital and Health Statistics, Current Estimates From the

National Health Interview Survey, 1994, Series 10: Data From the

National Health Survey, No. 193, PHS 96-1521, December 1995.

30. Center for Disease Control Wonder HIV/AIDS statistics.

31. World Health Organization, Provisional Working Estimates of

Adult HIV Prevalence as of end of 1994 by Country.

32. SEER 1989, Available Through CDC Wonder, ICD 140-239.

33. Vital and Health Statistics, National Hospital Discharge

Survey: Annual Summary, 1995, Series 13, No. 133, PHS 98-1794, January

1998.

34. Vital and Health Statistics, Detailed Diagnoses and Procedures,

National Hospital Discharge Survey, 1995, Series 13: Data From the

National Health Survey, No. 130, PHS 98-1791, November 1997.

35. Statistics From the HCUP-3 Nationwide Inpatient Sample for

1994: Principal Diagnoses, http://www.ahcpr.gov/data/94dcchpr.htm,

current as of September 1997, AHCPR Pub. No. 97-0058.

36. Health Care Financing Administration, Office of Research and

Demonstrations, Health Care Financing Review: 1997 Statistical

Supplement, November 1997.

37. ``Potential Benefits of Pediatric Information,'' Economics

Staff, Office of Planning and Evaluation, FDA, April 1998.

38. IMS, National Disease and Therapeutic Index, IMS America:

Plymouth Meeting, PA.

List of Subjects

21 CFR Part 201

Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical

research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 314

Administrative practice and procedure, Confidential business

information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

Administrative practice and procedure, Biologics, Confidential

business information.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, and under authority delegated to the

Commissioner of Food and Drugs, 21 CFR parts 201, 312, 314, and 601 are

amended as follows:

PART 201--LABELING

1. The authority citation for 21 CFR part 201 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 358,

360, 360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262,

264.

2. Section 201.23 is added to subpart A to read as follows:

Sec. 201.23 Required pediatric studies.

(a) A manufacturer of a marketed drug product, including a

biological drug product, that is used in a substantial number of

pediatric patients, or that provides a meaningful therapeutic benefit

over existing treatments for pediatric patients, as defined in

Secs. 314.55(c)(5) and 601.27(c)(5) of this chapter, but whose label

does not provide adequate information to support its safe and effective

use in pediatric populations for the approved indications may be

required to submit an application containing data adequate to assess

whether the drug product is safe and effective in pediatric

populations. The application may be required to contain adequate

evidence to support dosage and administration in some or all pediatric

subpopulations, including neonates, infants, children, and adolescents,

depending upon the known or appropriate use of the drug product in such

subpopulations. The applicant may also be required to develop a

pediatric formulation for a drug product that represents a meaningful

therapeutic benefit over existing therapies for pediatric populations

for whom a pediatric formulation is necessary, unless the manufacturer

demonstrates that reasonable attempts to produce a pediatric

formulation have failed.

(b) The Food and Drug Administration (FDA) may by order, in the

form of a letter, after notifying the manufacturer of its intent to

require an assessment of pediatric safety and effectiveness of a

pediatric formulation, and after offering an opportunity for a written

response and a meeting, which may include an advisory committee

meeting, require a manufacturer to submit an application containing the

information or request for approval of a pediatric formulation

described in paragraph (a) of this section within a time specified in

the order, if FDA finds that:

(1) The drug product is used in a substantial number of pediatric

patients for the labeled indications and the absence of adequate

labeling could pose significant risks to pediatric patients; or

(2) There is reason to believe that the drug product would

represent a meaningful therapeutic benefit over

[[Page 66669]]

existing treatments for pediatric patients for one or more of the

claimed indications, and the absence of adequate labeling could pose

significant risks to pediatric patients.

(c)(1) An applicant may request a full waiver of the requirements

of paragraph (a) of this section if the applicant certifies that:

(i) Necessary studies are impossible or highly impractical because,

e.g., the number of such patients is so small or geographically

dispersed, or

(ii) There is evidence strongly suggesting that the product would

be ineffective or unsafe in all pediatric age groups.

(2) An applicant may request a partial waiver of the requirements

of paragraph (a) of this section with respect to a specified pediatric

age group, if the applicant certifies that:

(i) The product:

(A) Does not represent a meaningful therapeutic benefit over

existing therapies for pediatric patients in that age group, and

(B) Is not likely to be used in a substantial number of patients in

that age group, and

(C) The absence of adequate labeling could not pose significant

risks to pediatric patients; or

(ii) Necessary studies are impossible or highly impractical

because, e.g., the number of patients in that age group is so small or

geographically dispersed, or

(iii) There is evidence strongly suggesting that the product would

be ineffective or unsafe in that age group, or

(iv) The applicant can demonstrate that reasonable attempts to

produce a pediatric formulation necessary for that age group have

failed.

(3) FDA shall grant a full or partial waiver, as appropriate, if

the agency finds that there is a reasonable basis on which to conclude

that one or more of the grounds for waiver specified in paragraphs

(c)(2) or (c)(3) of this section have been met. If a waiver is granted

on the ground that it is not possible to develop a pediatric

formulation, the waiver will cover only those pediatric age groups

requiring that formulation. If a waiver is granted because there is

evidence that the product would be ineffective or unsafe in pediatric

populations, this information will be included in the product's

labeling.

(d) If a manufacturer fails to submit a supplemental application

containing the information or request for approval of a pediatric

formulation described in paragraph (a) of this section within the time

specified by FDA, the drug product may be considered misbranded or an

unapproved new drug or unlicensed biologic.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

3. The authority citation for 21 CFR part 312 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371; 42

U.S.C. 262.

4. Section 312.23 is amended by redesignating paragraph

(a)(10)(iii) as paragraph (a)(10)(iv) and adding new paragraph

(a)(10)(iii) to read as follows:

Sec. 312.23 IND content and format.

(a) * * *

(10) * * *

(iii) Pediatric studies. Plans for assessing pediatric safety and

effectiveness.

* * * * *

5. Section 312.47 is amended by revising paragraph (b)(1)(i) and

the first sentence of paragraph (b)(1)(iv), by removing the fifth

sentence of paragraph (b)(1)(v) and adding two sentences in its place,

by revising the heading of paragraph (b)(2) and the second and last

sentences of the introductory text of paragraph (b)(2), and by

redesignating paragraph (b)(2)(iii) as paragraph (b)(2)(iv) and by

adding new paragraph (b)(2)(iii) to read as follows:

Sec. 312.47 Meetings.

* * * * *

(b) * * *

(1) End-of-Phase 2 meetings--(i) Purpose. The purpose of an end-of-

phase 2 meeting is to determine the safety of proceeding to Phase 3, to

evaluate the Phase 3 plan and protocols and the adequacy of current

studies and plans to assess pediatric safety and effectiveness, and to

identify any additional information necessary to support a marketing

application for the uses under investigation.

* * * * *

(iv) Advance information. At least 1 month in advance of an end-of-

Phase 2 meeting, the sponsor should submit background information on

the sponsor's plan for Phase 3, including summaries of the Phase 1 and

2 investigations, the specific protocols for Phase 3 clinical studies,

plans for any additional nonclinical studies, plans for pediatric

studies, including a time line for protocol finalization, enrollment,

completion, and data analysis, or information to support any planned

request for waiver or deferral of pediatric studies, and, if available,

tentative labeling for the drug. * * *

(v) Conduct of meeting. * * * The adequacy of the technical

information to support Phase 3 studies and/or a marketing application

may also be discussed. FDA will also provide its best judgment, at that

time, of the pediatric studies that will be required for the drug

product and whether their submission will be deferred until after

approval. * * *

(2) ``Pre-NDA'' and ``pre-BLA'' meetings. * * * The primary purpose

of this kind of exchange is to uncover any major unresolved problems,

to identify those studies that the sponsor is relying on as adequate

and well-controlled to establish the drug's effectiveness, to identify

the status of ongoing or needed studies adequate to assess pediatric

safety and effectiveness, to acquaint FDA reviewers with the general

information to be submitted in the marketing application (including

technical information), to discuss appropriate methods for statistical

analysis of the data, and to discuss the best approach to the

presentation and formatting of data in the marketing application. * * *

To permit FDA to provide the sponsor with the most useful advice on

preparing a marketing application, the sponsor should submit to FDA's

reviewing division at least 1 month in advance of the meeting the

following information:

* * * * *

(iii) Information on the status of needed or ongoing pediatric

studies.

* * * * *

6. Section 312.82 is amended by revising the last sentence of

paragraph (a) and by removing the second sentence of paragraph (b) and

adding two sentences in its place to read as follows:

Sec. 312.82 Early consultation.

* * * * *

(a) Pre-investigational new drug (IND) meetings. * * * The meeting

may also provide an opportunity for discussing the scope and design of

phase 1 testing, plans for studying the drug product in pediatric

populations, and the best approach for presentation and formatting of

data in the IND.

(b) End-of-phase 1 meetings. * * * The primary purpose of this

meeting is to review and reach agreement on the design of phase 2

controlled clinical trials, with the goal that such testing will be

adequate to provide sufficient data on the drug's safety and

effectiveness to support a decision on its approvability for marketing,

and to discuss the need for, as well as the design and timing of,

studies of the drug in pediatric patients. For drugs for life-

threatening diseases, FDA will provide its best judgment, at that time,

whether pediatric studies will be required and whether their submission

will be deferred until after approval. * * *

[[Page 66670]]

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN

ANTIBIOTIC DRUG

7. The authority citation for 21 CFR part 314 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371,

374, 379e.

8. Section 314.50 is amended by adding paragraph (d)(7) to read as

follows:

Sec. 314.50 Content and format of an application.

* * * * *

(d) * * *

(7) Pediatric use section. A section describing the investigation

of the drug for use in pediatric populations, including an integrated

summary of the information (the clinical pharmacology studies,

controlled clinical studies, or uncontrolled clinical studies, or other

data or information) that is relevant to the safety and effectiveness

and benefits and risks of the drug in pediatric populations for the

claimed indications, a reference to the full descriptions of such

studies provided under paragraphs (d)(3) and (d)(5) of this section,

and information required to be submitted under Sec. 314.55.

* * * * *

9. Section 314.55 is added to subpart B to read as follows:

Sec. 314.55 Pediatric use information.

(a) Required assessment. Except as provided in paragraphs (b), (c),

and (d) of this section, each application for a new active ingredient,

new indication, new dosage form, new dosing regimen, or new route of

administration shall contain data that are adequate to assess the

safety and effectiveness of the drug product for the claimed

indications in all relevant pediatric subpopulations, and to support

dosing and administration for each pediatric subpopulation for which

the drug is safe and effective. Where the course of the disease and the

effects of the drug are sufficiently similar in adults and pediatric

patients, FDA may conclude that pediatric effectiveness can be

extrapolated from adequate and well-controlled studies in adults

usually supplemented with other information obtained in pediatric

patients, such as pharmacokinetic studies. Studies may not be needed in

each pediatric age group, if data from one age group can be

extrapolated to another. Assessments of safety and effectiveness

required under this section for a drug product that represents a

meaningful therapeutic benefit over existing treatments for pediatric

patients must be carried out using appropriate formulations for each

age group(s) for which the assessment is required.

(b) Deferred submission. (1) FDA may, on its own initiative or at

the request of an applicant, defer submission of some or all

assessments of safety and effectiveness described in paragraph (a) of

this section until after approval of the drug product for use in

adults. Deferral may be granted if, among other reasons, the drug is

ready for approval in adults before studies in pediatric patients are

complete, or pediatric studies should be delayed until additional

safety or effectiveness data have been collected. If an applicant

requests deferred submission, the request must provide a certification

from the applicant of the grounds for delaying pediatric studies, a

description of the planned or ongoing studies, and evidence that the

studies are being or will be conducted with due diligence and at the

earliest possible time.

(2) If FDA determines that there is an adequate justification for

temporarily delaying the submission of assessments of pediatric safety

and effectiveness, the drug product may be approved for use in adults

subject to the requirement that the applicant submit the required

assessments within a specified time.

(c) Waivers--(1) General. FDA may grant a full or partial waiver of

the requirements of paragraph (a) of this section on its own initiative

or at the request of an applicant. A request for a waiver must provide

an adequate justification.

(2) Full waiver. An applicant may request a waiver of the

requirements of paragraph (a) of this section if the applicant

certifies that:

(i) The drug product does not represent a meaningful therapeutic

benefit over existing treatments for pediatric patients and is not

likely to be used in a substantial number of pediatric patients;

(ii) Necessary studies are impossible or highly impractical

because, e.g., the number of such patients is so small or

geographically dispersed; or

(iii) There is evidence strongly suggesting that the drug product

would be ineffective or unsafe in all pediatric age groups.

(3) Partial waiver. An applicant may request a waiver of the

requirements of paragraph (a) of this section with respect to a

specified pediatric age group, if the applicant certifies that:

(i) The drug product does not represent a meaningful therapeutic

benefit over existing treatments for pediatric patients in that age

group, and is not likely to be used in a substantial number of patients

in that age group;

(ii) Necessary studies are impossible or highly impractical

because, e.g., the number of patients in that age group is so small or

geographically dispersed;

(iii) There is evidence strongly suggesting that the drug product

would be ineffective or unsafe in that age group; or

(iv) The applicant can demonstrate that reasonable attempts to

produce a pediatric formulation necessary for that age group have

failed.

(4) FDA action on waiver. FDA shall grant a full or partial waiver,

as appropriate, if the agency finds that there is a reasonable basis on

which to conclude that one or more of the grounds for waiver specified

in paragraphs (c)(2) or (c)(3) of this section have been met. If a

waiver is granted on the ground that it is not possible to develop a

pediatric formulation, the waiver will cover only those pediatric age

groups requiring that formulation. If a waiver is granted because there

is evidence that the product would be ineffective or unsafe in

pediatric populations, this information will be included in the

product's labeling.

(5) Definition of ``meaningful therapeutic benefit''. For purposes

of this section and Sec. 201.23 of this chapter, a drug will be

considered to offer a meaningful therapeutic benefit over existing

therapies if FDA estimates that:

(i) If approved, the drug would represent a significant improvement

in the treatment, diagnosis, or prevention of a disease, compared to

marketed products adequately labeled for that use in the relevant

pediatric population. Examples of how improvement might be demonstrated

include, for example, evidence of increased effectiveness in treatment,

prevention, or diagnosis of disease, elimination or substantial

reduction of a treatment-limiting drug reaction, documented enhancement

of compliance, or evidence of safety and effectiveness in a new

subpopulation; or

(ii) The drug is in a class of drugs or for an indication for which

there is a need for additional therapeutic options.

(d) Exemption for orphan drugs. This section does not apply to any

drug for an indication or indications for which orphan designation has

been granted under part 316, subpart C, of this chapter.

10. Section 314.81 is amended by revising paragraph (b)(2)(i) and

(b)(2)(vii), and by adding paragraph (b)(2)(vi)(c) to read as follows:

Sec. 314.81 Other postmarketing reports.

* * * * *

(b) * * *

(2) * * *

[[Page 66671]]

(i) Summary. A brief summary of significant new information from

the previous year that might affect the safety, effectiveness, or

labeling of the drug product. The report is also required to contain a

brief description of actions the applicant has taken or intends to take

as a result of this new information, for example, submit a labeling

supplement, add a warning to the labeling, or initiate a new study. The

summary shall briefly state whether labeling supplements for pediatric

use have been submitted and whether new studies in the pediatric

population to support appropriate labeling for the pediatric population

have been initiated. Where possible, an estimate of patient exposure to

the drug product, with special reference to the pediatric population

(neonates, infants, children, and adolescents) shall be provided,

including dosage form.

* * * * *

(vi) * * *

(c) Analysis of available safety and efficacy data in the pediatric

population and changes proposed in the labeling based on this

information. An assessment of data needed to ensure appropriate

labeling for the pediatric population shall be included.

(vii) Status reports. A statement on the current status of any

postmarketing studies performed by, or on behalf of, the applicant. The

statement shall include whether postmarketing clinical studies in

pediatric populations were required or agreed to, and if so, the status

of these studies, e.g., to be initiated, ongoing (with projected

completion date), completed (including date), completed and results

submitted to the NDA (including date). To facilitate communications

between FDA and the applicant, the report may, at the applicant's

discretion, also contain a list of any open regulatory business with

FDA concerning the drug product subject to the application.

* * * * *

PART 601--LICENSING

11. The authority citation for 21 CFR part 601 is revised to read

as follows:

Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 321, 351, 352, 353,

355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,

241, 262, 263.

12. Section 601.27 is added to subpart C to read as follows:

Sec. 601.27 Pediatric studies.

(a) Required assessment. Except as provided in paragraphs (b), (c),

and (d) of this section, each application for a new active ingredient,

new indication, new dosage form, new dosing regimen, or new route of

administration shall contain data that are adequate to assess the

safety and effectiveness of the product for the claimed indications in

all relevant pediatric subpopulations, and to support dosing and

administration for each pediatric subpopulation for which the product

is safe and effective. Where the course of the disease and the effects

of the product are similar in adults and pediatric patients, FDA may

conclude that pediatric effectiveness can be extrapolated from adequate

and well-controlled effectiveness studies in adults, usually

supplemented with other information in pediatric patients, such as

pharmacokinetic studies. In addition, studies may not be needed in each

pediatric age group, if data from one age group can be extrapolated to

another. Assessments required under this section for a product that

represents a meaningful therapeutic benefit over existing treatments

must be carried out using appropriate formulations for the age group(s)

for which the assessment is required.

(b) Deferred submission. (1) FDA may, on its own initiative or at

the request of an applicant, defer submission of some or all

assessments of safety and effectiveness described in paragraph (a) of

this section until after licensing of the product for use in adults.

Deferral may be granted if, among other reasons, the product is ready

for approval in adults before studies in pediatric patients are

complete, pediatric studies should be delayed until additional safety

or effectiveness data have been collected. If an applicant requests

deferred submission, the request must provide an adequate justification

for delaying pediatric studies, a description of the planned or ongoing

studies, and evidence that the studies are being or will be conducted

with due diligence and at the earliest possible time.

(2) If FDA determines that there is an adequate justification for

temporarily delaying the submission of assessments of pediatric safety

and effectiveness, the product may be licensed for use in adults

subject to the requirement that the applicant submit the required

assessments within a specified time.

(c) Waivers--(1) General. FDA may grant a full or partial waiver of

the requirements of paragraph (a) of this section on its own initiative

or at the request of an applicant. A request for a waiver must provide

an adequate justification.

(2) Full waiver. An applicant may request a waiver of the

requirements of paragraph (a) of this section if the applicant

certifies that:

(i) The product does not represent a meaningful therapeutic benefit

over existing therapies for pediatric patients and is not likely to be

used in a substantial number of pediatric patients;

(ii) Necessary studies are impossible or highly impractical

because, e.g., the number of such patients is so small or

geographically dispersed; or

(iii) There is evidence strongly suggesting that the product would

be ineffective or unsafe in all pediatric age groups.

(3) Partial waiver. An applicant may request a waiver of the

requirements of paragraph (a) of this section with respect to a

specified pediatric age group, if the applicant certifies that:

(i) The product does not represent a meaningful therapeutic benefit

over existing therapies for pediatric patients in that age group, and

is not likely to be used in a substantial number of patients in that

age group;

(ii) Necessary studies are impossible or highly impractical

because, e.g., the number of patients in that age group is so small or

geographically dispersed;

(iii) There is evidence strongly suggesting that the product would

be ineffective or unsafe in that age group; or

(iv) The applicant can demonstrate that reasonable attempts to

produce a pediatric formulation necessary for that age group have

failed.

(4) FDA action on waiver. FDA shall grant a full or partial waiver,

as appropriate, if the agency finds that there is a reasonable basis on

which to conclude that one or more of the grounds for waiver specified

in paragraphs (c)(2) or (c)(3) of this section have been met. If a

waiver is granted on the ground that it is not possible to develop a

pediatric formulation, the waiver will cover only those pediatric age

groups requiring that formulation. If a waiver is granted because there

is evidence that the product would be ineffective or unsafe in

pediatric populations, this information will be included in the

product's labeling.

(5) Definition of ``meaningful therapeutic benefit''. For purposes

of this section, a product will be considered to offer a meaningful

therapeutic benefit over existing therapies if FDA estimates that:

(i) If approved, the product would represent a significant

improvement in the treatment, diagnosis, or prevention of a disease,

compared to marketed products adequately labeled for that use in the

relevant pediatric population. Examples of how improvement might be

demonstrated include, e.g., evidence of increased effectiveness in

treatment, prevention, or diagnosis of disease;

[[Page 66672]]

elimination or substantial reduction of a treatment-limiting drug

reaction; documented enhancement of compliance; or evidence of safety

and effectiveness in a new subpopulation; or

(ii) The product is in a class of products or for an indication for

which there is a need for additional therapeutic options.

(d) Exemption for orphan drugs. This section does not apply to any

product for an indication or indications for which orphan designation

has been granted under part 316, subpart C, of this chapter.

13. Section 601.37 is added to subpart D to read as follows:

Sec. 601.37 Annual reports of postmarketing pediatric studies.

Sponsors of licensed biological products shall submit the following

information each year within 60 days of the anniversary date of

approval of the license, to the Director, Center for Biologics

Evaluation and Research:

(a) Summary. A brief summary stating whether labeling supplements

for pediatric use have been submitted and whether new studies in the

pediatric population to support appropriate labeling for the pediatric

population have been initiated. Where possible, an estimate of patient

exposure to the drug product, with special reference to the pediatric

population (neonates, infants, children, and adolescents) shall be

provided, including dosage form.

(b) Clinical data. Analysis of available safety and efficacy data

in the pediatric population and changes proposed in the labeling based

on this information. An assessment of data needed to ensure appropriate

labeling for the pediatric population shall be included.

(c) Status reports. A statement on the current status of any

postmarketing studies in the pediatric population performed by, or on

behalf of, the applicant. The statement shall include whether

postmarketing clinical studies in pediatric populations were required

or agreed to, and if so, the status of these studies, e.g., to be

initiated, ongoing (with projected completion date), completed

(including date), completed and results submitted to the BLA (including

date).

Dated: November 24, 1998.

Michael A. Friedman,

Acting Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 98-31902 Filed 11-27-98; 8:45 am]

BILLING CODE 4160-01-P