Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients

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\,\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

[[Page 66644]]

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

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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

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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 mar

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