43900 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 312, 314, and 601

[Docket No. 97N–0165]

RIN 0910–AB20

Regulations Requiring Manufacturers

To Assess the Safety and

Effectiveness of New Drugs and

Biological Products in Pediatric

Patients

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing new

regulations requiring pediatric studies

of certain new drug and biological

products. Many new drugs and

biological products represent treatments

that are, at least at times, the best

available treatment for children, but

most of them 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. The

proposed rule would attempt to

partially address this lack of pediatric

use information by requiring that

manufacturers of a limited class of new

drugs and new biological products

provide sufficient data and information

to support directions for pediatric use

for the claimed indications, before or

soon after approval. Manufacturers of a

limited class of marketed drugs and

biologics would also in compelling

circumstances have to provide such

data. This proposed rule is part of a

comprehensive effort to increase the

number of new drugs and biological

products with clinically significant use

in children that carry adequate labeling

for use in that subpopulation.

DATES: Written comments and

recommendations by November 13,

1997. Written comments on the

information collection provisions

should be submitted by September 15,

1997. For further information of the

agency’s implementation plan, see

section VII of SUPPLEMENTARY

INFORMATION in this document.

ADDRESSES: Submit written comments

and recommendations to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Submit written comments on the

information collection provision to the

Office of Information and Regulatory

Affairs, OMB, New Executive Office

Bldg., 725 17th St. NW., rm. 10235,

Washington, DC 20503, Attn: Desk

Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Paula Botstein, Center for Drug

Evaluation and Research (HFD–103),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–827–3144, and Ann M. Witt, Office

of Policy (HF–22), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–827–5321.

SUPPLEMENTARY INFORMATION:

I. Introduction

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.

According to the American Academy of

Pediatrics, however, only a small

fraction of all drugs and biological

products marketed in the United States

have had clinical trials performed in

pediatric patients and a majority of

marketed drugs are not labeled for use

in pediatric patients or for use in

specific pediatric age groups (Ref. 1). A

recent FDA survey similarly concluded

that most products that are indicated for

diseases occurring in both adults and

children have very little information

about pediatric use in their labeling

(Ref. 2). For some products, including

vaccines and antibiotics, pediatric use

information is generally adequate. Many

drugs used in the treatment of both

common childhood illnesses and more

serious conditions, however, carry little

information about use in pediatric

patients. Less than half the drugs

approved for treatment of human

immunodeficiency virus (HIV) infection

or accompanying opportunistic

infections carry any pediatric safety or

effectiveness information, and, of those

that do, the data are often incomplete

and limited to certain pediatric age

groups. Pediatric labeling is also

inadequate for such drug classes as

steroids, drugs to treat gastrointestinal

problems, prescription pain

medications, antihypertensives,

antidepressants, antirheumatic drugs,

and drugs to treat ulcerative colitis.

Safety and effectiveness information

for some pediatric age groups is

particularly sparse. For example, there

is almost no information on use in

patients under 2 years of age for most

drug classes (Ref. 2).

Many of the drugs and biological

products most widely used in pediatric

patients carry disclaimers stating that

safety and effectiveness in pediatric

patients have not been established (Refs.

2 and 3). Based on 1994 data from IMS

America, Ltd., a research firm that

provides data on prescription drug

usage, FDA compiled a list of the 10

drugs that were most widely prescribed

for pediatric patients, on an outpatient

basis, despite inadequate pediatric

labeling. In each case, the label lacked

any use information for the age group

prescribed to, or the information was

inadequate. The drugs were: Albuterol

inhalation solution for nebulization for

treatment of asthma (prescribed

1,626,000 times to pediatric patients

under 12); Phenergan for treatment of

allergic reactions (prescribed 663,000

times to pediatric patients under 2);

ampicillin injections for treatment of

infection (prescribed 639,000 times to

pediatric patients under 12); Auralgan

otic solution for treatment of ear pain

(prescribed 600,000 times to pediatric

patients under 16); Lotrisone cream for

treatment of topical infections

(prescribed 325,000 times to pediatric

patients under 12); Prozac for treatment

of depression and obsessive compulsive

disorder (prescribed 349,000 times to

pediatric patients under 16, including

3,000 times to infants under 1); Intal for

treatment of asthma (solution prescribed

109,000 times to pediatric patients

under 2; aerosol prescribed 399,000

times to pediatric patients under 5);

Zoloft for treatment of depression

(prescribed 248,000 times to pediatric

patients under 16); Ritalin for treatment

of attention deficit disorders and

narcolepsy (prescribed 226,000 times to

pediatric patients under 6); Alupent for

treatment of asthma (184,000 times to

pediatric patients under 6). These 10

drugs were thus prescribed over 5

million times in 1 year for pediatric

patients in age groups for which the

label carried a disclaimer or lacked

adequate use information (Ref. 2).

The absence of pediatric labeling

information may sometimes require the

physician caring for children to choose

between prescribing drugs without wellfounded dosing and safety information

or utilizing other, potentially less

effective, therapy.

Inadequate pediatric labeling thus

exposes children to the risk of

unexpected adverse reactions or lack of

optimal treatment. Even after a drug has

been used in pediatric patients for some

time, and there has been substantial

clinical experience with the drug,

directions for safe and effective use in

pediatric patients are not provided on

the label.

Children were once viewed as a

population entirely distinct from adults,

in whom safety and effectiveness of new

drugs had to be established entirely

independently. It has become

increasingly clear, however, that

children may be considered a
Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules 43901

demographic subpopulation with many

similarities to the adult population. In

most cases, drugs and biological

products behave similarly in

demographic subgroups, including age

and gender subgroups, even though

there may be variations because of

differences in, for example,

pharmacokinetics. As FDA has already

stated in a Federal Register document,

where the disease and the drug’s effects

are similar in adults and children,

adequate and well-controlled trials may

not be needed in children to establish

pediatric use information (59 FR 64240,

December 13, 1994) (hereinafter referred

to as the 1994 rule).

Although use of a drug in children is

no longer considered a new indication

(with the exception of specific

‘‘pediatric indications’’), the

development of additional information

in pediatric patients is needed to

provide appropriate dosing

recommendations. Correct pediatric

dosing cannot necessarily be

extrapolated from adult dosing

information using an equivalence based

either on weight milligrams per

kilogram (mg/kg) or body surface area

(mg/square meter (m2)). Potentially

significant differences in

pharmacokinetics may alter a drug’s

effect in pediatric patients. The effects

of growth and maturation of various

organs, maturation of the immune

system, alterations in metabolism

throughout infancy and childhood,

changes in body proportions, and other

developmental changes may result in

significant differences in the doses

needed by pediatric patients and adults.

For example, studies have shown that

fentanyl, a potent opioid, widely used

in anesthetic management of infants and

small children but not labeled for use in

pediatric patients under 2 years of age,

demonstrates differences in clearance

between the neonatal period and 2 or

more months of age due to improving

hepatic blood flow and hepatic

microsomal maturation (Ref. 4).

Comparable doses in adults and

neonates (calculated on a microgram

(μg)/kg basis) produce twofold to

threefold higher plasma concentrations

in neonates (Ref. 5). Pharmacokinetic

differences of this kind demonstrate the

importance of studying the

pharmacokinetics of a drug in pediatric

patients of different ages before they are

widely exposed to it. Inadequate dosing

information may expose pediatric

patients to dangerously high doses or to

ineffective treatment. The absence of

pediatric testing may thus result in less

than optimal treatment for many

pediatric patients.

Pediatric patients receiving

inadequately tested and labeled drugs

are also exposed to the risk of

unexpected adverse reactions. One of

the earliest cases in which serious

adverse events were observed in

neonates following administration of a

drug that had not been adequately

studied in pediatric patients was the

development of ‘‘gray baby syndrome’’

from chloramphenicol, an antibiotic

(Ref. 6). After an initial report of 5

deaths and a subsequent report of 18

deaths in neonates, it was learned that

the immature livers of these infants

were unable to clear chloramphenicol

from the body, allowing toxic doses of

the drug to accumulate. Other cases in

which inadequately studied drugs have

resulted in serious adverse effects in

pediatric patients include teeth staining

from tetracycline, kernicterus from sulfa

drugs, withdrawal symptoms following

prolonged administration of fentanyl in

infants and small children, seizures and

cardiac arrest caused by bupivacaine

toxicity, development of colonic

strictures in pediatric cystic fibrosis

patients after exposure to high-dose

pancreatic enzymes, and hazardous

interactions between erythromycin and

midazolam (Refs. 7, 8, 9, 10, 11, 12, 13,

14, 15, and 16). Many such adverse

reactions could be avoided if pediatric

studies were conducted before drugs

were widely used in pediatric patients.

Failure to conduct pediatric testing

may, in unusual cases, deprive pediatric

patients of significant therapeutic

advances. Failure to develop a pediatric

formulation of a drug, where younger

pediatric populations cannot take the

adult formulation, may also deny

pediatric patients access to important

therapeutic advances, or require

pediatric patients to take the drug in

homemade, poorly bioavailable

formulations.

II. FDA Initiatives To Improve Pediatric

Use Information

FDA has taken a number of steps in

recent years to address inadequate

pediatric drug testing and inadequate

pediatric use information in drug

labeling. Perhaps the most significant

step was the issuance of the 1994 rule

requiring drug manufacturers to survey

existing data and determine whether

those data are sufficient to support

additional pediatric use information in

the drug’s labeling (59 FR 64240). 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. The

rule explicitly recognizes that controlled

clinical studies to support pediatric use

information need not have been carried

out in pediatric patients where the

course of the disease and the effects of

the drug are sufficiently similar in

children and adults to permit

extrapolation from the adult

effectiveness data to pediatric patients.

In these cases, controlled clinical

studies in adults together with

pharmacokinetic and adverse reaction

data in pediatric patients may be

sufficient to establish pediatric safety

and effectiveness.

Although the preamble to the 1994

rule recognizes FDA’s authority to

require drug manufacturers to conduct

pediatric studies on a case-by-case basis,

the rule does not impose a general

requirement that manufacturers carry

out studies if existing information is not

sufficient to support pediatric use

information. Instead, where there is

insufficient information to support a

pediatric indication or pediatric use

statement, the rule requires the

manufacturer to include in the drug’s

labeling the statement: ‘‘Safety and

effectiveness in pediatric patients have

not been established.’’ Because the rule

focuses on gathering existing

information about pediatric use, rather

than carrying out new studies,

supplements filed in response to the

rule will be for marketed drugs. The rule

does not apply to products first entering

the marketplace, except to the extent

that pediatric studies conducted on

such products before approval can take

advantage of the rule’s explicit

authorization to rely on

pharmacokinetic data rather than

adequate and well-controlled studies in

pediatric patients, and that labeling

statements about pediatric use must

conform to the rule’s labeling

requirements.

FDA’s Center for Drug Evaluation and

Research (CDER) and Center for

Biologics Evaluation (CBER) 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. At specified points during

the investigation of a new drug or

biological product, FDA staff discuss

with the sponsor the data needed to

support pediatric labeling and

encourage them to conduct needed

studies. CDER and CBER have also

begun to implement a program in

which, after review of an NDA, biologics

license application (BLA), or

supplemental application, the FDA

reviewer fills out a ‘‘pediatric page.’’

The pediatric page does not itself
43902 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

impose any requirements, but describes

the adequacy of product labeling for

pediatric patients and plans for further

pediatric studies. If pediatric labeling is

found to be inadequate, the pediatric

page states whether additional pediatric

studies are needed. If pediatric studies

are needed, the pediatric page states

whether the applicant has agreed to

conduct the necessary studies and, if

necessary, to develop a pediatric

formulation. FDA is also developing a

draft guidance document on pediatric

pharmacokinetics.

In addition, FDA has taken steps to

improve pediatric use information for

marketed drugs under the pediatric

plan. CDER has identified the 10 drugs

most used in pediatric populations for

which there is no pediatric use

information or for which the pediatric

use information is inadequate given the

pattern of use in pediatric patients. The

manufacturers of these drugs have been

notified of the widespread use of their

drugs in the pediatric population and

asked to respond to the 1994 rule. CBER

is currently identifying the biological

products most frequently used in

pediatric patients without labeling

information. FDA has developed

guidance to manufacturers on the

content and format for pediatric use

supplements under the 1994 rule and is

tracking pediatric use supplements and

commitments.

III. Results of Actions to Date and Need

for Additional Steps

Although the actions taken by FDA to

date have produced some gains in

pediatric labeling, they have not yet

substantially increased the number of

drugs and biological products for which

there is adequate pediatric use

information. The percentage of new

products entering the marketplace that

contain adequate pediatric safety and

effectiveness information has not shown

consistent improvement in the last

decade. An informal survey conducted

by the American Academy of Pediatrics

in 1990 found that of all new molecular

entities (NME’s) approved between 1984

and 1990, 20 percent had information

on pediatric use. Not all NME’s have

usefulness in pediatric patients,

however. For example, for NME’s

approved in the years 1991–1996, 53

percent were regarded by FDA as having

potential usefulness in pediatric

patients. Presumably, if only the NME’s

with usefulness in pediatric patients

had been considered in the survey, the

percentage with pediatric labeling

would have been somewhat higher, and

as high as 42 percent.

FDA compared the number of NME’s

approved in 1991 and 1996 with

potential usefulness in pediatric

patients and looked at the adequacy of

pediatric labeling for those drugs. Fiftysix percent (9/16) 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 labeled for

all age groups in which the drug was

useful.) The manufacturers of an

additional 17 drugs promised to

conduct pediatric studies after approval.

It is uncertain how many of these

promises will result in pediatric

labeling. Of the seven NME’s approved

in 1991 for which postapproval

pediatric studies were promised, only

one now has pediatric labeling.

These data indicate that voluntary

efforts have, thus far, not substantially

increased the number of products

entering the marketplace with adequate

pediatric labeling. Therefore, FDA has

tentatively concluded that additional

steps are necessary to ensure the safety

and effectiveness of drug and biological

products for pediatric patients. This

proposed rule includes provisions that

would require the manufacturers of

certain new and marketed drugs and

biological products to evaluate the

safety and effectiveness of their

products in pediatric patients, where

existing information is not sufficient to

support pediatric use labeling but the

product is likely to be commonly used

in pediatric patients, the product is a

new drug or biological product which

would provide a meaningful therapeutic

benefit to pediatric patients over

existing treatments, or the product is a

marketed drug or biological product

which is indicated for a very significant

or life threatening illness.

Although this proposal would address

the lack of pediatric labeling through

the imposition of regulatory

requirements, the agency solicits

comment on whether there are other

ways to assure that manufacturers

reliably conduct pre- or postapproval

studies in pediatric patients.

At the same time as it is issuing this

proposed rule, FDA has initiated other

actions that it hopes will encourage the

development of adequate pediatric use

information. FDA plans to develop

guidance on clinical trial designs for

assessing pediatric safety and

effectiveness. The agency has also

discussed with the pharmaceutical

industry a policy on user fees for

pediatric studies designed to encourage

the submission of these studies. Such a

policy could be implemented through

legislation at the time of reauthorization

of the Prescription Drug User Fee Act of

1992. FDA has proposed that user fees

be waived for supplements to add

pediatric use labeling, unless the

supplements contain adequate and wellcontrolled clinical trials. Thus,

supplements that rely on

pharmacokinetic data to extrapolate

from existing adult studies would not be

subject to user fees. FDA might also be

prepared to waive the user fee for

supplements containing pediatric use

studies for which FDA granted a request

to defer submission until after approval.

Finally, FDA has issued a policy

statement describing the types of

evidence necessary to support

supplements. In that policy, FDA

provides guidance to manufacturers on

the circumstances in which FDA may

approve a supplement in which

confirmation 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 by studies without the extensive

documentation ordinarily required.

The agency believes that financial and

other incentives to manufacturers,

although largely beyond FDA’s current

authority, could further increase the

number of drugs and biologics with

adequate pediatric labeling.

IV. Public Hearing

Because of the importance of ensuring

the safety and effectiveness of the

medications administered to children

and the need to address the absence of

pediatric labeling in the most effective

manner possible, FDA intends to hold a

public hearing at which recognized

experts in the field, members of the

pharmaceutical industry, and other

interested parties will have an

opportunity to discuss the issues raised

by this proposal.

V. Description of the Proposed Rule

The proposed rule is designed to

ensure that new drugs and biological

products that are likely to be commonly

used in children or that represent a

meaningful therapeutic benefit over

existing treatments for children contain

adequate pediatric labeling for the

approved indications at the time of, or

soon after, approval. The rule would

therefore require a manufacturer of a

drug classified as a ‘‘new chemical

entity’’ or a new (never-beforeapproved) biological product to submit,

before approval, safety and effectiveness

information on relevant pediatric age

groups for the claimed indications. The
Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules 43903

submission of information could be

deferred until after approval if, for

example, pediatric studies should not

begin until information on adults was

collected, or where the collection and

filing of pediatric data would delay the

availability of a product that provides a

significant therapeutic advantage to

adults. The requirement would be

waived for some or all pediatric age

groups, if: (1) The product did not

represent a meaningful therapeutic

benefit over existing treatments for

pediatric patients and was unlikely to

be used in a substantial number of

pediatric patients, (2) studies on the

product were impossible or highly

impractical because, for example, the

population was too small or

geographically dispersed, (3) the

product were likely to be unsafe or

ineffective in pediatric patients, or (4)

reasonable efforts to develop a pediatric

formulation (if one were needed) had

failed.

The rule is also intended to assist in

improving pediatric use information for

already marketed drugs and biological

products where there is a compelling

need for more information. The rule

would therefore codify FDA’s authority,

discussed in the 1994 rule, to require, in

compelling circumstances, that

manufacturers of already marketed

drugs and biological products conduct

studies to support pediatric use labeling

for the claimed indications.

The proposed rule also contains

provisions designed to encourage

discussions of the need for pediatric

studies early in the drug development

process, as well as 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.

FDA notes that the Federal Food,

Drug, and Cosmetic Act (the act)

authorizes FDA, under certain

circumstances, to grant periods of

exclusive marketing to manufacturers

who obtain approval of labeling

supplements adding pediatric use

information to a drug’s label. First, a

manufacturer is entitled to 3 years of

exclusive marketing under section

505(c)(3)(D)(iii) and (j)(4)(D)(iv) of the

act (21 U.S.C. 355(c)(3)(D)(iii) and

(j)(4)(D)(iv)) for obtaining approval of

pediatric use labeling based on clinical

studies, other than bioavailability

studies. Second, a manufacturer may be

entitled to 7 years of exclusive

marketing under the Orphan Drug

Amendments for obtaining approval of

an application for use of a drug to treat

a disease or condition affecting a

pediatric population of less than

200,000.

A. Scope

The proposed rule would cover only

original applications for those drugs

classified as ‘‘new chemical entities,’’

including antibiotics, and new

biological drug products that have 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.

(An ‘‘active moiety,’’ also defined in

§ 314.108(a), is the molecule or ion,

excluding certain appendages, that is

responsible for the physiological or

pharmacological action of the drug.)

New chemical entities and new

biological products are generally the

most innovative and therapeutically

significant of the new drug products

approved by FDA.

In an effort to limit the scope of the

rule to those products for which

pediatric labeling is most urgently

needed and to minimize the burden on

manufacturers and on agency resources

available to review new product

applications, FDA has tentatively

concluded that the pediatric study

requirement would not apply to

subsequent applications for the drug or

biological product, e.g. to supplements

for new indications or dosage forms.

FDA recognizes that, in some cases, a

change to an approved product,

particularly a new indication, may have

clinically significant use in children.

FDA seeks 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, and, if so, how

the rule could be applied in a manner

that does not impose undue burdens on

manufacturers or agency resources.

The proposed rule would require an

assessment of safety and effectiveness in

one subpopulation (pediatric patients)

only for the indications already claimed

by the manufacturer. It would not

require a manufacturer to study its

product for unapproved (‘‘off-label’’)

indications, even if the product were

widely used in pediatric patients for

those indications. Although the

proposed rule would not apply to

unapproved pediatric indications,

nothing in the rule would diminish the

physician’s power to prescribe drugs

and biological products for such

unapproved indications.

B. Not-Yet-Marketed Drug and

Biological Products

1. Sections 312.23(a)(3)(v), 312.33(a)(8),

and 312.47(b)(1)(i) and (b)(2) (21 CFR

312.23(a)(3)(v), 312.33(a)(8), and

312.47(b)(1)(i) and (b)(2))—Early

Discussion of Plans for Pediatric Studies

In the development of a new drug or

biological product, decisions about

appropriate populations to study and

the design of such studies must often be

made well before the submission of an

NDA or BLA. FDA has 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-investigational new

drug application (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 preBLA 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 meeting are codified

in part 312, FDA’s regulations governing

IND’s.

FDA has already proposed to amend

the IND annual report requirement to

include discussion of pediatric studies

(60 FR 46794, September 8, 1995). FDA

is proposing to amend the remaining

regulations 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

proposed rule, FDA is also proposing to

inform manufacturers at the ‘‘end of

phase 2’’ meeting, or at the earliest

appropriate opportunity, of the agency’s

best judgment, at that time, of the

pediatric studies that will be required

for the product and when the studies

should be submitted.

In addition to the discussions of

pediatric testing codified in this

proposed rule, FDA will also assist

manufacturers by providing early

consultations on chemistry and

formulation issues raised by

requirements under this rule.

2. Sections 314.50(g)(1) and 601.27—

Required Studies

Under proposed §§ 314.50(g) and

601.27(a), an original application for a

drug classified as a new chemical entity

or an application for a new biological
43904 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

product would be required to contain

data adequate to assess the safety and

effectiveness of the drug product for all

pediatric age groups for the claimed

indications, unless FDA granted a

deferral or full or partial waiver of the

requirement. Assessments required

under this section for a product that

represented a meaningful therapeutic

benefit over existing treatments would

have to be carried out using appropriate

formulations for the age group(s) for

which the assessment is required (see

‘‘Pediatric Formulations,’’ in section V.E

of this document), unless reasonable

efforts to produce a pediatric

formulation had failed (see ‘‘Waivers,’’

in section V.B.4 of this document).

The proposed rule does not mandate

particular types of studies. The sponsor

should consult with FDA on the types

of data that will be considered adequate

to assess pediatric safety and

effectiveness. 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 children, FDA may conclude that

pediatric safety and effectiveness can be

based on adult effectiveness data

together with pharmacokinetic and

safety data in pediatric patients. The

proposed 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.

3. Sections 314.50(g)(2),

314.81(b)(2)(vii), and 601.27(b)—

Deferred Submission and Postmarketing

Reports

In some cases, pediatric testing

should not begin until certain safety

and/or effectiveness information in

adults has been collected. FDA believes

that in certain cases it may be

appropriate to defer submission of

pediatric studies. For example, in such

cases, an NDA or biological product

license could be ready for approval for

adult use before pediatric studies were

completed. Also, where a product was

needed to treat a serious or lifethreatening disease for which there were

not satisfactory alternative therapies or

where the product represented a

meaningful therapeutic benefit over

existing therapies, it would be contrary

to the public health to delay approval

until pediatric studies were submitted.

Proposed §§ 314.50(g)(2) and

601.27(b) would permit FDA 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. 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. FDA would consult with

the sponsor in determining a deadline

for the deferred submission, but would

ordinarily require the submission not

more than 2 years after the date of the

initial approval. The deadline for

submission of studies would take

account of likely or actual difficulties

encountered in recruiting pediatric

patients to the study. FDA seeks

comment on the circumstances in which

FDA should permit deferral. FDA also

seeks comment on factors that should be

considered in determining whether a

product is among those that should be

studied in adults before children.

To ensure that deferral would not

unnecessarily delay the submission of

pediatric use information, FDA has

tentatively concluded that a request for

deferred submission should 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. To

permit FDA to monitor the conduct of

postapproval studies to ensure that they

were carried out with due diligence,

FDA is proposing to amend

§ 314.81(b)(ii) of the postmarketing

reports requirements to require

applicants to include in their annual

reports whether they have been required

to conduct postmarket pediatric studies

and, if so, to report the status of those

studies. (Additional postmarketing

reporting requirements are described

under ‘‘Remedies,’’ in section V.G of

this document.) FDA seeks comment on

the types of evidence FDA should

examine to ensure that deferred studies

are carried out in a timely fashion.

4. Sections 314.50(g)(3) and 601.27(c)—

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 widely

used in pediatric patients. FDA also

does not intend to require pediatric

assessments in other situations where

the study(ies) necessary to carry out the

assessment are impossible or highly

impractical or would pose undue risks

to pediatric patients. Thus,

§§ 314.50(g)(3) and 601.27(c) would

require FDA to grant a waiver of the

pediatric study requirement on its own

initiative or at the request of the

applicant if: (1) The product (a) did not

represent a meaningful therapeutic

benefit over existing treatments, and (b)

was not likely to be used in a substantial

number of pediatric patients as a whole,

or was not likely to be used in a

substantial number of one or more

pediatric subpopulations, or (2)

necessary studies were impossible or

highly impractical, because, for

example, the number of such patients

was so small or geographically

dispersed, or (3) there were 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 proposed rule would

authorize FDA to grant a partial waiver

for those age groups for which a

pediatric formulation was required (see

‘‘Pediatric Formulations,’’ in section V.E

of this document), if reasonable

attempts to produce a pediatric

formulation had failed.

The proposed rule 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.

For example, the waiver request could

demonstrate that the product was

indicated for a disease that does not

occur in a substantial number of

pediatric patients (e.g., drugs for breast

or prostate cancer). The waiver request

could demonstrate that the product was

a member of a drug class known to be

unsafe in specific pediatric age groups

(e.g., chloramphenicol, an antibiotic,

which has caused serious adverse

events in neonates. Also, it is widely

known that, except for serious or life

threatening diseases where alternative

therapy is needed, quinolones, antimalarial agents, are not recommended

in young children due to concerns about

cartilage and bone development).
Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules 43905

1 IMS, National Disease and Therapeutic Index,

IMS America; Plymouth Meeting, PA.

Animal toxicity data or imautere

metabolic pathways for newborns are

examples of data that may be used to

demonstrate that the product was a

member of a drug class known to be

unsafe in specific pediatric age groups.

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. A full waiver would be

appropriate where, for example, the

product did not represent a meaningful

therapeutic advance and was not likely

to be used in a substantial proportion of

any pediatric age group. A partial

waiver would be appropriate where, for

example, the product was likely to be

used in substantial numbers in some

pediatric age groups but not others,

where the product was likely to be

unsafe or ineffective in some age groups,

or where reasonable efforts to develop a

pediatric formulation necessary for

some age groups had failed. 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 solicits comments on the

proposed grounds for waiving the

pediatric study requirement and

whether additional grounds may exist,

such as whether cost should justify

waiver of the pediatric study

requirement. Additionally, FDA seeks

comment on defining the term

‘‘meaningful therapeutic benefit’’.

Comment is also requested on, what

should be considered a ‘‘substantial

number’’ of pediatric patients, i.e., how

the agency should establish a level of

expected use in pediatric patients below

which pediatric labeling would not be

required for a drug that did not

represent a meaningful therapeutic

advance. FDA is considering two

possible methods. The first method

would focus on the number of times the

drug was expected to be used in

pediatric patients, annually. Under this

method, FDA has tentatively concluded

that 100,000 or more prescriptions or

uses per year in all pediatric age groups

would be considered a substantial

number. Products that might require

studies under this test include

anesthetics, anticonvulsants, asthma

drugs, antidepressants, antimicrobials

and antivirals, vaccines, and drugs to

treat certain skin conditions. FDA has

also tentatively concluded that a partial

waiver for a particular pediatric age

group would be available under this

method if the product were expected to

be prescribed or used fewer than 15,000

times per year in that age group.

The second possible method for

establishing the level of expected use

would focus on the number of pediatric

patients affected by the disease or

condition for which the product is

intended. Physician mention data from

the IMS National Disease and

Therapeutic Index 1, shows pediatric use

of certain products generally falling

within two ranges (i.e., those products

either exceeding 100,000 physician

mentions for pediatric use per year or

those falling below 15,000 physician

mentions for pediatric use per year.

Thus, under this method, FDA has

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. A partial waiver for a

particular pediatric age group would be

available under this method if fewer

that 15,000 patients in that age group

were affected by the disease or

condition. FDA seeks comment on these

methods of assessing expected pediatric

exposure and on the specific numerical

thresholds suggested.

5. Section 314.50(d)(7)—Pediatric Use

Section of Application

Under proposed § 314.50(d)(7),

applicants would be required to include

in their applications a section

summarizing and analyzing the data

supporting pediatric use information for

the claimed indications. The proposed

new section of the application would

contain an integrated summary of the

clinical pharmacology studies,

controlled clinical studies, uncontrolled

clinical studies, or other data or

information that are relevant to the

safety and effectiveness, and benefits

and risks of the drug in pediatric

populations. Because full descriptions

of all such studies must already be

provided under § 314.50 (d)(3) and

(d)(5), the new pediatric use section

would 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.

C. Marketed Drug and Biological

Products

1. Section 201.23—Required Studies

As discussed in the preamble to the

1994 rule, FDA has the authority, under

certain circumstances, to require the

manufacturers of marketed drugs that

are used in pediatric patients to submit

pediatric studies assessing safety and

effectiveness for the already approved

indications (59 FR 64240 at 64243).

Proposed § 201.23 would authorize FDA

to require a manufacturer of a marketed

drug or biological drug product to

submit an application containing data

evaluating the safety and effectiveness

of the product in pediatric populations,

in compelling circumstances. FDA has

tentatively concluded that it should

impose such a requirement only where

the agency made one of two findings

that: (1) 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

§ 201.23, the appropriate center, CDER

or CBER, would 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

center’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 center. At the center’s

discretion, such a meeting could be an

advisory committee meeting. If, after

reviewing any written response and

conducting any requested meeting,

CDER or CBER determined that

additional pediatric use information

were necessary, the center director

would issue an order requiring the

manufacturer to submit a supplemental

application containing pediatric safety

and effectiveness data within a specified

time. The manufacturer would be able

to request reconsideration by the

Commissioner for Food and Drugs (the

Commissioner) of the order under the

provisions at 21 CFR 10.33.

Proposed § 201.23(c) would require

FDA to grant full or partial waivers of

study requirements on their own

initiative or at request of the applicant

for reasons analogous to those which

would entitle not-yet-marketed drug and

biologic products to waivers.

FDA seeks comment on whether it

should codify its authority to require the

manufacturers of marketed drugs to

conduct pediatric studies, and, if so, the

circumstances under which the agency

should exercise that authority. The

agency also solicits comment on the

proposed grounds for waiving the

pediatric study requirement for already

marketed drug and biological products

and whether additional ground may

exist, such as whether cost should

justify waiver of the pediatric study

requirement. Comment is also sought on
43906 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

defining the term ‘‘very significant

illness’’.

D. 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, it could be necessary to

conduct studies in more than one

pediatric age group. The following age

categories for the pediatric population

are commonly distinguished: (1)

Neonates; (2) infants; (3) children, and

(4) adolescents. In the 1994 rule, FDA

defined neonates as birth up to 1 month,

infants as 1 month to 2 years, children

as 2 years to 12 years, and adolescents

as 12 years to 16 years (59 FR 64242).

The need for studies in more than one

age group would depend on whether the

drug or biological product was likely to

be used in each age group (see

‘‘Waivers,’’ in sections V.B.4 and V.C.1

of this document) and whether safety

and effectiveness in one age group could

be extrapolated to other age groups. The

metabolism and elimination of the drug

and the stage of development of the

child may be important in determining

which age groups should be tested.

There would generally need to be

sufficient data, including

pharmacokinetic data to establish

dosing and safety for each group.

(Pharmacokinetic data are generally

collected from pediatric patients

receiving the drug or biologic as

treatment rather than from healthy

children.) In cases where the product

was expected to have similar

pharmacokinetics in more than one age

group, pharmacokinetic data from one

age group could be sufficient to support

labeling for other age groups. Such

extrapolation would not be routine.

FDA recognizes that studies in

neonates and young infants present

special problems. On one hand, failure

to adequately test drugs in this age

group has led to both under treatment

and, conversely, some of the most

serious therapeutic mishaps known to

have occurred among pediatric patients.

On the other hand, studies in this age

group may be significantly more

difficult to carry out in the period before

or soon after approval than studies in

older age groups. However, FDA

recognizes that for some conditions,

early study would be advantageous.

FDA would therefore expect to apply

the study requirement to patients in this

age group with caution and would,

whenever appropriate, permit such

studies to occur after the product has

been successfully studied in older

children. The agency seeks comment on

the issues raised by requiring studies in

this age group.

E. Pediatric Formulations

In some cases, testing of a product in

pediatric patients could require the

development of a pediatric formulation.

Many children below a certain age are

unable to swallow pills and may require

a liquid, chewable or injectable form of

the product. The need to develop a

pediatric formulation does not

necessarily mean that the product

would not have been used in children

in its adult dosage form. In many cases,

physicians prescribing tablets to young

children direct the parent to grind up

the tablet and sprinkle the powder into

the child’s food. In other cases,

pharmacists may compound tablets into

pediatric formulations of their own

choosing. These methods of

administering adult dosage forms to

children may be unsatisfactory,

however, because the bioavailability of

any particular product in this form is

untested and dosing may be highly

variable. A standardized pediatric

formulation ensures bioavailability and

consistency of dosing, and permits

meaningful testing of safety and

effectiveness.

FDA has tentatively concluded that it

would be reasonable to expect a

manufacturer of a product 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. Proposed

§§ 201.23, 314.50(g)(1) and 601.27(a)

contain this requirement. The type of

formulation needed would vary

depending on the age group in which

the product were to be used and the

disease being treated. Young children

unaccustomed to taking drugs may need

liquid or chewable formulations, while

children with serious and chronic

diseases may need only smaller tablets.

The difficulty and cost of producing

a pediatric formulation may vary greatly

depending upon such factors as

solubility of the compound and taste.

FDA would waive the requirement for

pediatric studies (see ‘‘Waivers,’’ in

section V.B.4 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 solicits comment on whether it

is appropriate to require a manufacturer

to develop a pediatric formulation and,

if so, the circumstances in which it

would be appropriate to impose such a

requirement. For example, should the

cost of developing a pediatric

formulation justify a waiver of the

pediatric study requirement? Should the

number of patients affected by the

disease or condition in the relevant age

group be considered in determining

whether to require the development of

a pediatric formulation for that age

group? Is it appropriate to ask the

manufacturer of a not-yet-approved

product to allocate resources to

developing pediatric formulation(s)?

Where cost is a significant issue, would

it be appropriate to defer development

of a pediatric formulation until after

approval of the product? What should

be considered ‘‘reasonable attempts’’ to

develop a pediatric formulation?

As noted above, FDA was unable to

quantify the potential benefits of this

rule due to the unavailability of relevant

data and studies. Nevertheless, the

agency will attempt to assess the

benefits of the final rule and solicits

comment on the appropriate design and

methodology of such measurement. In

particular, FDA seeks information and

data that would help the agency to: (1)

Quantify the societal costs of the

adverse drug events experienced by

pediatric populations and (2) assess the

proportion of these adverse drug events

that would be eliminated by the new

information that would result from the

rule. In addition, FDA seeks information

and data that would help the agency to:

(1) Quantify the societal costs of the

underused or inadequate drug therapies

prescribed to pediatric populations and

to (2) assess the proportion of these

costs that would be eliminated by the

new information that would result from

the rule.

F. Ethical Issues

Ethical concerns may have

contributed to reluctance to conduct

studies in pediatric patients. To address

these concerns, both the American

Academy of Pediatrics (Ref. 1) and the

Department of Health and Human

Services, 45 CFR part 46, subpart D,

have developed guidelines or

regulations for the ethical conduct of

clinical studies in pediatric patients.

Because pediatric patients represent a

vulnerable population, special

protections are needed to protect their

rights and to shield them from undue

risk. As the American Academy of

Pediatrics has observed, however,

administration of untested drugs ‘‘may

place more children at risk than if the

drugs were administered as part of welldesigned, controlled clinical trials’’ (Ref.

1 at p. 286). The ethical guidelines

currently in place are designed to
Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules 43907

protect children’s rights and protect

them from undue risk. Sponsors should

adhere to these guidelines for pediatric

studies conducted under this rule. The

agency seeks comment on ethical issues

that may be raised by this proposal.

G. Remedies

FDA has tentatively concluded that

the most practical remedy for failure to

submit a required study is an injunctive

action brought under the ‘‘misbranding’’

or ‘‘new drug’’ provisions of the act.

Denying or withdrawing approval of an

otherwise safe and effective drug or

biological product is not a satisfactory

remedy, because removal of a product

from the marketplace could deprive

other patients of the benefits of a useful

medical product. FDA does not intend

to deny or withdraw approval of a

product for failure to conduct pediatric

studies, except possibly in rare

circumstances.

If a manufacturer failed, in the time

allowed, to submit adequate studies to

evaluate pediatric safety and

effectiveness, under proposed

§§ 201.23(d) or 314.50(g), FDA could

consider the product misbranded under

section 502 of the act (21 U.S.C. 352) or

an unapproved new drug under section

505(a) of the act (see ‘‘Legal Authority,’’

in section VI of this document). When

a product is misbranded or an

unapproved new drug, sections 302, 303

and 304 of the act (21 U.S.C. 332, 333,

and 334) authorize injunction,

prosecution or seizure. For violations of

this rule, should it become final, FDA

would ordinarily expect to file an

enforcement action for an injunction,

asking a Federal court 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.

To assist FDA in determining whether

pediatric assessments are needed or are

being carried out with due diligence,

FDA is proposing to amend § 314.81

(other postmarketing reports) to require

that annual reports filed by the

manufacturer contain information on

labeling changes that have been

initiated in response to new pediatric

data, analysis of clinical data that have

been gathered on pediatric use,

assessment of data needed to ensure

appropriate labeling for the pediatric

population, and information on the

status of ongoing pediatric studies.

Where possible, the annual report

would also contain an estimate of

patient exposure to the drug product,

with special reference to the pediatric

population.

FDA seeks comment on appropriate

remedies for failure to conduct a

required pediatric study and the

circumstances, if any, in which the

agency should deny or withdraw

approval of a drug product.

VI. Legal Authority

Therapeutic tragedies in pediatric

patients have prompted some of the

most important federal legislation to

ensure that drugs are safe and effective.

For example, the act was enacted in

1938 in the wake of a tragedy in which

many pediatric patients died after taking

an untested medicine called Elixir of

Sulfanilamide. The legislative history of

this enactment demonstrates that

Congress intended to ensure that

children, as well as adults, received

adequately tested and appropriately

labeled drugs. (See, e.g., 78

Congressional Record 567–573 (1934)

(statement of Sen. Copeland).)

Every mother is anxious that the food and

medicine given her baby shall be above

suspicion. The welfare of every man, woman,

and child is involved in the quality and

preparation of the foods and drugs sold in

America * * *. [T]he purpose of this

legislation * * * is to protect the public, to

protect the mothers and the children * * *

81 Congressional Record 7312 (1937)

(remarks of Rep. Coffee)

The agency has stated, in the context

of both pediatric studies and studies in

women, 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). The agency has further

stated that in some cases it could

require studies in pediatric patients and

in women for both not-yet-approved

products and marketed products (Id).

The primary rationale for such a

requirement is the same for women and

pediatric patients. In most cases, drugs

and biological products behave

similarly in demographic subgroups,

including age and gender subgroups,

even though there may be variations

among the subgroups, based on, for

example, differences in

pharmacokinetics. Thus, where a drug

or biological product is indicated for a

disease suffered equally by men,

women, and children, and is not

contraindicated in women or pediatric

patients, the product will be widely

prescribed for all three subgroups even

if it were studied only in, or labeled

only for, men. As described above, there

is extensive evidence that many drugs

labeled only for adult use are in fact

widely used in pediatric patients for the

same indications.

FDA notes that this proposal

addresses only use of drug products for

their approved indications in a

significant subpopulation. The proposed

rule does not address ‘‘off-label’’ or

unapproved uses of approved drugs and

biological products, in which an

approved product is used for diseases or

conditions other than those in the label.

This rule would apply only where a

product was expected to have clinically

significant use in pediatric populations

for the indications already claimed by

the manufacturer.

In addition to the provisions cited

below as authority for the proposed

rule, the agency relies on section 701(a)

of the act (21 U.S.C. 371(a)), which

authorizes FDA to issue regulations for

the efficient enforcement of the act.

A. New Drug and Biological Products

Biological drug products are subject

both to section 351 of the Public Health

Service Act (the PHS Act) and to the

provisions of the act and implementing

regulations applicable to drugs, except

that manufacturers of biological

products covered by approved BLA’s are

not required to submit NDA’s under

section 505 of the act. References to

‘‘drugs’’ in the following sections

include biological drugs.

1. Sections 502(a), 502(f), 505(d)(7), and

201(n) of the Act

A drug is misbranded under section

502(a) of the act if its labeling is ‘‘false

or misleading in any particular.’’

Similarly, a new drug application must

contain labeling that is not false or

misleading (section 505(d)(7) of the act).

Section 201(n) of the act (21 U.S.C.

321(n)) defines labeling as misleading if

it ‘‘fails to reveal facts

material * * * with respect to

consequences which may result’’ not

only from use of the product as labeled,

but ‘‘from the use of the

[product] * * * under such conditions

of use as are customary or usual.’’

Information on dosing and adverse

effects are facts ‘‘material’’ to the

consequences that may result from

customary use in pediatric patients. A

drug product is misbranded under

section 502(f) of the act, if its label fails

to provide adequate directions for each

intended use. 21 CFR 201.5 states that

adequate directions must be provided

for each use recommended in the

labeling and each use ‘‘for which the

drug is commonly used.’’ Thus, FDA

may require a product to carry labeling

that provides safety and effectiveness

information on use in subpopulations in

which the product is customarily or

commonly used.
43908 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

There is extensive evidence that drugs

for diseases that affect both adults and

pediatric patients are routinely used in

pediatric patients despite the absence of

pediatric labeling, and even in the face

of disclaimers stating that safety and

effectiveness have not been established

in children. FDA may therefore consider

pediatric use to be ‘‘customary or usual’’

or ‘‘commonly used’’ where the drug is

indicated for a disease or condition that

affects both adults and children, and the

drug is not contraindicated in pediatric

patients. In many cases, the use in

pediatric patients of a drug labeled only

for adults will increase over time, as

physicians become aware of the drug’s

potential usefulness in children and

familiar with the drug’s uses and effects.

Thus, FDA may conclude that a drug

that was appropriately labeled for adult

use at the time of approval is, at some

later date, no longer appropriately

labeled.

2. Sections 201(p), 301(a), and 505(a) of

the Act

Under section 301 (a) and (d) of the

act (21 U.S.C. 331 (a) and (d)) and

section 505(a) of the act, a drug product

is subject to enforcement action if it is

a ‘‘new drug’’ for which no NDA has

been approved. A product is a new drug

under section 201(p) of the act if it is not

recognized to be safe and effective

under the conditions ‘‘prescribed,

recommended, or suggested’’ in the

drug’s labeling. There is widespread

evidence that, despite the absence of

pediatric labeling, drugs are routinely

used in pediatric patients for the labeled

indications. FDA may therefore consider

pediatric use to be ‘‘suggested’’ in a

drug’s labeling where the drug is

indicated for a disease or condition that

affects both adults and pediatric

patients, unless the drug is specifically

contraindicated for pediatric patients.

As described above, because pediatric

use of new drugs often increases over

time, FDA may conclude that labeling

that is appropriate at the time of

approval is later no longer appropriate.

3. Section 502(j) of the Act

Section 502(j) of the act defines as

misbranded those drugs that are

dangerous to health when used in the

manner prescribed, recommended, or

suggested in their labeling. FDA may

consider pediatric use to be ‘‘suggested’’

in a drug’s labeling where the drug is

indicated for a disease or condition that

affects both adults and pediatric

patients, unless the drug is specifically

contraindicated for pediatric patients.

As described earlier in this notice, the

absence of pediatric testing and labeling

poses risks to children including the

risk of unanticipated adverse reactions,

and under- and over-dosing.

4. Section 505 (i) and (k) of the Act

Section 505(i) of the act that

authorizes the issuance of regulations

governing the use of investigational

drugs, and the proviso in 505(k) of the

act, which requires regulations issued

under 505(i) to have ‘‘due

regard * * * for the interests of

patients,’’ together authorize FDA to

impose conditions on the investigation

of new drugs, including conditions

related to the ethics of a proposed

investigation and to the interests of

patients. Fairness in distribution of the

burdens and benefits of research is one

of the ethical principles underlying

federal regulations on investigational

drugs. (See, e.g., 44 FR 23192 at 23194,

April 18, 1979 (‘‘Belmont Report:

Ethical Principles and Guidelines for

the Protection of Human Subjects of

Research’’).) Because exclusion of

pediatric patients from clinical trials

may deny them an equitable share of the

benefits of research, section 505 (i) and

(k) authorize FDA to require their

inclusion in clinical trials.

5. Section 351 of the Public Health

Service Act

Section 351 of the PHS Act (42 U.S.C.

262) provides authority to regulate the

labeling and shipment of biological

products. Under section 351(d), licenses

for biological products are to be issued

only upon a showing that they meet

standards ‘‘designed to insure the

continued safety, purity, and potency of

such products’’ prescribed in

regulations. The ‘‘potency’’ of a

biological product includes its

effectiveness (21 CFR 600.3(s)).

B. Marketed Drug Products

1. Section 502(f) of the Act and 21 CFR

201.5

A drug product is misbranded under

section 502(f) of the act, if its label fails

to provide adequate directions for each

intended use. 21 CFR 201.5 states that

adequate directions must be provided

for each use recommended in the

labeling and each use ‘‘for which the

drug is commonly used.’’ Where there is

evidence that a drug product is widely

used in pediatric patients, failure to

provide adequate directions for the use

could misbrand the product.

2. Sections 502(a) and 201(n) of the Act

A drug is misbranded under section

502(a) of the act if its labeling is false

or misleading. Section 201(n) of the act

defines labeling as misleading if it fails

to reveal facts that are material in light

of the consequences of the customary or

usual use of the product. Where a drug

is widely used in pediatric patients,

FDA may consider pediatric use to be

‘‘customary.’’ Failure to provide

adequate information on dosing and

adverse effects in the pediatric

population could render the product

misbranded, even where the

manufacturer does not promote the

product for that subpopulation.

3. Section 502(j) of the Act

Section 502(j) of the act defines as

misbranded those drugs that are

dangerous to health when used in the

manner prescribed, recommended, or

suggested in their labeling. FDA may

consider pediatric use to be ‘‘suggested’’

in a drug’s labeling where the drug is

indicated for a disease or condition that

affects both adults and pediatric

patients, unless the drug is specifically

contraindicated for pediatric patients.

As described earlier in this notice, the

absence of pediatric testing and labeling

poses risks to children including the

risk of unanticipated adverse reactions,

and under- and over-dosing.

4. Section 505(k) of the Act

Section 505(k) of the act authorizes

FDA to order the holder of an approved

NDA to submit reports of data necessary

to determine whether there are grounds

to withdraw approval of the NDA. FDA

has in the past issued regulations under

section 505(k) of the act (formerly

section 505(j) of the act) requiring

postapproval studies of certain drugs

(see, e.g., 21 CFR 310.303

(‘‘Continuation of long-term studies,

records, and reports on certain drugs for

which new drug applications have been

approved’’)(1972); 21 CFR 310.304

(‘‘Drugs that are subjects of approved

new drug applications and that require

special studies, records, and

reports’’)(1972); and 21 CFR 310.500

(‘‘Digoxin products for oral use;

conditions for marketing’’)(1974)).

Section 505(k) of the act also authorizes

the agency to require other

postmarketing reports on drug products.

5. Section 351 of the Public Health

Service Act

Section 351(d) of the PHS Act

authorizes FDA to ensure the

‘‘continued safety, purity, and potency’’

of biological products. Section 351(b) of

the PHS Act prohibits false labeling of

a biological product.

VII. Implementation Plan

All applications for drug and

biological products covered by the final

rule would be required to contain an

assessment of pediatric safety and

effectiveness for the claimed
Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules 43909

indications, unless the applicant has

obtained a waiver or deferral of this

requirement from FDA.

FDA proposes that the final rule

become effective 90 days after the date

of its publication in the Federal

Register. For new drug and biologic

product applications submitted before

the effective date of the final rule, the

agency proposes a compliance date of

21 months after the effective date of the

final rule. For new drug and biologic

product applications submitted on or

after the effective date of the final rule,

the agency proposes a compliance date

of 15 months after the effective date of

the final rule. The agency solicits

comments on the proposed effective

date and proposed compliance dates.

VIII. Paperwork Reduction Act of 1995

This proposed rule contains

information collection provisions that

are subject to review by the Office of

Management and Budget (OMB) under

the Paperwork Reduction Act of 1995

(44 U.S.C. 3501–3520). The title,

description, and respondent description

of the information collection provisions

are shown below with an estimate of the

annual reporting and recordkeeping

burden. Included in the estimate is the

time for reviewing instructions,

searching existing data sources,

gathering and maintaining the data

needed, and completing and reviewing

each collection of information.

FDA invites comments on: (1)

Whether the proposed collection of

information is necessary for the proper

performance of FDA’s functions,

including whether the information will

have practical utility; (2) the accuracy of

FDA’s estimate of the burden of the

proposed collection of information,

including the validity of the

methodology and assumptions used; (3)

ways to enhance the quality, utility, and

clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology.

Title: Pediatric Safety and

Effectiveness Reporting Requirements

for Certain Drugs and Biological

Products.

Description: FDA is proposing

reporting requirements that include: (1)

Reports on planned pediatric studies in

investigational new drug applications

(IND’s) (proposed § 312.23(a)(10)(iii));

(2) Reports assessing the safety and

effectiveness of certain drugs and

biological products for pediatric use in

new drug applications (NDA’s) and

biologic license applications (BLA’s) or

in supplemental applications (proposed

§ 314.50(g)(1)); (3) Analyses of data on

pediatric safety and effectiveness in

NDA’s (proposed § 314.50(d)(7)); (4)

Postmarketing reports of analyses of

data on pediatric safety and

effectiveness (proposed

§ 314.81(b)(2)(vi)(C)); (5) Postmarketing

reports on patient exposure to certain

marketed drug products, analyzed and

age (proposed § 314.81(b)(2)(i)); (6)

Postmarketing reports on labeling

changes initiated in response to new

pediatric data (proposed

§ 314.81(b)(2)(vi)(C)); and (7)

Postmarketing reports on the status of

required postapproval studies in

pediatric patients (proposed

§ 314.81(b)(2)(vii)). The purpose of these

reporting requirements is to address the

lack of adequate pediatric labeling of

drugs and biological products by

requiring the submission of evidence on

pediatric safety and effectiveness for

products with clinically significant use

in children.

Description of Respondents: Sponsors

and manufacturers of drugs and

biological products.

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN

CFR section Number of

respondents

Annual frequency per

response

Total annual

responses

Hours per response Total hours

201.23 ................................................................................................... 2 1 2 16 32

314.50(d)(7) .......................................................................................... 150 1 150 8 1,200

314.50(g)(1) .......................................................................................... 10 1 10 16 160

314.50(g)(2) .......................................................................................... 9 1 9 8 72

314.50(g)(3) .......................................................................................... 15 1 15 8 120

314.81(b)(2)(i) ....................................................................................... 625 1 625 1.5 937.5

314.81(b)(2)(vi)(c) ................................................................................. 625 1 625 1.5 937.5

314.81(b)(2)(vii) .................................................................................... 625 1 625 1.5 937.5

601.27(a) ............................................................................................... 1 1 1 16 16

601.27(b) ............................................................................................... 1 1 1 16 16

601.27(c) ............................................................................................... 1 1 1 16 16

Total: .............................................................................................. .................... .................... .................... ...................... 4,444.5

There are no capital or operating and maintenance costs associated with this collection of information.

The agency has submitted the

information collection provisions of this

proposed rule to OMB for review.

Interested persons are requested to send

comments regarding information

collection by September 15, 1997 to the

Office of Information and Regulatory

Affairs, OMB, New Executive Office

Bldg., 725 17th St. NW., rm. 10235,

Washington, DC 20503, Attn: Desk

Officer for FDA.

IX. Environmental Impact

The agency has determined under 21

CFR 25.24 (a)(8), (a)(11), and (e)(6) that

this action is of a type that does not

individually or cumulatively have a

significant effect on the human

environment. Therefore, neither an

environmental assessment nor an

environmental impact statement is

required.

X. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866, the Regulatory Flexibility Act (5

U.S.C. 601–612), and the Unfunded

Mandates Reform Act (Pub. L. 104–4).

Executive Order 12866 directs agencies

to assess all costs and benefits of

available regulatory alternatives and,

when regulation is necessary, to select

regulatory approaches that maximize

net benefits (including potential

economic, environmental, public health

and safety, and other advantages;

distributive impacts; and equity). Under

the Regulatory Flexibility Act, unless an

agency certifies that a rule will not have
43910 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

2 IMS, National Disease and Therapeutic Index,

IMS America; Plymouth Meeting, PA. FDA’s

analysis does not include data from 1996 because

the IMS data are not yet available.

a significant economic impact on a

substantial number of small entities, the

agency must analyze regulatory options

that would minimize the impact of the

rule on small entities. The Unfunded

Mandates Reform Act (Pub. L. 104–4)

(in section 202) requires that agencies

prepare an assessment of anticipated

costs and benefits before proposing any

rule that may result in an annual

expenditure by State, local, and tribal

governments, in the aggregate, or by the

private sector, of $100,000,000 or more

(adjusted annually for inflation).

The agency has reviewed this

proposed rule and has determined that

the proposed rule is consistent with the

regulatory philosophy and principles

identified in Executive Order 12866,

and these two statutes. This proposal is

a significant regulatory action as defined

by the Executive Order due to the novel

policy issues it raises. With respect to

the Regulatory Flexibility Act, the

Commissioner certifies that the rule will

not have a significant economic impact

on a substantial number of small

entities. Since the proposed rule does

not impose any mandates on State,

local, or tribal governments, or the

private sector that will result in an

annual expenditure of $100,000,000 or

more, FDA is not required to perform a

cost-benefit analysis according to the

Unfunded Mandates Reform Act.

A. Purpose

The FDA is proposing that a limited

class of important new drugs and

biologicals that are likely to be used in

pediatric patients contain sufficient data

and information to support directions

for this use. As the approved labeling

for many of these new products lack

relevant pediatric information, any use

in children greatly increases the risk of

inappropriate dosing, unexpected

adverse effects, and suboptimal

therapeutic outcomes. The proposed

rule is designed to ensure that new

drugs, including biological drugs, that

are therapeutically important and/or

likely to be widely used in children

contain adequate pediatric labeling at

the time of, or soon after, approval.

B. Number of Affected Products and

Required Studies

Neither the precise number of new

drugs that would require additional

pediatric studies nor the cost of these

studies can be predicted with certainty.

To develop plausible estimates, FDA

examined the pediatric labeling status at

time of approval for each NME and

important biological approved from

1991 to 1995, and used these estimates

to project the cost that would have

occurred had the proposed rule been in

place over that period. The agency

assumes that future costs would be

reasonably similar. As shown in Table

2, each new drug was assigned to one

of three categories: (1) Therapeutically

important, some potential pediatric use,

(2) other approvals, potential for wide

pediatric use, and (3) all other

approvals. (The first two categories

include all products that the agency

believes would have met the therapeutic

importance and pediatric use threshold

criteria set forth in this proposed rule.

The third category includes all products

that would not have met these criteria.)

For NME’s, these category assignments

were based on pediatric pages

completed by CDER’s reviewing

division at the time of each approval,

the priority review designation for each

drug, and physician mention data from

the IMS National Disease and

Therapeutic Index.2 All priority NME’s

were assumed to be therapeutically

important, and assigned to the first

category, unless the drug’s pediatric

page specifically noted a low potential

for pediatric use or the IMS data

indicated no pediatric use. For

nonpriority NME’s, FDA assumed that

wide pediatric use would have been

expected for only those products that

exceeded 100,000 physician mentions

for pediatric use during 1995.

Assessments of therapeutic importance

for biologicals were developed

retrospectively by CBER.

As shown, 60 of the 142 approvals (42

percent) over this 5-year period fell into

the first two categories; that is, 47 drugs

were classified as therapeutically

important with at least some potential

pediatric use and 13 less therapeutically

important drugs were designated as

offering a potential for wide pediatric

use based on physician mentions. The

82 drugs (58 percent) grouped under the

third category would presumably not

have met the therapeutic importance

and pediatric use criteria of the

proposed rule.

TABLE 2.—ESTIMATED NUMBER OF

NME’S AND BIOLOGICALS APPROVED

IN 1991–95

[That Would Have Been Affected by the

Proposed Rule]

Pediatric labeling status

Number

of approved

drugs

Percent

of approved

drugs

Therapeutically important, some potential

pediatric use .............. 47 33

Some pediatric labeling .................. 16 ..............

No pediatric labeling ....................... 31 ..............

Other approvals,

potential for wide

pediatric use ....... 13 9

Some pediatric labeling .................. 7 ..............

No pediatric labeling ....................... 6 ..............

Subtotal ........... 60 42

Some pediatric labeling .................. 23 ..............

No pediatric labeling ....................... 1 37 ..............

All other approvals ........ 82 58

Total Approvals 142 100

1Pediatric page shows seven ongoing pediatric studies.

In assessing the amount of additional

research that would have been required

for the 60 drugs from the first two

categories (those that would have

potentially been affected by the

proposed rule), FDA believes that most

would not have required extensive

additional clinical trials. As FDA

explained in the 1994 final rule (59 FR

64240), extrapolations from adult

effectiveness data based on

pharmacokinetics studies and other

safety data can be sufficient to provide

the necessary dosing pediatric

information for those drugs that work by

similar mechanisms in adults and

children. The agency estimates that the

majority of these 60 drugs could, to

some extent, rely on such

extrapolations. Although the proposed

rule identifies four pediatric subgroups:

(1) Neonates, (2) infants, (3) children,

and (4) adolescents, the need for studies

in more than one age group depends on

the likely use of the drug in each age

group and on whether relevant data can

be extrapolated to other age groups. As

a rule, individual clinical trials would

rarely be required for each age group for

a given drug.

Estimates of the size of the studies

that would have been required to

support pediatric labeling for these 60

drugs vary from 20 patients where the

simplest type of pharmacokinetic study
Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules 43911

3 DataEdge, LLC, Faxed data, March 7, 1997.

4Thomas Hill, ‘‘Calculating the Cost of Clinical

Research,’’ Scrip Magazine, p. 29, March 1994.

would be adequate, to 70 to 120

pediatric patients for studies where

some safety and effectiveness data

would be needed, to several hundred

pediatric patients for studies where

more substantial safety and

effectiveness data would be required.

Thus, for the purpose of developing

order-of-magnitude cost estimates, FDA

further subdivided the 60 potentially

affected drugs into three distinct

groupings. The first group of 30 drugs

would have required the least amount of

new data and includes both the 7 drugs

for which the CDER pediatric pages

indicate that pediatric trials were

already underway and the 23 drugs that

already had at least some pediatric

labeling at the time of approval. Based

on a review of those labels at approval

time, FDA estimated that up to half, or

15 of these 30 drugs may have needed

limited additional data that would have

involved new studies with, on average,

50 pediatric patients each.

Next, FDA assumed that 23 drugs

(about three quarters of the remaining

30) would have required new pediatric

studies with data from about 100

patients each. Finally, FDA assumed

that the remaining 7 drugs would have

needed more extensive safety and

effectiveness data, requiring 300

pediatric patients for each drug.

Consequently, FDA estimates that, if

this proposed rule had been in effect

from 1991 to 1995, sponsors of 45 of the

60 potentially affected drugs would

have needed to obtain additional data

from about 5,150 pediatric patients (15

drugs × 50 patients + 23 drugs × 100

patients + 7 drugs × 300 patients). The

proposed regulation, therefore, would

have required additional pediatric

research for an estimated average of 9

new drugs and about 1,030 pediatric

patients per year.

In addition, the proposed rule permits

the agency to request pediatric data for

certain drugs that are already marketed.

While the precise impact of this

regulatory provision is uncertain, FDA

expects that it would affect no more

than two drugs per year. If the

submission for one of these drugs relied

on data from 100 pediatric patients and

the other from 300 pediatric patients,

the total number of drugs that would

have required additional research

reaches 11 per year and the total

number of pediatric patients about 1,430

per year.

Other costs for pediatric research may

accrue to drugs that ultimately fail to

gain regulatory approval. Although

many drug sponsors would wait until

they are relatively certain that their

product will be shown safe and effective

for the indicated use in adults before

spending substantial resources on

pediatric uses, other sponsors may need

to begin pediatric examinations earlier

to have data included with the new drug

or product licence application. It is

difficult for FDA to judge how much

additional pediatric research would be

directed towards products that are not

approvable. The agency notes, however,

that because only about 65 percent of all

NME’s that enter phase III trials are

eventually approved, the number of

drugs entering phase III trials is about

54 percent greater than the number of

actual approvals (100/65 = 1.54). Since

some, but not all, of these unapprovable

drugs would initiate some pediatric

research, FDA has increased its estimate

of the annual number of affected drugs

and pediatric patients by 30 percent, to

a projected total of 14 drugs and about

1,850 pediatric patients per year.

The agency is aware that forecasting

future trends based on historical data

can be imprecise. For example, over

time, even in the absence of this rule,

the percentage of new drugs with labels

that provide adequate pediatric use

information could change. At this time,

however, FDA is not aware of any

marked trend. Also, the above estimates

ignore those pediatric studies that were

promised, but not yet underway at the

time of drug approval. To the extent that

these commitments are honored, the

above estimates of research attributable

to the regulation are overstated. Finally,

the methodology implies that the

standards used by FDA to judge the

1991–1995 approvals would remain

unchanged. While subsequent change is

possible, FDA does not anticipate that

its present views would differ

substantially. Thus, while

acknowledging substantial uncertainty,

the agency’s cost estimates are based on

the assumption that the proposed rule

would require additional research on

about 14 drugs, involving a total of

1,850 pediatric patients per year.

C. Cost of Studies

The agency finds that the cost of

conducting clinical research with

pediatric patients varies directly with

the size, duration, and complexity of the

clinical research. Although FDA has

little detailed information on the cost to

drug sponsors of conducting research on

clinical patients, one private consulting

firm reports that the costs of hiring

clinical investigators to conduct phase

IV pediatric drug trials ranges from

$300–$500 per patient for studies on

vaccines or fevers to $3,600 and $5,000

per patient for renal disease and

epilepsy, respectively. 3 Similarly, a

number of academic researchers have

reported average costs of from $1,500 to

$3,400 per patient for pediatric trials.

These estimates, however, do not

account for the many administrative,

monitoring, data analysis, and

document preparation tasks that would

be required of a drug sponsor. Since a

published study suggests that a total

accounting of all sponsor costs may be

three times as great as investigator

costs, 4 FDA has assumed that the

average costs of conducting the newly

required studies would range from

$5,000 to $9,000 per pediatric patient.

As a result, the estimated 1,850

additional pediatric patients that would

need to be studied annually suggests

new research costs to the

pharmaceutical industry of between

$9.25 million and $16.65 million per

year.

In addition, the testing of a new drug

in children would sometimes require

the development of a new pediatric

dosage form. (Typically a liquid or

suspension formulation in place of a

tablet or capsule.) Of the 47 drugs

identified in the first category of Table

2 (therapeutically important with some

potential pediatric use), 14 (30 percent)

were available only in tablets or hard

capsules at the time of approval.

(Manufacturers of 4 of these 14 have

since developed oral suspensions.) It

seems reasonable, therefore, to assume

that, of the 14 new drugs per year

estimated to require additional pediatric

research, about 4 might require new

formulations. The agency solicits

comment on the estimate that four new

formulations would be required per

year.

The effort and cost of developing such

formulations could be substantial. Drug

developers and manufacturers would

have to find appropriate solvents and

develop additional data for

demonstrating adequate product

stability, bioavailability, and production

process validation. While such costs

would vary with the particular drug

type, one industry consultant suggests

that per drug laboratory costs could

average from $300,000 to $500,000 and

corresponding regulatory requirements

could bring this figure close to $1

million. Moreover, this estimate

assumes the availability of adequate

preclinical data on animal toxicity and

metabolic rates. Since the proposed rule

permits FDA to waive the requirement

for reformulation where reasonable

attempts have failed, the agency

assumes that the additional costs would

not exceed $1 million apiece for 4
43912 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

5Time, March 1997.

drugs, or an additional $4 million per

year.

Finally, the rule will impose

additional paperwork burdens related to

new label content, postmarket reporting

requirements, and written requests for

deferred submissions and waivers. As

shown above, FDA estimates that these

paperwork activities will require about

4,400 hours annually. At an average

compensation rate of $50 an hour, this

cost amounts to about $220,000 per

year.

In sum, FDA anticipates that the

annual costs of this proposed rule will

total between $13.5 and $20.9 million

per year.

D. Other Impacts

Other potential impacts would occur

if the requirements contributed to

delays in the submittal of NDA’s.

Extended drug development times

would be associated with significant

additional industry costs. FDA has

attempted to minimize the likelihood of

regulatory delays through plans for early

consultation with drug sponsors and a

willingness to consider deferred

submissions for pediatric studies.

However, the agency recognizes the

importance of this issue and solicits

public comment on the best means to

obtain adequate and timely pediatric

information without slowing the process

for bringing new drugs to market. Also,

as noted earlier in this preamble, the

agency is aware that new pediatric

supplements could impose additional

user fees on drug sponsors and is

considering means to alleviate this

added burden. All user fee issues will

be resolved before issuance of the final

rule. Overall, therefore, compared to the

hundreds of millions of dollars typically

required to bring a new drug to market,

FDA believes that the added regulatory

impact imposed by this rule would be

unlikely to threaten the economic

viability of any promising research and

development project.

E. Benefits

This proposed rule is aimed at

addressing two problems associated

with inadequate directions for pediatric

uses of drugs: (1) Avoidable adverse

drug reactions in children, i.e., drug

reactions that occur because of the use

of inadvertent drug overdoses or other

drug administration problems that could

have been avoided with better

information on appropriate pediatric

use; and (2) undertreatment of children

with a potentially safe and effective

drug, because the physician either

prescribed an inadequate dosage or

regimen, prescribed a less effective

drug, or did not prescribe a drug, due

to the physician’s uncertainty about

whether the drug or the dose was safe

and effective in children. Thus, the

primary benefits expected from this

proposed rule are the reductions in

avoidable adverse drug reactions and

undertreatments that would result from

better informing physicians about

whether, and in what dosages, a given

drug was safe and effective for use in

children.

FDA is aware of no systematic data in

the literature that evaluate the

magnitude of harm that results from

inadequate information on the use of

drugs in children, although numerous

anecdotes and case examples exist.

Physicians who care for HIV-infected

children, for example, have expressed

frustration at their inability to treat

these children with drugs known to be

effective in adults, because they lack

information on how to do so safely or

effectively.5 As mentioned previously in

this preamble, history is replete with

examples of children who have died or

suffered other serious adverse effects as

a result of the use of drugs that have not

been tested in children and for which

better, alternative treatments were

available. Many of these adverse events

(e.g., ‘‘gray baby syndrome’’ in babies

treated with chloramphenicol) develop

quickly and would be detected in early

clinical studies.

While FDA could not develop a

quantitative estimate of the potential

benefits of the proposed rule, the agency

attempted to gain some more systematic

insight into the benefits that might

accrue by examining the rate at which

each of 20 NME’s (approved between

1991 and 1995) were mentioned in the

1996 IMS National Drug and

Therapeutics Index (an outpatient drug

use data base). The drugs examined

were all of those that could be analyzed

in this IMS data base, lack full pediatric

labeling, were considered to need

further pediatric studies at the time of

approval, and would have been affected

by the proposed rule. FDA found that,

after adjusting for the prevalence of the

relevant diagnoses in children and

adults, 15 of the 20 drugs were

mentioned less frequently in association

with pediatric treatments than with

adult treatments for the same set of

approved indications. In 11 of these 15

drugs, pediatric treatment mentions

were less than half as frequent.

Although it is not possible to conclude,

based on these data, that children with

those diagnoses are necessarily

undertreated relative to adults, these

data are consistent with the hypothesis

that the lack of pediatric labeling leads

to suboptimal treatment of children.

FDA also examined the number of

adverse drug events (ADE’s) reported to

the agency from 1991 through 1996 for

all NME’s approved during that time. Of

the 25 NME’s associated with the

highest number of ADE’s in children, 8

NME’s (responsible for 1,273 pediatric

ADE’s sufficiently severe to be reported

to FDA) had no labeling for use in

children at all. An additional 5 NME’s

(responsible for 434 pediatric ADE’s)

were labeled for use only in children

age 12 and over. Furthermore, of these

13 NME’s, 11 would probably have been

required to be the subject of further

pediatric studies (or of a justification for

the lack of studies) under the conditions

of this proposed rule if it had been in

place at the time of the drug’s approval.

While it is not possible to conclude that

all (or even most) of these ADE’s would

have been avoided had these drugs been

fully labeled for pediatric use, these

data confirm that there is substantial

pediatric use of drugs not labeled for

such use; that this use is associated with

ADE’s, including serious ADE’s; and

that the improved knowledge and

labeling that would result from this

proposed rule could bring significant

benefits to children treated with these

drugs. The agency solicits information

on any available studies or data related

to the incidence and costs of either

undertreatment or avoidable ADE’s in

pediatric age groups due to the lack of

information on the effects of

pharmaceuticals.

F. Small Entities

FDA believes that this proposed rule

will not have a significant economic

impact on a substantial number of small

entities. New drug development is

typically an activity completed by large

multinational drug firms. FDA reviewed

the size of every company that

submitted the 60 new drug and

biological applications that would likely

have been affected by this rule between

1991 and 1995 (see the first two

categories in Table 1). Over this 5-year

period, only two were for products

sponsored by small businesses as

defined by the Small Business

Administration. Because so few small

firms are likely to be significantly

affected in any given year, the

Commissioner certifies that this rule

will not have a significant economic

impact on a substantial number of small

entities. Therefore, no further analysis is

required under the Regulatory

Flexibility Act. The agency notes,

however, that where pediatric use

qualifies as an orphan indication, some

of these added research costs could be
Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules 43913

reimbursed under the various grant and

tax deduction provisions of the Orphan

Drug Act.

XI. Request for Comments

Interested persons may, on or before

November 13, 1997, submit to the

Dockets Management Branch (address

above) written comments regarding this

proposal. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. Received

comments may be seen in the Dockets

Management Branch between 9 a.m. and

4 p.m., Monday through Friday. Submit

written comments on the information

collection provisions to the Office of

Information and Regulatory Affairs,

OMB, New Executive Office Bldg., 725

17th St. NW., rm. 10235, Washington,

DC 20503, Attn: Desk Officer for FDA.

XII. References

The following references have been

placed on display in the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. Committee on Drugs, American

Academy of Pediatrics, Guidelines for the

Ethical Conduct of Studies to Evaluate Drugs

in Pediatric Populations, Pediatrics,

95(2):286–294, 1995.

2. Pina, L. M., Drugs widely used off label

in pediatrics, Report of the pediatric use

survey working group of the pediatric

subcommittee. Draft.

3. Cote, C. J. et al., ‘‘Is the therapeutic

orphan about to be adopted?’’ Pediatrics,

98(1):118–123, 1996.

4. Koren, G. et al., ‘‘Unexpected alterations

in fentanyl pharmacokinetics in pediatric

patients undergoing cardiac surgery: age

related or disease related?’’ Developmental

Pharmacology Therapeutics, 9:183–191,

1986.

5. Gauntlett, I. S. et al., ‘‘Pharmacokinetics

of fentanyl in neonatal humans and lambs:

Effects of age,’’ Anesthesiology, 69:683–687,

1988.

6. Powell, D. A. et al., ‘‘Chloramphenicol:

New perspectives on an old drug,’’ Drug

Intelligences & Clinical Pharmacy, 16:295–

300, 1982.

7. Oski, F. A. et al., Principles and Practice

of Pediatrics, 2d Edition, J. B. Lippincott Co.,

Philadelphia, p. 864, 1994.

8. Nathan, D. G. et al., Hematology of

Infancy and Childhood, 4th Edition, W. B.

Saunders Co., Philadelphia, p. 92, 1993.

9. Kauffman, R. E., ‘‘Fentanyl, fads, and

folly: who will adopt the therapeutic

orphans?’’ Journal of Pediatrics, 119:588–

589, 1991.

10. McCloskey, J. J. et al., ‘‘Bupivacaine

toxicity secondary to continuous caudal

epidural infusion in pediatric patients,’’

Anesthesia and Analgesia, 75:287–290, 1992.

11. Fisher, D. M. et al., ‘‘Neuromuscular

effects of vecuronium (ORG NC45) in infants

and pediatric patients during N2O halothane

anesthesia,’’ Anesthesiology, 58:519–523,

1983.

12. Agarwal, R. et al., ‘‘Seizures occurring

in pediatric patients receiving continuous

infusion of bupivacaine,’’ Anesthesia and

Analgesia, 75:284–286, 1992.

13. Mevorach, D. L. et al., ‘‘Bupivacaine

toxicity secondary to continuous caudal

epidural infusion in pediatric patients,’’

Anesthesia and Analgesia, 77:13005–1306,

1993.

14. Editorial: ‘‘Cystic fibrosis and colonic

strictures,’’ Journal of Clinical

Gastroenterology, 21(1):2–5, 1995.

15. Olkkola, K. T. et al., ‘‘A potentially

hazardous interaction between erythromycin

and midazolam,’’ Clinical Pharmacology

Therapeutics, 53:298–305, 1993.

16. Hiller, A. et al., ‘‘Unconsciousness

associated with midazolam and

erythromycin,’’ British Journal of

Anaesthesia, 65:826–828, 1994.

List of Subjects

21 CFR Part 201

Drugs, Labeling, Reporting and

recordkeeping requirements.

21 CFR Part 312

Drugs, Exports, Imports,

Investigations, Labeling, Medical

research, Reporting and recordkeeping

requirements, and Safety.

21 CFR Part 314

Administrative practice and

procedure, Confidential business

information, Drugs, Reporting and

recordkeeping requirements.

21 CFR Part 601

Administrative practice and

procedure, Biologics, Confidential

business information.

Therefore under the Federal Food,

Drug, and Cosmetic Act, the Public

Health Service Act, and under authority

delegated to the Commissioner of Food

and Drugs, it is proposed that 21 CFR

parts 201, 312, 314, and 601 be

amended as follows:

PART 201—LABELING

1. The authority citation for 21 CFR

part 201 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 508, 510, 512, 530–542, 701,

704, 721 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 331, 351, 352,

353, 355, 356, 357, 358, 360, 360b, 360gg–

360ss, 371, 374, 379e); secs. 215, 301, 351,

361 of the Public Health Service Act (42

U.S.C. 216, 241, 262, 264).

2. New § 201.23 is added to subpart A

to read as follows:

§ 201.23 Required pediatric studies.

(a) A manufacturer of a drug product,

including a biological drug product, that

is widely used in pediatric patients, or

that is indicated for a very significant or

life threatening illness, but whose label

does not provide adequate information

to support its safe and effective use in

pediatric populations for the claimed

indications may, in compelling

circumstances, be required to submit an

application containing data adequate to

assess whether the drug product is safe

and effective in pediatric populations.

The application may be required to

contain adequate evidence to support

dosage and administration in some or

all pediatric subpopulations, including

neonates, infants, children, and

adolescents, depending upon the known

or appropriate use of the drug product

in such subpopulations. The applicant

may be required to develop a pediatric

formulation for a drug product that is

indicated for a very significant or life

threatening illness for which a pediatric

formulation is necessary, unless the

manufacturer demonstrates that

reasonable attempts to produce a

pediatric formulation have failed.

(b) The Food and Drug

Administration (FDA) may, by order

issued by the Center for Drug Evaluation

and Research (CDER) or Center for

Biologic Evaluation and Research

(CBER) Center Director, after notifying

the manufacturer of its intent and

offering an opportunity for a written

response and a meeting, which may

include an advisory committee meeting,

require a manufacturer to submit an

application containing the information

described in paragraph (a) of this

section within a time specified in the

letter, if FDA finds that:

(1) The drug product is widely used

in pediatric populations for the claimed

indications and the absence of adequate

labeling could pose significant risks to

pediatric patients; or

(2) The drug product is indicated for

a very significant or life threatening

illness, but additional dosing or safety

information is needed to permit its safe

and effective use in pediatric patients.

(c)(1) FDA may grant a full or partial

waiver of the requirements of paragraph

(a) of this section on its own initiative

or at the request of an applicant.

(2) An applicant may request a full

waiver of the requirements of paragraph

(a) of this section if the applicant

certifies that:

(i) Necessary studies are impossible or

highly impractical, e.g., because the

number of such patients is so small or

geographically dispersed; or

(ii) There is evidence strongly

suggesting that the drug product would
43914 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

be ineffective or unsafe in all pediatric

age groups.

(3) An applicant may request a partial

waiver of the requirements of paragraph

(a) of this section with respect to a

specified pediatric age group, if the

applicant certifies that:

(i) The drug product:

(A) Is not indicated for a very

significant or life threatening illness;

and

(B) Is not likely to be used in a

substantial number of patients in that

age group; or

(ii) Necessary studies are impossible

or highly impractical because, e.g., the

number of patients in that age group is

so small or geographically dispersed; or

(iii) There is evidence strongly

suggesting that the drug product would

be ineffective or unsafe in that age

group; or

(iv) The applicant can demonstrate

that reasonable attempts to produce a

pediatric formulation necessary for that

age group have failed.

(4) The request for a waiver must

provide an adequate justification.

(5) FDA shall grant a full or partial

waiver, as appropriate, if the agency

finds that there is a reasonable basis on

which to conclude that one or more of

the grounds for waiver specified in

paragraph (c)(2) or (c)(3) of this section

have been met. If a waiver is granted on

the ground that it is not possible to

develop a pediatric formulation, the

waiver will cover only those pediatric

age groups requiring that formulation. If

a waiver is granted because there is

evidence that the product would be

ineffective or unsafe in pediatric

populations, this information will be

included in the product’s labeling.

(d) If a manufacturer fails to submit a

supplemental application containing the

evidence described in paragraph (a) of

this section within the time specified by

FDA, and the Center Director of CDER

or CBER, under the requirements of

paragraph (c) of this section, has not

granted a waiver, the drug product may

be considered misbranded or an

unapproved new drug.

PART 312—INVESTIGATIONAL NEW

DRUG APPLICATION

3. The authority citation for 21 CFR

part 312 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 701 of the Federal Food, Drug,

and Cosmetic Act (21 U.S.C. 321, 331, 351,

352, 353, 355, 356, 357, 371); sec. 351 of the

Public Health Service Act (42 U.S.C. 262).

4. Section 312.23 is amended by

redesignating paragraph (a)(10)(iii) as

paragraph (a)(10)(iv) and adding new

paragraph (a)(10)(iii) to read as follows:

§ 312.23 IND content and format.

(a) * * *

(10) * * *

(iii) Pediatric studies. If the drug is a

new chemical entity, plans for assessing

pediatric safety and effectiveness.

* * * * *

5. Section 312.47 is amended by

revising paragraph (b)(1)(i) and the

second sentence of paragraph (b)(2) and

by adding a new sentence after the fifth

sentence to paragraph (b)(1)(v) to read as

follows:

§ 312.47 Meetings.

* * * * *

(b) * * *

(1) End-of-Phase 2 meetings—(i)

Purpose. The purpose of an end-ofphase 2 meeting is to determine the

safety of proceeding to phase 3, to

evaluate the phase 3 plan and protocols

and the adequacy of plans to assess

pediatric safety and effectiveness, and to

identify any additional information

necessary to support a marketing

application for the uses under

investigation.

* * * * *

(v) Conduct of meeting. * * * FDA

will also provide its best judgment, at

that time, of the pediatric studies that

will be required for the drug product

and their timing. * * *

(2) ‘‘Pre-NDA’’ meetings. * * * The

primary purpose of this kind of

exchange is to uncover any major

unresolved problems, to identify those

studies that the sponsor is relying on as

adequate and well-controlled to

establish the drug’s effectiveness, to

identify current or planned studies

adequate to assess pediatric safety and

effectiveness, to acquaint FDA reviewers

with the general information to be

submitted in the marketing application

(including technical information), to

discuss appropriate methods for

statistical analysis of the data, and to

discuss the best approach to the

presentation and formatting of data in

the marketing application.* * *

* * * * *

6. Section 312.82 is amended by

revising the last sentence of paragraph

(a) and the second sentence of

paragraph (b) to read as follows:

§ 312.82 Early consultation.

* * * * *

(a) Pre-investigational new drug (IND)

meetings. * * * The meeting may also

provide an opportunity for discussing

the scope and design of phase 1 testing,

plans for studying the drug product in

pediatric populations, and the best

approach for presentation and

formatting of data in the IND.

(b) End-of-phase 1 meetings. * * * The

primary purpose of this meeting is to

review and reach agreement on the

design of phase 2 controlled clinical

trials, with the goal that such testing

will be adequate to provide sufficient

data on the drug’s safety and

effectiveness to support a decision on its

approvability for marketing, and to

discuss the need for, as well as the

design and timing of, studies of the drug

in pediatric patients. * * *

PART 314—APPLICATIONS FOR FDA

APPROVAL TO MARKET A NEW DRUG

OR AN ANTIBIOTIC DRUG

7. The authority citation for 21 CFR

part 314 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 701, 704, 721 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C. 321,

331, 351, 352, 353, 355, 356, 357, 371, 374,

379e).

8. Section 314.50 is amended in

subpart B by redesignating paragraphs

(g) through (k) as paragraphs (h) through

(l) and by adding new paragraphs (d)(7)

and (g) to read as follows:

§ 314.50 Content and format of an

application.

* * * * *

(d) * * *

(7) Pediatric use section. A section

describing the investigation of the drug

for use in pediatric populations,

including an integrated summary of the

information (the clinical pharmacology

studies, controlled clinical studies, or

uncontrolled clinical studies, or other

data or information) that is relevant to

the safety and effectiveness and benefits

and risks of the drug in pediatric

populations for the claimed indications,

and a reference to the full descriptions

of such studies provided under

paragraphs (d)(3) and (d)(5) of this

section.

* * * * *

(g) Pediatric use information—(1)

General requirements. Except as

provided in paragraphs (d)(2) and (d)(3)

of this section, each application for a

new chemical entity shall contain data

that are adequate to assess the safety

and effectiveness of the drug product for

the claimed indications in pediatric

populations, including neonates,

infants, children, and adolescents, and

to support dosing and administration

information for each pediatric

subpopulation for which the drug is safe

and effective. Where the course of the

disease and the effects of the drug are

sufficiently similar in adults and

pediatric patients, FDA may conclude

that pediatric effectiveness can be

extrapolated from adequate and well-
Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules 43915

controlled studies in adults based on

other information, such as

pharmacokinetic studies. Studies may

not have to be carried out in each

pediatric age group, if data from one age

group can be extrapolated to others.

Assessments of safety and effectiveness

required under this section for a drug

product that represents a meaningful

therapeutic benefit over existing

treatments for pediatric patients must be

carried out using appropriate

formulations for each age group(s) for

which the assessment is required.

(2) Deferred submission. FDA may, on

its own initiative or at the request of an

applicant, defer submission of some or

all assessments of safety and

effectiveness described in paragraph

(g)(1) of this section until after approval

of the drug product for use in adults. If

an applicant requests deferred

submission, the request must provide a

certification from the applicant of the

grounds for delaying pediatric studies, a

description of the planned or ongoing

studies, and evidence that the studies

are being or will be conducted with due

diligence and at the earliest possible

time. If FDA determines that there is an

adequate justification for temporarily

delaying the submission of assessments

of pediatric safety and effectiveness, the

drug product may be approved for use

in adults subject to the requirement that

the applicant submit the required

assessments within a specified time.

(3) Waivers—(i) FDA may grant a full

or partial waiver of the requirements of

paragraph (g)(1) of this section on its

own initiative or at the request of an

applicant.

(ii) An applicant may request a full

waiver of the requirements of paragraph

(g)(1) of this section if the applicant

certifies that:

(A) The drug product:

(1) Does not represent a meaningful

therapeutic benefit over existing

treatments for pediatric patients; and

(2) Is not likely to be used in a

substantial number of pediatric patients;

or

(B) Necessary studies are impossible

or highly impractical, e.g., because the

number of such patients is so small or

geographically dispersed; or

(C) There is evidence strongly

suggesting that the drug product would

be ineffective or unsafe in all pediatric

age groups.

(iii) An applicant may request a

partial waiver of the requirements of

paragraph (g)(1) of this section with

respect to a specified pediatric age

group, if the applicant certifies that:

(A) The drug product:

(1) Does not represent a meaningful

therapeutic benefit over existing

treatments for pediatric patients in that

age group; and

(2) Is not likely to be used in a

substantial number of patients in that

age group; or

(B) Necessary studies are impossible

or highly impractical because, e.g., the

number of patients in that age group is

so small or geographically dispersed; or

(C) There is evidence strongly

suggesting that the drug product would

be ineffective or unsafe in that age

group; or

(D) The applicant can demonstrate

that reasonable attempts to produce a

pediatric formulation necessary for that

age group have failed.

(iv) The request for a waiver must

provide an adequate justification.

(v) FDA shall grant a full or partial

waiver, as appropriate, if the agency

finds that there is a reasonable basis on

which to conclude that one or more of

the grounds for waiver specified in

paragraph (g)(2) or (g)(3) of this section

have been met. If a waiver is granted on

the ground that it is not possible to

develop a pediatric formulation, the

waiver will cover only those pediatric

age groups requiring that formulation. If

a waiver is granted because there is

evidence that the product would be

ineffective or unsafe in pediatric

populations, this information will be

included in the product’s labeling.

* * * * *

9. Section 314.81 is amended by

adding two new sentences at the end of

paragraph (b)(2)(i) and a new paragraph

(b)(2)(vi)(c) and by revising paragraph

(b)(2)(vii) to read as follows:

§ 314.81 Other postmarketing reports.

* * * * *

(b) * * *

(2) * * *

(i) Summary. * * * The summary

shall briefly state whether labeling

supplements for pediatric use have been

submitted and whether new studies in

the pediatric population to support

appropriate labeling for the pediatric

population have been initiated. Where

possible, an estimate of patient exposure

to the drug product, with special

reference to the pediatric population

(neonates, infants, children, and

adolescents) should be provided,

including dosage form.

* * * * *

(vi) * * *

(c) Analysis of available safety and

efficacy data conducted or obtained by

the applicant in the pediatric

population and changes proposed in the

label based on this information. An

assessment of data needed to ensure

appropriate labeling for the pediatric

population should be included.

(vii) Status reports. A statement on

the current status of any postmarketing

studies performed by, or on behalf of,

the applicant. The statement shall

include the status of postmarketing

clinical studies in pediatric populations

required or agreed to, e.g., to be

initiated, ongoing (with projected

completion date), completed (including

date), completed and results submitted

to the NDA (including date). To

facilitate communications between FDA

and the applicant, the report may, at the

applicant’s discretion, also contain a list

of any open regulatory business with

FDA concerning the drug product

subject to the application.

* * * * *

PART 601—LICENSING

10. The authority citation for 21 CFR

part 601 continues to read as follows:

Authority: Secs. 201, 501, 502, 503, 505,

510, 513–516, 518–520, 701, 704, 721, 801 of

the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 351, 352, 353, 355, 360, 360c–

360f, 360h–360j, 371, 374, 379e, 381); secs.

215, 301, 351, 352 of the Public Health

Service Act (42 U.S.C. 216, 241, 262, 263);

secs. 2–12 of the Fair Packaging and Labeling

Act (15 U.S.C. 1451–1461).

11. New § 601.27 is added to subpart

C to read as follows:

§ 601.27 Pediatric studies.

(a) General requirements. Except as

provided in paragraphs (b) and (c) of

this section, each application for a new

biological product for which the

applicant has not previously obtained

approval shall contain data that are

adequate to assess the safety and

effectiveness of the product for the

claimed indications in pediatric

populations, including neonates,

infants, children, and adolescents, and

to support dosing and administration

information for each pediatric

subpopulation for which the product is

safe and effective. Where the course of

the disease and the effects of the

product are similar in adults and

pediatric patients, FDA may conclude

that pediatric effectiveness can be

extrapolated from adequate and wellcontrolled effectiveness studies in

adults, based on other information, such

as pharmacokinetic studies. In addition,

studies may not have to be carried out

in each pediatric age group, if data from

one age group can be extrapolated to

others. 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.
43916 Federal Register / Vol. 62, No. 158 / Friday, August 15, 1997 / Proposed Rules

(b) Deferred submission. FDA may, on

its own initiative or at the request of an

applicant, defer submission of some or

all assessments of safety and

effectiveness described in paragraph (a)

of this section until after licensing of the

product for use in adults. If an applicant

requests deferred submission, the

request must provide an adequate

justification for delaying pediatric

studies, a description of the planned or

ongoing studies, and evidence that the

studies are being or will be conducted

with due diligence and at the earliest

possible time. If FDA determines that

there is an adequate justification for

temporarily delaying the submission of

assessments of pediatric safety and

effectiveness, the product may be

licensed for use in adults subject to the

requirement that the applicant submit

the required assessments within a

specified time.

(c) Waivers. (1) FDA may grant a full

or partial waiver of the requirements of

paragraph (a) of this section on its own

initiative or at the request of an

applicant.

(2) An applicant may request a full

waiver of the requirements of paragraph

(a) of this section if:

(i) The product:

(A) Does not represent a meaningful

therapeutic benefit over existing

therapies for pediatric patients; and

(B) Is not likely to be used in a

substantial number of pediatric patients;

or

(ii) Necessary studies are impossible

or highly impractical because, e.g., the

number of such patients is so small or

geographically dispersed; or

(iii) There is evidence strongly

suggesting that the product would be

ineffective or unsafe in all pediatric age

groups.

(3) An applicant may request a partial

waiver of the requirements of paragraph

(a) of this section with respect to a

specified pediatric age group, if:

(i) The product:

(A) Does not represent a meaningful

therapeutic benefit over existing

therapies for pediatric patients in that

age group; and

(B) Is not likely to be used in a

substantial number of patients in that

age group; or

(ii) Necessary studies are impossible

or highly impractical, e.g., because the

number of patients in that age group is

so small or geographically dispersed; or

(iii) There is evidence strongly

suggesting that the product would be

ineffective or unsafe in that age group;

or

(iv) The applicant can demonstrate

that reasonable attempts to produce a

pediatric formulation necessary for that

age group have failed.

(4) The request for a waiver must

provide an adequate justification.

(5) FDA shall grant a full or partial

waiver, as appropriate, if the agency

finds that there is a reasonable basis on

which to conclude that one or more of

the grounds for waiver specified in

paragraph (c) (2) or (3) of this section

have been met. If a waiver is granted on

the ground that it is not possible to

develop a pediatric formulation, the

waiver will cover only those pediatric

age groups requiring that formulation. If

a waiver is granted because there is

evidence that the product would be

ineffective or unsafe in pediatric

populations, this information will be

included in the product’s labeling.

Dated: July 24, 1997.

Michael A. Friedman,

Lead Deputy Commissioner for the Food and

Drug Administration.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 97–21646 Filed 8–13–97; 2:00 pm]

BILLING CODE 4160–01–P