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

SUMMARY: The Food and Drug Administration (FDA) is 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 well-founded 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

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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 (g)/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

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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. Fifty-six 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 well-controlled 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-before-approved) biological product

to submit, before approval, safety and effectiveness information on

relevant pediatric age groups for the claimed indications. The

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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 Sec. 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 pre-BLA meeting. Of these, the pre-IND meeting, the ``end of

phase 1'' meeting, the IND submission, the IND annual report, the ``end

of phase 2'' meeting, and the pre-NDA 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 Secs. 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

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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 life-threatening 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 Secs. 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 Sec. 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, Secs. 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,

anti-malarial agents, are not recommended in young children due to

concerns about cartilage and bone development).

[[Page 43905]]

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.

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

\1\ IMS, National Disease and Therapeutic Index, IMS America;

Plymouth Meeting, PA.

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

5. Section 314.50(d)(7)--Pediatric Use Section of Application

Under proposed Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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

[[Page 43906]]

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 Secs. 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 well-designed, controlled clinical trials'' (Ref. 1 at p.

286). The ethical guidelines currently in place are designed to

[[Page 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

Secs. 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 Sec. 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.

[[Page 43908]]

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

[[Page 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 Sec. 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 Sec. 314.50(g)(1)); (3) Analyses of data on pediatric safety

and effectiveness in NDA's (proposed Sec. 314.50(d)(7)); (4)

Postmarketing reports of analyses of data on pediatric safety and

effectiveness (proposed Sec. 314.81(b)(2)(vi)(C)); (5) Postmarketing

reports on patient exposure to certain marketed drug products, analyzed

and age (proposed Sec. 314.81(b)(2)(i)); (6) Postmarketing reports on

labeling changes initiated in response to new pediatric data (proposed

Sec. 314.81(b)(2)(vi)(C)); and (7) Postmarketing reports on the status

of required postapproval studies in pediatric patients (proposed

Sec. 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

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

Annual

Number of frequency Total Hours per

CFR section respondents per annual response Total hours

response responses

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

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

[[Page 43910]]

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.

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

\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.

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

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]

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

Number Percent

of of

Pediatric labeling status approved approved

drugs 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

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

\1\ Pediatric 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

[[Page 43911]]

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 x 50 patients + 23 drugs x 100 patients + 7 drugs x 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.

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

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

\4\ Thomas Hill, ``Calculating the Cost of Clinical Research,''

Scrip Magazine, p. 29, March 1994.

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

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

[[Page 43912]]

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.

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

\5\ Time, March 1997.

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

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

[[Page 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 Sec. 201.23 is added to subpart A to read as follows:

Sec. 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

[[Page 43914]]

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:

Sec. 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:

Sec. 312.47 Meetings.

* * * * *

(b) * * *

(1) End-of-Phase 2 meetings--(i) Purpose. The purpose of an end-of-

phase 2 meeting is to determine the safety of proceeding to phase 3, to

evaluate the phase 3 plan and protocols and the adequacy of 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:

Sec. 312.82 Early consultation.

* * * * *

(a) Pre-investigational new drug (IND) meetings. * * * The meeting

may also provide an opportunity for discussing the scope and design of

phase 1 testing, plans for studying the drug product in pediatric

populations, and the best approach for presentation and formatting of

data in the IND.

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

meeting is to review and reach agreement on the design of phase 2

controlled clinical trials, with the goal that such testing will be

adequate to provide sufficient data on the drug's safety and

effectiveness to support a decision on its approvability for marketing,

and to discuss the need for, as well as the design and timing of,

studies of the drug in pediatric patients. * * *

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:

Sec. 314.50 Content and format of an application.

* * * * *

(d) * * *

(7) Pediatric use section. A section describing the investigation

of the drug for use in pediatric populations, including an integrated

summary of the information (the clinical pharmacology studies,

controlled clinical studies, or uncontrolled clinical studies, or other

data or information) that is relevant to the safety and effectiveness

and benefits and risks of the drug in pediatric populations for the

claimed indications, 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-

[[Page 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:

Sec. 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 Sec. 601.27 is added to subpart C to read as follows:

Sec. 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 well-controlled 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.

[[Page 43916]]

(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