`[Federal Register Volume 62, Number 158 (Friday, August 15, 1997)]
[Proposed Rules]
[Pages 43900-43916]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-21646]



[[Page 43899]]

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Part V





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Parts 201, 312, 314, and 601



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

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

[[Page 43900]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 312, 314, and 601

[Docket No. 97N-0165]
RIN 0910-AB20


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

SUMMARY: The Food and Drug Administration (FDA) is proposing new 
regulations requiring pediatric studies of certain new drug and 
biological products. Many new drugs and biological products represent 
treatments that are, at least at times, the best available treatment 
for children, but most of them have not been adequately tested in the 
pediatric subpopulation. As a result, product labeling frequently fails 
to provide directions for safe and effective use in pediatric patients. 
The proposed rule would attempt to partially address this lack of 
pediatric use information by requiring that manufacturers of a limited 
class of new drugs and new biological products provide sufficient data 
and information to support directions for pediatric use for the claimed 
indications, before or soon after approval. Manufacturers of a limited 
class of marketed drugs and biologics would also in compelling 
circumstances have to provide such data. This proposed rule is part of 
a comprehensive effort to increase the number of new drugs and 
biological products with clinically significant use in children that 
carry adequate labeling for use in that subpopulation.

DATES: Written comments and recommendations by November 13, 1997. 
Written comments on the information collection provisions should be 
submitted by September 15, 1997. For further information of the 
agency's implementation plan, see section VII of SUPPLEMENTARY 
INFORMATION in this document.

ADDRESSES: Submit written comments and recommendations to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Submit written comments on 
the information collection provision to the Office of Information and 
Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., 
rm. 10235, Washington, DC 20503, Attn: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Paula Botstein, Center for Drug 
Evaluation and Research (HFD-103), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-3144, and Ann M. Witt, 
Office of Policy (HF-22), Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, 301-827-5321.

SUPPLEMENTARY INFORMATION:

I. Introduction

    Children are subject to many of the same diseases as adults, and 
are, by necessity, often treated with the same drugs and biological 
products as adults. According to the American Academy of Pediatrics, 
however, only a small fraction of all drugs and biological products 
marketed in the United States have had clinical trials performed in 
pediatric patients and a majority of marketed drugs are not labeled for 
use in pediatric patients or for use in specific pediatric age groups 
(Ref. 1). A recent FDA survey similarly concluded that most products 
that are indicated for diseases occurring in both adults and children 
have very little information about pediatric use in their labeling 
(Ref. 2). For some products, including vaccines and antibiotics, 
pediatric use information is generally adequate. Many drugs used in the 
treatment of both common childhood illnesses and more serious 
conditions, however, carry little information about use in pediatric 
patients. Less than half the drugs approved for treatment of human 
immunodeficiency virus (HIV) infection or accompanying opportunistic 
infections carry any pediatric safety or effectiveness information, 
and, of those that do, the data are often incomplete and limited to 
certain pediatric age groups. Pediatric labeling is also inadequate for 
such drug classes as steroids, drugs to treat gastrointestinal 
problems, prescription pain medications, antihypertensives, 
antidepressants, antirheumatic drugs, and drugs to treat ulcerative 
colitis.
    Safety and effectiveness information for some pediatric age groups 
is particularly sparse. For example, there is almost no information on 
use in patients under 2 years of age for most drug classes (Ref. 2).
    Many of the drugs and biological products most widely used in 
pediatric patients carry disclaimers stating that safety and 
effectiveness in pediatric patients have not been established (Refs. 2 
and 3). Based on 1994 data from IMS America, Ltd., a research firm that 
provides data on prescription drug usage, FDA compiled a list of the 10 
drugs that were most widely prescribed for pediatric patients, on an 
outpatient basis, despite inadequate pediatric labeling. In each case, 
the label lacked any use information for the age group prescribed to, 
or the information was inadequate. The drugs were: Albuterol inhalation 
solution for nebulization for treatment of asthma (prescribed 1,626,000 
times to pediatric patients under 12); Phenergan for treatment of 
allergic reactions (prescribed 663,000 times to pediatric patients 
under 2); ampicillin injections for treatment of infection (prescribed 
639,000 times to pediatric patients under 12); Auralgan otic solution 
for treatment of ear pain (prescribed 600,000 times to pediatric 
patients under 16); Lotrisone cream for treatment of topical infections 
(prescribed 325,000 times to pediatric patients under 12); Prozac for 
treatment of depression and obsessive compulsive disorder (prescribed 
349,000 times to pediatric patients under 16, including 3,000 times to 
infants under 1); Intal for treatment of asthma (solution prescribed 
109,000 times to pediatric patients under 2; aerosol prescribed 399,000 
times to pediatric patients under 5); Zoloft for treatment of 
depression (prescribed 248,000 times to pediatric patients under 16); 
Ritalin for treatment of attention deficit disorders and narcolepsy 
(prescribed 226,000 times to pediatric patients under 6); Alupent for 
treatment of asthma (184,000 times to pediatric patients under 6). 
These 10 drugs were thus prescribed over 5 million times in 1 year for 
pediatric patients in age groups for which the label carried a 
disclaimer or lacked adequate use information (Ref. 2).
    The absence of pediatric labeling information may sometimes require 
the physician caring for children to choose between prescribing drugs 
without 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

[[Page 43901]]

demographic subpopulation with many similarities to the adult 
population. In most cases, drugs and biological products behave 
similarly in demographic subgroups, including age and gender subgroups, 
even though there may be variations because of differences in, for 
example, pharmacokinetics. As FDA has already stated in a Federal 
Register document, where the disease and the drug's effects are similar 
in adults and children, adequate and well-controlled trials may not be 
needed in children to establish pediatric use information (59 FR 64240, 
December 13, 1994) (hereinafter referred to as the 1994 rule).
    Although use of a drug in children is no longer considered a new 
indication (with the exception of specific ``pediatric indications''), 
the development of additional information in pediatric patients is 
needed to provide appropriate dosing recommendations. Correct pediatric 
dosing cannot necessarily be extrapolated from adult dosing information 
using an equivalence based either on weight milligrams per kilogram 
(mg/kg) or body surface area (mg/square meter (m2)). 
Potentially significant differences in pharmacokinetics may alter a 
drug's effect in pediatric patients. The effects of growth and 
maturation of various organs, maturation of the immune system, 
alterations in metabolism throughout infancy and childhood, changes in 
body proportions, and other developmental changes may result in 
significant differences in the doses needed by pediatric patients and 
adults. For example, studies have shown that fentanyl, a potent opioid, 
widely used in anesthetic management of infants and small children but 
not labeled for use in pediatric patients under 2 years of age, 
demonstrates differences in clearance between the neonatal period and 2 
or more months of age due to improving hepatic blood flow and hepatic 
microsomal maturation (Ref. 4). Comparable doses in adults and neonates 
(calculated on a microgram (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`