[Federal Register Volume 67, Number 79 (Wednesday, April 24, 2002)]
[Proposed Rules]
[Pages 20070-20072]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-9980]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 312, 314, and 601

[Docket No. 02N-0152]


Obtaining Timely Pediatric Studies of and Adequate Pediatric 
Labelingfor Human Drugs and Biologics

AGENCY: Food and Drug Administration, HHS.

ACTION: Advanced notice of proposed rulemaking.

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SUMMARY: Given the present authorities contained in the Best 
Pharmaceuticals for Children Act (BPCA), which was signed into law 
January 2002, the Food and Drug Administration (FDA) is issuing this 
advanced notice of proposed rulemaking (ANPRM) to solicit comments on 
the most appropriate ways to update the 1998

[[Page 20071]]

``pediatric rule'' so that it can most effectively address FDA's 
interest in timely pediatric studies of and adequate pediatric labeling 
for human drugs and biological products that are used or will be used 
in the treatment of children. FDA is interested in what mechanisms, if 
any, may be necessary to augment the programs described in the BPCA and 
what present authorities, if any, have not proven effective, are now 
redundant, or need to be updated because of the BPCA.

DATES: Submit written or electronic comments on the ANPRM by July 8, 
2002.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Terrie Crescenzi, Office of Pediatric 
Drug Development and Program Initiatives (HFD-960), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, 301-594-7337, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of December 2, 1998, FDA issued the final 
pediatric rule that requires manufacturers to assess the safety and 
effectiveness of certain human drugs and biological products in 
pediatric patients. This rule became effective in April 1999.
    Under this rule, any application for approval of a human drug or 
biologic with a new active ingredient, new indication, new dosage form, 
new dosing regimen, or new route of administration is expected to 
contain data to assess the safety and effectiveness of the drug or 
biologic in pediatric patients. The pediatric rule also contains 
provisions for industry-FDA meetings and early consultation during the 
investigational study of a drug or biologic to facilitate the design 
and timely conduct of adequate pediatric studies of the drug or 
biologic, when appropriate to conduct such studies. In addition, this 
rule also provided FDA with the ability to require the development of a 
pediatric formulation, if necessary, to study a particular pediatric 
group; and to require manufacturers of already marketed human drugs and 
biologics to conduct certain pediatric studies when they seek approval 
for certain other changes to their drug or biologic. Manufacturers may 
obtain from FDA a waiver (e.g., the disease does not occur in the 
pediatric population) or deferral (e.g., pediatric studies to be 
conducted later in the development cycle) of some or all of these 
requirements. Under these provisions, many drugs have been studied in 
children and many companies have built an infrastructure that fosters 
pediatric studies of their products. In addition, under these 
provisions, as new drugs are developed, it has become more routine for 
companies to evaluate and plan appropriately for studying the new 
product in children.
    For certain human drugs and biologics already on the market, under 
certain circumstances, the pediatric rule further authorizes FDA to 
require manufacturers to submit an application containing data adequate 
to assess whether the product is safe and effective in pediatric 
populations, even when the company has not submitted an application for 
certain other changes to their drug or biologic. FDA has, to date, not 
invoked this latter aspect of the pediatric rule.
    After FDA issued its proposed pediatric rule (62 FR 43900, August 
15, 1997), but before it issued the final pediatric rule, Congress 
passed the Food and Drug Administration Modernization Act of 1997 
(FDAMA). This act included a provision that authorized specific market 
exclusivity incentives to manufacturers who voluntarily conducted and 
submitted to FDA pediatric studies of their drugs as requested by FDA 
and who met certain statutory criteria. This provision has resulted in 
numerous pediatric studies of many of the drugs to which it applied. 
Nonetheless, when FDA issued the pediatric rule, the agency indicated 
that the FDAMA provisions left some significant gaps in obtaining 
pediatric studies to provide safety and effectiveness labeling 
information for certain products. Examples of these ``gap'' products 
include already marketed drugs no longer under patent or market 
exclusivity protection, certain antibiotics, biological products 
approved under section 351 of the Public Health Service Act (PHSA), and 
products for which the manufacturers simply choose not to perform 
pediatric studies requested by FDA, despite the exclusivity incentive 
to do so. The exclusivity incentive provision of FDAMA, as written, 
does not to apply to biological products approved under section 351 of 
the PHSA, certain antibiotics, and products that did not have specific 
existing patent or exclusivity protection that could be prolonged under 
this authority. In addition, the exclusivity provision could only 
effectively be employed once with respect to an active ingredient. 
Thus, if further studies in certain groups of children (for example, 
neonates) were needed at a later date, the exclusivity provision was 
restricted and thus did not provide an economic incentive for the 
additional needed studies. Also, the exclusivity incentive provisions 
of FDAMA expired on January 1, 2002.
    On January 4, 2002, the President signed into law the BPCA. This 
legislation both reauthorizes the exclusivity incentive program enacted 
originally in FDAMA (essentially without any change relevant here) and 
establishes an additional mechanism for obtaining information on the 
safe and effective use of drugs in pediatric patients. The new BPCA 
mechanism consists primarily of authorizing several National Institutes 
of Health (NIH) funding mechanisms, including the NIH Foundation, as 
vehicles for funding, using both public and private funds, studies of 
certain drugs under certain circumstances if the manufacturers of those 
drugs decline to conduct the requested pediatric studies. BPCA also 
provides a mechanism for including information from such studies in the 
label of pediatric products. Because it involves paying others to do 
the studies rather than having to litigate with a company to force it 
to conduct needed studies, some have argued that this new BPCA 
mechanism is a more cost- and time-efficient way of achieving the goal 
of adequate pediatric safety and efficacy labeling of these ``gap'' 
products than are some of the provisions of the pediatric rule. Others 
point out that while these NIH funding mechanisms may be used to 
contract for pediatric studies of certain human drugs, the provision of 
BPCA for awarding study contracts does not extend to awarding contracts 
to study human biologics and certain antibiotics. In addition, the 
public funding of these mechanisms is dependent on yearly congressional 
appropriations and the private donations are purely voluntary. Whether 
funds appropriated for such studies will be adequate to ensure that 
studies are performed and data submitted for all needed drug products 
remains uncertain. By statute, the BPCA is to sunset in 2007. Because 
of these uncertainties in funding, limitations on the products covered, 
and the lack of required early planning regarding pediatrics in a 
drug's development process, some have argued that without the 
``requirement'' provisions of the pediatric rule, FDA will not have the 
authority it needs to ensure that all medicines used in children of all 
ages

[[Page 20072]]

are indeed safe and effective for that use.
    Given the present authorities contained in the BPCA and the 
pediatric rule, this ANPRM is intended to solicit comments on the most 
appropriate ways to balance FDA's interest in timely pediatric studies 
of and adequate pediatric labeling for human drugs and biological 
products that are used or will be used in the treatment of children and 
FDA's interest in not imposing unnecessary human drug and biologic 
study requirements. FDA is particularly interested in what mechanisms, 
if any, may be necessary to augment the programs described in the BPCA 
and what present authorities, if any, are perhaps now redundant because 
of the BPCA.
    Therefore, FDA is soliciting comments on these issues. The agency 
is particularly interested in the relationship between the approach to 
acquiring pediatric labeling information promulgated in the pediatric 
rule, and the approaches authorized in the BPCA. While FDA is 
interested in hearing any comments the public would like to submit on 
this issue, questions of specific interest to FDA include:
    1. What changes to the pediatric rule, if any, would be necessary 
to integrate the BPCA and the pediatric rule more effectively?
    2. How would the criteria used by NIH and FDA under section 3 of 
the BPCA to request studies of already approved drugs relate to the 
standards promulgated in the pediatric rule and described in 21 CFR 
201.23, 314.55, and 601.27 for requiring pediatric labeling for certain 
drugs and biological products? Which criteria are more appropriate for 
determining when studies are conducted?
    3. What provisions, if any, of the BPCA could apply to biological 
products regulated under section 351 of the PHSA?
    4. How does the provision in section 3 of the BPCA providing for a 
recommendation for a formulation change relate to the pediatric rule 
provision stating that in certain cases a sponsor may be required to 
develop a pediatric formulation? Should pediatric formulations be 
required in certain cases?
    Resolution of these and other questions will be required before FDA 
can determine the optimum approach to ensuring that human drugs and 
biologics used in children have adequate information regarding the safe 
and effective use of these products in pediatric patients.

II. Requests for Comments

    Interested persons may submit to the Dockets Management Branch (see 
ADDRESSES) written or electronic comments regarding this document by 
July 8, 2002. 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 Docket Management Branch 
between 9 a.m. and 4 p.m., Monday through Friday.
    This document was reviewed by the Office of Management and Budget 
under Executive Order 12866.

    Dated: April 18, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-9980 Filed 4-19-02; 12:00 pm]
BILLING CODE 4160-01-S