History of Pediatric Studies, Rule, Legislation and Litigation

FDA's Pediatric Rule

  1. Early Rule. In 1994 FDA issued a regulation requiring manufacturers of marketed drugs to survey existing data and to determine whether the data were sufficient to support additional pediatric use information in the drug's labeling. If the data existed, manufacturers were encouraged to submit a supplemental NDA seeking a labeling change. If the information was insufficient, the rule required the labeling of the drug to state that "safety and effectiveness in pediatric patients have not been established."

  2. FDA Pediatric Rule. Stating that the voluntary approach under the 1994 rule did not substantively increase the number of products with adequate pediatric labeling, FDA proposed (August 1997) and finalized (December 1998) a much more regulatory approach to pediatric labeling. These regulations establish the presumption that all not-yet-approved new drugs and biological products must be studied in pediatric patients, and assert the authority to require pediatric studies for currently marketed new drugs and biologics. Under the rule, pediatric safety and effectiveness data must be included not only in NDAs and BLAs but also in supplemental applications for new active ingredients, new indications, new dosage forms, new dosing regimens, and new routes of administration. However, manufacturers may obtain waivers from the pediatric studies requirement if the 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.

    For currently marketed drugs and biological products, the rule authorizes FDA to require pediatric studies if (1) they are used for a labeled indication in a substantial number of pediatric patients (defined as 50,000 or more) and the absence of adequate labeling could pose a significant risk to pediatric patients, or (2) the product would provide a meaningful therapeutic benefit over existing treatments of pediatric patients and the absence of labeling could impose significant risks.

    Waivers are available for marketed drugs if (1) pediatric studies are impossible or highly impractical (e.g. the patient populations are small or geographically diverse) or (2) evidence suggests strongly that the product would be ineffective or unsafe in pediatric populations. There is also opportunity for partial waiver for a specified pediatric age group. Although in its preamble to the final rule FDA estimated that approximately two marketed drugs per year would be required to submit pediatric studies, to our knowledge, this portion of the rule has never been used by the agency


  • Pediatric Studies Incentive. In November 1977, several months after FDA proposed the Pediatric Rule, FDAMA was enacted. Section III of FDAMA established a program of incentives for the conduct of studies in pediatric populations (Section 505A of the Federal Food, Drug and Cosmetic Act). The incentives apply to both investigational and approved new drugs (but not biological products) that are eligible for patent term extension under the 1984 Hatch-Waxman law, or the market exclusivity provisions of the 1984 law or the Orphan Drug Act. One of these provisions may be extended by an additional six months for products for which pediatric studies are conducted under the terms of Section 505A. In an effort to reconcile the new incentive program with what was then the proposed Pediatric Rule, the law provided that any study required by regulations would be deemed to satisfy the requirements for market exclusivity if other relevant requirements of Section 505A were met.

    The program established under Section 505A expired effective January 1, 2002.



  • The Best Pharmaceuticals for Children Act (BPCA). Enacted on January 4, 2002, the BPCA makes several important changes to the Section 505A incentive program:

    1. Extension. It extends, for an additional five years, the incentive program.
    2. Studies of Already-Marketed Drugs. It establishes an elaborate, public program for pediatric studies of already-marketed drugs that do not have market exclusivity, but for which:
      1. there is an approved ANDA, or a submitted ADNA that could be approved (ADNA provisions require that patents on pioneers have expired or have been declared invalid);
      2. there is no patent protection or market exclusivity protection (presumably, either under Hatch-Waxman or the Orphan Drug Act); or
      3. there is market exclusivity for the drug but FDA has referred the drug for inclusion on the list under new provisions of the incentive program (discussed in paragraph (f) below) because the NDA holder does not agree to a request for pediatric studies, and the request has been referred for the conduct of studies to the Foundation for the NIH, but the Foundation certifies that it does not have funds available to conduct the study.
    3. Request for Studies; NIH List. The BPCA authorizes FDA to request pediatric studies of marketed drugs in categories described in (b)(i) and (b)(ii) upon a determination that "information relating to the use… in the pediatric population may produce health benefits in that population." It requires the National Institutes of Health (in consultation with FDA) to develop, prioritize and publish an annual list of approved drugs in the two categories for which additional studies are needed to assess safety and effectiveness in the pediatric population. It authorizes the Secretary (via NIH) to award contracts to conduct pediatric studies of drugs on the annual list.
    4. Conduct of Studies.
      1. BPCA authorizes FDA (in consultation with NIH) to issue a written request for the conduct of pediatric studies to holders of approved NDAs and ANDAs for drugs on the NIH list. The request must include "a timeframe for negotiations for an agreement."
      2. If there is no response to the request within 30 days, the NIH must publish a request for contract proposals to conduct the pediatric studies. NDA and ANDA holders who did not respond to the request to conduct the studies are not eligible to respond to the contract proposal. Following their completion, reports of studies, including all data generated, must be submitted to NIH and FDA. The reports (other than trade secret information) must be made public and assigned an FDA docket number; written comments on them may be submitted.
      3. During the 180-day period after submission of a report, FDA is to negotiate label changes with holders of approved applications, place in the FDA docket a copy of the report and requested labeling changes, and publish in the Federal Register a summary of the report and copy of requested label changes. If, following the 180-day period the NDA and ANDA holder do not agree to labeling changes requested by FDA, then FDA must refer the request to FDA's Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee. Within 90 days after such referral, the subcommittee must recommend appropriate changes to the FDA; 30 days after receiving such recommendations, the Commissioner must, if appropriate, make a request for a label change to each NDA/ADNA holder. If an application holder fails to agree to the request within 30 days, FDA may deem the drug to be misbranded. Provision is also made for FDA to recommend nonbinding formulary changes to application holders, based on recommendations under pediatric studies funded by contract.
    5. Request by FDA for Pediatric Studies of Approved Drugs . The BPCA also amends the Section 505 incentive program to stimulate pediatric studies of drugs with approved NDAs. Under the 1997 law, FDA is authorized to request that an NDA holder conduct pediatric studies on its drug, but the holder need not respond to the request. Under the new law as amended by BPCA, the NDA holder must respond to a written request by FDA for pediatric studies within 180 days; the holder must indicate when such studies will be initiated, or that it does not agree to the request. If the holder does not agree, and FDA concludes that there is a continuing need for pediatric information relating to the use of the drug, then the "drug" is to be referred to the Foundation for the National Institutes of Health. (The Foundation is a nonprofit entity established several years ago under the PHS Act that may receive gifts in order to support the mission of the NIH. BPCA charges it with the specific authority to collect funds for pediatric studies on drugs referred by FDA, and authorizes donations to be designated for pediatric studies.) On referral of the drug, the Foundation must issue a proposal to award a grant to conduct the requested studies or certify that it does not have funds to do so. Upon such certification, the drug must be referred to the annual list of approved drugs needing studies published by NIH, and the process involving potential agreements between FDA and the NDA holder, requests for contract proposals and efforts to negotiate label changes (described above) apply.
    6. Appropriations. Appropriations of $200 million for FY 2002, and sums as necessary for the next five years are authorized to carry out the program--presumably most of the appropriations would be for contracts.


  • Legal Challenge to FDA Pediatric Rule.
    1. In 2000, the Association of Physicians and Surgeons sued FDA, asking that the agency's pediatric rule be invalidated, arguing that FDA had no statutory authority to promulgate the rule.
    2. Following the enactment of BPCA, plaintiffs filed copies of the Act with the court, suggesting that the procedure established by Congress for pediatric studies of approved drugs-whether or not the drugs are eligible for patent term or market exclusivity protection-delineated Congressional authority in this area.
    3. In March 2002, FDA requested a stay of all proceedings for 8 weeks and announced that FDA intended to stay the Pediatric Rule for two years "to provide time to asses both how BPCA and the Pediatric Rule relate to one another and whether… the Pediatric Rule remains necessary." In response to complaints by Senate authors of the BPCA, in April HHS announced that it would continue to enforce the Pediatric Rule. FDA quickly published an Advanced Notice of Proposed Rulemaking soliciting comments on the "most appropriate ways to update" the rule.
    4. On October 17, 2002, Judge Henry H. Kennedy of the U.S. District Court for District of Columbia struck down FDA's pediatric rule. Judge Kennedy concluded that Congress had not granted FDA authority to promulgate the rule and that the recently-enacted BPCA indicated that Congress preferred "an incentive scheme" to the rule's "command and control" approach. As a result, he struck down the rule and enjoined FDA from its enforcement.



  • Current Status
    1. The pediatric incentive program, which provides 6 months of additional marketing exclusivity for approved drugs (not biological products) is in effect; the law sunsets on January 1, 2007.
    2. The other provisions of BCPA, which authorize FDA to request pediatric studies of already-marketed drugs with NIH and FDA involvement, and studies by others if the manufacturer refuses, remain in effect.
    3. FDA's 1997 Pediatric Rule, which was applicable to both drugs and biological products, is not in effect.