US Pharm. 2019;44(5):29-31.

In view of this issue’s focus on Pediatric and Adolescent Health, reviewing federal legislation related to the development of drug products for use by children will advance readers’ understanding in that area. That legislation includes the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA). The two acts, which are part of the Federal Food, Drug, and Cosmetic Act (FDCA), apply to pediatric drug studies and labeling. The BPCA extends market exclusivity in exchange for certain pediatric studies, while the PREA requires pediatric assessments of the safety and effectiveness of a drug or biological product used by children.1

Pediatric Research Equity Act

The PREA allows the FDA to require pediatric assessments by a pharmaceutical manufacturer or company of a drug or biological product in certain circumstances. The FDA may require pediatric assessments when an application or a supplement to an application is submitted for a new active ingredient, a new indication, a new dosage form, a new dosage regimen, or a new route of administration. In those circumstances, the assessment may be required when the FDA finds that the drug or biological product is used for a substantial number of pediatric patients for the labeled indications and when adequate pediatric labeling could confer a benefit on pediatric patients. The assessment may be required when the FDA finds that there is reason to believe that the drug or biological product represents a meaningful therapeutic benefit over existing therapies for pediatric patients for one or more of the claimed indications or that the absence of adequate pediatric labeling could pose a risk to pediatric patients.2

The PREA does not apply to a drug or biological product with an orphan designation unless the FDA requires otherwise by regulation. In addition, the PREA does not apply to an abbreviated new drug application (ANDA) for a generic drug that is a duplicate version of a previously approved drug product. However, an ANDA submitted under an approved suitability petition pursuant to section 505(j)(2)(C) of the FDCA for changes in dosage form, route of administration, or a new active ingredient in combination products is subject to the potential pediatric assessment requirements under PREA.3

Stringent Data Requirements

The pediatric assessments must include data using appropriate formulations for each age group for which the assessment is required and that are adequate to assess the safety and effectiveness of the drug or the biological product for the claimed indications in all relevant pediatric subpopulations. The assembled data also must be adequate to support dosing and administration for each pediatric subpopulation for which the drug or the biological product is safe and effective.

If the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, the FDA may conclude that pediatric effectiveness can be extrapolated from adequate, well-controlled studies in adults, usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies. A study may not be needed in each pediatric age group if data from one age group can be extrapolated to another age group. Under the PREA, the FDA has the authority to grant full or partial waivers of the requirement to provide a pediatric assessment or to defer submission of some or all of the required pediatric assessment.4

The results of the pediatric assessments, whether positive or negative, are included in the product labeling. If the FDA determines that a pediatric assessment does or does not demonstrate that the applicable drug is safe and effective in pediatric populations or subpopulations, including whether such assessment results are inconclusive, the FDA must order the product label to include information about the results of the assessment and a statement of the FDA’s determination.5

Best Pharmaceuticals for Children Act

The BPCA incentivizes pharmaceutical companies to voluntarily conduct pediatric studies for therapies with potential public-health benefits for children by providing pediatric market exclusivity under certain circumstances when the FDA determines that information relating to the use of a new drug (prior to approval of an application submitted under Section 505(b)(1) of the FDCA) in the pediatric population may produce health benefits in that population.

Under the BPCA, the FDA may request a pharmaceutical company to conduct a pediatric study that relates to more than one use of a drug and addresses approved and unapproved uses. In this manner, the BPCA differs from the PREA, under which the FDA may require pediatric assessments related to approved indications. If valproic acid or divalproex sodium is submitted for a new approval to treat seizures in adults, for example, the PREA may require a pediatric assessment and submission for a new approval to treat seizures in children or the same indication. However, under the BPCA, the FDA may request studies for migraine, migraine prophylaxis, and for the treatment of mania since the drug also treats those indications. Under the BPCA, the pharmaceutical company also may submit a pediatric study request that summarizes all of the studies the company would perform to qualify for market exclusivity. The FDA may agree with the company’s request or require other studies for another indication or for nonclinical studies.6

A pharmaceutical company that agrees to the request for a pediatric study must provide to the FDA, at the same time as the submission of the study report, all of the relevant postmarket adverse event reports related to the drug and available prior to submission of the report.7

Pediatric Market Exclusivity

For drugs protected by patent or other extensions, the FDA may offer pharmaceutical companies an additional 6 months of pediatric market exclusivity in exchange for the pediatric studies requested by the FDA.8 This BPCA mechanism is available for drugs with applications not yet approved as well as drugs already on the market, except when the patent or patent extension is due to expire in fewer than 9 months. Positive study results are not required for the pharmaceutical company to receive pediatric exclusivity. If the company conducts all studies of a drug for a certain indication, the company may get pediatric exclusivity—even if efficacy is not demonstrated or a new safety signal is not identified. The information from these studies is included in the labeling.9

The BPCA also establishes a research fund at the National Institutes of Health (NIH) in connection with drugs that are off patent and requires the FDA to list drugs for which pediatric studies are needed and to assess their safety and efficacy. If funds are available through the NIH, then the FDA must issue a grant to conduct the studies. If funds are not available, then the FDA must refer the drug for inclusion on the list. When the pharmaceutical company declines a written request by the FDA to conduct a study, the FDA may refer the drug to the NIH Foundation for a pediatric study.10


The PREA and BPCA represent a dual approach toward the development of drugs for pediatric use. Assessments of pediatric safety and efficacy may be required by the FDA under the PREA in connection with approved indications, while the BPCA seeks to induce pharmaceutical companies to conduct pediatric studies by offering extended pediatric market exclusivity. The two statutes thus operate in tandem to direct product labeling for indications and further use of drug products in the pediatric population.

The information in this article is general in nature and is not intended to provide legal or other professional advice.


1. Office of New Drugs Module, PREA vs. BPCA. Accessed April 9, 2019. See also Thaul S, FDA’s Authority to Ensure that Drugs Prescribed to Children are Safe and Effective, Congressional Research Service Report RL33986; 2012: p. 5. Accessed April 9, 2019.
2. Pediatric Research Equity Act of 2007, 21 U.S.C. §§355c(a) and (b) (2017). In addition, the PREA was amended in 2017 to require that any person that submits an original application for a new active ingredient must investigate and submit a report as to whether the drug or biological product is intended for the treatment of adult cancer and is substantially relevant to the growth or progression of a pediatric cancer. Pediatric Research Equity Act of 2007, 21 U.S.C. §355c(a)(1)(b).
3. The Orphan Drug Act (ODA) provides pharmaceutical companies tax credits and other incentives to develop drugs for rare diseases and conditions. Under the ODA, the FDA may designate a drug product as an orphan drug if it is intended to treat a rare disease or condition that affects fewer than 200,000 individuals in the U.S., or for which there is no reasonable expectation that the cost of developing and making a drug product available in the U.S. for the treatment of the disease or condition will be recovered from sales of the product in the U.S. See 21 U.S.C. §§360aa-360ee; 21 C.F.R. Part 316. If the disease in the pediatric population is in fact a different disease from the disease in the adult population and the prevalence of that pediatric population is fewer than 200,000, the disease in the pediatric population is itself a rare disease for which a drug may be eligible for orphan-drug designation. If the prevalence of a disease is 200,000 or more, a drug may still be eligible for orphan designation for a valid orphan subset of the disease. For example, if the prevalence of the pediatric population affected by the disease is fewer than 200,000 and if it would not be appropriate to use the drug in the adult population, the drug may be eligible for orphan designation for the pediatric population as an orphan subset. FDA, Clarification of Orphan Designation of Drugs and Biologics for Pediatric Subpopulations of Common Diseases: Guidance for Industry; July 2018: p. 2. Accessed April 9, 2019. In that guidance, however, the FDA announced that it does not expect to grant any additional pediatric-subpopulation designations that may exempt the pharmaceutical company from conducting the pediatric studies normally required under the PREA when seeking approval of the adult indication of the same common disease. Id. at p. 5. See also 21 U.S.C. §355c(k). See FDA, Guidance for Industry: How to Comply with the Pediatric Research Equity Act (Draft Sept. 2005). Accessed April 8, 2019.
4. 21 U.S.C. §§355c(a)(2) and (b)(2).
5. 21 U.S.C. §355c(g)(2).
6. 21 U.S.C. §355a(d)(1)(B). See FDA Guidance regarding BPCA, CDER WORLD, Pediatric Regulations: Best Pharmaceuticals for Children Act, pp. 1-2. Accessed April 9, 2019.
7. 21 U.S.C. §355a(d)(2)(B).
8. Lengthening the time period for market exclusivity delays the time before a generic version of a drug may be granted marketing approval by the FDA. Exclusivity information is posted in the FDA’s Orange Book as the official vehicle for dissemination of exclusivity information. FDA Frequently Asked Questions on Patents and Exclusivity: Nos. 1-7. Accessed April 9, 2019.
9. See 21 U.S.C. §355a(b) and (c); see FDA Guidance re BPCA, p. 3. Accessed April 9, 2019.
10. See 42 U.S.C. §284m

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