ARNOLD & PORTER UPDATE

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1 ARNOLD & PORTER UPDATE Require Pediatric Studies December 2003 On December 3, 2003, President Bush signed the Pediatric Research Equity Act of 2003, Pub. L. No , 117 Stat. 1936, which is available at This new statute amends the Federal Food, Drug, and Cosmetic Act ( FFDCA ) by adding section 505B, which provides FDA with the statutory authority to require sponsors to submit assessments regarding the use of drugs and biologics in pediatric patients in certain specified circumstances. BACKGROUND As part of the Food and Drug Administration Modernization Act of 1997 ( FDAMA ), Congress provided an incentive of 6 months of additional exclusivity in exchange for the voluntary performance of clinical studies of drugs in the pediatric population in response to a written request from FDA. These pediatric exclusivity provisions were reauthorized and enhanced in 2002 by the Best Pharmaceuticals for Children Act ( BPCA ). The BPCA also created programs administered by the NIH to issue grants and contracts for researchers to conduct additional pediatric studies with privately donated and publicly appropriated funds. In 1998, FDA, in order to promote more comprehensive pediatric testing, issued a regulation known as the Pediatric Rule, asserting the authority to require pediatric testing in certain circumstances. 1 On October 17, 2002, the U.S. District Court for the District of Columbia held that FDA lacked the authority to promulgate the Pediatric Rule, and the court declared the rule invalid. 2 The Pediatric Research Equity Act of 2003 now provides FDA with the statutory authority to require pediatric studies in certain defined circumstances. In fact, the authority granted by the new legislation tracks many elements of the former Pediatric Rule. 3 Below is an overview of these new statutory provisions. SUMMARY OF PROVISIONS New Statutory Authority for FDA to Require Certain Pediatric Tests New Drugs and Biologics Each new drug application under 505 of the FFDCA or biologics license application under 351 of the Public Health Service Act ( PHSA ) for a new active ingredient, new indication, new dosage form, new WASHINGTON 555 Twelfth Street, NW Washington, DC Fax NEW YORK 399 Park Avenue New York, NY Fax LONDON Tower Old Broad Street London EC2N 1HQ UNITED KINGDOM +44 (0) (0) Fax BRUSSELS 11, Rue des Colonies - Koloniënstraat 11 B-1000 Brussels BELGIUM +32 (0) (0) Fax LOS ANGELES 44th Floor 777 South Figueroa Street Los Angeles, CA Fax CENTURY CITY 17th Floor 1900 Avenue of the Stars Los Angeles, CA Fax NORTHERN VIRGINIA Suite Tysons Boulevard McLean, VA Fax DENVER Suite Seventeenth Street Denver, CO Fax arnoldporter.com

2 dosing regimen, or new route of administration 4 must contain data adequate to assess the safety and effectiveness of the product for its claimed indications in all relevant pediatric subpopulations. 5 There must also be data to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. 6 FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults or other pediatric age groups. 7 Unless FDA requires otherwise by regulation, these provisions do not apply to any drug for an indication for which orphan designation has been granted. 8 Observations Because pediatric data is only required to assess the safety and effectiveness of a product for the claimed indications, no studies of unapproved uses may be required. 9 Because the statute applies only to new indications, dosage forms, etc., it affects generic applicants only in connection with some 505(b)(2) applications and when a variation from the listed drug is suggested in a suitability petition. Note, however, that under the previous Pediatric Rule, FDA indicated that a suitability petition submitted for a change that would require a pediatric study might be denied because such petitions cannot be granted if clinical studies are required for approval of the ANDA. 10 The same results may occur under the new legislation. There is an argument that these provisions do not apply to ANDAs in any circumstances, as the conforming amendments add the requirement of a pediatric assessment to 505(b) (NDAs), but not to 505(j) (ANDAs). 11 Marketed Drugs and Biologics After exhausting pediatric exclusivity and funding options (as discussed below), and after having provided the holders with notice and an opportunity for written response and a meeting, 12 FDA may require that all holders of approved applications submit data on safety and effectiveness and dosing and administration for the product s claimed indications in relevant pediatric subpopulations, if: The product is used for a substantial number of pediatric patients for the labeled indications 13 and the absence of adequate labeling could pose significant risks to pediatric patients, 14 or There is reason to believe that the product would represent a meaningful therapeutic benefit over existing therapies for pediatric patients for one or more of the claimed indications 15 and the absence of adequate labeling could pose significant risks to pediatric patients. 16 Observation In this legislation and the accompanying legislative history, Congress did not specifically address the application of these new statutory provisions to multisource drugs (i.e., drugs for which there are multiple applicants, typically with at least one generic manufacturer). In response to a comment on the Pediatric Rule, FDA said that where it requires pediatric studies on a multi-source marketed drug, each applicant will be responsible for satisfying the study requirement, but that it will encourage all applicants to fund joint studies. 17 FDA may adopt a similar position under the new legislation. Require Pediatric Studies 2

3 The Legislation Clarifies the Interaction of the New Pediatric Study Requirements with the Pediatric Exclusivity Provisions For already-marketed drugs, the legislation provides that FDA may only impose pediatric study requirements for already marketed drugs when the pediatric exclusivity incentive provisions of 505A of the FFDCA and the NIH grant and contract programs of 409I and 499 of the PHSA have failed to yield necessary pediatric information. Thus, FDA may invoke the provisions of the new Act only if: FDA issues a request for the study under 505A of the FFDCA or 409I of the PHSA, 18 and If the request was made under 505A(c), then either the recipient of the request does not agree to the request or FDA does not receive a response. 19 If the request was made under 409I of the PHSA, then either the recipient of the request does not agree to the request or FDA does not receive a response, 20 and The Secretary certifies that there are insufficient funds to conduct the study, 21 or The Secretary publishes in the Federal Register a certification that no contract or grant has been awarded and not less than 270 days have passed since the date of certification that there are sufficient funds to conduct the study. 22 For new applications, FDA is not required to request pediatric studies or wait until voluntary mechanisms have been exhausted before invoking this new requirement. 23 However, if the sponsor performs pediatric studies in compliance with 505B, such studies may qualify for pediatric exclusivity. 24 Conditions for Waiver or Deferral of Studies Waiver FDA is required to grant a full or partial (relating to a specific pediatric age group) waiver of the pediatric data requirement for a product for certain reasons, including: FDA finds that necessary studies are impossible or highly impractical, because, for example, the number of such pediatric patients is small or geographically dispersed; 25 There is evidence strongly suggesting that the product would be ineffective or unsafe in the pediatric age groups 26 (such information must appear in the labeling 27 ); The product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients; 28 and The product is not likely to be used by a substantial number of pediatric patients, and the absence of adequate labeling would not pose significant risks to pediatric patients. 29 If a waiver is granted because it is not possible to develop a pediatric formulation, the waiver will only cover the pediatric age groups requiring that formulation. 30 Deferral FDA, on its own initiative or at the request of the applicant, may defer the submission of some or all of the assessments required under the Act until a specified date after the approval of the drug or after the license for the biological product is granted if two requirements are met: Require Pediatric Studies 3

4 FDA finds that the drug is ready for approval for use in adults before the pediatric studies are complete, 31 or the pediatric studies should be delayed until additional safety or effectiveness data have been collected, 32 or there is another appropriate reason for deferral, 33 and The applicant has submitted to FDA certification for the grounds for deferring, a description of the planned or ongoing studies, and evidence that the studies are being conducted or will be conducted with due diligence at the earliest possible time. 34 Enforcement of the Requirement to Submit Timely Pediatric Assessments The legislation provides that a product for which a pediatric assessment is not filed by the date specified by FDA may be considered misbranded and subject to relevant enforcement action. 35 Timing The effective date of the Act is December 3, 2003, except that 505B(a), the new application provision, shall apply to applications submitted on or after April 1, The Act sunsets on October 1, 2007, the same date that the pediatric exclusivity authority is to sunset. 37 * * * * * If you would like to discuss this new legislation, or have questions about it, please contact: Bill Vodra William_Vodra@aporter.com Don Beers Donald_Beers@aporter.com David Korn David_Korn@aporter.com 1 63 Fed. Reg. 66,632 (Dec. 2, 1998). 2 Ass n of Am. Physicians and Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204 (D.D.C. 2002). 3 S. Rep. No , at 6 (2003). 4 Pediatric Research Equity Act of 2003, Pub. L. No , 117 Stat (a), creating new FFDCA 505B(a)(1). 5 Id. 505B(a)(2)(A)(i). 6 Id. 505B(a)(2)(A)(ii). 7 Id. 505B(a)(2)(B). 8 Id. 505B(g). 9 Id. 505B(a)(2)(A)(i) Fed. Reg. at 66, Pediatric Research Equity Act of (b)(1)(B). 12 Id. 2(a), creating new FFDCA 505B(b)(1). 13 Id. 505B(b)(1)(A)(i). Require Pediatric Studies 4

5 14 Id. 505B(b)(1)(A)(ii). 15 Id. 505B(b)(1)(B)(i). 16 Id. 505B(b)(1)(B)(ii). 17 See 63 Fed. Reg. at 66, Pediatric Research Equity Act of (a), creating new FFDCA 505B(b)(3)(A)(i). 19 Id. 505B(b)(3)(A)(ii)(I). 20 Id. 505B(b)(3)(A)(ii)(II). 21 Id. 505B(b)(3)(A)(iii)(I). Subparagraph 505B(b)(3)(B) states that no later than 60 days after determining that no holder will agree to the written request, the Secretary shall certify whether the Secretary has sufficient funds to conduct the study. Id. 505B(b)(3)(B). 22 Id. 505B(b)(3)(A)(iii)(II). 23 See S. Rep. No , at 17; See also 149 Cong. Rec. S9814 (2003) (statement of Sen. Kennedy); Id. at S9816 (statement of Sen. Gregg). 24 Pediatric Research Equity Act of (b)(2). 25 See, e.g., Id. 2(a), creating new FFDCA 505B(a)(4)(A)(i). 26 See, e.g., Id. 505B(a)(4)(A)(ii). 27 Id. 505B(b)(2)(D). 28 See, e.g., Id. 505B(a)(4)(A)(iii)(I). 29 See, e.g., Id. 505B(a)(4)(A)(iii)(II). 30 Id. 505B(b)(2)(C). 31 Id. 505B(a)(3)(A)(i). 32 Id. 505B(a)(3)(A)(ii). 33 Id. 505B(a)(3)(A)(iii). No guidance is provided by the statute or legislative history as to what constitutes another appropriate reason for deferral. 34 Id. 505B(a)(3)(B). 35 Id. 505B(d)(1). 36 Id Id. 2(a), creating new 505B(h). Require Pediatric Studies 5