Pediatric Drugs and Biologics Laws:Institute of Medicine Study

Daniel A.C. Frattarelli, MD, FAAPFebruary 2, 2011

The History of BPCA and PREA

• Many of the laws which led to the formation of the Food and Drug Administration (FDA) as we know it today came as the result of therapeutic tragedies in children

• Since 1977, the American Academy of Pediatrics (AAP) has advocated strongly that medicines used in children should be tested in children

• In 1997, Food and Drug Administration Modernization Act (FDAMA)contained pediatric exclusivity, an incentive to study drugs in children

• Program reauthorized as Best Pharmaceuticals for Children Act (BPCA) in 2002

• Pediatric Research Equity Act (PREA), a requirement for pediatric studies, passed in 2003 after the Pediatric Rule was struck down

• BPCA and PREA were reauthorized together in 2007, creating an integrated system of pediatric research incentives and requirements

Pediatric Advocacy

• The AAP has been the lead champion of these programs since their inception

• At each stage, the AAP was engaged directly with the legislative authors to develop and improve these important laws

• In 2007, the AAP worked with Sen. Chris Dodd, Sen. Hillary Clinton, and Rep. Anna Eshoo to include an Institute of Medicine study in the reauthorization of BPCA and PREA

• With the departure of Sen. Dodd and Sen. Clinton from the Senate, the AAP will be working with other longtime children’s advocates reauthorize BPCA and PREA

A Track Record of Success

• We learned that “we didn’t know what we didn’t know”

• BPCA and PREA studies have revealed safety issues, altered dosing, led to new indications, and shown some drugs to lack efficacy in children

• 394 drugs have been labeled for children with the benefit of BPCA and PREA

• Led to the development of a parallel pediatric program used in Europe

• BPCA and PREA have dramatically improved pediatric practice

Political and Economic Context

• Pediatric exclusivity is a powerful tool in pediatric drug development

• The program does incur social costs

• Appropriate longitudinal evaluation to demonstrate benefit of the program is essential

Legislation Requiring StudyBest Pharmaceuticals for Children Act

§502, Food and Drug Administration Amendments Act

Public Law 110-85

Pediatric Research Equity Act

§402, Food and Drug Administration Amendments Act

Public Law 110-85

Biologics Price Competition and Innovation Act

§7002, Affordable Care Act

Public Law 111-148

(p) INSTITUTE OF MEDICINE STUDY—Not later than 3 years after the date of the enactment of the Best Pharmaceuticals for Children Act of 2007, the Secretary shall enter into a contract with the Institute of Medicine to conduct a study and report to Congress regarding the written requests made and the studies conducted pursuant to this section. The Institute of Medicine may devise an appropriate mechanism to review a representative sample of requests made and studies conducted pursuant to this section in order to conduct such study. Such study shall—

(1) review such representative written requests issued by the Secretary since 1997 under subsections (b) and (c);

(2) review and assess such representative pediatric studies conducted under subsections (b) and (c) since 1997 and labeling changes made as a result of such studies;

(3) review the use of extrapolation for pediatric subpopulations, the use of alternative endpoints for pediatric populations, neonatal assessment tools, and ethical issues in pediatric clinical trials;

(4) review and assess the pediatric studies of biological products as required under subsections (a) and (b) of section 505B; and

(5) make recommendations regarding appropriate incentives for encouraging pediatric studies of biologics.

(l) INSTITUTE OF MEDICINE STUDY—

(1) IN GENERAL—Not later than three years after the date of the enactment of the Pediatric Research Equity Act of 2007, the Secretary shall contract with the Institute of Medicine to conduct a study and report to Congress regarding the pediatric studies conducted pursuant to this section or precursor regulations since 1997 and labeling changes made as a result of such studies.

(2) CONTENT OF STUDY—The study under paragraph (1) shall review and assess the use of extrapolation for pediatric subpopulations, the use of alternative endpoints for pediatric populations, neonatal assessment tools, the number and type of pediatric adverse events, and ethical issues in pediatric clinical trials.

(3) REPRESENTATIVE SAMPLE—The Institute of Medicine may devise an appropriate mechanism to review a representative sample of studies conducted pursuant to this section from each review division within the Center for Drug Evaluation and Research in order to make the requested assessment.

(B) INSTITUTE OF MEDICINE STUDY—Section 505A(p) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355b(p)) is amended by striking paragraphs (4) and (5) and inserting the following:

‘(4) review and assess the number and importance of biological products for children that are being tested as a result of the amendments made by the Biologics Price Competition and Innovation Act of 2009 and the importance for children, health care providers, parents, and others of labeling changes made as a result of such testing;

‘(5) review and assess the number, importance, and prioritization of any biological products that are not being tested for pediatric use; and

‘(6) offer recommendations for ensuring pediatric testing of biological products, including consideration of any incentives, such as those provided under this section or section 351(m) of the Public Health Service Act.’.

Task 1

IOM Task

Review and assess a representative sample of written requests issued by the Secretary and studies conducted under BPCA since 1997, and labeling changes made as a result of such studies

Legislative Language

1) review such representative written requests issued by the Secretary since 1997 under [BPCA]

2) review and assess such representative pediatric studies conducted under [BPCA] since 1997 and labeling changes made as a result of such studies

Task 1: Recommendations

AAP Recommends: Conduct review of written requests based on the (1) clinical relevance to child health of the questions asked and (2) the resulting therapeutic benefits for children

AAP Recommends: Use representative sample of written requests over time, from 1997 to the present

Task 2

IOM Task

Review and assess a representative sample of studies conducted since 1997 under PREA or precursor regulations, and labeling changes made as a result of such studies

Legislative Language1) … conduct a study and report to

Congress regarding the pediatric studies conducted pursuant to [PREA] or precursor regulations since 1997 and labeling changes made as a result of such studies…

2) …The Institute of Medicine may devise an appropriate mechanism to review a representative sample of studies conducted pursuant to [PREA] from each review division within the Center for Drug Evaluation and Research…

Task 2: Recommendations

AAP Recommends: Conduct analysis of studies under PREA dating back to 2003 and consider usefulness of including studies conducting under the Pediatric Rule

AAP Recommends: Full assessment of PREA studies requires analysis of a representative sample of waivers, deferrals, and studies

Task 3

IOM Task

Using a representative sample of written requests issued by the Secretary and studies conducted under BPCA since 1997 and studies conducted since 1997 under PREA or precursor regulations, review and assess (a) the use of extrapolation for pediatric subpopulations; (b) the use of alternative endpoints for pediatric populations; (c) neonatal assessment tools; and (d) ethical issues in pediatric clinical trials

Legislative Language

review the use of extrapolation for pediatric subpopulations, the use of alternative endpoints for pediatric populations, neonatal assessment tools, and ethical issues in pediatric clinical trials

Task 3: Recommendations

AAP Recommends: Complete these assessments based on a representative sample of BPCA, PREA, and Pediatric Rule requests and studies over the full history of these programs

Task 4

IOM Task

Using a representative sample of studies conducted since 1997 under PREA or precursor regulations, review and assess the number and type of pediatric adverse events

Legislative Language

review and assess the use of extrapolation for pediatric subpopulations, the use of alternative endpoints for pediatric populations, neonatal assessment tools, the number and type of pediatric adverse events, and ethical issues in pediatric clinical trials

Task 4: Recommendations

AAP Recommends: Assess the process by which FDA and the Pediatric Advisory Committee review adverse events for drugs subject to BPCA and PREA and make any necessary recommendations regarding criteria necessitating reviews, the process of conducting those reviews, and the methods that are used

Task 5

IOM Task

Review and assess the number and importance of biological products for children that are being tested as a result of amendments made by the Biologics Price Competition and Innovation Act of 2009 and the importance for children, health care providers, parents, and others of labeling changes made as a result of such testing

Legislative Language

review and assess the number and importance of biological products for children that are being tested as a result of the amendments made by the Biologics Price Competition and Innovation Act of 2009 and the importance for children, health care providers, parents, and others of labeling changes made as a result of such testing

Task 5: Recommendations

AAP Recommends: Provide an accurate assessment of the current state of biologics research incentives for pediatrics

Task 6

IOM Task

Review and assess the number, importance, and prioritization of any biological products that are not being tested for pediatric use

Legislative Language

review and assess the number, importance, and prioritization of any biological products that are not being tested for pediatric use

Task 6: Recommendations

AAP Recommends: Assess the importance of the study of biologics in children and identify particular areas of priority

AAP Recommends: Do not duplicate the NIH prioritization process for off-patent drugs as a model for this assessment

Task 7

IOM Task

Offer recommendations for ensuring pediatric testing of biological products, including consideration of any incentives, such as those provided under section 505A of the Federal Food, Drug , and Cosmetic Act or section 351(m) of the Public Health Service Act

Legislative Language

offer recommendations for ensuring pediatric testing of biological products, including consideration of any incentives, such as those provided under this section or section 351(m) of the Public Health Service Act

Task 7: Recommendations

AAP Recommends: Provide recommendations to FDA on the implementation of BPCA and PREA for biological products

AAP Recommends: Address other incentives that may be necessary for the study of biologics if exclusivity under the new follow-on pathway is insufficient