A

Study Activities, Methods,
and Public Meetings

In late 2009, the Food and Drug Administration (FDA) approached the Institute of Medicine (IOM) about an examination of pediatric studies of drugs and biologics conducted under the provisions of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) as called for in the reauthorizations of these two acts in the FDA Amendments Act of 2007. In March 2010, as part of the Patient Protection and Affordable Care Act, Congress changed the task specifications for biological products to reflect changes elsewhere in the legislation affecting incentives for the development of these products. Taking these revisions into account, FDA asked that an IOM committee

1. review and assess a representative sample of written requests issued by the Secretary [of the U.S. Department of Health and Human Services] and studies conducted under BPCA since 1997, and labeling changes made as a result of such studies;

2. 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;

3. 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;



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A Study Activities, Methods, and Public Meetings I n late 2009, the Food and Drug Administration (FDA) approached the Institute of Medicine (IOM) about an examination of pediatric studies of drugs and biologics conducted under the provisions of the Best Phar- maceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) as called for in the reauthorizations of these two acts in the FDA Amendments Act of 2007. In March 2010, as part of the Patient Protec- tion and Affordable Care Act, Congress changed the task specifications for biological products to reflect changes elsewhere in the legislation affecting incentives for the development of these products. Taking these revisions into account, FDA asked that an IOM committee 1. review and assess a representative sample of written requests issued by the Secretary [of the U.S. Department of Health and Human Ser- vices] and studies conducted under BPCA since 1997, and labeling changes made as a result of such studies; 2. 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; 3. using a representative sample of written requests issued by the Sec- retary 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; 261

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262 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN 4. using a representative sample of studies conducted since 1997 un- der PREA or precursor regulations, review and assess the number and type of pediatric adverse events; 5. review and assess the number and importance of biological prod- ucts for children that are being tested as a result of the amendments made by the Biologics Price Competition and Innovation Act of 2009 [passed in 2010] and the importance for children, health care providers, parents, and others of labeling changes made as a result of such testing; 6. review and assess the number, importance, and prioritization of any biological products that are not being tested for pediatric use; and 7. 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 Cos- metic Act or section 351(m) of the Public Health Service Act. The 13-member study committee appointed by the IOM met five times between December 2010 and October 2011. Three of these meetings in- cluded public sessions during which the committee heard from a range of interested parties, including government officials from FDA and the Na- tional Institutes of Health and individuals from organizations representing pharmaceutical and biotechnology companies, pediatricians, researchers, and advocates. The agendas for the public sessions follow this overview of study activities and methods. The committee also sought assistance from consultants for the prepa- ration of background papers and other analyses to supplement those un- dertaken by the committee. The consultants are listed after the committee members in the front of this report. The background papers prepared by consultants appear as Appendixes B and C, and Appendix D presents in- formation on biologics studied in children, much of which was checked or compiled by a consultant. The committee’s statement of task refers to written requests, studies, and labeling changes that have been occurred since 1997. However, the provisions of the FDA Modernization Act creating the written request mechanism and the pediatric exclusivity incentive did not go into effect until July 1, 1998, and the effective date of the 1998 Pediatric Rule was April 1, 1999. Therefore, the committee used these dates as the start dates for its sampling of FDA documents. Because FDA may not post relevant documents for some period after the approval of a product or labeling change, the committee chose December 31, 2010, to be the cutoff point for its sample. FDA supplied the committee with its master list of labeling changes for the specified 1998 to 2010 time period. It also supplied a list of 14 products

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263 APPENDIX A for which exclusivity had been granted but labeling changes did not occur. The lists characterized the products by therapeutic area and policy origin. Some products had more than one labeling change. Neither the list supplied by FDA nor an online table of labeling changes explained that the list omitted changes made before September 27, 2007, for biologics that are regulated under the Public Health Service Act.1 FDA was unable to supply a list of these omitted labeling changes. Thus, the list supplied to the committee understates to an unknown extent the number of labeling changes made as a result of studies of biologics that were required under PREA. Prior to the September 27, 2007, reauthorizations of BPCA and PREA, FDA was not required to make public either the clinical, clinical pharmacol- ogy, and statistical reviews associated with labeling changes or the written requests associated with the granting of pediatric exclusivity. The IOM could request documents associated with earlier labeling changes and ex- clusivity determinations, but the FDA could not release them until they had been reviewed and redacted to remove proprietary and other information that FDA considers not releasable. One key question that was discussed over a period of months was whether FDA could agree to a schedule for redacting and releasing re- quested documents that would allow the IOM time to do its assessments, analyze them, consider the results in developing its report, and stay on schedule to deliver the report. After the committee’s second meeting in Feb- ruary 2011, FDA agreed that it would provide requested documents for up to 50 products that are now regulated by the Center for Drug Evaluation and Research. The agreement did not cover products now regulated by the Center for Biologics Evaluation and Research. It also did not cover at least 12 products for which exclusivity was granted without a labeling change. Because the committee had already selected a sample of products for as- sessment based on the availability of documents for labeling changes made after September 26, 2007, it had to identify a new sample for the period from July 1, 1998 through December 31, 2010. Insofar as possible, the committee sought to include labeling changes 1 As the committee was preparing to release this report in February 2012, FDA posted a revised table of labeling changes related to BPCA and PREA. It included an explanation that labeling changes for relevant biological products regulated by the Center for Biologics Evalu- ation and Research were included in the table beginning September 27, 2007 (but not before that date). Although it is not noted, the table also omits biologics that are now regulated by the Center for Drug Evaluation and Research and that had labeling changes prior to the same date (see, e.g., Drugs@FDA for September 2001 and December 2005 approval letters for darbepoetin alfa [Aranesp]) and a 2002 letter for rasburicase [Elitek] for changes not included in the table).

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264 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN for products for similar clinical indications from three time periods that roughly correspond to different regulatory eras. These periods were • July 1, 1998–December 31, 2002 (early period, representing the early implementation of the pediatric exclusivity provisions from the FDA Modernization Act of 1997, effective July 1, 1998, and the Pediatric Rule, effective April 1, 1999, but overturned by the courts in October 2002); • January 1, 2003–September 26, 2007 (middle period); and • September 27, 2007–December 31, 2010 (recent period, following the reauthorizations of BPCA and PREA in 2007). Consistent with the provision that the IOM use a representative sample for its assessments, the committee selected products from the major thera- peutic areas identified by the Government Accountability Office (which were reported in the list supplied by FDA). These areas, which generally parallel FDA review divisions, were analgesia/anesthesia, anti-inflammatory, cardiovascular disease, dermatology, endocrinology/metabolism, gastroen- terology, hematology/coagulation, infectious disease (nonviral), infectious disease (viral), medical imaging, neurology, oncology, ophthalmology, and pulmonary. The committee excluded vaccines from its sample. Most vaccine devel- opment programs include studies or expectations of studies with pediatric age groups from the outset. Moreover, the need for vaccines for various diseases and populations is closely monitored by several government agen- cies, including the National Vaccine Program, the Advisory Committee on Immunization Practices, and the FDA’s Vaccines and Related Biological Products Advisory Committee. Appendix D includes a brief description of the extent of pediatric labeling and pediatric studies for vaccines for which FDA has posted some supporting documents. The committee also excluded contraceptive products, which are routinely approved for use by postpu- bertal adolescents on the basis of extrapolation of safety and efficacy data from studies with adults without pediatric studies. With these exclusions, the universe of relevant labeling changes totaled 381. In an effort to learn more about how FDA requests or requirements might have changed over time, the committee generally selected products within each therapeutic area with similar indications, for example, juvenile rheumatoid arthritis. After a few older products with particularly confusing or poorly documented regulatory histories were excluded, the committee’s final sample included 46 FDA actions that involved 45 labeling changes and 44 distinct products, including 1 product for which exclusivity was granted but no information was added to the label. To structure its assessments, the committee devised a form that in-

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265 APPENDIX A cluded both descriptive items (e.g., characteristics of requested studies, pediatric subgroups for which PREA studies were waived, and types of pediatric information added to product labels) and subjective assessments (e.g., appropriateness of permitting extrapolation for a pediatric age group, value of information generated by requested or required pediatric studies, and ethical considerations for a placebo-controlled clinical trial). The form required revisions as the specific circumstances identified in different assess- ments revealed the need for changes. The committee began requesting redacted documents in early March 2011. The documents included written requests (and amendments); ap- proval letters; and clinical, clinical pharmacology, and statistical reviews. For some products for which labeling changes were made in the late 1990s, the review documents were already posted at Drugs@FDA and thus did not need to be requested. The committee supplemented the sample of written requests with ad- ditional requests in three areas: migraine, pediatric hypertension, and gas- troesophageal reflux disease. It also reviewed requests, reviews, and other documents for many additional products or labeling changes as it investi- gated particular issues (e.g., neonatal studies). As described in Chapter 8, the committee examined a substantial number of documents for biologics as part of its work to identify biologics not evaluated in studies with children. In addition, it reviewed some FDA actions taken after December 31, 2010, to learn more about current practices (e.g., in waiving studies required under PREA). ***** INSTITUTE OF MEDICINE COMMITTEE ON PEDIATRIC STUDIES CONDUCTED UNDER BPCA AND PREA MEETING 1: December 17, 2010 Keck Building, 500 Fifth Street, NW, Washington, DC AGENDA: OPEN SESSION 9:30–Noon OPEN SESSION I Introductions and chair’s statement U.S. Food and Drug Administration presentations Overview and impact of the pediatric legislation (since 1997) Dianne Murphy, M.D., Office of Pediatric Therapeutics

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266 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Elements of FDAAA 2007 and their implementation within CDER Lisa Mathis, M.D., Center for Drug Evaluation and Research Elements of FDAAA 2007 and their implementation within CBER and comments on IOM Tasks 5, 6, and 7 Jennifer Ross, Ph.D., Center for Biologics Evaluation and Research Overview of the IOM task order, including data available Robert “Skip” Nelson, M.D., Ph.D., Office of Pediatric Therapeutics Comments on specific topics for IOM assessment Drug labeling (IOM Tasks 1 and 2) Dianne Murphy, M.D., Office of Pediatric Therapeutics Extrapolation (IOM Task 3) Julia Dunne, M.D., Office of Pediatric Therapeutics Ethics, neonates, alternate endpoints (IOM Task 3) Robert “Skip” Nelson, M.D., Ph.D., Office of Pediatric Therapeutics Adverse events (IOM Task 4) Judith Cope, M.D., M.P.H., Office of Pediatric Therapeutics Questions from the committee 1:30–2:45 OPEN SESSION II Welcome and introductions Role of the National Institute of Child Health and Human Development in BPCA Anne Zajicek, M.D., Pharm.D., Chief, Obstetric and Pediatric Pharmacology Branch, Center for Research for Mothers and Children Information and process to support priority setting Clifford Goodman, Ph.D., Vice President, The Lewin Group Cynthia Schuster, M.P.P., The Lewin Group Questions from the committee

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267 APPENDIX A *** INSTITUTE OF MEDICINE COMMITTEE ON PEDIATRIC STUDIES CONDUCTED UNDER BPCA AND PREA MEETING 2: February 2, 2011 Keck Building, 500 Fifth Street, NW, Washington, DC AGENDA: OPEN SESSION 11:00–Noon Thomas Boat, M.D., Committee Chair Welcome and chair’s statement Lisa Mathis, M.D., Center for Drug Evaluation and Research PREA waivers and deferrals and other issues Julia Dunne, M.D., Office of Pediatric Therapeutics European Medicines Agency (EMEA) Questions from the committee Noon Lunch 12:45–1:45 Continued FDA presentations and discussion 1:45–3:00 Daniel Frattarelli, M.D., F.A.A.P. Chair of the American Academy of Pediatrics Committee on Drugs Questions from the committee 3:00 Adjourn ***

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268 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN INSTITUTE OF MEDICINE COMMITTEE ON PEDIATRIC STUDIES CONDUCTED UNDER BPCA AND PREA MEETING 3: April 28, 2011 Keck Building, 500 Fifth Street, NW, Washington, DC AGENDA: OPEN SESSION 1:00 Public Session Welcome and chair’s statement Thomas Boat, M.D., Committee Chair Biotechnology Industry Organization Ronald J. Portman, M.D. Chair, Pediatric Drug Development Committee Group Director, Pediatric Programs/CV/Metabolics Bristol-Myers Squibb Pharmaceutical Research and Manufacturers Association Samuel D. Maldonado, M.D., M.P.H. Vice-President and Head Pediatric Drug Development Center of Excellence Johnson & Johnson PRD American Academy of Child and Adolescent Psychiatry (AACAP) Adelaide Robb, M.D. Chair, AACAP Pediatric Psychopharmacology Initiative Director of Psychiatric Clinical Trials Children’s National Medical Center, Washington, DC Pediatric Rheumatology Collaborative Study Group Daniel J. Lovell, M.D., M.P.H. Chair, Pediatric Rheumatology Collaborative Study Group Professor of Pediatrics and Associate Director, Division of Rheumatology Children’s Hospital Medical Center, Cincinnati. Perspectives from Clinicians and Parents Caring for Children with HIV Infection Natella Y. Rakhmanina, M.D. Associate Professor of Pediatrics, George Washington University

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269 APPENDIX A Director, Special Immunology Pediatric HIV Program Children’s National Medical Center, Washington, DC Questions from the committee 3:00 Adjourn Written statements submitted for this meeting: Childhood Arthritis and Rheumatology Research Alliance (CARRA) Friends of CARRA

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