RARE DISEASES AND ORPHAN PRODUCTS
Accelerating Research and Development
Marilyn J. Field and Thomas F. Boat, Editors
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This study was supported by Contract No. N01-OD-4-2139, TO # 215 between the National Academy of Sciences and the National Institutes of Health. Additional support was provided by the Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for the project.
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Front cover photographs (top to bottom):
Using electropheresis apparatus to separate proteins by molecular weight. Photo courtesy of National Institute of Arthritis and Musculoskeletal and Skin Diseases.
96-well, 384-well, and 1,536-well plates used in pharmaceutical and life science research. Photo courtesy of National Human Genome Research Institute.
Children with ectodermal dysplasia. Used with permission. Photo courtesy of the National Foundation for Ectodermal Dysplasias.
Image of chromosomal abnormalities in mouse cells from a study of leukemia-promoting effects of tumor necrosis factor-alpha in Fanconi anemia group C stem cells. Photo courtesy of the laboratory of Dr. Qishen Pang at Cincinnati Children’s Hospital Medical Center. U.S.A. Copyright 2007, American Society for Clinical Investigation. Used with permission.
Friedreich’s ataxia patient and Friedreich’s Ataxia Research Alliance (FARA) spokeperson, Kyle Bryant, on his recumbent trike during the cycling competition Race Across America. Copyright 2010, www.SLOtography.com. Used with permission.
Children with sickle cell disease. Used with permission. Photo courtesy of Cincinnati Children’s Hospital Medical Center.
Suggested citation: IOM (Institute of Medicine). 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press.
THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council.
COMMITTEE ON ACCELERATING RARE DISEASES RESEARCH AND ORPHAN PRODUCT DEVELOPMENT
THOMAS F. BOAT (Chair), Executive Associate Dean,
University of Cincinnati College of Medicine
PETER C. ADAMSON, Chief,
Clinical Pharmacology and Therapeutics,
Director,
Office of Clinical and Translational Research, Children’s Hospital of Philadelphia
CAROLYN ASBURY, Chair of the Board,
National Organization for Rare Diseases,
Senior Consultant,
Dana Foundation,
Senior Fellow,
Leonard David Institute
PAUL CITRON, Vice President of Technology Policy and Academic Relations,
Medtronic Inc. (retired),
Senior Fellow,
School of Engineering, University of California, San Diego
PETER B. CORR, Founder and General Partner,
Celtic Therapeutics LLP
MICHAEL DEBAUN, Ferring Family Chair in Pediatrics and Professor of Biostatistics and Neurology,
Washington University in St. Louis,
Director,
Sickle Cell Medical Treatment and Education Center, St. Louis Children’s Hospital
HARRY C. DIETZ, Victor A. McKusick Professor of Medicine and Genetics and Professor of Pediatrics,
Institute of Genetic Medicine, Johns Hopkins University School of Medicine
ELLEN J. FLANNERY, Partner,
Covington & Burling LLP
PAT FURLONG, President and Chief Executive Officer,
Parent Project Muscular Dystrophy
MARLENE HAFFNER, President,
Haffner Associates LLC
HAIDEN HUSKAMP, Professor of Health Care Policy,
Harvard Medical School
ANTHONY SO, Professor of the Practice of Public Policy Studies, Director,
Program on Global Health and Technology Access, Duke University
ROBERT D. STEINER,
Credit Unions for Kids Professor of Pediatric Research, Vice Chair for Research, Faculty:
Program in Molecular and Cellular Biosciences,
Pediatrics, and Molecular and Medical Genetics,
Child Development and Rehabilitation Center, Doernbecher Children’s Hospital, Oregon Health & Science University
NANCY S. SUNG, Senior Program Officer,
Burroughs Wellcome Fund
Consultants
LAURA BROOKS FADEN, Doctoral Student,
Harvard University Program in Health Policy
AARON SETH KESSELHEIM, Instructor in Medicine,
Harvard Medical School; Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital
ALISON MACK, Independent Consultant
IOM Staff
MARILYN J. FIELD, Senior Program Officer
CLAIRE GIAMMARIA, Research Associate (from August 2010)
ERIN S. HAMMERS, Research Associate (until May 2010)
ROBIN E. PARSELL, Senior Program Assistant
ANDREW M. POPE, Director,
Board on Health Sciences Policy
Acknowledgments
In preparing this report, the committee and project staff benefited greatly from the assistance and expertise of many individuals and groups. Important information and insights came from three public meetings that the committee organized to collect information and perspectives from a range of academic, professional, consumer, patient, and other organizations and individuals. A number of speakers at these meetings also shared their knowledge at other times during the course of the study. Appendix A includes the agendas of the public meetings and a list of organizations that submitted written statements of views. The committee appreciates the contributions of Aaron Kesselheim, author of Appendix B, and Laura Brooks Faden, coauthor of Appendix C.
Our project officer at the National Institutes of Health (NIH), Stephen Groft, was an invaluable resource and unfailingly helpful. We also were advised by others at NIH including Stephen Hirschfield (National Institute for Child Health and Human Development) and Jeffrey Abrams and Isis Mikhail (National Cancer Institute). Our project officer at the Food and Drug Administration (FDA), Timothy Coté, likewise was a great help, patiently answering questions about the workings of the Orphan Drug Act and its results. We also were assisted by other FDA staff, particularly Debra Lewis and Anne Pariser as well as Kui Xu, Menfo Imoisili, and Katherine Needleman. Joan Sokolovsky at the Medicare Payment Advisory Commission helped with questions about drug coverage under Medicare Parts B and D. Scott Grosse at the Centers for Disease Control and Prevention offered useful insights into the complexities of epidemiologic research on rare conditions.
Sharon Terry and colleagues at the Genetic Alliance and Peter Saltonstall, Mary Dunkle, and colleagues at the National Organization for Rare Diseases worked with the committee on an invitation for their members to submit statements of views on issues before the committee. At Orphanet, Seygolene Ayme provided important information and guidance about their information resources. A number of individuals in other organizations were also helpful in a variety of ways. In addition to those who made presentations during committee meetings and with whom we talked at other meetings, among those we consulted were Stephen Bajardi and Anthony Horton (International Rett Syndrome Foundation), Ron Bartek (Freidriech’s Ataxia Research Alliance), Robert Beall (Cystic Fibrosis Foundation), Wendy Book (American Partnership for Eosinophilic Disorders), Amy Hewitt (Scleroderma Research Foundation), Cynthia Joyce (Spinal Muscular Atrophy Association), Jill Raleigh (LAM [Lymphangioleiomyomatosis] Foundation), Jodi Edgar Reinhardt (National Foundation for Ectodermal Dysplasias), and John Walsh (Alpha-1 Foundation). We also called on Carl Whalen at the National Disease Research Interchange; Yann Le Cam (Eurodis); Marty Liggett, Ulvana Desiderio, and Stephanie Kart (American Society of Hematology); Qishen Pang, Vicky Klensch, and Kori Siroky (Cincinnati Children’s Hospital Medical Center); and Enrique Seoane-Vazquez (Ohio State University).
In addition, the committee and project staff appreciate the work of copy editor Florence Poillon; Debra Gilliam, Chanda Chay, and John Bowers of Caset Associates; and temporary research assistant Cassandra Fletcher. Within the National Academies, we particularly acknowledge the assistance of Clyde Behney, Adam Berger, Robert Giffin (now at the Center for Medical Technology Policy), Greta Gorman, Christine Micheel, Amy Packman, Donna Randall, and Vilija Teel.
Reviewers
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published reports as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report:
Ronald J. Bartek, Friedreich’s Ataxia Research Alliance
Edward M. Basile, King & Spalding
Jim Burns, Genzyme Corporation
David Frohnmayer, Fanconi Anemia Research Fund
Elaine Gallin, Doris Duke Charitable Foundation
Robert C. Griggs, University of Rochester School of Medicine
Susan Kelley, Multiple Myeloma Research Consortium
Chaitan Khosla, Stanford University
Michael Knowles, University of North Carolina at Chapel Hill
Roger J. Lewis, University of California, Los Angeles
John Linehan, Stanford University
Dawn S. Milliner, Mayo Clinic
Carol Mimura, University of California, Berkeley
John A. Parrish, Massachusetts General Hospital
Reed E. Pyeritz, University of Pennsylvania
Joan Sokolovsky, Medicare Payment Advisory Committee
Jess G. Thoene, University of Michigan
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Neal A. Vanselow and Floyd E. Bloom, Scripps Research Institute. Appointed by the National Research Council and the Institute of Medicine, these individuals were responsible for making certain that an independent examination of this report was carried out in accordance with the institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
Preface
Rare diseases are not rare, at least in aggregate. Approximately 7,000 rare diseases afflict millions of individuals in the United States and are responsible for untold losses in terms of physical health, behavioral health, and socioeconomic condition. Physicians, nurses, and others who care for this group of patients recognize the huge burden on patients, families, communities, the health care system, and the health care financing system. All too frequently, providers are reminded of the gap between patient needs and our inability individually and collectively to meet those needs.
Although rare diseases taken together have an enormous impact, there has been no “war on rare diseases” and no designation of a National Institutes of Health (NIH) institute (as for cancer) to address research on rare diseases, even though some U.S. prevalence figures for all rare diseases fall in the range of estimates of those with a history of a cancer diagnosis. Although neither of these cancer-specific responses to need may be suited to rare diseases, many patients with rare diseases today have difficulty in finding providers with the expertise and resources to diagnose and treat their conditions. In addition, research progress has suffered from segmented, disorder-specific approaches to projects and their funding.
The Institute of Medicine committee was asked to examine the current state of research on health care for rare diseases and products to better prevent, diagnose, and treat the large number of these diseases. The committee also was charged to consider how the development of research and therapeutics might be fostered. This task proved to be daunting in a number of respects. Each rare disease has its particular unmet needs, and these may not even have been documented for hundreds if not thousands
of extremely rare conditions. Relatively few efforts have successfully addressed scientific or technical questions across a spectrum of rare diseases. Furthermore, incentives for pharmaceutical, biotechnology, and medical device companies, starting with the Orphan Drug Act in 1983, to invest in the development of new diagnostics, therapeutics, and preventive interventions for rare diseases have had a limited impact on the gap between needs and effective responses.
As documented in this report, opportunities now exist to accelerate progress toward understanding the basis for many more rare diseases and for developing innovative medical approaches. For example, the genomic era some 20 years ago promised when it was launched to unravel the mysteries of genetic contributions to disease. Estimates that 80 percent or more of rare diseases have a genetic cause provided hope for many that solutions to their health problems might be around the corner. However, much of the initial effort to understand the genetic basis of disease was understandably focused on more common problems. It has, however, become increasingly evident that many common diseases have a very complex genetic basis that is taking much longer to map than was originally expected. Because many rare conditions stem from defects in a single gene, they offer opportunities for faster progress, especially given scientific and technological advances that identify the genetic basis of rare diseases and find molecular targets for the development of new treatments for these diseases. Thus, we are poised to make rapid advances in the understanding and, in an increasing number of cases, the treatment of rare diseases. As past research has demonstrated, some of these advances will undoubtedly illuminate disease mechanisms and treatment avenues for more common conditions.
At the same time, many obstacles still complicate efforts to accelerate rare diseases research and product development. Regulatory efforts to ensure the safety and efficacy of new products for rare diseases need attention so that they do not impose avoidable delays or apply inappropriate standards in the evaluation of products for rare conditions. Funding for research for many rare diseases has lagged and lacked coordination, and investigators interested in pursuing research on rare diseases face many obstacles related not just to the availability of funding but to the mechanisms under which research grants are awarded. Furthermore, the cost of drug development under current models and the high costs of new drugs for rare conditions raise questions about whether it is time to create alternative pathways for drug development, including public-private partnerships.
For these reasons, the committee came to the conclusion that a more coordinated national, and ideally global, effort to plan and begin systematically to implement new strategies for addressing the needs of patients with rare diseases is a timely consideration. Leadership of this planning and implementation effort, as well as mechanisms to sustain the effort
over time, present formidable challenges but are not insurmountable with the commitment of patients and families, advocacy groups, policy makers, companies, investigators, and others. The committee is hopeful that its efforts will catalyze thought and action that will benefit millions of our citizens with rare diseases and thereby contribute to the overall health of the nation.
As chair of the committee, I acknowledge the strong contributions of two groups. The committee members quickly created an effective team and gave generously of their time and expertise for committee meetings, phone calls, and writing and review assignments. The Institute of Medicine staff brought together the myriad and disparate inputs and assembled them in a lengthy and complex report. The report would not have materialized without the persistent gentle prodding and guidance of our study director, Dr. Marilyn Field. Without her insistence on documentation of report elements to ensure that the report’s content and presentation met the highest standards under a very ambitious time line, the multifaceted and interdependent dimensions of the committee’s charge could not have been so thoughtfully addressed.
Thomas F. Boat, Chair
Committee on Accelerating Rare Diseases Research and Orphan Product Development
Contents
Boxes, Figures, and Tables
BOXES
S-1 |
Elements of an Integrated National Strategy to Accelerate Research and Product Development for Rare Diseases, |
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1-1 |
Examples of Rare Diseases, |
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1-2 |
Elements of an Integrated National Strategy to Accelerate Research and Product Development for Rare Diseases, |
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1-3 |
Organized Research on Exceptionally Rare Diseases Is Possible, |
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1-4 |
Examples of Ongoing Reporting of New Rare Syndromes in Orphanet Newsletter, |
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1-5 |
Rare by Genotype or Rare by Phenotype: The Example of Hemochromatosis, |
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1-6 |
Types of Clinical Trials, |
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3-1 |
Options for Patients to Obtain Access to Investigational Drugs When the Primary Purpose Is to Diagnose, Monitor, or Treat a Patient’s Disease or Condition, |
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3-2 |
Primary Incentives Provided by the Orphan Drug Act, |
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3-3 |
Examples of Variations in Types of Efficacy Studies Accepted by FDA in Orphan Drug Approvals, |
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3-4 |
Examples of Problem Areas for Sponsors Developing Evidence for Orphan Drug Approval, |
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3-5 |
NIH Request for Applications on Advancing Regulatory Science Through Novel Research and Science-Based Technologies (February 24, 2010), |
4-1 |
Examples of Research on Rare Diseases with Implications for Treatment of Common Conditions, |
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4-2 |
Improving Rare Disease Diagnostics: Enabling Technologies, |
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5-1 |
Summary of Earlier IOM Report Recommendations for Effective Biomarker Evaluation, |
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5-2 |
Examples of Initiatives to Increase Information About Clinical Trials and FDA or Company Decisions About Products, |
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7-1 |
Examples of Devices Approved Under the Humanitarian Device Exemption, |
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7-2 |
Expectations for Consortia to Stimulate Pediatric Device Development, |
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7-3 |
Stanford University Biodesign Program, |
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7-4 |
Innovations in Engineering and Biological Sciences and Medical Device Innovation, |
FIGURES
2-1A |
Number of rare diseases by prevalence up to 50/100,000, |
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2-1B |
Number of rare diseases by prevalence of 10/100,000 or less, |
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2-1C |
Number of rare diseases by number of individual cases in literature, |
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2-1D |
Number of rare diseases by number of family cases in literature, |
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4-1 |
Plot of NIH grants for illustrative rare diseases by disease prevalence, |
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5-1 |
Drug development: from idea to market, |
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7-1 |
Total product life cycle for medical devices, |
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B-1 |
Annual orphan drug approvals by “newness,” |
TABLES
1-4 |
Prevalence Criteria for the Definition of Rare Disease in Selected Countries, |
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2-1 |
Differences in Prevalence for Three Cancers with Similar Numbers of New Cases per Year but Different Survival Rates, 2006, |
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2-2 |
Examples of Currently Available Treatments or Treatments in Development for Rare Diseases, |
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2-3 |
Characteristics of Child and Adolescent Health That May Affect the Complexity of Health Care Transitions, |
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4-1 |
Active NIH Awards for Four Rare Diseases by Number, Funding Total, and Type as of April 2010, |
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6-1 |
Coverage of Part D-Eligible Drugs by Type of Medicare Prescription Drug Plan, |
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7-1 |
Complex Medical Devices Tend to Differ from Drugs, |
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7-2 |
Incentive Comparison: Drugs or Biologics Versus Devices, |
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B-1 |
Orphan Approvals for Somatropin Products, |
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C-1 |
Average Premium and Use of Deductible for Different Types of Medicare Prescription Drug Plans, |
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C-2 |
Orphan Drug Coverage by Type of Medicare Prescription Drug Plan, |
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C-3 |
Orphan Drugs with No, Very Low, or Low Plan Coverage, |
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C-4 |
Orphan Drugs by Rate of Tier 4 Placement and Type of Medicare Prescription Drug Plan, |
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C-5 |
Orphan Drugs by Rate of Prior Authorization Use and Type of Medicare Prescription Drug Plan, |
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C-A1 |
Orphan Drugs Relevant to Medicare Population, |
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C-A2 |
Medicare Stand-Alone PDP Coverage of Orphan Drugs: Inclusion on Formulary (i.e., Plan Coverage), Tier Placement, and Utilization Management, |
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C-A3 |
Drugs with a Pediatric Orphan Indication, |
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C-A4 |
Medicare Stand-Alone PDP Coverage for Drugs with a Pediatric Orphan Indication: Inclusion on Formulary (i.e., Plan Coverage), Tier Placement, and Utilization Management, |
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F-1 |
Spending on Research or Research Grants for Selected Advocacy Organizations, 2008, |