Rare Diseases and Orphan Products Accelerating Research and Development (2010) / Chapter Skim
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1 Introduction
1 Introduction
Pages 15-40
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. Studies of Tangier disease (an extremely rare condition in which a gene associated with cholesterol processing does not function properly)
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They may be offering support to a relative or friend who has been diagnosed with ovarian cancer or amyotrophic lateral sclerosis in mid- or late life. Although most of the conditions just cited affect tens of thousands of Americans, each meets the definition of rare disease established in a 1984 amendment to the 1983 Orphan Drug Act (P.L.
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INTRODUCTION BOX 1-1 Examples of Rare Diseases Dystonia: a group of rare movement disorders that cause involuntary muscle spasms and contractions. Dystonias may be inherited, arise from other conditions (e.g., tumors, infections, stroke)
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Thus, this report proposes further steps to develop a more integrated approach to rare diseases research and product development. BOX 1-2 Elements of an Integrated National Strategy to Accelerate Research and Product Development for Rare Diseases • Active involvement and collaboration by a wide range of public and private interests, including government agencies, commercial companies, academic in stitutions and investigators, and advocacy groups • Timely application of advances in science and technology that can make rare diseases research and product development faster, easier, and less expensive • Creative strategies for sharing research resources and infrastructure to make good and efficient use of scarce funding, expertise, data, biological specimens, and participation in research by people with rare diseases • Appropriate use and further development of trial design and analytic methods tailored to the special challenges of conducting research on small populations • Reasonable rewards and incentives for private-sector innovation and prudent use of public resources for product development when the latter appears a faster or less costly way to respond to important unmet needs • Adequate organizations and resources, including staff with expertise on rare diseases research and product development, for the public agencies that fund biomedical research and regulate drugs and medical devices • Mechanisms for weighing priorities for rare diseases research and product development, establishing collaborative as well as organization-specific goals, and assessing progress toward these goals
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Chapter 3 presents a brief overview of the regulation of pharmaceuticals and biological products in the United States before examining the Orphan Drug Act and other policies that establish incentives for the development of products for rare conditions. The chapter also provides summary information about drugs approved under the legislation; Appendix B provides more detailed information.
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Advances in engineering and bioengineering are likewise contributing to the development of innovative medical devices to treat certain rare conditions. The National Institutes of Health (NIH)
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Several small companies now focus on the development of drugs to treat rare diseases, and some large pharmaceutical companies are expressing increased interest in the incentives of the Orphan Drug Act. Moreover, patient advocacy groups have become increasingly active and have helped create innovative models for funding and organizing rare diseases research and product development, including various kinds of public-private partnerships as discussed in Chapter 5.
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HISTORICAL AND POLICY CONTEXT Creating Policy Incentives for Product Development The development of significant drugs of limited commercial value repre sents an activity in the public interest calling for the combined support of government, industry, voluntary organizations, and others concerned with health care. In our society, it should be possible to provide assistance to small groups of patients as well as the general population, and to encour age research on medical problems of limited scope which may later have great beneficial effect.
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Congressional hearings in the early 1980s focused public attention on rare diseases and laid the foundation for passage of the Orphan Drug Act. Signed into law in 1983, the legislation marked the first significant public commitment by any nation to promote the development of drugs for people with rare diseases.
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affects fewer than 200,000 persons in the United States or (2) affects "more than 200,000 persons in the United States, but for which there is no reasonable expectation that the sales of the drug treatment will recover the costs" Congress directs the creation of a National Commission on Orphan Diseases to assess the research activities of NIH and other public and private organizations in connection with drug development 1989 National Commission on Orphan Diseases issues report 1990 Congress passes legislation to differentiate incentives for orphan drug development depending on commercial value but the President vetoes it Congress passes Safe Medical Devices Act of 1990, which (among other provisions)
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and requires NIH to support regional centers of excellence for clinical research into, training in, and demonstration of diagnostic, prevention, control, and treatment methods for rare diseases 2003 NIH Office of Rare Diseases creates Rare Diseases Clinical Research Network beginning with seven research consortia 2007 FDA Amendments Act includes the Pediatric Medical Device Safety and Improvement Act, which provides incentives for industry and researchers to design devices for children 2008 Congress enacts the Genetic Nondiscrimination Act to prohibit discrimination in health insurance and employment based on genetic information. 2009 NIH announces Therapeutics for Rare and Neglected Diseases Program NIH announces expansion of Rare Diseases Clinical Research Network SOURCES: Scheinberg and Walshe, 1986; Asbury, 1991; Haffner, 1991; Henkel, 1999; Villarreal, 2001; Iribarne, 2003; Meyers and DiPaola, 2003; Dorman, 2008; NIH, 2009a,b; Waxman, undated.
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The scientific context of rare diseases research and orphan product development has changed in many ways since the report was drafted. Nonetheless, the 1989 report sounds some of the same themes as this report, including the importance of public-private partnerships; mechanisms to 1 Some of the groups involved in NORD's early years include the Cystinosis Foundation, Dystonia Medical Research Foundation, National Huntington's Disease Association, National Marfan Association, National Neurofibromatosis Foundation, Parkinson's Disease Foundation, Paget Disease Foundation, and Tourette Syndrome Association (Jean Campbell, Vice President of Membership Development, National Organization for Rare Disorders, December 16, 2009, personal communication)
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Although the 1989 report devoted relatively little attention to medical devices, it did recommend that Congress amend the Orphan Drug Act to provide incentives for the development of orphan medical devices and medical foods. As discussed in Chapter 7, developing equivalent incentives for medical devices has proved challenging, given that unlike an approved drug, a complex medical device typically is the object of ongoing refinements that make the marketing protections of the orphan drug much less meaningful as an incentive.
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In addition, sometimes in coordination with ORDR but also independently, several NIH institutes fund research on rare diseases, for example, a number of rare cancers, sickle cell diseases and related blood disorders, and rare neurological disorders, such as various forms of muscular dystrophy. The grants program of the FDA's Office of Orphan Products Development also supports clinical development of products for use in rare diseases or conditions.
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The United States was the earliest adopter of formal incentives for orphan drug development, but a number of other nations have followed with policies that are broadly similar, although differing in some details. The European Union has developed a common policy for its member states on some issues (e.g., length of market exclusivity period)
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study grew out of discussions with the NIH Office of Rare Diseases Research and the FDA Office of Orphan Products Development about opportunities to accelerate rare diseases research and orphan product development. As discussions progressed, the focus expanded from drugs and biologics to include medical devices.
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The literature review was complicated by both the very large number of diseases categorized as rare and the limited base of knowledge about most of these conditions. The committee also solicited information and perspectives from a range of individuals and organizations, including voluntary organizations that promote research on specific conditions or rare conditions more generally, companies that develop drugs and medical devices, and researchers engaged in various aspects of basic, translational, and clinical research.
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Disease, Condition, and Disorder Consistent with the preamble of the Orphan Drug Act, this report generally uses the terms disease, condition, and disorder interchangeably. The term condition is useful in describing injuries and entities such as hemochromatosis and sickle cell trait that do not cause symptoms or distress in the majority of people who have them.
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A European organization, Orphanet,4 has been working more system 4 On its website, Orphanet describes its mission as follows: "Orphanet is a database of information on rare diseases and orphan drugs for all publics. Its aim is to contribute to the improvement of the diagnosis, care and treatment of patients with rare diseases.
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. The OMIM database, which is not limited to rare conditions, likewise was a useful resource that the committee consulted for its relatively extensive summaries of information on a great many rare diseases.5 The committee also consulted the NORD Guide to Rare Disorders (NORD, 2003)
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INTRODUCTION • names used for the same condition;7 and • criteria and procedures for tracking and evaluating newly identified conditions or other information and for reviewing and updating lists. When newly reported syndromes or genetic anomalies should be categorized as a rare disease is, to some degree, a matter of judgment as is the determination that certain genetic or other variations within a common condition warrant designation as a rare disease.
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Medical Products, Drugs, Biologics, Medical Devices, Orphan Products This report uses the term medical product to cover drugs, biologic products, and medical devices. The legal definition of drugs includes products "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease" and (except for foods)
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For example, clinical studies involving medical devices are eligible for the research grants program created by the Orphan Drug Act. Devices targeted by these incentives may be included under the general label of orphan medical products or orphan products.
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. This report generally follows the description developed by the IOM Clinical Research Roundtable, which distinguished two arenas of translational research (Sung et al., 2003)
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. As discussed in Chapters 3 and 5, studies involving products to treat rare diseases often differ from BOX 1-6 Types of Clinical Trials Phase I trials initiate the study of candidate drugs in humans.
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However, the latter typically is viewed as building on the discoveries of basic research and focusing on the preclinical and clinical studies necessary to demonstrate safety and efficacy as required for FDA to authorize the marketing of drugs and certain medical devices. The phrase research and development is commonly used for this spectrum of activity, which is usually undertaken by commercial firms.
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