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Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development; Field MJ, Boat TF, editors. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington (DC): National Academies Press (US); 2010.

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Rare Diseases and Orphan Products: Accelerating Research and Development.

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Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease.

William Harvey, 1657

William Harvey's observation, familiar to many who study rare diseases, is echoed today in explanations of the broader significance of research on diseases that affect small populations. For example, research on Wilms tumor, a rare pediatric cancer, has been cited as a model for understanding the genetics, epigenetics, and molecular biology of pediatric cancers and cancers generally (see, e.g., Feinberg and Williams, 2003). Studies of Tangier disease (an extremely rare condition in which a gene associated with cholesterol processing does not function properly) have illuminated a target for therapies to reduce the risk of heart disease and have also provided insights into Alzheimer disease (Delude, 2009). Research on Liddle syndrome (a rare inherited kidney disorder associated with early and severe hypertension) has contributed to knowledge about the pathology of hypertension (Lifton et al., 2001), and studies of Fanconi anemia have illuminated disease mechanisms of bone marrow failure, cancer, and resistance to chemotherapy (D'Andrea, 2010). More generally, “patients with rare genetic disorders have fueled progress in the fields of human genetics and molecular therapeutics through their enthusiastic participation in research, often based on a remote promise of personal gain and at a very real personal expense” (Dietz, 2010, p. 862).

Delineating the general value or multiplier effect of research on specific rare diseases is important because such research may otherwise be undervalued when policy makers consider the absolute numbers of people likely to benefit from a particular public investment in research. Studies of rare diseases often meet other criteria that policy makers consider, for example, that the condition to be studied imposes a serious burden on the health and well-being of affected individuals.

Notwithstanding the label rare disease, most adults probably have known at least one person and possibly several people who have a rare condition. They may have grieved with a family that lost an infant to trisomy 13 or another rare chromosomal disorder. They may know a child or young adult who is living with sickle cell disease or Marfan syndrome. 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. 97-414): a disease or condition that affects fewer than 200,000 people in the United States (21 USC 360bb). Less common is a large group of rare diseases that affect perhaps a few hundred to a few thousand individuals each but that are generally unknown to most people, including many physicians. In addition, the published literature includes hundreds of extremely rare conditions with reported numbers of affected individuals in the single or double digits, for example, atransferrinemia (a metabolic disorder affecting the transport of iron through the blood) (Beutler et al., 2000) and reticular dysgenesis (a severe immunodeficiency disorder) (Pannicke et al., 2009).

Various estimates place the number of rare conditions at 5,000 to 8,000, and newly identified disorders are reported almost weekly (see Chapter 2). Box 1-1 shows just a few examples of the variety of rare diseases. Most result from genetic mutations, often inherited. Others are caused by infectious or toxic agents. The cause of some is unknown.

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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), or be of unknown origin. One literature (more...)

In aggregate, rare diseases afflict millions of Americans of all ages and more millions globally. Most are serious and life-altering, and many are life-threatening or fatal. Because the number of people affected with any one specific rare disease is relatively small, a host of challenges complicates the development of effective drugs and medical devices to prevent, diagnose, treat, or cure these conditions. In recent decades, scientists, advocates, policy makers, and others have done much to try to address these challenges. Yet despite these efforts, only a small fraction of rare diseases currently have effective treatments.

This report describes how scientific and technological advances on many fronts—combined with supportive public policies and private initiative— offer opportunities to intensify research on the causes and mechanisms of rare diseases and to reduce the number of rare diseases with no or inadequate means of prevention or treatment. It proposes an integrated strategy for the United States to accelerate research on rare diseases and increase the options for diagnosing, treating, and preventing these diseases. Box 1-2 outlines the elements of an integrated strategy.

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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 (more...)

Components of each of these elements of an integrated strategy already exist, some more robust than others. It is, however, difficult to achieve coherence because so many participants with differing perspectives and priorities are necessarily involved. Collaboration and continuing evaluation, which are always challenges, are particularly difficult given the number and diversity of rare diseases and the limited and even undocumented resources devoted to them individually and collectively. Thus, this report proposes further steps to develop a more integrated approach to rare diseases research and product development.

The rest of this chapter provides an introduction to rare diseases and orphan products, including a policy overview and definitions of key terms. Chapter 2 presents a profile of rare diseases, including information about their epidemiology and causes; their prevention, diagnosis, and treatment; and their impact on individuals and families. 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. Chapter 4 highlights some of the scientific and technological advances that are reshaping the study of rare diseases and the identification of promising therapies. In Chapter 5, the focus shifts to the complexities of moving from a promising therapy to an approved drug. Chapters 4 and 5 both discuss the infrastructure needed for the conduct of basic and clinical research on rare diseases and models of innovation to accelerate research and development. (Appendix E lists the consortia funded by the NIH Rare Diseases Clinical Research Network, and Appendix F presents illustrative examples of the research strategies of selected advocacy groups.)

Because the coverage and payment policies of Medicare, Medicaid, and private health plans may influence the product development decisions of pharmaceutical and biotechnology companies, Chapter 6 describes some key features of these policies. It also briefly reviews health plan coverage of certain clinical care expenses in clinical trials. (Appendix C analyzes the coverage of orphan drugs by private prescription drug plans for Medicare beneficiaries.)

The development and regulation of drugs and medical devices differ in significant respects. Chapter 7 consolidates much of the discussion of medical devices, including device regulation, incentives for the development of devices for small populations, and coverage and reimbursement. Chapter 8 recaps the elements of a more integrated approach to rare diseases research and product development and proposes a process to encourage the implementation of this approach.


For some rare conditions, scientific progress has brought dramatic improvements in the length and quality of life for patients. The following are just a few examples.

  • In the 1960s, children with cystic fibrosis faced an average life expectancy of less than 10 years; today, a cure remains elusive, but targeted treatments have helped increase average life expectancy to nearly 40 years (CFF, 2008).
  • Research into the basic mechanisms of disease has laid the foundation for therapeutic advances that have transformed the lives of patients (and families) affected by such diverse conditions as phenylketonuria (an enzyme deficiency disorder) and chronic myeloid leukemia.
  • Other research has contributed to progress in prevention, for example, by providing the knowledge that has allowed women to follow simple nutritional measures before and during pregnancy to reduce the incidence of birth defects such as spina bifida.

Notwithstanding the successes, many rare conditions still lack even basic understanding of the mechanisms that underlie them—much less effective treatments. In clinical practice, one of the complexities of rare diseases is that many are so rare that most physicians, even specialists, have never encountered a single patient with the condition. Diagnosis is often difficult and may take years as one diagnosis after another is considered and eventually ruled out. If an effective treatment is available, a patient with a delayed diagnosis may suffer preventable and irreparable harm.

In recent years, innovative approaches to basic research have made the identification of genetic causes of rare diseases easier, faster, and less expensive, although painstaking work may then be required to delineate how a genetic defect in combination with other factors leads to the physical or mental expressions of a disease. At the same time, the study of common conditions is subdividing many of them into smaller and smaller—even rare—molecularly defined subgroups with different therapeutic profiles and different product development requirements. These investigations offer the promise of personalized medicine with more targeted treatments, but researchers studying therapies for narrower and narrower disease subgroups of common conditions will also likely share with rare disease researchers the difficulties of conducting clinical studies on small patient populations.

Some of the same research approaches and technologies that contribute to the faster and more efficient identification of genes are also altering the processes of drug discovery and development and increasing the efficiency of procedures to identify and refine promising drug candidates to treat rare conditions. These strategies could reduce the time and cost of drug development for both common and rare conditions. Scientific advances have also revolutionized the development of medicines derived from biological sources. Such biological products are particularly prominent in treatments for a number of very rare conditions that arise from an array of different enzyme deficiencies. 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) is allocating more resources to promote the translation of basic science discoveries into clinically significant products and is investing in sophisticated informatics and other tools to support the sharing of data, biological specimens, and other research resources.

In addition to the dramatically changing landscape of science and technology, other political and social developments have also altered the environment of rare diseases research and product development. As described further below, the Orphan Drug Act, enacted in 1983, provides incentives for companies to develop products for rare diseases. Since 1983, the Food and Drug Administration (FDA) has approved more than 350 orphan drug applications. Drugs for rare conditions accounted for more than 30 percent of the innovative drugs approved by FDA from 2004 to 2008 (Coté, 2009). NIH has created the Rare Diseases Clinical Research Network and other targeted programs of research for a number of rare diseases. 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.

Certainly, daunting obstacles remain to continued advances in rare diseases research and product development. These obstacles range from attracting funding from public agencies for basic and translational research to securing commercial investments to develop products for very small markets. Even with funding, researchers often struggle to obtain enough biological specimens for critical preclinical studies or to identify and recruit enough research participants for clinical trials of a product's safety and efficacy. Difficulties and costs mount to the extent that a product under study has a subtle effect or one that emerges slowly. Identifying and winning acceptance of biological markers and surrogate measures of disease and treatment effects is challenging for researchers investigating common conditions and even more so when the condition is rare. Attracting trained investigators to the study of a rare disease is another challenge.

Despite the obstacles, with support from NIH, FDA, and a variety of philanthropic and industry sources, researchers are studying hundreds if not thousands of rare diseases, including some that are extremely rare. Box 1-3 highlights one example of research progress involving Hutchinson-Gilford progeria syndrome, an extremely rare condition that physicians have diagnosed in only a few dozen children worldwide. These and other examples of scientific progress with rare diseases offer encouragement and motivation for continuing efforts to bring the advances in science and technology more fully to bear on rare diseases and thereby accelerate the creation of knowledge that will lead to more and more effective means of prevention, diagnosis, and treatment.

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BOX 1-3

Organized Research on Exceptionally Rare Diseases Is Possible. Hutchinson-Gilford progeria syndrome is a lethal condition caused by a mutation in a single gene. Children with the condition appear to age prematurely and experience stiffness of joints, (more...)


Creating Policy Incentives for Product Development

The development of significant drugs of limited commercial value represents 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 encourage research on medical problems of limited scope which may later have great beneficial effect.

Interagency Task Force, 1979, p. 1

More than 30 years ago and after years of discussion and concern, a task force created by what is now the U.S. Department of Health and Human Services (DHHS) issued a call for action in a report on what might be done to promote the development of drugs with limited commercial value. Although a particular focus was drugs aimed at small groups of patients affected by rare diseases, concern extended to drugs intended for larger populations that were, for various reasons (e.g., lack of patentability; need for long-term trials to demonstrate efficacy), not attractive development targets for pharmaceutical companies (see, e.g., Asbury, 1985). Creation of the interagency task force in 1978 came after hearings on the recommendations of a congressionally created Commission for the Control of Huntington's Disease and Its Consequences, calls for action from the Neurologic Drugs Advisory Committee of FDA, and pressure from other individuals and groups that were highlighting the barriers to the development of therapies for rare conditions and proposing government action to overcome these barriers (Asbury, 1985). (Table 1-1 highlights these and other significant events in the evolution of public policy on rare diseases and orphan products.)

TABLE 1-1. Time Line of Selected Events Relevant to Policies Promoting Research and Development for Rare Diseases and Orphan Products.


Time Line of Selected Events Relevant to Policies Promoting Research and Development for Rare Diseases and Orphan Products.

The pharmaceutical industry reportedly declined to participate in the task force, but the Pharmaceutical Manufacturers Association (now the Pharmaceutical Research and Manufacturers of America) surveyed its member firms in 1978 and developed an inventory of company activities related to drugs for rare conditions (Asbury, 1985; Haffner, 1991). This survey reported that the association's member companies had marketed 34 drugs that were primarily for rare conditions. Of these, 28 targeted conditions that affected fewer than 100,000 people in the United States; 3 were for conditions affecting 100,000 to 500,000 people, and the other 3 were for conditions affecting 500,000 to 1 million people (Asbury, 1991). Of the 34 products, 24 benefited significantly from federal funding for research and development. In addition to marketed products, the survey reported another 24 experimental drugs that companies had made available to specialists treating patients with rare conditions. Other sources identified an additional 13 approved products for rare conditions that had federal agencies or academic scientists as sponsors (Asbury, 1991).

The 1979 interagency task force report proposed a voluntary program to encourage drug development by pharmaceutical companies, nonprofit organizations, or consortia. The federal government would act as a catalyst, for example, by providing some form of financial subsidy (e.g., loans, contracts, or purchase arrangements with individual companies) and by offering priority in the review of new drug approval applications. The report also mentioned the possibility of legislation creating tax and patent incentives. Although the subsidy concept was not particularly influential, the ideas for tax and patent-like incentives were featured in legislation that was adopted just a few years later.

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. The legislation defined rare disease or condition to mean “any disease or condition which occurs so infrequently in the United States that there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States of such drug” (21 USC 360bb(a)(2)). Reflecting difficulties in applying this definition to actual situations, Congress amended the law in 1984 to define a rare disease as a disease or condition that affected fewer than 200,000 people in the United States—without regard to the expected commercial value of a product to such a condition. Commercial value is, however, a consideration in a second provision that allows the law's incentives to apply to products affecting more than 200,000 people if there is no reasonable expectation that the sales of the drug will recover the costs of developing it. In regulations issued in 1992, FDA clarified that when a sponsor is seeking orphan designation for a drug to treat a subset of persons with a particular disease or condition, the sponsor must shown that the subset is medically plausible (57 FR 62076; 21 CFR 316.20(b)(6)).

As described in more detail in Chapter 3, the Orphan Drug Act and other policies provide several incentives for orphan drug development. They include

  • seven years' protection from market competition for approved orphan drugs (market exclusivity);
  • grants to support product development;
  • tax credits for certain costs associated with clinical trials on orphan drugs;
  • waiver of fees charged to those applying for FDA approval of a drug; and
  • advice to product developers on the design of studies of safety and effectiveness to meet regulatory standards.

The first approvals of orphan drugs came the year the law was passed. Although the research supporting these drugs had to have been well under way or completed before 1983, the early applications for approval indicated industry's recognition of the incentives of the new law.

Also in 1983, several individuals who were active in pressing for legislation formed the National Organization for Rare Disorders (NORD). As an umbrella organization for groups supporting patients and families affected by rare conditions, NORD advocates for the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and service.1

In 1985 amendments to the Orphan Drug Act, Congress directed DHHS to create a new commission to take a broad look at orphan diseases. The National Commission on Orphan Diseases issued its report in 1989. It made a number of wide-ranging recommendations, including recommendations for the provision of better information for patients and physicians; increased funding of FDA product approval activities; and coverage by insurers for patients with rare diseases who are prescribed “off-label” use of drugs that were FDA approved only for nonorphan indications (NCOD, 1989). The report particularly focused on the need for expanded research on rare diseases and additional promotion of orphan product development.

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 support sharing of data, biological specimens, and other resources (especially “precompetitively”); better tracking of NIH funding of rare diseases research; efforts to assure that drug development studies sponsored by NIH meet FDA criteria for marketing approval; and, generally, adequate resources and expertise to support FDA guidance for drug and device developers and review of marketing applications.

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. In the Safe Medical Devices Act of 1990, Congress created the Humanitarian Device Exemption for devices to treat or diagnose a disease or condition that affects fewer than 4,000 individuals and that meet certain other conditions. This process allows FDA to approve a complex medical device based on evidence of safety and probable benefit without evidence of efficacy. This provision may reduce the time and costs required to develop evidence to support FDA approval, but an approval comes with significant restrictions, including a provision for cost recovery but not profits and limits on annual shipments of a device.

Periodically, legislators and others become concerned about reports citing the high price of some orphan drugs, including drugs that achieve blockbuster status (earning more than $1 billion a year). Several proposals have been introduced in response to such concerns. In 1990, Congress passed legislation that would have limited market exclusivity in some circumstances, but the President vetoed it (Schact and Thomas, 2009).

Promoting Research on Rare Diseases

In addition to promoting the creation of public policies to encourage industry to invest in product research and development, advocates also sought to establish a focus for rare disease research in the National Institutes of Health.2 In 1993, the National Institutes of Health created the Office of Rare Diseases to promote research on rare conditions and help develop a more systematic strategy for such research. Congress provided statutory authorization for the office in 2002 and directed it, among other tasks, to recommend a research agenda, promote coordination within NIH, promote use of NIH resources for rare diseases research, and support the creation of a central clearinghouse of information on rare diseases. In 2000, an NIH panel produced a congressionally mandated report that led to the permanent establishment of the Office of Rare Diseases Research (ORDR) and the creation of a rare diseases clinical research initiative. By 2009, ORDR had designated as parts of a Rare Diseases Clinical Research Network nearly 20 research consortia, each involving a number of research institutions studying several related rare conditions (NIH, 2009a). (Appendix E lists the consortia and conditions.)

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. A number of grants have led to approved products.

Beyond DHHS, other federal agencies also have other research programs and activities that fund some research on rare conditions or orphan products. At the Department of Defense, the Congressionally Directed Medical Research Programs, which began with a directive for research on breast cancer, has also administered earmarked programs of research on other conditions, including several rare conditions—neurofibromatosis, ovarian cancer, tuberous sclerosis, and amyotrophic lateral sclerosis (CDMRP, 2008; see also Chapter 2).

Notwithstanding the visibility of the research programs of NIH, pharmaceutical, biotechnology, and medical device companies fund the major part of biomedical research in the United States (Table 1-2). Together, their spending accounted for nearly three-fifths (58 percent) of the total.

Table 1-2. Funding for Biomedical Research in the United States by Source, 2007.

Table 1-2

Funding for Biomedical Research in the United States by Source, 2007.

In addition to financing product development, commercial firms are almost always responsible for meeting the regulatory requirements necessary to obtain FDA approval to market drugs, biologics, and certain complex medical devices. They likewise manufacture and distribute products consistent with regulatory standards. Chapters 5 and 7 discuss the role of the private sector in product development in more depth.

Following the early initiatives of the Cystic Fibrosis Foundation and the Committee to Combat Huntington's Disease, an increasing number of patient advocacy groups have become active in research. They have helped create innovative models for funding and organizing research and product development. The emphases of advocacy groups vary, depending in part on the state of the science within different disease areas and in part on other factors that may include the number of affected individuals, the interests and skills of organizational founders and leaders, and the success of fundraising strategies. If researchers have not yet identified the genetic or other cause of a condition or delineated how the disease develops, a group may concentrate its grants and other activities on closing these gaps in knowledge.

Policies of Other Countries and International Initiatives

The policies of the United States on orphan drugs and pharmaceuticals do not exist in isolation. 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) but not all (e.g., the availability of grants). Table 1-3 summarizes selected policies.

TABLE 1-3. Comparison of Selected National Policy Incentives for Orphan Drug Development.


Comparison of Selected National Policy Incentives for Orphan Drug Development.

FDA, regulatory agencies in other countries, industry, and advocacy groups have engaged in discussions to harmonize various aspects of orphan product policies (see, e.g., Wechsler, 2008). One result is that the European Medicines Agency (EMEA) and the FDA have adopted a joint application form for orphan product designation. Each agency still makes its own decisions, but the two regularly communicate about application reviews. Work to harmonize views on what constitutes acceptable clinical trial design and analytic strategies is particularly important when patient populations are small, multi-nation studies are essential, and confirmatory trials are difficult or impossible.


This Institute of Medicine (IOM) 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. In 2009, the IOM appointed a 14-person committee to oversee the study. Consistent with its charge (which is presented in full in Appendix A), the committee

  • examined the epidemiology, impact, and treatment of rare diseases as context for an assessment of research and development;
  • investigated the strengths and limitations of the current development pathways for new drugs, medical devices, and biologics for rare diseases;
  • assessed public policies that may influence research and development decisions involving rare diseases and orphan products; and
  • developed recommendations for an integrated national policy on rare diseases research and orphan product development.

This report presents the committee's conclusions and recommendations. It is written for a broad and diverse audience, including public officials in research and regulatory agencies; advocacy and philanthropic groups that support rare diseases research and orphan product development; companies that develop pharmaceutical, medical device, and biologic products; academic medical centers, research institutes, and researchers engaged in basic and clinical research; and the interested general public.

In developing its conclusions and recommendations, the committee reviewed the literature on rare diseases and orphan product development and also examined the broader literature on scientific and policy issues related to medical product discovery and development. 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. (Committee activities are summarized in Appendix A.)

Given the very broad scope of its task, the committee did not investigate international strategies to promote research and product development for diseases that are rare in the United States but common in less developed countries. Thus, this report does not examine in depth the various initiatives related to neglected tropical diseases such as Chagas disease, onchocerciasis (river blindness), and trypanosomiasis or sleeping sickness.

In addition, some issues were outside the committee's task, for example, research and development related to medical foods.3 Also, consistent with its statement of task, the committee largely limited its investigations to rare diseases research and orphan product development through the stage of FDA approval of a product for marketing. Many products for rare diseases are approved with requirements for postmarket studies, but the committee did not examine the conduct, outcomes, or FDA review of these studies. It also did not review health services research on the translation of research findings and achievements into clinical practice.

Notwithstanding its focus on research and development, the committee recognized the crucial importance of applying preventive, diagnostic, and therapeutic advances in clinical care, public health practice, and personal behavior. Without this further effort, scientific advances will not benefit individual and public health. Also, it is often in clinical practice that the limitations of products are revealed when drugs or devices that were studied under highly controlled conditions with carefully selected populations are used in real-world conditions with broader populations.


This section discusses a number of key concepts and definitions. Appendix D includes a glossary that defines additional terms.

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.

Defining and Tabulating Rare Diseases

This report follows the statutory definition of a rare disease or condition as one that affects fewer than 200,000 people in the United States. As is true of many qualitative descriptions or definitions of magnitude, any operational definition of a term such as “rare” is subjective. That subjectivity is reflected in the variations in definitions adopted by different national policymakers as shown in Table 1-4. Some definitions specify absolute numbers of affected people whereas others specify rates. Japan and, in particular, Australia define “rare” more conservatively than the United States or the European Union. In contrast to the policy of the European Union, the U.S. definition does not specify that a disease condition must be chronically debilitating or life-threatening. In general, however, the committee found that public programs and industry activities tended to concentrate on serious conditions.

TABLE 1-4. Prevalence Criteria for the Definition of Rare Disease in Selected Countries.


Prevalence Criteria for the Definition of Rare Disease in Selected Countries.

Because the U.S. figure as defined in 1984 amendments to the Orphan Product Act is an absolute number—200,000—and because the U.S. population has grown since 1984, the prevalence threshold expressed as a rate has dropped in the United States from 85 per 100,000 population in 1984 to 66 per 100,000 population in 2008. It is thus coming nearer to the European rate of 50/100,000. If the legislative definition of rare disease had been expressed as the 1984 rate, a rare disease could have affected nearly 258,000 people in the United States as of 2008.

Overall, the committee views the choice of a number rather than a rate to be reasonable. It is consistent with the rationale that conditions affecting small numbers of people may create particular problems for research and product development that may require special responses, including incentives of the kind adopted by Congress in 1983.

Estimates of the number of rare diseases in the United States and Europe range from approximately 5,000 conditions to approximately 8,000 (see, e.g., European Commission, 2007; FDA, 2009c; NIH, 2009a). The Office of Rare Diseases Research at the National Institutes of Health includes more than 6,800 conditions in its list of rare diseases, which is available online ( The preface to the list states that it is based on “either (1) terms for which information requests have been made to the Office of Rare Diseases Research, the Genetic and Rare Diseases Information Center, or the National Human Genome Research Institute; or (2) diseases that have been suggested as being rare.” It acknowledges that inclusion in the list does not guarantee that a condition is rare.

A European organization, Orphanet,4 has been working more systematically to identify and classify rare conditions along several dimensions. These include prevalence, age at onset, pattern of inheritance, prevalence, clinical category (e.g., neurological), and identifier in the Online Mendelian Inheritance in Man (OMIM) database.

Although the committee concluded that the Orphanet database was not yet sufficiently developed to use for a comprehensive quantitative categorization of rare diseases, it proved a useful resource (see Chapter 2). 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), which summarizes information (e.g., differential diagnosis, signs and symptoms, etiology/epidemiology, and treatment) on 800 conditions. The emphasis in the guide is on conditions that are not adequately described in medical texts or are frequently misdiagnosed.6

The NIH and the Orphanet lists of rare diseases are similar but not entirely consistent. For example, the latter includes familial breast cancer, whereas the NIH list does not. Conversely, only the NIH list includes inflammatory breast cancer and childhood breast cancer. The discussion at the Orphanet website observes that “whether a single pattern is considered unique depends on the state of our knowledge, on the accuracy of clinical and investigative analysis and on the way we choose to classify diseases in general” (Orphanet, undatedb). Factors that are likely to contribute to inconsistencies in the two lists include differences in

  • prevalence thresholds for labeling a condition as rare in the United States compared to the European Union (see Table 1.3 above);
  • actual frequency of certain conditions in the United States compared to Europe;
  • decisions about listing subsets of common conditions that are defined by clinical features such as age, magnitude of an anatomical defect, or injury or failures to respond to conventional treatment;
  • 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. Reports of new diseases and syndromes are frequent. In 2009, the monthly Orphanet newsletters announced 48 newly reported syndromes, most of which involved very small numbers of individuals (see Box 1-4 for examples).

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BOX 1-4

Examples of Ongoing Reporting of New Rare Syndromes in Orphanet Newsletter. Combined immunodeficiency, facial dysmorphism, optic nerve atrophy, skeletal anomalies and developmental delay: Combined immunodeficiency can be isolated or associated with abnormalities (more...)

Another complexity in categorizing a condition as rare involves conditions that are common when defined by genotype (the number of people who have a genetic mutation) but not common if defined by phenotype (the number of people who have clinically evident disease as determined by symptoms and tests). Box 1-5 summarizes the issue as presented by hemochromatosis, a disorder of iron metabolism. Classic hemochromatosis is not listed among rare diseases by ORDR. Orphanet lists the condition but describes the major form as not rare based on genotype alone.

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BOX 1-5

Rare by Genotype or Rare by Phenotype: The Example of Hemochromatosis. Hemochromatosis is a disorder of iron metabolism. In 2001, analysts estimated that 718,000 individuals in the United States were homozygous for the C282Y mutation, which is associated (more...)

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) “intended to affect the structure or any function of the body of man or other animals” (21 USC 321(g)(1)). FDA includes biological products in this definition, although drugs are chemically based and biologics are derived from natural sources such as human cells or microorganisms (see Chapter 3 and Appendix D for fuller definitions). A medical device is a product that is intended for diagnostic, preventive, or therapeutic use that does not achieve its primary effect through chemical action on the body or through metabolic processes (see the more detailed legal definition in Chapter 7 and Appendix D).

As defined by statute, orphan drugs are, in general, medicines (including biological products) intended for people with rare diseases, that is, diseases affecting fewer than 200,000 people in the United States. If, however, the drug is a vaccine, diagnostic drug, or preventive drug, then orphan designation is possible if the drug would be administered in the United States to fewer than 200,000 per year. Moreover, if it is to treat a disease that affects a larger number of people, then a drug may be still designated as an orphan in certain situations in which there is no reasonable expectation that costs of research and development of the drug for a particular medical indication can be recovered by sales in the United States.

No law creates a category of orphan medical devices, but policymakers have created some incentives to encourage the development of devices for small populations with unmet needs. 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.

Drugs, including orphan drugs, are designated and approved for specific indications. An indication describes a particular use of a drug or device. That use may involve a disease generally. The approved indication may also be limited to a medically plausible subset of people with a disease or condition, for example, those with advanced disease that is not responsive to commonly used treatments. As a case in point, FDA recently approved collagenase clostridium histolyticum (Xiaflex) for treatment of advanced Dupuytren contracture, a condition that can severely limit hand functioning (Rosebraugh, 2010). Physicians may legally use drugs off-label for unapproved indications, but companies may not promote such uses.

Neglected Diseases

As noted above, the committee did not examine research and drug development for diseases that are rare in the United States and other wealthy countries but common in many developing nations. The term neglected disease is applied, in particular, to certain tropical infections that are overwhelmingly concentrated in the world's poorest countries and that still lack adequate incentives for drug development or mechanisms to make existing treatments available. Examples include

  • leishmaniases, a parasitic disease that has several forms (most commonly affecting the skin or the internal organs). It is estimated to infect an estimated 12 million people worldwide (WHO, 2009b) but is reported only occasionally in the United States in people who are thought to have acquired the disease outside the country (CDC, 2008a);
  • dengue fever, which is caused by one of four viruses transmitted by mosquitoes, is rare in the continental United States (and generally is acquired during travel elsewhere). It has emerged as a significant health concern in the past half century and now affects an estimated 50 to 100 million people each year worldwide (CDC, 2009a); and
  • schistosomiasis, a multi-organ disease caused by parasitic worms that infects approximately 200 million people worldwide but is not present in the United States (CDC, 2008c).

For some diseases such as tuberculosis and malaria, cost and other factors have limited the use of existing treatments and preventive strategies in poor countries.8 Beyond humanitarian considerations, the increase in drug-resistant strains of infectious diseases that are now rare in developed countries has added to interest in the development of innovative preventive and therapeutic approaches to such diseases.

Research and Product Development

Broadly defined, basic research in medicine involves systematic study intended to build fundamental knowledge and understanding of the biological mechanisms and processes that underlie illness and health. Its practical applications are often unanticipated, although studies such as those to identify the genes that cause disease and the ways in which they do so are generally undertaken with the hope that success will provide the foundation for further research to develop means of preventing, diagnosing, or treating the disease.

Translational research has been variously defined (see, e.g., Woolf, 2008). This report generally follows the description developed by the IOM Clinical Research Roundtable, which distinguished two arenas of translational research (Sung et al., 2003). The first, which is the focus of this report, involves “the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans” (p. 1279). Such research aims to traverse what is sometimes called the “valley of death,” an allusion to the shortfall in the applied research and support activities (e.g., establishing collaborations with industry, attending to intellectual property issues, and planning for FDA requirements) that is necessary to achieve this movement. The second area of translational research involves “the translation of results from clinical studies into everyday clinical practice and health decision making” (p. 1279), which is essential if patients, families, and society are to benefit.

Clinical research involves studies with humans. Chapter 5 discusses the stages of clinical research from the earliest human studies of safety and drug dosing through the usually complex investigations of safety and efficacy that are used to support FDA approval of a product.

Four stages or phases of clinical research are typically distinguished (Box 1-6). The focus initially is on establishing safety and then extends to include effectiveness (see, e.g., CDER, 1998). As discussed in Chapters 3 and 5, studies involving products to treat rare diseases often differ from studies that are typical for common diseases (e.g., by involving many fewer research participants).

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BOX 1-6

Types of Clinical Trials. Phase I trials initiate the study of candidate drugs in humans. Such trials typically assess the safety and tolerability of a drug, routes of administration and safe dose ranges, and the way the body processes the drug (e.g., (more...)

The biomedical research enterprise overlaps with many aspects of medical product development. 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.

Efficacy and Effectiveness

The achievement of desired results in controlled clinical studies (efficacy) is not the same as the achievement of desired results in actual clinical practice (effectiveness). After a product enters clinical use, problems may emerge that were not evident in clinical testing. Although FDA statutes and regulations use the term effectiveness to describe positive results reported in clinical trials, FDA review documents often employ the term efficacy rather than effectiveness in discussing clinical data used in approving a new drug.

When it approves a drug or medical device for marketing, FDA may require the sponsor to undertake postmarketing studies to provide additional evidence of safety or effectiveness or both. This report focuses on research to demonstrate safety and efficacy through the stage of clinical testing prior to FDA approval of a product.



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). Some of these groups have since merged with similar groups or have changed their names. (Note: This report generally does not use the possessive form for eponymous disease names except when referring to organizations that use the possessive form.)


References to NIH in this report refer (unless otherwise specified) to all programs of the NIH, which is composed of 27 research institutes and centers. Medical research activities are supported and conducted by the Extramural Research Programs and the Intramural Research Scientific Programs, including the NIH Clinical Center hospital.


FDA says that to be considered a medical food, a product generally “must, at a minimum, meet the following criteria: the product must be a food for oral or tube feeding; the product must be labeled for the dietary management of a specific medical disorder, disease, or condition for which there are distinctive nutritional requirements; and the product must be intended to be used under medical supervision” (CFSAN, 2007). FDA does not review or approve medical foods before they are marketed.


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. Orphanet includes a Professional Encyclopaedia, which is expert-authored and peer-reviewed, a Patient Encyclopaedia and a Directory of Expert Services. This Directory includes information on relevant clinics, clinical laboratories, research activities and patient organisations” (Orphanet, undateda).


OMIM is a catalog of human genes and genetic disorders that emphasizes inherited conditions. For a particular genetic disorder, it will summarize and cite literature about the clinical features of a genetic disorder, its diagnosis, and its pattern of inheritance, molecular genetics, prevalence data, and other features.


NORD also has an online index of more than 1,100 conditions on which it has reports for sale. Some of the conditions, for example, sleep apnea and tinnitus, are not rare.


One useful feature of the OMIM and Orphanet listings is that they include alternative names for conditions—although they may differ in the alternatives offered. For example, for familial Mediterranean fever, the OMIM entry lists “polyserositis, recurrent” and “polyserositis, familial paroxysmal” whereas the alternative in the Orphanet entry is “periodic disease.”


The United States saw approximately 12,900 new cases of tuberculosis reported in 2008 (CDC, 2009b), but more than 9.25 million new active cases were estimated worldwide in 2007 (WHO, 2009a). Approximately 1,500 new cases of malaria were reported in the United States in 2002 with a worldwide estimate of 350 million to 500 million new and previously diagnosed cases (CDC, 2007b). Tuberculosis and malaria are the subjects of substantial international research and development investments to improve treatments, and related initiatives seek to make treatments affordable for poor countries and individuals.

Copyright © 2010, National Academy of Sciences.
Bookshelf ID: NBK56194


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