In aggregate, rare diseases affect millions of Americans of all ages and additional millions of people globally. Most of these conditions are serious and life-altering. Many are life-threatening or fatal.
Some rare conditions are extremely rare, with the number of reported cases in the single or low double digits. Others occur in hundreds, thousands, or tens of thousands of people. Many of the estimated 5,000 to 8,000 rare conditions are genetic or have a genetic component. Others arise from exposure to infectious agents or toxins and, occasionally, from adverse responses to therapeutic interventions. Although prevalence information is incomplete and often unsatisfactory and frequently consists only of case reports, it appears that the distribution of rare conditions is skewed to the rarest.
Because the number of people affected with any particular rare disease is relatively small and the number of rare diseases is so large, a host of challenges complicates the development of safe and effective drugs, biologics, and medical devices to prevent, diagnose, treat, or cure these conditions. These challenges include difficulties in attracting public and private funding for research and development, recruiting sufficient numbers of research participants for clinical studies, appropriately using clinical research designs for small populations, and securing adequate expertise at the government agencies that review rare diseases research applications or authorize the marketing of products for rare conditions.
In recent decades, scientists, advocates, policy makers, medical product companies, and others have done much to respond to these challenges. Innovative approaches to basic research are making the identification of
genetic causes of rare diseases easier, faster, and less expensive. Some of the same research approaches and technologies are also altering the processes and efficiency of therapeutic discovery and product development for rare conditions.
Political and social developments also have altered the environment of rare diseases research and product development. Nearly 30 years ago, Congress passed the Orphan Drug Act, which provided incentives for companies to develop drugs for rare diseases. The law defines a rare disease or condition as one affecting fewer than 200,000 people in the United States. Since 1983, the Food and Drug Administration (FDA) has approved orphan drugs for approximately 355 uses or indications, and orphan drugs account for a significant proportion of the innovative drugs recently approved by the agency. Devising effective incentives for medical device developers has been particularly difficult, but more than four dozen devices have been approved under policies to encourage the development of devices for small populations.
At the National Institutes of Health (NIH), the Office of Rare Diseases Research (ORDR) undertakes a range of activities to encourage and support research on rare conditions. The Rare Diseases Clinical Research Network funds consortia to study groups of related rare conditions. The new Therapeutics for Rare and Neglected Diseases program aims to bring promising compounds to the point of clinical testing and adoption for further development by commercial interests. In the private sector, several small pharmaceutical companies now focus on drugs for rare diseases, and some large companies are expressing increased interest in the incentives for orphan drug development.
In addition, the substantial physical, emotional, and financial impact of rare diseases on individuals and families has motivated many to join together to try to have an impact on these diseases through research that unravels their causes and yields effective therapies. An increasing number of advocacy groups not only promote and fund research but also initiate and organize research in partnership with academic researchers, industry, and government.
Notwithstanding the successes, many rare conditions still lack even a basic understanding of their cause or the mechanisms that underlie them. Effective products are now available for only a small fraction of rare diseases.
In response to the difficulties confronting rare diseases research and orphan product development, NIH with support from FDA approached the Institute of Medicine (IOM) about a study to examine the opportunities for and obstacles to the development of drugs and medical devices to treat rare diseases. They requested a report that would assess strategies and propose an integrated national policy to accelerate rare diseases research and
orphan product development. Consistent with its charge, the study committee that prepared this report did not examine medical foods or dietary supplements. Although it did not investigate initiatives involving neglected tropical diseases that are rare in the United States but common in many less developed countries, it did consider the applicability of some of these initiatives to this country. The committee was not asked to examine strategies for moving scientific advances into clinical care, public health practice, and health-related personal behavior and ensuring that they actually benefit individual and public health. The challenges of doing so are many and will raise difficult questions of affordability and equitable access.
As envisioned by the committee, an integrated national strategy to promote rare diseases research and product development has several dimensions (Box S-1). Elements of each already exist but lack a coordinated focus. 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.
Elements of an Integrated National Strategy to Accelerate Research and Product Development for Rare Diseases
REGULATION OF DRUGS AND BIOLOGICS FOR RARE DISEASES
The Orphan Drug Act and other policies provide incentives for the development of drugs and biologic products for rare diseases. The incentives include 7 years of marketing exclusivity (a period of protection from competition), tax credits for certain research expenses, exemption from certain FDA fees, and research grants. (Except for the grants program, the statute does not otherwise cover medical devices.) The marketing exclusivity provisions of the act are widely viewed as the most important incentive of the Orphan Drug Act. In common with other drugs, sponsors of orphan drugs secure approval of the product from the Center for Drug Evaluation and Research (CDER) based on “adequate and well-controlled” investigations supporting the drug’s safety and efficacy. (Certain orphan biologic products are approved by the Center for Biologics Evaluation and Research.)
Criticisms of FDA procedures related to orphan drug development and approval tend to focus on three issues—insufficient resources for timely meetings and guidance for sponsors; inconsistency in reviews of applications for orphan drug approvals across CDER divisions; and inadequate resources for the orphan products grants program. In addition, it is sometimes stated that FDA inappropriately requires two phase III, randomized, placebo-controlled, double-blind trials to support orphan drug approvals. Analyses of recent approval records for orphan drugs, however, show that a substantial proportion did not require two phase III trials. Some have been approved on the basis of phase II trials, and at least one approval has been based on a small historical case series.
At the same time, agency staff have identified a number of problems with studies that sponsors have submitted. These include delayed toxicology studies; inadequate characterization of chemical compounds; lack of natural history studies to characterize the disease process; poor use of early-phase studies (e.g., safety, dosing) to guide the design of phase III studies; inadequate trial design (including lack of a formal protocol, well-defined question, adequate controls, validated biomarkers, and appropriate surrogate measures), and lack of advance communication with FDA about the adequacy of clinical trial plans. Given the scarce resources available for rare diseases research and orphan product development, it is particularly unfortunate for these resources to be used ineffectively.
The recent creation by FDA of the new position of Associate Director for Rare Diseases within CDER is a positive step; it underscores that the review of drugs and biologics intended for rare diseases requires special scientific and methodological attention and expertise. In general, this new emphasis in CDER should find reinforcement in FDA’s increasing efforts to strengthen regulatory science. One broad goal should be to achieve reasonable consistency in the review of similarly situated products (e.g., products
for diseases with reasonably similar prevalence and time frames or magnitudes of product effects) and to justify reasoned flexibility in expectations for differently situated products.
RECOMMENDATION 3-1: The Center for Drug Evaluation and Research should undertake an assessment of staff reviews of applications for the approval of orphan drugs to identify problems and areas for further attention, including inconsistencies across CDER divisions in the evaluations of applications that appear to present similar issues for review. Based on this assessment, CDER should
develop guidelines for CDER reviewers to promote appropriate consistency and reasoned flexibility in the review of orphan drugs, taking into account such considerations as the prevalence of the disease, its course and severity, and the characteristics of the drug; and
use the analysis and the review guidelines to inform the advice and formal guidance provided to sponsors on the evidence needed to support orphan drug approvals.
The proposed analysis should help CDER develop a better overall understanding of the adequacy of the evidence submitted and the appropriateness of clinical trial designs. This understanding may suggest modifications in educational programs and guidance on trial design.
RECOMMENDATION 3-2: The Center for Drug Evaluation and Research should evaluate the extent to which studies submitted in support of orphan drugs are consistent with advances in the science of small clinical trials and associated analytic methods. Based on its findings, CDER should work with others at FDA, NIH, and outside organizations and experts, as appropriate, to
adjust and expand existing educational programs on the design and conduct of small clinical trials;
specify which CDER and NIH personnel should complete these educational programs;
revise guidance for sponsors on trial design and analysis and on safety and efficacy reviews of products for rare diseases; and
support further work to develop and test clinical research and data analysis strategies for small populations.
The identification of possible problem areas in drug approval reviews may guide the efforts of FDA and NIH to work collaboratively on mechanisms to ensure that all phases of NIH-funded product development stud-
ies are designed to be consistent with the requirements for FDA approval. Provision of communications and assistance to sponsors should reduce the likelihood that the investments of sponsors, funders, and research participants will be used unproductively or even wasted.
RECOMMENDATION 3-3: To ensure that NIH-funded product development studies involving rare diseases are designed to fulfill requirements for FDA approval, NIH and FDA should develop a procedure for NIH grantees undertaking such studies to receive assistance from appropriate CDER drug review divisions that is similar to the assistance provided to investigators who receive orphan products grants. NIH study section review of rare diseases clinical trial applications should involve reviewers who are knowledgeable about clinical trial methods for small populations. For all sponsors of drugs for rare diseases, CDER should have resources to support sufficient and adequate meetings and discussions with sponsors from the earliest stages of the development process.
The committee concluded that funding for the orphan products grants program has lagged far behind inflation and seriously undermined an important resource. An increase would allow more qualified researchers to benefit from this focused product development program.
OPPORTUNITIES TO ACCELERATE DISCOVERY RESEARCH
Basic and then therapeutic discovery research is the foundation for the development of new preventive, diagnostic, and therapeutic products for patients with rare diseases. It identifies the causes and delineates the molecular mechanisms of these diseases as a basis for discovering therapeutic targets. The basic research tools available to biomedical investigators have changed dramatically over the past 20 years, with technological advances generating new knowledge at an unprecedented pace and, often, at lower cost for a given task. Some tools hold particular promise for rare diseases research. Also promising is the growth of innovative public-private partnerships and other collaborations to bridge the gulf between basic research findings and beneficial products.
Making the best use possible of research resources calls for arrangements that make existing knowledge and resources more accessible to rare diseases researchers and that also discourage a duplicative infrastructure of, for example, natural history data, animal models of disease, biorepositories, and chemical compound libraries. Although many barriers will have to be overcome, a “rare diseases research commons” with several unlinked or loosely linked elements should yield significant benefits.
RECOMMENDATION 4-1: NIH should initiate a collaborative effort involving government, industry, academia, and voluntary organizations to develop a comprehensive system of shared resources for discovery research on rare diseases and to facilitate communication and cooperation for such research.
This research resource would include, among other features, a repository of publicly available animal models for rare disorders and a publicly accessible database that includes mechanistic biological data on rare diseases generated by investigators funded by NIH, private foundations, and industry. It would develop model arrangements and agreements (e.g., template language on intellectual property) for making relevant portions of compound libraries available to researchers investigating rare disease.
Given the important role that NIH plays in supporting rare diseases research, a comprehensive NIH action plan on rare diseases would be useful to better integrate and expand existing work and attract new resources and investigators to the field. The following recommendation spans all phases of research on rare diseases and orphan products, including research on medical devices for people with rare diseases.
RECOMMENDATION 4-2: NIH should develop a comprehensive action plan for rare diseases research that covers all institutes and centers and that also defines and integrates goals and strategies across units. This plan should cover research program planning, grant review, training, and coordination of all phases of research on rare diseases.
DEVELOPMENT OF NEW DRUGS AND BIOLOGICS FOR RARE DISEASES
Once a potential therapeutic drug or biologic has been discovered, the process of developing the therapeutic for a particular disease, whether rare or not, begins with preclinical development and continues through increasingly complex and demanding phases of clinical testing. Much of this work has traditionally been done within companies and is expensive and risky, so companies usually choose to develop therapies with the greatest promise to generate a good financial return. As a result, potential therapies for rare diseases have often languished, even with the incentives of the Orphan Drug Act.
For product development as for basic research, a stronger infrastructure is again critically important. A major need is for innovative collaborative strategies to share and leverage resources to decrease research and development costs without sacrificing product safety or efficacy. To this end, one
priority is to expand resources and options at the preclinical stage of drug development.
RECOMMENDATION 5-1: NIH should create a centralized preclinical development service that is dedicated to rare diseases and available to all nonprofit entities.
An important strategy to reduce the time and costs for clinical studies of drugs for rare diseases involves the development and validation of biomarkers for use as surrogate endpoints in such studies. Validation is critical for FDA’s acceptance of the use of such endpoints in studies submitted to support approval of an orphan drug.
RECOMMENDATION 5-2: In collaboration with industry, academic researchers, NIH and FDA scientists, and patient organizations, FDA should expand its Critical Path Initiative to define criteria for the evaluation of surrogate endpoints for use in trials of products for rare conditions.
The expansion and improvement of patient registries and biorepositories is another important element in a strategy to accelerate rare diseases research and product development. Today, an uncounted number of organizations and researchers in this country and around the world maintain rare diseases registries in some form, sometimes for the same condition. No uniform, accepted standards govern the collection, organization, or availability of these data. The result is sometimes wasteful duplication and sometimes underuse of information or samples contributed by patients or research participants. Although it would undoubtedly be a complicated undertaking, moving toward common standards, including protections for patients and research participants, and data sharing arrangements should help resolve many of these problems.
RECOMMENDATION 5-3: The NIH should support a collaborative public-private partnership to develop and manage a freely available platform for creating or restructuring patient registries and biorepositories for rare diseases and for sharing de-identified data. The platform should include mechanisms to create standards for data collection, specimen storage, and informed consent by patients or research participants.
The committee recognizes the value of the Rare Diseases Clinical Research Network but notes its relatively limited scope and thus its limited opportunities to take advantage of unanticipated scientific discoveries. In some cases, other NIH research networks may respond with more flexibil-
ity. These networks, however, lack a specific focus on rare diseases. Existing clinical research activities can be enhanced and expanded by a program or programs that are not strictly organized around specific disease areas but rather have the flexibility to partner with or recruit other existing networks or sites to rapidly capitalize upon research advances and achieve common and broadly defined goals in rare diseases research.
RECOMMENDATION 5-4: NIH should increase its capacity and flexibility to support all phases of clinical research related to rare diseases, including clinical trials of new and repurposed therapeutic agents. Opportunities to be explored include
expanding the Rare Diseases Clinical Research Network to address opportunities for diagnostic and therapeutic advances for a greater number of rare diseases;
setting priorities for rare diseases research within other NIH clinical trials networks;
creating a study group approach to rare diseases, modeled after the Children's Oncology Group; and
building additional capability for rare diseases clinical research within the Clinical and Translational Science Awards program.
A new NIH program that is not restricted to rare diseases research but will likely benefit such research is the Cures Acceleration Network. This program will focus on significant unmet medical needs, particularly in areas that are not attractive to commercial interests. The network should supplement and build on the current infrastructure for rare diseases research.
RECOMMENDATION 5-5: NIH should establish procedures to ensure coordination of the activities of the Cures Acceleration Network with those of the Office of Rare Diseases Research, FDA’s orphan products grants program, and other existing initiatives to promote and facilitate the translation of basic science discoveries into effective treatments for rare diseases. It should build on existing resources when appropriate, avoid creating duplicative research infrastructure, and engage advocacy groups in its work.
COVERAGE AND REIMBURSEMENT
A small market is generally viewed as a disincentive for the development of pharmaceuticals. Many of the costs of developing a new drug are incurred regardless of the size of the potential market. If, however, a company can expect to set a price that is high enough to recover its costs
and to generate profits because public and private health insurance plans and patients and families will pay that price, then a manufacturer may not be deterred by a small target market. Public and private health plans that cover orphan drugs generally lack leverage to negotiate prices in the absence of alternative brand-name or generic products. The most expensive orphan drugs cost more than $400,000 per year.
The committee’s analysis focused on Medicare, which covers many individuals with severe, disabling rare conditions. Based on its examination of drug coverage under Medicare Part B (which covers drugs administered by physicians and outpatient facilities) and Medicare Part D (which covers prescription drugs in private plans administered according to government rules), the committee concluded that nearly all orphan drugs are, within a relatively short period following approval, covered either under Part B or by a majority of Part D plans. Part D plans often place orphan drugs in a “specialty” category of coverage that requires much higher out-of-pocket costs, and they often require prior authorization before a drug will be covered. Little is known about how such requirements are implemented and whether they may restrict access.
RECOMMENDATION 6-1: The Centers for Medicare and Medicaid Services or the Medicare Payment Advisory Commission should study how the implementation of prior authorization requirements by Medicare Part D and state Medicaid plans affects beneficiary access to orphan drugs. The findings should guide recommendations and actions to improve policies and practices for the Part D program.
In addition, little is known about the application of coverage restrictions when orphan or nonorphan drugs are used off-label to treat people with rare conditions that may have few or no FDA-approved treatments. Medicare requires coverage for off-label uses that are described in certain compendia (comprehensive listings of drugs with descriptions of their recommended uses). The creation of an evidence-based compendium focused specifically on off-label uses of drugs for rare diseases could inform clinicians, health plans, and potentially patients and families. It could also suggest areas for future research or literature reviews.
RECOMMENDATION 6-2: The Agency for Healthcare Research and Quality or a similar appropriate agency should undertake a pilot project to develop an evidence-based compendium to inform health plan decisions on both orphan and nonorphan drugs that may have indications for rare conditions that have not been evaluated or approved by FDA.
MEDICAL DEVICES FOR SMALL POPULATIONS
Compared to pharmaceuticals, medical devices are an extremely diverse group of products. Some are as simple as adhesive bandages and tongue depressors. Others are complex, for example, various implanted cardiac, neurological, and orthopedic devices. For rare diseases, efforts to accelerate research and development have clearly focused on drugs and biological products. Given the differing characteristics of the device development process and the device industry, the incentives designed to stimulate orphan drug development have not transferred neatly to this sector.
The law usually does not require submission of clinical data before FDA can authorize a device for marketing. However, for a small percentage of high-risk devices, manufacturers must submit a premarket approval application that includes safety and efficacy data from clinical trials. Securing FDA approval of such devices is usually complex, costly, and time-consuming, which may discourage companies from pursuing devices for small populations. Such populations also present the practical challenges of ensuring sufficient research participants for clinical trials to demonstrate safety and effectiveness.
Devising meaningful alternative incentives to encourage the development of medical devices for small populations has proved a persistent challenge. For example, because medical device companies often engage in a continuous process of product refinement and innovation, marketing exclusivity may be less important as a source of competitive advantage for device companies than for pharmaceutical and biotechnology companies.
In 1990, Congress authorized the Humanitarian Device Exemption (HDE) to encourage the development and introduction of needed device technologies for small populations. To be eligible for this exemption, a manufacturer must first have a device designated as a Humanitarian Use Device, which is a “medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.”
An HDE application must include evidence that the device is safe but need not include evidence of effectiveness. The application must, however, contain sufficient information for FDA to judge whether the device presents an unreasonable or significant risk of illness or injury and whether its probable benefit to health outweighs the potential for harm. Sponsors of an HDE device are allowed to recover certain development costs but may not make a profit on the device. Congress recently relaxed the profit restriction for HDE devices for children.
One unique and sometimes confusing feature of the HDE policy is the requirement that use of a Humanitarian Use Device requires approval by
an institutional review board (IRB). The primary responsibility of IRBs is to protect human research participants through review of proposed research.
The committee found it difficult to assess the possible extent of unmet device needs for adults with rare conditions and the extent to which changes in FDA policies might promote innovation to meet these needs. A first step in understanding the potential for device innovation for rare conditions is a needs assessment.
RECOMMENDATION 7-1: FDA and NIH should collaborate on an assessment of unmet device needs and priorities relevant to rare diseases. That assessment should focus on the most plausible areas of unmet need, identify impediments to meeting these needs, and examine options for overcoming impediments and stimulating high-priority innovations.
The options examined might include the additional orphan products grants and NIH awards for the development of devices to meet priority needs; tax credits for certain research and development costs; and the creation of inducement prizes for the design and initial testing of novel devices in areas of unmet need. Changes in the HDE incentives for pediatric devices, including removal of the restriction on profits, may provide an opportunity to gauge whether similar changes could encourage innovative devices for conditions affecting small populations of adults.
RECOMMENDATION 7-2: Congress should consider whether the rationale for creating additional incentives for pediatric device development also supports the use of such incentives to promote the development of devices to meet the needs of adults with rare conditions.
A modest step to encourage some additional company interest in devices for small populations would involve greater flexibility in the limits on annual shipments of HDE-covered devices. For devices covered by an HDE, information on the number of device units shipped is not readily available nor are the estimates submitted by companies of the number of affected individuals. An analysis of such data might help in assessing how often the 4,000-per-year shipment limit is approached and thus how often the limit might restrict access within the framework of HDE policy.
RECOMMENDATION 7-3: As a basis for possible congressional action, the Center for Devices and Radiological Health should analyze the supporting justifications offered in successful and unsuccessful Humanitarian Device Exemption applications related to the 4,000-person-per-
year limit and should evaluate the subsequent experience with actual device shipments for approved applications, including any communications about projections that a company might exceed the limits. Taking the findings into account, Congress should consider authorizing FDA to permit a small, defined deviation from the yearly limit on shipments for a specific device when the agency determines that such a deviation would benefit patients with a rare disease.
The HDE process is generally viewed as confusing and burdensome. FDA could act, within existing law, to make the process less intimidating and potentially more attractive to device developers.
RECOMMENDATION 7-4: FDA should take steps to reduce the burdens on potential sponsors of Humanitarian Use Devices, including
assigning an ombudsman to help sponsors navigate the regulatory process for these applications;
providing more specific guidance and technical assistance on the documentation of the size of the patient population as required for humanitarian use designations; and
developing better guidance (including step-by-step instructions and sample documents) for sponsors and IRBs on their roles and responsibilities related to IRB review of HDEs.
INTEGRATING STRATEGIES FOR RARE DISEASES RESEARCH AND ORPHAN PRODUCT DEVELOPMENT
An integrated national strategy for rare diseases research and orphan product development will have many elements. As outlined earlier, such a strategy will actively involve the many parties that play essential roles in the process—government, industry, academic investigators, advocacy groups, and others. In response to sometimes duplicative, competing, and uncoordinated efforts, it will promote collaboration and cooperation and the elimination of wasteful and costly duplication of research and development efforts. An integrated strategy will include an array of mechanisms at NIH and elsewhere for devising partnerships and sharing resources—including, for example, chemical compound libraries and biological specimens. An integrated strategy will also include focused investigations of possible areas of unmet needs (e.g., for medical devices). FDA will continue to play an essential role in ensuring that products are safe and effective, taking into account the special challenges of developing products for rare conditions and providing sponsor guidance and product reviews that combine reasonable consistency and reasoned flexibility based on expert knowledge.
To encourage more collaboration and more efficient use of resources and build on the initiatives and recommendations discussed in this report, the committee proposes the creation of a time-limited task force on accelerating rare diseases research and product development. Because mobilizing such a task force might be difficult in the private sector and because high-level backing is crucial, the responsibility for creating the task force should rest with the Secretary of Health and Human Services. This task force, which might operate for 4 to 8 years, would bring together leaders in rare diseases research and product development from government, industry, academic and other research institutions, and advocacy groups and would involve international entities as appropriate.
RECOMMENDATION 8-1: The Secretary of Health and Human Services should establish a national task force on accelerating rare diseases research and product development. The objectives of the task force would be to promote, coordinate, monitor, and assess the implementation of NIH, FDA, and other public- and private-sector initiatives on rare diseases and orphan products and to support additional opportunities for public-private collaboration.
A task force on rare diseases research and product development will not lessen the need for all participants to improve their individual efforts and relationships as outlined in this report. Individual improvement will strengthen the foundation for collaboration.