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Toward an Integrated Approach to Accelerating Research and Product Development for Rare Diseases

Rare diseases collectively account for significant unmet health care needs in the United States. As described in this report, rare diseases research and product development is now attracting considerable attention from public and private funders of research, regulatory bodies, industry, advocacy groups, and the academic research community. The genomics era has contributed a rapidly expanding opportunity to describe the molecular basis for individual rare disorders, the targets for therapeutic interventions, and the development of therapies based on these advances. In general, scientific and technological advances are making it easier, faster, and less expensive to study rare diseases, which should aid the development of products to prevent, diagnose, and treat these diseases.

Nonetheless, despite these advances, the molecular basis for many rare diseases is still unknown, and the number of rare diseases for which the Food and Drug Administration (FDA) has approved treatments is small in relation to the total number of rare diseases. Closing the gap between what has been and what can now be accomplished is the challenge for rare diseases research and product development.

A critical question is how to take better advantage of scientific and technological advances and investments in biomedical research in ways that will deliver improved health outcomes for the millions of Americans with rare diseases. Chapter 1 has outlined the elements of an integrated national strategy to accelerate rare diseases research and product development. This chapter begins by briefly reviewing how the analyses and recommendations in preceding chapters relate to these elements. It then presents an additional recommendation for a high-level process to promote greater collaboration



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8 Toward an Integrated Approach to Accelerating Research and Product Development for Rare Diseases Rare diseases collectively account for significant unmet health care needs in the United States. As described in this report, rare diseases research and product development is now attracting considerable attention from public and private funders of research, regulatory bodies, industry, advo- cacy groups, and the academic research community. The genomics era has contributed a rapidly expanding opportunity to describe the molecular basis for individual rare disorders, the targets for therapeutic interventions, and the development of therapies based on these advances. In general, scientific and technological advances are making it easier, faster, and less expensive to study rare diseases, which should aid the development of products to prevent, diagnose, and treat these diseases. Nonetheless, despite these advances, the molecular basis for many rare diseases is still unknown, and the number of rare diseases for which the Food and Drug Administration (FDA) has approved treatments is small in relation to the total number of rare diseases. Closing the gap between what has been and what can now be accomplished is the challenge for rare diseases research and product development. A critical question is how to take better advantage of scientific and technological advances and investments in biomedical research in ways that will deliver improved health outcomes for the millions of Americans with rare diseases. Chapter 1 has outlined the elements of an integrated national strategy to accelerate rare diseases research and product development. This chapter begins by briefly reviewing how the analyses and recommendations in preceding chapters relate to these elements. It then presents an additional recommendation for a high-level process to promote greater collaboration 

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 RARE DISEASES AND ORPHAN PRODUCTS and more efficient use of resources, a process that would build on exist- ing initiatives as well as the recommendations discussed in this report. Although many elements of a national rare diseases research policy already exist, they are not integrated or overseen in a way that supports the sys- tematic identification of key research and development gaps or the setting of priorities, even within government. ELEMENTS OF AN INTEGRATED NATIONAL STRATEGY Given the broad scope of this report, the analyses and recommenda- tions focus selectively on the range of issues and activities related to rare diseases research and product development. They emphasize actions to be initiated by the National Institutes of Health (NIH) or the Food and Drug Administration (FDA) but also call for participation by advocacy groups, industry, research institutions, and others. Active Involvement and Collaboration by a Wide Range of Public and Private Interests A number of recommendations in this report relate to this element of a national policy, including those that explicitly call for cooperative efforts to improve the design and analysis of trials for small populations (Recommen- dation 3-2); collaborative sharing of resources to facilitate the application of scientific advances in basic and translational research (Recommendation 4-1); an expansion of the FDA’s Critical Path Initiative to work on sur- rogate endpoints for clinical trials in rare diseases (Recommendation 5-2); creation of a public-private partnership on patient registries and bioreposi- tories for rare diseases (Recommendation 5-3); coordination of the Cures Acceleration Network with various rare diseases research initiatives and with advocacy groups (Recommendation 5-5); and the assessment of unmet needs for medical devices for rare diseases and conditions (Recommenda- tion 7-1). In addition, other activities will necessarily involve cooperation, for example, the creation of an action plan for rare diseases research and product development at NIH (Recommendation 4-2) and the expansion of a centralized preclinical development service at NIH that is available to nonprofit organizations (Recommendation 5-2). At the end of this chapter is another recommendation for a high-level collaboration to promote and monitor the implementation of existing and new initiatives to accelerate rare diseases research and orphan product development (Recommendation 8-1). Although this report does not direct any recommendations narrowly at advocacy groups and companies, it has described increasing interest and involvement from the private sector in public-private and other collaborations. In addition, the report has not

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 TOWARD AN INTEGRATED APPROACH systematically considered international collaboration, although it has cited efforts to harmonize certain aspects of national regulatory policies and opportunities to learn from innovative international initiatives, including those directed at neglected diseases. Timely Application of Scientific Advances: Creative Strategies for Sharing Research Resources and Infrastructure This report has summarized a number of technological and scientific advances that can speed the pace of some aspects of basic and translational research on rare diseases and, in some cases, lower its cost. It has cited examples of the application of these advances in rare diseases research, but several recommendations should support their more widespread and timely use. These include particularly the recommendation for precompetitive resource sharing for discovery research (Recommendation 4-1), an NIH action plan (Recommendation 4-2), preclinical resource development (Rec- ommendation 5-1), evaluation of surrogate endpoints (Recommendation 5-2), and increasing rare diseases research flexibility and capacity (Recom- mendations 5-4 and 5-5). Resource sharing arrangements should support the productive and efficient use of scarce funding, expertise, data, biological specimens, and research participants. As highlighted in the next section, continued ef- forts to promote the appropriate use of clinical trial designs and analytic methods for small populations (Recommendations 3-2 and 3-3) should likewise support these outcomes. A particular focus of the recommended NIH action plan for rare diseases research (Recommendation 4-2) would be training of researchers on rare diseases and methods particularly applicable to rare diseases. This would attract to the field new investigators who are ready to take advantage of developments in biotechnology and information technology. Use and Expansion of Trial Designs for Small Populations Although scientists have unraveled the genetic basis of a number of rare, single-gene conditions more easily than has been the case for more genetically complex conditions, they have often faced special challenges in obtaining biological specimens for basic research and in recruiting patients for clinical studies. For all conditions but especially for rare conditions, it is important that these crucial resources be used to best advantage. In clinical research, one key is to employ appropriate clinical trial and analytic methods that can guide decisions about trial size and design and minimize the number of participants needed for valid investigations while improving the interpretation of findings. This report stresses the importance

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 RARE DISEASES AND ORPHAN PRODUCTS of FDA and NIH collaboration to ensure that NIH-funded studies meet FDA standards, including standards for clinical trial design and analysis (Recommendation 3-2). The committee also recommends that FDA and NIH support further work to develop and test clinical research strategies for small populations (Recommendation 3-2). Also important are natural history studies to support valid use of historical controls and efforts to develop acceptable surrogate endpoints for use in rare diseases trials (Rec- ommendation 5-2) and patient registries to facilitate recruitment of study participants (Recommendation 5-3). Reasonable Rewards and Incentives for Innovation and Prudent Use of Public Resources The Orphan Drug Act is generally regarded as having created incentives that have attracted new private resources to research and development on products that help people with rare diseases. The nature of medical device innovation and characteristics of the medical device industry have compli- cated the identification of effective incentives for medical device develop- ment for rare diseases. More generally, unmet needs for medical devices for rare diseases have received relatively little attention, and an assessment of such needs and impediments to meeting them would be useful (Recommen- dation 7-1). Experience with some newly created incentives for pediatric device development—including lifting the restriction on profits for devices approved through the Humanitarian Device Exemption process—may have relevance for policies that could encourage device development for adults with rare conditions. Incentives for private action sometimes will be viewed as unlikely to be productive or judged to have costs that are disproportionate to the expected benefit. Prudence may then call for the additional use of public funding to support product development (Recommendations 5-4 and 5-5). In addition to positive incentives, it is also important to reduce or eliminate unreasonable disincentives to research and development involving products for small populations. In particular, uncertainty about the appli- cation of FDA standards for product approval can discourage companies from considering orphan product development. The analysis of FDA staff reviews of orphan products may identify inappropriate variation in FDA reviews and other information that will aid the development of guidelines for staff reviews as well as for staff assistance to drug sponsors through consultation beginning with the early stages of product development (Rec- ommendation 3-1). Greater flexibility in yearly shipment limits for devices approved under the Humanitarian Device Exemption process (Recommen- dation 7-3) and the provision of additional assistance to medical device

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 TOWARD AN INTEGRATED APPROACH sponsors on navigating the regulatory process might help make that process less confusing or burdensome (Recommendation 7-4). Analyses of health plan administrative practices for orphan drugs (Rec- ommendation 6-1) could identify barriers to patient access to these prod- ucts, for example, high rates of denied requests for prior approval of orphan drug prescriptions. Systematic review of the evidence on the outcomes of off-label use of drugs for rare diseases (Recommendation 6-2) could encour- age health plans to reimburse uses that are backed by evidence. Adequate Organization and Resources Adequate organizational structures and resources are the foundation for all other elements of a national policy. Chapter 3 discusses the mismatch between FDA’s resources and its responsibilities for review, guidance, and consultation. Chapters 3, 4, 5, and 7 describe shortcomings in public and private resources for rare diseases research and product development. The committee recognizes that increasing resources will be more difficult than ever given current and projected budget deficits, but it also notes the poten- tial benefits of modest but well-placed additions of resources, for example, in the orphan products grants program. As described in this report, some of the recommended investments in resource sharing and other infrastructure for rare diseases research will likely produce spillover benefits in the form of better understanding of common diseases. Resources include not only financing but also infrastructure and other support for rare diseases researchers and sponsors of orphan products. Sev- eral aspects of the recommendation for an NIH action plan (Recommenda- tion 4-1) would target infrastructure, as would steps to promote resource sharing (Recommendations 4-1 and 5-1). In addition, it is important that FDA and NIH cooperate to provide those who receive NIH awards for rare diseases product development with the guidance they need to design studies that meet FDA expectations (Recommendation 3-3). Mechanisms for Weighing Priorities, Establishing Organization- Specific and Collective Goals, and Assessing Progress As with any complex process or any complex organization, the de- velopment of a coherent strategy for setting priorities, establishing goals, and assessing progress is itself complex. None of these activities is cost- free, and as noted above, increases in federal funding face a very difficult environment. The creation of an NIH action plan (Recommendation 4-2) would focus attention on key aspects of rare diseases research and orphan product devel-

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 RARE DISEASES AND ORPHAN PRODUCTS opment and would draw other parties into the planning process. That action plan proposal is, however, focused on NIH. The recommendation below calls for a task force on rare diseases that would extend beyond NIH and contrib- ute to a broader process of setting priorities and assessing progress. RECOMMENDATION The analyses presented in earlier chapters support the emphasis in the policy framework on a coordinated, collaborative approach to rare diseases research and product development. Today, each of the many public and private groups involved in rare diseases research and product development contributes to the common goals of understanding rare diseases and devel- oping more effective means to prevent, diagnose, and treat them. Nonethe- less, gaps and duplication of effort are evident. Current collaborations and coordinated efforts are promising but fall short of what is possible. For example, at NIH, support by the individual institutes for research on rare diseases is difficult to track and therefore to assess and coordi- nate. The extent to which institute-specific research programs on rare and neglected diseases, unmet needs, and translational research will reinforce each other or work together is unclear. The NIH Office of Rare Diseases Research was established to coordinate and stimulate attention to the study of rare diseases, but it has limited resources and limited influence on the decisions of individual institutes. Other concerns are that NIH study sec- tions sometimes lack the guidance and resources to properly evaluate rare diseases research proposals and that NIH-funded research sometimes fails to meet FDA requirements for the approval of new drugs. Within FDA, the degree of consistency in review unit evaluations of orphan drugs is a concern and an issue for the new Associate Director for Rare Diseases in the Center for Drug Evaluation and Research. Outside NIH and FDA, the Centers for Disease Control and Prevention and the Department of Defense (under specific Congressional mandates) also independently fund some research on rare diseases. In the private sec- tor, patient advocacy groups often cooperate but also sometimes compete with each other in areas such as the development of patient registries and the pursuit of disease-specific congressional earmarks. Groups also vary in their experience in working with federal agencies, industry, and academic investigators. Pharmaceutical, biotechnology, and medical device companies have not traditionally worked with their peers, although some pharma- ceutical companies are now developing precompetitive shared resources as discussed in Chapter 4. The potential for medical devices to treat rare conditions is too often not considered. In an area defined by scarce re- sources, incremental increases in efficiency can have a disproportionately large impact.

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 TOWARD AN INTEGRATED APPROACH To encourage more collaboration and more efficient use of resources and build on the initiatives and recommendations discussed in earlier chap- ters, the committee proposes the creation of a time-limited task force on ac- celerating rare diseases research and product development. This task force would bring together leaders of key groups. Recognizing that mobilizing such a task force might be difficult in the private sector and that high-level backing is crucial, the committee concluded that the responsibility for creating the task force should rest with the Secretary of Health and Hu- man Services. Nearly all of the government agencies discussed here report ultimately to the Secretary. RECOMMENDATION 8-1: The Secretary of Health and Human Ser- vices 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 implementa- tion of NIH, FDA, and other public- and private-sector initiatives on rare diseases and orphan products and to support additional opportuni- ties for public-private collaboration. As envisioned here, the task force would bring together a network of stakeholders for accelerating research and development. In the public sec- tor, it would draw on representatives of the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the Department of Defense, and other relevant federal agencies. From the private sector, it would recruit senior participants from the phar- maceutical, biotechnology, and medical device industries; patient advocacy groups; private foundations; and academic and other research institutions. International agencies and other relevant parties would be involved as appropriate. The committee does not envision the task force as open-ended. It might extend for 4 to 8 years, at which point alternatives would be evaluated. If this approach is to be effective, identifying and engaging the key public- and private-sector stakeholders is an important first step. The in- volvement of international counterparts of federal agencies and private organizations will also be desirable, especially for many extremely rare diseases for which global research participation is critical. Creating a venue for meaningful interactions and decision making among these groups will require arrangements for convening task force meetings, conducting analy- ses and developing strategies, following through on recommendations, and creating a scheme for monitoring progress. One major challenge will be identifying and sustaining a stable funding source for these administrative and analytic activities. The proposed task force would build on existing initiatives and part-

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 RARE DISEASES AND ORPHAN PRODUCTS nerships as well as explore new arrangements. For example, this report recommends that NIH and FDA cooperate to ensure that NIH-funded research for product development meets FDA expectations for regulatory approval. Another example is the potential for new public-private partner- ships involving the federal government, industry, and patient advocacy groups to identify high-priority lines of research, jointly fund such research, and otherwise combine resources to accelerate the process of converting basic research findings into therapeutic discoveries and ultimately into ef- fective preventive, diagnostic, and therapeutic measures. Although research on individual disease pathogenesis and treatment is essential, this research can potentially be further accelerated by identifying networks of biological pathways that are common to clusters of rare diseases. The task force can also explore incentives and other strategies beyond those identified in this report to further engage the biopharmaceutical and medical device industry in various stages of the drug and device development process. Common diseases are increasingly “personalized” as researchers iden- tify a spectrum of genotypes that can cause these diseases and find that patients with different genotypes may respond differently to different treat- ments. As a result, rare conditions that are actually subsets of common conditions will become more frequent. Researchers and companies studying these subsets will encounter the challenges of conducting research and de- veloping products for small populations. Tensions may arise in health care delivery and financing between current concepts of evidence-based medicine (often promoting the best treatment for the “average” patient with a dis- ease or identifying patient variables that warrant differences in treatment) and an emerging emphasis on personalized medicine (where the use of conventional methods to meet evidence thresholds on outcomes is inher- ently constrained). Well-organized and appropriately funded collaborative initiatives to accelerate research and product development for rare diseases may provide models for a broader array of diseases in the future. A task force on rare diseases research and product development will not lessen the need for participants to improve their individual efforts and rela- tionships as outlined in this report. Individual improvement will strengthen the foundation for collaboration. In summary, the development of more effective drugs and medical devices for people with rare diseases represents an enormous challenge as well as a timely opportunity to improve public health. A successful response depends on further movement toward a more collaborative, coordinated, open, and sustained approach to rare diseases. Although the effort and in- vestment needed are great, the stakes are high. The potential benefits justify a renewed, high-level commitment to accelerating rare diseases research and product development.