1
Introduction
Rare diseases are a heterogenous group of between 7,000 and 10,000 life-threatening and chronically debilitating conditions (Haendel et al., 2019; NIH, 2023). Each condition may only affect a small percentage of the population, but they collectively affect up to 30 million people in the United States, 36 million in the European Union, and at least 300 million across the globe (EMA, n.d.; GAO, 2021; Gopal-Srivastava and Kaufmann, 2017; Haendel et al., 2019; NIH, 2023; Wakap et al., 2020). The majority of rare diseases have genetic precursors and over half manifest during childhood (Chung et al., 2022b; FDA, 2023c; Wakap et al., 2020). The impact of rare diseases extends well beyond the affected individual to include family members and caregivers, imposing a significant burden on an estimated 1 billion people globally, when accounting for both patients and their caregivers (Groft and Posada de la Paz, 2017).
The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) play a critical role in ensuring that drugs to treat rare diseases and conditions are safe and effective. Additionally, regulatory agencies help advance public health by actively promoting scientific and technological innovation for advancing drug development. Before the Orphan Drug Act1 was passed in 1983 (see Box 1-1), the development of drugs to treat rare diseases was largely neglected by the pharmaceutical industry (IOM, 2009). Following passage of the Orphan Drug Act and the subsequent policy measures implemented around the world, including the European Union (EU) regulation on orphan medicinal products, which was
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1 P.L. 97-414. Orphan Drug Act (January 4, 1983).
BOX 1-1
Orphan Designation
U.S. Food and Drug Administration
The Orphan Drug Designation program at the U.S. Food and Drug Administration was launched following enactment of the Orphan Drug Act in 1983 with the goal of stimulating development of drugs and biologics for rare diseases. A drug may qualify for orphan drug designation if it is intended to treat a condition affecting fewer than 200,000 individuals in the United States, or if it affects more than 200,000 individuals but there is “no reasonable expectation that the cost of developing a drug for the condition would be recovered by sales of the drug.” Once designated as an orphan drug, sponsors receive the following incentives:
- Tax credits worth 25 percent of costs for qualified clinical trials;
- Waiver of the prescription drug user fee ($4 million for fiscal year 2024); and
- Potential 7 years of market exclusivity after approval.
European Medicines Agency
To qualify for orphan designation by the European Medicines Agency, a medicine must meet a number of criteria:
- “It must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;
- “The prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development; and
- “No satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition” (EMA, n.d.)
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NOTES: See Chapter 2 for more details on FDA’s Orphan Drug Designation Program. See Chapter 3 for more details on EMA’s Orphan Designation.
SOURCES: EMA, n.d.; FDA, 2022c, 2024b; Michaeli et al. 2023.
adopted in 1999, there has been a marked increase in the investment and successful development of drugs to treat rare diseases and conditions. Prior to 1983, only 38 drugs were available to treat rare diseases in the United States; by the end of 2022, FDA had cumulatively approved 882 drugs for 392 rare diseases (Saltonstall et al., 2024).
Over the past 40 years, patient groups, policy makers, research funders, drug sponsors, researchers, and regulatory agencies have worked to address the devastating impact of rare diseases on millions of patients and their families by facilitating and accelerating the development and approval of new therapies. There has been tremendous progress made in research and innovation as well as in regulatory policy, and yet today, only around 5 percent of rare diseases and conditions have FDA approved products on the market (Fermaglich and Miller, 2023).
The path to diagnosis for a patient living with a rare disease or condition is often long and arduous (GAO, 2021). Studies have shown that many patients visit multiple doctors and receive multiple misdiagnoses before receiving an accurate diagnosis; others remain undiagnosed (EURODIS, 2017; Shire, 2013; The Lancet Diabetes & Endocrinology, 2019). All hospitals and health care providers covered by the Health Insurance Portability and Accountability Act (HIPAA)2 in the United States and most hospital systems in the European Union record patient diagnoses using the World Health Organization’s International Classification of Diseases (ICD). Only around 500 hundred rare diseases were listed in the 10th ICD version (ICD-10) and only half of these had a specific code (Rath et al., 2012). A retrospective analysis of 2019 claims data showed that most (92 percent) of the assigned ICD-10 diagnosis codes associated with a rare disease were broadly defined and only 16 percent were diagnosed using a specific code (Kuester et al., 2022). In the 11th ICD version (ICD-11) published in 2022, there is an estimated 5,500 rare diseases included—around 11 times more than ICD-10 (WHO, n.d.). Prior to this increase, it was difficult for clinicians to appropriately document the care and treatment of patients with rare diseases and conditions. Additionally, the lack of ICD-10 codes made it hard for researchers to identify and track patients with rare diseases or conditions and study the epidemiology. Even still with a diagnosis in hand, patients face additional hurdles to receiving appropriate care and treatment, including the fact that very few approved therapies are on the market.
As is the case for other therapeutic areas, limited access to appropriate diagnosis and treatment of rare diseases and conditions for minority populations—African Americans, Native Americans, Hispanics, and several Asian subgroups—is further exacerbated by preexisting inequities in access to clinical care and social determinants of health. Inequities are further
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2 P.L. 104-191. Health Insurance Portability and Accountability Act (August 21, 1996).
embedded in the context of an appreciable geographic dispersion in rare disease presentation and prevalence across the United States and European Union (Adachi et al., 2023). Such inequities are particularly problematic for certain rare diseases (Everylife Foundation for Rare Diseases, 2024), including sickle cell disease (Pokhrel et al., 2023) and thalassemia (Lorey et al., 1996), which have higher prevalence and mortality rates for ethnic and racial minorities in the United States. These realities reinforce the importance of identifying and addressing barriers to research, development, and approval of new therapies for rare diseases and conditions to help ensure that products are made readily accessible to the full breadth of patients and communities who most need them.
While beyond the scope of this report, it is important to recognize that the economic burden and impact of rare diseases should be acknowledged. In the United States alone, the annual economic burden of rare disease, including direct and indirect health care costs, has been estimated to be in the range of $1.0 trillion to $8.6 trillion (Andreu et al., 2022; Yang et al., 2022). On an individual level, the average health care cost per year for people with a rare disease may be 2.8 to 4.8 times higher than for people without a rare disease (Tisdale et al., 2021). Rare disease drug products are also associated with higher costs compared to other therapeutic areas (EvaluatePharma, 2019). Some of the most expensive drugs on the market are for the treatment of rare diseases and conditions, which creates disproportionate barriers for patient access and a strain on public and private health care payers (Tozzi, 2019). These barriers are particularly severe for underserved communities, for which inequities in access to clinical care and underlying community health risks further complicate access to diagnosis and treatment. While payer programs should be designed to protect patients from high orphan drug prices, in practice this protection is not equally distributed or enforced among patients with rare diseases (Hyde and Dobrovolny, 2010). Ensuring equitable access to rare disease treatments will require vigilance on the economic burden and cost structure of diagnosing and treating rare diseases (Adachi et al., 2023), particularly given increased applications for more complex medical therapies.
CLINICAL TRIALS FOR RARE DISEASES AND CONDITIONS
Clinical trials are the primary method by which drug sponsors can demonstrate whether a new form of drug treatment or prevention is likely to be safe and effective in people (see Box 1-2). When it comes to rare diseases and conditions, there are several barriers that make it particularly difficult to design and implement clinical trials, a few of which are described below.
Small Patient Populations
By definition, rare disease populations are small and often geographically dispersed, which can limit the ability of researchers to enroll adequate numbers of trial participants in an interventional study. In general, trials that involve small numbers of participants raise methodologic concerns, given that results are more prone to variability and may lack statistical power and generalizability. The following concerns with small trials have been identified: low-power leaving too much to chance, lower probability that an observed effect reaches statistical significance, multiple variables making it hard to determine cause and effect to a meaningful degree, safety issues not being adequately studied, and subgroups cannot be analyzed (IOM, 2001). With small sample sizes, p-values (the probability that an observed effect would have occurred by chance if the test drug had no effect) are vulnerable to small deviations in observed effect and may inaccurately convey the statistical significance of results (Mitani and Haneuse, 2020). If an intervention has a large effect on clinical trial participants, the effect can be detected even with a relatively small sample size. Conversely, if the effect size is small, the trial needs a larger sample size to detect the effect with statistical significance (Serdar et al., 2021). Given that trials for rare diseases have small sample sizes, it may be difficult or impossible to detect an effect based on a traditional randomized clinical trial design; a product that has a real but small impact on patient outcomes may not show statistically significant efficacy and thus not be approved for marketing.
While randomized controlled clinical trials are the gold standard for establishing the safety and efficacy of a test drug, this approach may not be feasible for certain rare disease populations. In addition to the lack of patients who may be eligible to participate in a clinical trial, there may be ethical or logistical considerations that make it difficult to enroll people in a given study (Pizzamiglio et al., 2022). For many rare diseases and conditions, including an untreated or placebo control group can raise ethical concerns due to a greater risk of harm for participants who do not receive the active treatment. In such cases, different trial designs, such as crossover, adaptive, master protocol, and decentralized trial designs, may offer additional options for testing new drugs for the treatment of rare diseases or conditions (see Table 1-1).
As described in Chapter 4, alternative and confirmatory data—data that are collected outside the setting of a randomized controlled clinical trial—can be used to support regulatory submission and review of a drug product. Additionally, advanced statistical methods can be applied to address some of the analytic challenges with rare disease trials.
BOX 1-2
Types of Clinical Trials
“Clinical trials are research studies in which researchers assign participants to get one or more interventions to test what happens in people. Because of this, clinical trials are also called interventional studies. Often, the intervention is investigational, which means it is not approved for doctors to prescribe to people. In some clinical trials, researchers assign participants to interventions randomly. This means that researchers assign the participants by chance. Usually, participants (or their doctors) don’t choose what intervention they will get when they join a clinical trial” (NIH, 2023)
Types of Clinical Trials
- Phase 1 trials initiate the study of candidate drugs in humans. Such trials 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., how it is absorbed, distributed, metabolized, and excreted). Phase 1 trials are often conducted in healthy volunteers, typically 20–100 participants. However, for some products, such as gene therapies or certain types of oncology drugs, phase 1 trials may not be feasible due to a lack of eligible participants or a toxicity risk and may be conducted in the patient population for a disease instead. Given the small number of patients with a rare disease, phase 1 trials may involve small numbers of patients or may be combined with a phase 2 trial (often referred to as a phase 1-2 trial), and in some cases, may often involve only around 10–20 patients.
- Phase 2 trials continue the assessment of a drug’s safety and dosing, but also begin to test efficacy in people with the target disease. These studies may include a range of controls on potential bias, including the
Preexisting Health Inequities
Widespread demographic disparities in health care access and outcomes in Europe and the United States are well documented. Studies have consistently shown that racial and ethnic minorities, low-income populations, and other disadvantaged groups experience higher rates of chronic disease, worse health outcomes, and more limited access to quality health care than more privileged populations (Clark et al., 2019; Docteur and Berenson, 2014; Ndugga and Artiga, 2023; Satcher et al., 2005; Williams et al., 2010). These disparities are compounded by the unequal geographic distribution of health care resources and disease burden, both within countries and globally (Docteur and Berenson, 2014). Although the primary
- use of a control group that receives a standard treatment or a placebo, the random assignment of research participants to the experimental and control groups, and the concealment (blinding or masking) from participants and researchers of a participant’s assignment. For cases in which it may be unfeasible for a patient to receive a placebo or for randomization to occur (e.g., diseases with very low prevalence, ethical considerations with the use of a placebo control), as may be the case for some rare disease trials, all trial volunteers may receive the treatment, or phase 2 and 3 trials may be combined to answer research questions with fewer patients, or both. In these instances, trials may often only include tens of patients.
- Phase 3 trials are expanded investigations of safety and efficacy that are intended to allow a fuller assessment of a drug’s benefits and harms and to provide information sufficient to prepare labeling or instructions for the use of the drug. For common diseases, these studies may involve thousands of research participants and multiple sites and often include more than one trial. For rare diseases, especially for very low prevalence disorders, Phase 3 is often limited to a single clinical trial and may include fewer than 100 patients, where feasible.
- Post-marketing studies are conducted after a product is approved for marketing and are highly variable in their design. FDA may require post-marketing studies to gather additional information about the risks, benefits, and use of a given drug, such as outcomes in clinical practice or to assess safety in a larger patient population. Results from these studies can be useful for understanding how a drug performs in broader populations or over longer periods than studied in the trials used to support FDA approval.
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SOURCES: FDA, 2018b; IOM, 2010; NIH, 2023.
contributing causes are structural and may even be subject to legal sanction today, current approaches to drug research and development continue to reflect and contribute to preexisting disparities. Clinical trials often lack adequate representation from minority groups (Turner et al., 2022), leading to limited data on the safety and efficacy of treatments in diverse populations. This lack of representation may be due to several factors associated with health inequities: differential screening and diagnosis as well as increased prevalence of exclusion criteria in underserved populations (e.g., smoking cessation and mental illness) (NASEM, 2022). Medical devices and diagnostic tools may be designed based on data from predominantly White populations, resulting in worse performance for patients of color
TABLE 1-1 Clinical Trial Options for Rare Disease Drug Development
| Trial Design | Description | Relevance for Rare Diseases | FDA Resources |
|---|---|---|---|
| Adaptive | Enables prospectively planned modifications to a trial based on accumulated data from trial participants | Can help reduce the number of trial participants needed and increase the likelihood that trial participants receive the most effective investigational drug | FDA (2019a) |
| Crossover | Trial participants may receive a sequence of investigational drugs over time and serve as their own comparison control | Can help reduce the number of trial participants needed by allowing all trial participants to receive an investigational drug | 21 CFR §320.27 |
| Decentralized | Some or all trial activities take place at locations other than a traditional trial site; can range from hybrid (some activities involve in-person visits to traditional trial sites) to fully decentralized (all activities take place outside of a traditional clinical trial site) | Can help lower geographic barriers to trial participation and increase retention (e.g., trial participants may participate in trial activities at home or other convenient locations) | FDA (2023a) |
| Master Protocol | Allows multiple sub-studies, which can evaluate one or more investigational drug or one or more diseases or conditions | Can help expedite drug development and increase the likelihood a participant receives the experimental treatment | FDA (2022a) |
| Real-World Evidence | Clinical evidence about the use and potential benefits or risks of a drug product for disease/condition based on analysis of real-world data—data related to patient health status and/or delivery of health care that are routinely collected from various sources (e.g. electronic health records and patient registries) | Can help bridge evidence gaps not addressed by a traditional randomized clinical trial (e.g., serving as an external control, providing insights on the natural history of disease or condition) | FDA (2023e) |
SOURCES: Chodankar, 2021; Park et al., 2024; Pizzamiglio et al., 2022; Zhou and Chow, 2023.
(Kadambi, 2021). Inequitable access to cutting-edge treatments and technologies can further widen gaps in health outcomes between advantaged and disadvantaged communities. Addressing these ongoing issues will require concerted and sustained efforts to increase diversity in medical research, ensure equitable design of health technologies, and promote policies that dismantle structural barriers to accessing high-quality care for all.
The committee observed that current approaches to drug research and development for rare diseases may inadvertently perpetuate existing inequities for already marginalized populations. For example, in the current environment, patient groups, which include patient advocacy organizations, disease-advocacy organizations, and nonprofit organizations, play a critical role in raising awareness, driving research and innovation, and informing drug development. Therefore, the patient groups with the most economic and social means are more likely to succeed in effectively advocating for much-needed resources and therapeutic advances. Conversely, patient groups that represent marginalized populations with fewer resources and less social capital are more likely to be left behind (Halley et al., 2022). This further exacerbates the scarcity of rare disease advocates with a lived experience of a specific disease. Given this context, the current advocacy-based model primarily serves a small select population of rare disease patients and has the potential to worsen current health disparities for marginalized subpopulations.
Additional resources are needed to ensure that research and development for new drugs to treat rare diseases and conditions are predicated on current epidemiology, health services usage, public health impact, and patient-centered outcomes and that it helps close the health disparities gaps for the underserved, minorities, and other marginalized populations. Preexisting health inequities also present additional challenges in the regulation of treatments for rare diseases. Understanding of efficacy of a treatment depends on an understanding of the disease and its progression. A lack of research and information on a rare disease that affects predominately marginalized populations could result in inaccurate understandings of the efficacy of the treatment.
Pediatric Considerations
Rare diseases commonly present during childhood, and, for some diseases, irreparable harm or death may occur before a child reaches adulthood (Chung et al., 2022a). When this is the case, clinical trials aimed at a rare disease should enroll pediatric patients as early as possible. FDA encourages sponsors to study a product in all relevant pediatric populations, from birth through 17 years of age, and to consider the relevance and comparability of endpoints for patients of different ages (FDA, 2023b). Conducting trials
that include pediatric patients requires a number of special considerations, such as balancing of risks and benefits, obtaining informed consent of parents and agreement from children when possible, and ensuring the protection of child participants (IOM, 2004). The added layers of complexity for studying a treatment intended for a pediatric population makes regulation of these treatments more difficult.
Informed consent and privacy are fundamental principles of research; participants or their legal proxies need adequate information about the risks and benefits, the ability to make an informed choice whether to participate, and an assurance that data they provide will be kept private. In the context of rare disease research, informed consent and privacy are complicated by several issues. First, obtaining consent from parents while respecting the autonomy of the child can be a difficult balance. Second, due to the small numbers of available research participants, data sharing among researchers may be necessary, raising privacy concerns. Third, rare disease research may require the collection and sharing of genetic data as well as phenotypic data such as images or videos. Research participants may be able to be identified based on these data, particularly if they are one of only a few patients with a disease. These types of challenges require that researchers be thoughtful about how to conduct research while respecting the autonomy and privacy of rare disease patients (Nguyen et al., 2019). At the same time, people living with rare diseases may be highly motivated to participate in clinical trials and contribute to the research process, which further supports the need for informed consent that is person-centered and tailored to the needs and interests of the patient population (Gainotti et al., 2016)
As discussed in Chapter 2, there are several laws and regulatory policies in place to address barriers to pediatric drug development, but more is needed to address the unmet medical need for children living with rare diseases and conditions.
Complex and Heterogenous Clinical Manifestation of Disease
Successful drug development is built on a foundation of scientific insights, including an understanding of the natural history of disease—the progression of a disease or condition in a person over time. High-quality natural history data play a critical role in rare disease drug development as this information helps sponsors establish inclusion or exclusion criteria for interventional studies, determine clinical outcomes that are meaningful for patients, and identify relevant biomarkers and it can serve as or augment control arms in a clinical trial and serve as an external control to provide confirmatory evidence of a single adequate and well-controlled trial (FDA, 2023d). While natural history registries have been established for some rare
diseases and conditions, for most rare diseases, the natural history is poorly understood (Liu et al., 2022).
The same condition can present differently across individuals and over time; this heterogeneity in clinical manifestation is more acute in the case of rare diseases, which further complicates the design and implementation of clinical trials (Murray et al., 2023). Clinical trials are generally designed to study the effect of an intervention on one or more outcomes, but for conditions with heterogenous clinical manifestations, the targeted measure(s) may not be relevant for all trial participants (Murray et al., 2023). Poor understanding of disease symptoms or progression can further impede the selection of relevant outcome(s) (Murray et al., 2023). There are several approaches for addressing the challenge of heterogeneity, including using multicomponent or composite endpoints that combine several outcomes into one measure (Chow and Huang, 2019; Chow et al., 2020; Murray et al., 2023).
For most rare diseases, there are often few, if any, validated endpoints—reliable measurements of a clinical trial outcome (Busner et al., 2021). The endpoints chosen for a particular trial depend on the design of the trial as well as the nature of the condition or the expected effect of the drug or both (NIH, n.d.). Endpoints (including surrogate endpoints) can be developed and selected in a number of ways—through natural history data, using measures developed for other conditions, or based on measures used in clinical practice. However, there are challenges in applying each of these approaches for rare diseases. Natural history data are often lacking, measures for other conditions may not capture all relevant symptoms, and there may be few clinical measures, depending on the rarity of the condition.
While there are many challenges common to drug development for all rare diseases, some are particularly pronounced for diseases for which information may be extremely limited or nonexistent. Due to this lack of information, the benefit–risk assessment that is integral to the drug approval process can be more difficult to conduct. If a drug is approved based on the limited information available, post-marketing surveillance, post-marketing studies, and registries can be effective tools for collecting additional information about benefits and risks (Sardella and Belcher, 2018).
Due to the complexity and heterogeneity of rare diseases, it is often the case that drug development programs must be tailored to address particular challenges. FDA encourages sponsors seeking to develop new drug products for the treatment of rare diseases or conditions to engage with the agency early and often and to review relevant guidance documents. There is no one-size-fits-all regulatory process for rare disease products, which can increase the time, effort, and difficulty for sponsors pursuing rare disease development programs.
CONTEXT FOR THIS STUDY
For people living with rare disease and conditions, there is an urgent need to increase the pace and volume of drug development and of regulatory approval processes. Patient groups have expressed frustration with regulatory agencies, raising legitimate questions about how agencies analyze data gathered from small trials and consider patient and caregiver input in regulatory decision-making, noting seeming inconsistencies around drug products that are approved by one agency and not the other, and asking how and when FDA applies regulatory flexibilities across its centers and divisions (EveryLife Foundation for Rare Diseases, 2023; Haystack Project, 2023).
Given the challenges associated with rare disease research and development and the need for new drug products to treat rare diseases and conditions, policy makers have attempted to understand the underlying issues and find potential solutions.
BOX 1-3
Select Publications on Regulatory Processes for Evaluating the Safety and Efficacy of Drugs to Treat Rare Diseases and Conditions
- 2001: The U.S. Department of Health and Human Services (HHS) Office of Inspector General published a report that assessed the implementation and impact of the Orphan Drug Act of 1983. The report found that the Orphan Drug Act was successful in motivating pharmaceutical companies to develop orphan products, which were generally accessible to patients. The report also found that the Office of Orphan Products Development provides a valuable service to companies and patients (HHS, 2001).
- 2010: The Institute of Medicine published a consensus study report, Rare Diseases and Orphan Products: Accelerating Research and Development, which made recommendations for the U.S. Food and Drug Administration (FDA) to (1) “develop guidelines for CDER [Center for Drug Evaluation and Research] reviewers to promote consistency and reasoned flexibility in the review of orphan drugs” and “use the analysis and the review guidelines to inform the advice and formal guidance given to sponsors about the evidence needed to support orphan drug approvals”; (2) examine the use of small clinical trials and adjust educational programs and guidance to align with advances in the science of small clinical trials and associated analytical methods; and the National Institutes of Health (NIH) and FDA to support NIH-funded studies involving rare disease research and development that are designed to fulfill requirements for FDA approval (IOM, 2010).
The U.S. Congress requested that the National Academies of Sciences, Engineering, and Medicine (the National Academies) convene a committee to conduct a study on the processes for evaluating the safety and efficacy of drugs for rare diseases. The statement of task (see Box 1-4) asked the committee to examine processes in both the United States and the European Union, and specifically tasked the committee with identifying flexibilities and mechanisms available to regulators, considering the use of “supplemental data” during review (see Box 1-5 for key terminology), and assessing existing and potential collaborative efforts between the United States and the European Union. Several other publications on similar topics have been produced in the previous decades (see Box 1-3).
It is important to note that at the time of this report’s writing, there were several activities underway that could positively affect the landscape for the approval of treatments for rare diseases. As part of the Consolidated
- 2018: The U.S. Government Accountability Office (GAO) was tasked with examining the process by which FDA reviews applications for orphan designation and published a report that looked at (1) FDA actions to address the demand for orphan designations, (2) the extent to which FDA has used consistent criteria to review orphan designation applications, and (3) steps FDA has taken to address barriers to rare disease drug development. GAO recommended that FDA ensure that information from orphan drug applications is consistently recorded and evaluated by reviewers (GAO, 2018).
- 2019: The European Commission (EU) published a study that evaluated the extent to which the EU Orphan Regulation, which was introduced in 2000, has been effective, efficient, and relevant. The study found that the incentives for development of medicines for rare diseases that were put in place through the regulation helped improve drug development. The report also stated that “the needs and problems to which the EU Orphan Regulation responded still exist, and, as such, the objectives of the Regulation remain as important today as they were nearly two decades ago” (European Commission, 2019).
- 2024: The National Academies published a consensus study report, Living with ALS, which made recommendations for actions the NIH, the Centers for Disease Control and Prevention (CDC), and public–private partnerships funded under the Accelerating Access to Critical Therapies Act should take to improve research and development for drugs to treat ALS (NASEM, 2024).
BOX 1-4
Statement of Task
In response to a congressional request, an ad hoc committee of the National Academies of Sciences, Engineering, and Medicine will conduct a study on processes for evaluating the safety and efficacy of drugs for rare diseases or conditions in the United States and the European Union, including:
- flexibilities, authorities, or mechanisms available to regulators in the United States and the European Union applicable to rare diseases or conditions;
- the consideration and use of supplemental data submitted during review processes in the United States and the European Union, including data associated with open label extension studies and expanded access programs specific to rare diseases or conditions;
- an assessment of collaborative efforts between United States and European Union regulators related to:
- product development programs under review;
- policies under development and those recently issued; and
- scientific information related to product development or regulation.
Based on its information gathering and internal deliberations, the committee will develop a report with its findings, conclusions, and recommendations for actions that Congress, federal agencies, the pharmaceutical industry, and nongovernmental organizations can take to support collaborative efforts.
Appropriations Act of 2023,3 the Food and Drug Omnibus Reform Act of 2022 (FDORA) contains several provisions directed at improving the number of rare disease treatments. Among other provisions, FDORA:
- Requires FDA to publish a report summarizing its activities related to designating and approving or licensing drugs and biologics for rare diseases (Sec. 3202);
- Creates a Rare Disease Endpoint Advancement Pilot Program (Sec. 3208);
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3 P.L. 117-328. Consolidated Appropriations Act (December 29, 2023).
- Reauthorizes orphan drug grants (Sec. 3107); and
- Requires the drafting of a U.S. Government Accountability Office (GAO) report assessing FDA’s policies, practices, and programs regarding treatments for rare diseases (Sec. 3202).
In 2024, FDA announced a plan to establish a Rare Disease Innovation Hub (the Hub) to establish a new model for the agency to leverage cross-agency expertise and enhance shared learnings to spur drug development for rare diseases and conditions (FDA, 2024a). As outlined in this chapter and in the details of this report, there are numerous challenges for rare disease drug development—challenges that must be overcome to increase the likelihood of success for drug development across rare diseases and conditions and ensure that these therapies are accessible to patients to address their unmet medical needs.
Historically marginalized communities in the United States have faced heightened challenges in the realm of rare diseases and conditions. These challenges include inadequate federal and foundation funding, exclusionary research practices, and inequitable access to emerging therapies (Docteur and Berenson, 2014). As solutions are developed to address the needs of those affected by rare diseases, it will be imperative that the unique needs and perspectives of marginalized groups are centered in the process. Failure to do so will perpetuate health disparities and limit the overall impact of efforts to improve access to rare disease therapies. Inclusive funding, research, and treatment access strategies will be essential to comprehensively address the needs of all individuals affected by rare diseases and conditions in the United States.
This report evaluates and makes recommendations for one part of a multifaceted ecosystem that determines which diseases are studied, what types of drug research and development are prioritized, how the safety and efficacy of drug products are reviewed and approved, which products are brought to market, and how approved and marketed therapies are made available (or not) to patients. While the adoption of the recommendations in this report will serve to foster transparency, streamline regulatory processes, and facilitate more collaboration between FDA and EMA, regulators review what is submitted to them. The gap between the needs of patients living with rare diseases and conditions and the therapies available for treating them cannot be closed by focusing solely on regulatory processes. Filling the gap will require additional attention upstream of regulatory decision-making—investment in basic research to understand the underlying biology of rare diseases and conditions, approaches to ensure patient input is incorporated early on and throughout the research process—as well as downstream from the regulatory process—policies, incentives, and business models to address issues with drug pricing and
BOX 1-5
Key Terms and Definitions
- Adequate and Well-Controlled Trial: A clinical trial or clinical investigation that includes the characteristics defined in regulation:a a clear statement of objective, comparison with a valid control (types of valid control defined in regulation), adequate method of participant selection, method of patient assignment to treatment group (e.g., randomization), method to reduce bias (e.g., blinding), well-defined and reliable method of assessing participants’ response, and adequate analysis of the results to assess effect of the treatment (FDA, 2019b).
- Alternative and Confirmatory Data: For the purposes of this report, the committee uses the term alternative and confirmatory data to mean data that are collected outside the setting of a randomized controlled clinical trial and used as supplementary, alternative, or confirmatory evidence in support of regulatory submission and review of a drug product. See Chapter 4 for additional context.
- Benefit–Risk Assessment: A comprehensive evaluation of the benefits and risks (along with uncertainties in managing the risks) for a drug product that is part of the drug review and approval process. Regulatory agencies use benefit–risk assessments to help ensure that approved drugs offer therapeutic benefit while minimizing risk to patients.
- Biologics License Application: “A request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce (21 CFR 601.2). The BLA is regulated under 21 CFR 600 – 680” (FDA, 2021b).
- Biomarker: A drug development tool used to measure a biological or pathogenic process, a response to an exposure or intervention, including therapeutic interventions (e.g., molecular, histologic, radiographic, or physiologic measurements) (FDA, 2021a). Biomarkers are used in clinical trials to help diagnose, monitor, or stratify patients and to predict clinical outcomes and can also serve as surrogate endpoints.
- Clinical Trials: This report generally uses the term clinical trials to mean “voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.” (FDA, 2018a)
- Diseases and Conditions: This report generally uses the term disease to mean a disruption of normal functions of the body that can be diagnosed by a health care provider. A disease or condition is an affliction that causes harm to an organ, part, structure, or system of the body that results in improper functioning, or a state of health that causes such dysfunction, with the exception of diseases caused by essential nutrient deficiencies.
- Drug Effectiveness: How well a drug provides the expected therapeutic effect on a disease or symptom in clinical practice in the real world (NCATS, n.d.-a).
- Drug Efficacy: How well a drug provides the expected therapeutic effect on a disease or symptom under controlled conditions, such as a clinical trial (NCATS, n.d.-b).
- Drug Product: The finished dosage form containing a drug substance (may include other active or inactive ingredients), which is intended for the diagnosis, treatment, or prevention of a disease (FDA, 2017). Biological products are included within this definition.
- Drug Safety and Effectiveness: For a drug product to receive the U.S. Food and Drug Administration (FDA) approval or European marketing authorization, it must first undergo a rigorous evaluation process in which evidence is reviewed by regulatory personnel to evaluate the likelihood of adverse effects and ability of the drug to produce the desired result (IOM, 2010).
- Drug Research and Development: Broadly defined term that includes laboratory studies (e.g., investigation to understand the biological mechanisms and processes that underpin a disease or condition; testing of molecular compounds to find beneficial effects against a disease or condition), pre-clinical studies to answer basic questions about drug safety (e.g., gathering information on dosing and toxicity levels), and clinical trials to test a drug on people to make sure the drug is safe and effective.
- New Active Substance: “A chemical, biological, biotechnology or radiopharmaceutical substance that has not been previously available for therapeutic use in humans and is destined to be made available as a ‘prescription-only medicine,’ to be used for the cure, alleviation, treatment, prevention or in vivo diagnosis of diseases in humans.” (Centre for Innovation in Regulatory Science, 2020)
- New Drug Application: Mechanism through which a drug sponsor formally proposes that FDA approve a new drug product for sale and marketing in the United States. Includes relevant data and information (e.g., ingredients of the drug, results from animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged) that has been collected during research and development (FDA, 2022b).
- Orphan-Drug Designation:b A status given to drug products that show promise in diagnosing, treating, or preventing rare diseases or conditions. FDA and the European Medicines Agency (EMA) have similar, but not identical criteria for orphan designation. See Chapters 2 and 3 for additional information.
- People with Lived Experience: Individuals who have firsthand experience with a diagnosis or health condition. This may include individuals who have a rare disease or condition and individuals who are caregivers and/or family members of those who have a rare disease or condition.
- Sponsor: An applicant, such as pharmaceutical company, foundation, medical institution, patient group, or federal agency, that assumes responsibility for a marketing authorization application to a regulatory agency.
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a 21 CFR § 314.126(b).
b 21 U.S.C. § 360bb.
payer decisions that have outsized impacts on the accessibility and affordability of treatments for rare disease patients. The committee believes this framing is critical for understanding the report recommendations and considerations for implementation.
To carry out this study, the National Academies convened the Committee on Evaluating the Safety and Efficacy of Drugs for Rare Diseases or Conditions in the United States and the European Union (see Appendix A for biographical sketches of committee members). The project was supported by funding from the U.S. Department of Health and Human Services. This report presents the committee’s conclusions and recommendations and identifies the diverse set of stakeholders best positioned to address and implement its recommendations.
Committee’s Charge
Given the broad scope of the statement of task, and the limited time it had to carry out the study, the committee focused on certain types of drug products to treat rare diseases and conditions. Specifically, the committee was asked by the sponsor to focus on examining the regulatory processes for the review and approval of new molecular entities (NMEs) and biologics, rather than applications to repurpose or reposition drug products. As requested by the sponsor, drug repositioning or repurposing, new indications for drugs already approved, N-of-1 or single-participant clinical trials, devices, new modalities, and platform technologies were considered to be outside the scope of this report. Finally, while the committee looked at areas for collaboration between the United States and the European Union, recommendations are focused primarily on the U.S. regulatory landscape.
STUDY APPROACH
Committee Composition
To carry out the statement of task, a committee was convened that included experts from a broad array of fields, including bioethics, biomedical engineering, biostatistics, clinical trials, pharmaceutical research and development, patient advocacy, regulatory policy at FDA and EMA, risk analysis, translational science, and technology transfer.
Information Gathering
The committee gathered information through open presentations from topic experts, public comments from interested parties, literature review, commissioned data analysis, and semi-structured interviews. The committee
held three open sessions during the course of the study: November 6–7, 2023; December 4–5, 2023; and February 6–7, 2024 (see Appendix C for open session agendas). During these open sessions, the committee received presentations from FDA, EMA, patient advocates, industry drug developers, industry trade organizations, and experts on alternative and confirmatory data and trial design. Stakeholders that were interested in providing a public comment were able to speak as part of the open session meetings with the committee. Interested parties also had opportunities to submit written public comments for the committee’s consideration. At the beginning of the project, National Academies staff conducted a literature review to curate research materials for the committee’s consideration. The committee was provided with literature in preparation for each committee meeting that was tailored to the planned topics of the open session.
The commissioned analysis and semi-structured interviews were conducted at the request of the committee. Both were designed by the committee. The committee commissioned the Centre for Innovation in Regulatory Science (CIRS) to analyze: (1) the success rates of orphan product approval and authorization submissions at FDA and EMA, respectively; (2) the distribution of products approved by FDA and EMA by therapeutic area; (3) the use of expedited pathways by products approved by FDA and EMA; and (4) the use of “supplemental data” in applications for products approved by FDA and EMA (see Appendix D for a detailed description of CIRS’ methodology). At the request of the committee, National Academies staff conducted semi-structured interviews with industry stakeholders who led the clinical development or regulatory submission of rare disease drug products (see Appendix E for a detailed description of the approach, including a recruitment strategy and a summary of the stakeholders interviewed).
Concepts, Definitions, and Conceptual Framework
Orphan designation in the United States is available for drugs aimed at rare diseases that affect fewer than 200,000 people or drugs that are aimed at diseases that affect more than 200,000 people in the United States and “for which 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.”4
EU legislation defines a rare disease or condition as one for which the prevalence is no more than 5 in 10,000 people across the European Union.5 EMA orphan designation is available for drugs that meet all of the following criteria:
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4 Federal Food, Drug, and Cosmetic Act, SEC. 526(a)(2), 2023.
5 EU Pharmaceutical Legislation on Orphan Medicinal Products (Regulation (EC) 141/2000, 1999.
- “it must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;
- “the prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development;
- “no satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorized, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.” (EMA, n.d.)
While the definitions of a rare disease differ somewhat between FDA and EMA, the numbers are roughly similar. The population in the European Union in January 2023 was 448.4 million (European Commission, 2023); a rare disease or condition as defined by EMA would be one that affects less than 224,200 people (compared to the FDA definition of less than 200,000 people). The population in the United States in 2023 was estimated to be 334.9 million people (USAFacts, n.d.); a rare disease or condition as defined by FDA would be approximately 6 in 10,000 (compared to the EMA requirement of no more than 5 in 10,000 people). For consistency, this report will use the same definition for recurring key terms (see Box 1-5).
Organization of the Report
This report is organized into five chapters. The first chapter provides the context for the study and the committee’s approach and gives a brief overview of the topic. The second chapter describes the regulatory functions of FDA and its flexibilities, authorities, and mechanisms related to rare disease drug development, review, and approval. The third chapter reviews the same areas for EMA. In the fourth chapter, the committee explores the various approaches for generating and using alternative and confirmatory data and examines how these data are received by FDA and EMA for the purposes of drug approval. Chapter 5 provides a comparison between the regulatory approaches of FDA and EMA and identifies existing and potential areas for collaboration between the two agencies. The committee’s recommendations are presented throughout the report.
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