Benefit–Risk Assessment

As articulated in the 2024 National Academies report, Living with ALS, there are trade-offs between enabling patient access to new medications and the degree of uncertainty when it comes to the assessment of benefit and risks for a given drug (NASEM, 2024). There are several factors involved in the assessment of the benefits and risks of a particular drug, including the clinical context, the availability of other treatments, and the seriousness of the condition (see Box 2-1). FDA guidance for industry, Rare Diseases: Considerations for the Development of Drugs and Biological Products (FDA, 2023l), notes that “a feasible and sufficient safety assessment is a matter of scientific and regulatory judgment based on the particular challenges posed by each drug and disease, including patients’ tolerance and acceptance of risk in the setting of unmet medical need and the benefit offered by the drug.” The benefit–risk assessment also involves an evaluation of the degree of uncertainty in the identified risks and benefits. For example, a small trial may not detect certain adverse events, or it may overestimate the effect of the drug. FDA guidance Benefit–Risk Assessment for New Drug and Biological Products (FDA, 2023c) states that a higher degree of uncertainty is common in rare disease drug development due to limitations on study size and that when drugs are being developed for serious diseases with few or no approved therapies, “greater uncertainty or greater risks may be acceptable provided that the standard for substantial evidence of effectiveness has been met.”

BOX 2-1

Benefit–Risk Assessment.

In the case of serious rare diseases, FDA may thus exercise regulatory flexibility by accepting clinical trials that have smaller sample sizes. Accepting smaller sample sizes for serious rare diseases places even greater importance on maximizing the trial’s potential to provide interpretable scientific evidence about the drug’s benefits and risks in order to be respectful of patients’ willingness to participate in clinical trials. Patient contribution is optimized in clinical trials (and particularly in small sample size studies) by minimizing bias and maximizing precision with trial design features such as randomization, blinding, enrichment procedures, and adequate trial duration (FDA, 2023c).

Substantial Evidence of Effectiveness

Substantial evidence of effectiveness is defined in section 505(d) FD&C Act as:

evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.⁴

FDA has interpreted substantial evidence of effectiveness as generally requiring at least two adequate and well-controlled clinical investigations, each of which is convincing on its own (FDA, 2019a). Requiring two adequate and well-controlled clinical trials allows for independent substantiation of study results and protects against the possibility that a chance occurrence in one study would lead to an erroneous conclusion about the drug’s effectiveness (FDA, 1998, 2019a; Freilich, 2024). However, there is regulatory flexibility available in some circumstances for the amount and type of evidence needed to meet the substantial evidence standard, as described further in the FD&C Act and FDA guidance documents and discussed below.

In 1997, Congress amended the FD&C Act to clarify that substantial evidence of effectiveness could also consist of a single adequate and well-controlled study and confirmatory evidence “if [FDA] determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness.”⁵

This clarification reflected FDA’s then-current thinking given the rapidly evolving science and practice of clinical research and drug development. In 1998, FDA released subsequent guidance⁶ for industry, Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (FDA, 1998), to share the agency’s thinking on the quantity and quality of data that could be used for demonstrating effectiveness of drugs.⁷ In this guidance, FDA provided several illustrations of the “types of evidence that could be considered confirmatory evidence, with a specific focus on adequate and well-controlled trials of the test agent in related populations or indications, as well as a number of illustrations of a single adequate and well-controlled trial supported by convincing evidence of the drug’s mechanism of action in treating a disease or condition” (FDA, 2023f). For example, a pediatric indication might be approved based on a study on adults if the pathophysiology and drug effect are similar between the populations.

In December 2019, FDA issued draft guidance, Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, which complemented and expanded on the 1998 guidance. The new draft guidance stated, “Although FDA’s evidentiary standard for effectiveness has not changed since 1998, the evolution of drug development and science has led to changes in the types of drug development programs submitted to the Agency. Specifically, there are more programs studying serious diseases lacking effective treatment, more programs in rare diseases, and more programs for therapies targeted at disease subsets” (FDA, 2019a). Consequently, the 2019 guidance lists several illustrative examples of the types of evidence that could be considered as confirmatory of a single adequate and well-controlled study. Those examples included: (1) data from a single adequate and well-controlled study that demonstrated the drug’s effectiveness in another closely related approved indication; (2) data providing strong mechanistic support; (3) natural history data from the disease, and (4) scientific knowledge about the effectiveness of other drugs in the same pharmacological class. A single study could be sufficient for demonstrating effectiveness if the study is a large multicenter, adequate, and well-controlled trial and “the trial has demonstrated a clinically meaningful and statistically very persuasive effect on mortality, severe or irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be impractical or unethical” (FDA, 2019a).⁸

In 2023, FDA issued a draft guidance, Demonstrating Substantial Evidence of Effectiveness with One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence, which offers further clarification on when one study and confirmatory evidence may be sufficient for establishing effectiveness (FDA, 2023f). The guidance identifies types of confirmatory evidence that could be used to supplement one clinical investigation; FDA notes that the list is not exhaustive, and that each application is considered on a case-by-case basis. The types of confirmatory evidence listed include clinical evidence from a related indication, mechanistic or pharmacodynamic evidence, evidence from a relevant animal model, evidence from other members of the same pharmacological class, natural history evidence, real-world data, and evidence from expanded access use of an investigational drug (see Chapter 4).

FDA conducts a thorough review of an application to determine whether the submitted data constitutes substantial evidence of effectiveness. FDA examines both final summaries and data from nonclinical and clinical studies, from which it determines the safety and effectiveness of the product through its own independent analysis. The review team replicates the applicant’s analyses and, if necessary, conducts additional analyses to further inform the efficacy assessment (Bugin, n.d.).

Conclusion 2-1: While the statutory requirements for drug approval for rare diseases and conditions are the same as for non-rare diseases or conditions, FDA has long recognized the need to apply regulatory flexibility in the review and approval of marketing authorization applications.

Orphan Drug Designation

The orphan drug designation is an FDA incentive that began in 1983 following the enactment of the Orphan Drug Act, with the goal of stimulating the development of drugs and biological products for rare diseases by lessening the financial burdens associated with orphan drug development. A drug may qualify for orphan-drug designation (ODD) if the targeted disease or condition affects fewer than 200,000 individuals in the United States at the time of the sponsor’s request, 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.¹⁰ To be eligible for ODD, a drug or biological product must be for a distinct rare disease or condition. FDA determines what the distinct disease or condition is by considering such factors as the pathogenesis of the condition, course of the condition, prognosis of the condition, and resistance to treatment.¹¹ These factors are assessed in the context of the specific drug seeking ODD.

A sponsor can receive multiple designations for the same drug if it can be shown to treat more than one distinct disease or condition. A sponsor can also receive ODD for its version of a drug that is otherwise the “same drug” as an already approved drug for the same disease or condition as long as the sponsor can present a plausible hypothesis that its drug may be clinically superior to the first drug.¹²

A sponsor may receive ODD for a drug designed to treat an “orphan subset”¹³ of individuals with a disease that affects more than 200,000 people if it can be demonstrated that the subset affects less than 200,000 people in the United States and that the remaining individuals with the disease would not be appropriate candidates due to some property of the drug.¹⁴ To be considered for ODD under this “orphan subset” provision, the demonstration that other patients would not be appropriate candidates must be based on pharmacologic or biopharmaceutical properties of the drug, or previous clinical experience with the drug.¹⁵ For example, ODD could be granted if data demonstrate that the drug is only effective for patients with a certain biomarker, or that the toxicity of the drug makes it appropriate only for patients who do not respond to standard, less toxic treatments.¹⁶ FDA has clarified that an orphan subset does not refer to a clinically distinguishable subset of persons with a particular condition; eligibility for ODD under an orphan subset must be based on a property of the drug itself, not a subset of patients.¹⁷ A product targeted at just the pediatric population may be eligible for ODD in a number of ways (FDA, 2018a). First, if the disease is rare in the overall population, any product may be eligible. Second, if the disease is common in the general population, a product may be eligible for ODD if the affected pediatric population is less than 200,000 and is a valid orphan subset, meaning that the product would not be appropriate for use in the adult population owing to some property or properties of the drug; this would be considered an orphan subset designation. Third, a product may be eligible for ODD if the disease in the pediatric population is a different disease than in the adult population and the affected pediatric population is less than 200,000.

Approvals of Drugs with Orphan Drug Designation

Prior to the Orphan Drug Act, few drugs were approved by FDA for rare diseases and conditions (Asbury, 1991). During the last 40 years, over 6,300 drugs have received ODD for over 1,000 rare diseases. Of the ODDs granted by FDA, 882 resulted in at least one drug approval for 392 diseases (Fermaglich and Miller, 2023). As of 2022, between 4 and 6 percent of rare diseases had an approved drug, while between 11 and 15 percent had received an ODD (Fermaglich and Miller, 2023).

In 2010, CDER approved six new molecular entities with ODD, representing 29 percent of approved new products. In 2022, CDER approved 20 new molecular entities for orphan conditions, constituting 54 percent of all center approvals (see Figure 2-2). CBER product approvals followed a similar trend, increasing from zero ODD approvals in 2010 to five in 2022, constituting 63 percent of all center approvals (see Figure 2-3). Overall, from 2010 to 2022, the number of orphan drug approvals increased in both number and percentage of the total approved new products for both CDER and CBER, with orphan drugs making up over half of approved new products for both centers in 2021 and 2022.

FIGURE 2-2

Proportion of CDER novel drug approvals that were orphan from 2010 to 2022. NOTE: CDER = Center for Drug Evaluation and Research. SOURCE: Presented to the Committee by Kerry Jo Lee, on November 6, 2023.

FIGURE 2-3

Proportion of CBER novel biologic approvals that were orphan from 2010 to 2022. NOTES: These data exclude in vitro diagnostic products, reagents, and intermediate biological products approved for further manufacture, such as source plasma. CBER = Center (more...)

To understand the rates of FDA approvals for non-orphan and orphan drug products over time, the committee commissioned an analysis of marketing submissions, regulatory orphan designations, and marketing approvals of new drug products from 2013–2022 using new drug applications and biologics license applications (types 1 and 1,4). Due to a lack of available data on approval and non-approval rates, the committee requested information about new drug products received from 2013–2022. Data from 2015–2020 were obtained directly from the agency for CDER and CBER. Additional data on the therapeutic areas and use of expedited review pathways were obtained from agency public assessment reports (see Appendix D for full methodology). Overall, approval rates for orphan drug product applications received between 2015 and 2020 are higher than for non-orphan drug products at nearly all FDA offices, with approval rates ranging from 83 percent (Office of Cardiology, Hematology, Endocrinology, and Nephrology) to 100 percent (Office of Immunology and Inflammation) (see Figure 2-4). Despite the increasing number of ODD and associated drug approvals, much of the progress has been concentrated in a few therapeutic areas. Between 2013 and 2022, a large portion of orphan drug approvals were for anti-cancer and immunomodulator treatments, followed by alimentary and metabolism treatments and the blood and blood forming organs treatments (see Figure 2-5).²²

FIGURE 2-4

Novel approval rates for non-orphan and orphan new drug applications submitted to CDER from 2015 to 2020 by office. NOTES: CDER = Center for Drug Evaluation and Research; OCHEN = Office of Cardiology, Hematology, Endocrinology and Nephrology; OID = Office (more...)

FIGURE 2-5

FDA approval of orphan and non-orphan drugs by therapeutic area from 2013 to 2022. NOTES: FDA = U.S. Food and Drug Administration; NASs = new active substances; Other = other therapeutic areas not described in the top five therapeutic indications list. (more...)

Rare Pediatric Disease Priority Review Voucher Program

The rare pediatric disease priority review voucher (PRV) program, established in 2012 under section 908 of the Food and Drug Administration Safety and Innovation Act (FDASIA), was designed to incentivize the development of certain new drugs or biologics to prevent or treat rare diseases that affect pediatric populations.²³ Section 908 of FDASIA defines a rare pediatric disease as “a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years, including age groups often called neonates, infants, children, and adolescents,” and the disease is a rare disease or condition within the meaning of section 526 of the FD&C Act.²⁴ Under this program, sponsors who receive approval for a drug to treat a rare pediatric disease may qualify for a voucher for priority review of a subsequent product (FDA, 2019d). Priority review generally means a marketing authorization submission will be reviewed by FDA in 6 months rather than the standard 10-month period review time. The sponsor may transfer or sell the voucher to another sponsor. The program has been renewed by Congress in the past, typically for 4 years at a time. Under current legislation, the rare pediatric disease designation PRV program begins to sunset after September 30, 2024 (FDA, 2024q).

Accelerated Approval

The accelerated approval pathway was established by FDA in 1992 in response to the acquired immunodeficiency syndrome (AIDS) epidemic with the goal of bringing forward new therapies for patients who desperately needed treatment options. Today, the pathway is available for drugs that meet all of the following criteria (FDA, 2014b):

• The drug “treats a serious condition”; and
• The drug “generally provides a meaningful advantage over available therapies”; and
• The drug “demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit (i.e., an intermediate clinical endpoint).”

The pathway allows the use of a surrogate endpoint (e.g., a biomarker) or an intermediate clinical endpoint for accelerated approval—an approach viewed by some critics as subjecting patients to unnecessary risks (Kesselheim and Darrow, 2015; Redberg, 2015). Confirmatory trials are also required to verify and describe the clinical benefit (FDA, 2014b).²⁷ In the early years of the accelerated approval program, the pathway was primarily used for drugs to treat human immunodeficiency virus (HIV) and cancer. Between 2013 and 2022, 86 percent of all drugs approved through this pathway were orphan designated drug products (see Figure 2-8). The vast majority of drugs approved through this pathway between 2010 and 2020 have been for oncology indications; 85 percent of accelerated approval drugs treated cancers (Temkin and Trinh, 2021). Although the accelerated approval pathway is not used as frequently for non-oncology rare diseases as it is for rare types of cancers, if applied appropriately, it can be a beneficial tool for bringing safe and effective drugs to patients who suffer from serious and life-threatening conditions and for whom there are no meaningful alternative treatment options (Temkin and Trinh, 2021).

FIGURE 2-8

Number of orphan and non-orphan drug products that received accelerated approval designation by FDA between 2013 and 2022. NOTES: FDA = U.S. Food and Drug Administration; NASs = new active substances. SOURCE: CIRS Data Analysis, 2024.

As laid out in Chapter 1, the heterogeneity of rare diseases and conditions makes it difficult to identify and validate biomarkers for regulatory decision-making that are pertinent across the entire study population (Murray et al., 2023). To help fill this gap, efforts such as the Critical Path Institute’s Biomarker Data Repository, seek to advance ongoing research to advance new biomarkers for rare diseases and conditions (Critical Path Institute, n.d.).²⁸ In 2022, Congress made several reforms to the accelerated approval program through the Food and Drug Omnibus Reform Act of 2022 to help promote transparency and more accountable use of the pathway (see Box 2-2).

BOX 2-2

Reforms and Future Direction of Accelerated Approval.

Fast Track

FDA offers fast track designation for drugs that meet one of the following criteria:

• Intended to treat a serious or life-threatening disease or condition, and nonclinical or clinical evidence demonstrate the potential to address unmet medical need;²⁹ or
• Designated as a qualified infectious disease product³⁰ (section 505E of the FD&C Act).

Impact

Many products developed for rare diseases meet the criteria for fast track designation—targeted at a serious or life-threatening condition and having the potential to fill an unmet medical need—at a higher rate than products developed for non-rare diseases. Using the fast track program may benefit sponsors of rare disease products by facilitating earlier and more frequent communication so that unique study issues can be discussed, and problems can be identified and addressed early in the process. Since the launch of fast track designation, it has been used primarily by orphan products, which accounted for over 50 percent of all designated products between 1998 and 2014 (Miller and Lanthier, 2016) and 64 percent of all designated products between 2013 and 2022 (see Figure 2-9).

FIGURE 2-9

Number of orphan and non-orphan drug products that received fast track designation approved by FDA between 2013 and 2022. NOTES: FDA = U.S. Food and Drug Administration; NASs = new active substances. SOURCE: CIRS Data Analysis, 2024.

Breakthrough Therapy

Breakthrough therapy designation is available for drugs that meet both of the following criteria:

• Intended to treat a serious or life-threatening disease or condition; and
• Preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies (FDA, 2014b).

FDA guidance for industry, Expedited Programs for Serious Conditions (FDA, 2014b), goes into detail about the criteria that must be met for breakthrough therapy designation. FDA explains that “preliminary clinical evidence” means evidence generally from Phase 1 or Phase 2 clinical trials that is sufficient to indicate that the drug substantially improves upon available therapies but in most cases is not sufficient to establish safety and effectiveness for purposes of approval (FDA, 2014b). In general, to demonstrate a “substantial improvement,” preliminary clinical evidence should show a “clear advantage over available therapy.” The determination of whether there is substantial improvement over available therapy is a matter of judgment and depends on the size of the treatment effect and the importance of the effect to the treatment of the condition (FDA, 2014b). The “clinically significant endpoint” could be a measure of irreversible morbidity or mortality, specific symptoms that represent serious consequences of the disease, or an effect on a biomarker that strongly suggests an impact on a serious aspect of the disease (FDA, 2014b).

Due to the serious nature of rare diseases and the lack of available or adequate therapies, products aimed at rare diseases have received breakthrough therapy designation at a higher rate than products aimed at common diseases (see Table 2-2 for data on non-oncology drugs and biologics). Between 2013 and 2022, orphan medical products accounted for 75 percent of all drug products that received the breakthrough therapy designation (see Figure 2-10). Moreover, between 2018 and 2022, over half (52 percent) of novel approved orphan drugs received the designation. Experience to date has shown that the breakthrough therapy designation can dramatically speed the development and approval for selected products, improving access to effective drugs for patients with difficult-to-treat conditions (Collins et al., 2023; Shea et al., 2016).

TABLE 2-2

CDER Decisions to Grant or Deny Breakthrough Therapy Designation Requests for Non-Oncology Drugs and Biological Products from 2017 to 2019.

FIGURE 2-10

Number of orphan and non-orphan drug products that received breakthrough therapy designation approved by FDA between 2013 and 2022. NOTES: FDA = U.S. Food and Drug Administration; NASs = new active substances. SOURCE: CIRS Data Analysis, 2024.

Project Orbis

FDA’s OCE launched an international collaborative review program called Project Orbis in 2019. Applicants submitting marketing applications for products with great potential to address unmet medical needs can be considered for eligibility. Project Orbis partners can opt in or out of participating in the review of each application. The process allows for collaborative exchange of information and regulatory perspectives during the review process, while each country retains independent decision making. As of October 31, 2023, there were 81 Project Orbis applications that have resulted in product approval, with approximately one-third of these being new molecular entities in the United States (Donoghue, 2024).³² Project Orbis partners include representatives from Australia, Brazil, Canada, Israel, Singapore, Switzerland, and the United Kingdom. As of late 2023, the European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (Japan’s regulatory body) became observers of the program but are not full partners in Project Orbis.

Applications in Project Orbis can be identified by the FDA review team or a sponsor can request inclusion (FDA, 2022h). Applications identified by FDA are recommended based on a combination of “breakthrough designation, impressive results, and unmet need” (FDA, 2022h). When a sponsor requests inclusion, the application is considered based on various criteria, and “high impact, clinically significant applications, should generally qualify for priority review because of improvement in safety/efficacy” (FDA, 2022h). The project is open to NDAs, BLAs, and supplemental applications for oncology indications. Sponsors are encouraged to submit marketing applications to all Project Orbis partners but are not required to do so. While review is collaborative and agencies share analysis with partners, sponsors must work with each regulatory agency to comply with regulatory requirements and timelines.

As an example of how Project Orbis works, its first review in 2019 involved FDA, Health Canada, and the Australian Therapeutic Goods Administration. The three agencies collaboratively reviewed the application and identified all regulatory divergence; all three countries simultaneously approved the drug under their own accelerated approval programs. Each country used its own format for the drug label, although they exchanged labels to note any differences (FDA, 2022h). As a result of the collaborative process, the products—for a specific type of endometrial carcinoma—were approved. The approval came 3 months prior to the FDA goal date (FDA, 2019c). For rare disease patients and their families, gaining access to new treatments even a few months earlier can mean significantly improved health outcomes, reduced suffering, and a better quality of life.

The overarching intent of Project Orbis is to leverage a global patient population and evolve toward uniform global standards (“global regulatory convergence”) for the evaluation of oncology-related orphan drugs and biologics. This is broadly applicable and appropriate for other rare diseases and aligns with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The framework of Project Orbis that informs the concurrent submission and collaborative review process will also help the community of potential Collaboration on Gene Therapies Global Pilot (CoGenT Global) stakeholders engage productively with the program by shaping their expectations (see Box 2-3).

BOX 2-3

Pilot Program: Collaboration on Gene Therapies Global Pilot.

Real-Time Oncology Review

The real-time oncology review (RTOR) was implemented by OCE in 2018 to “facilitate earlier submission of top-line results.” To be eligible for RTOR, a product must meet all of the following criteria (FDA, 2023m):

• Clinical evidence indicates that the drug demonstrates substantial improvement on a clinically relevant endpoint(s) over available therapies; and
• Clinical trial endpoints are easily interpreted; and
• No aspect of the submission is likely to require a longer review time.

Though focused on cancers, RTOR has benefited rare diseases. Of the 10 new molecular entity (NME) product applications accepted by the initial pilot, 8 received orphan designation (Gao et al., 2022). Additionally, 11 of the 13 approvals through RTOR between 2013 and 2022 were for orphan products (see Figure 2-12).

FIGURE 2-12

Number of orphan and non-orphan drug products using the real-time oncology review program approved by FDA between 2013 and 2022. NOTES: FDA = U.S. Food and Drug Administration; NASs = new active substances. SOURCE: CIRS Data Analysis, 2024.

One lesson that is relevant to rare diseases is that the program’s resource-intensive nature (e.g., submitting multiple application components at different time points as outlined in the RTOR operating procedures) means that it is key to have close coordination and alignment between the sponsors, which are often small biotech companies, and agency reviewers on expectations and submission timelines related to datasets, analysis, key claims in labels, and safety update reports among others. The RTOR program implementation has been associated with faster approval times (see Figure 2-13) although this may be confounded by the concurrent usage of other expedited programs such as breakthrough designation and priority review (Gao et al., 2022). The frequent interactions with FDA reviewers during the submission and review lifecycle due to the RTOR has meaningfully informed industry practice with respect to application preparation and FDA engagement (Kim, 2022). The abbreviated time from submission to approval means that this framework has considerable applicability to non-oncology rare diseases more broadly. Applying a similar framework may be beneficial for the advancement of rare disease drug development beyond rare cancers.

FIGURE 2-13

Approval time of orphan and non-orphan drug products approved by FDA from 2018 to 2022 by regulatory pathway. NOTES: Box plot displays median approval time with 25–75% interquartile range. Range is not displayed when n < 3. FDA = U.S. (more...)

Closing the Gap

Despite legislative, regulatory, and scientific advances, meta-analysis has shown that off-label prescriptions for children accounted for up to 38 percent of all pediatric prescriptions between 2007 to 2017 (Allen et al., 2018). To this day, off-label drug use remains an issue for pediatric populations, particularly those living with rare diseases and conditions for which there is no available treatment on the market (Committee on Drugs et al., 2014). More is needed to meet the needs of children living with rare diseases and conditions.

In addition to measures taken by Congress to incentivize the inclusion of pediatric populations in rare disease drug development, FDA and NIH, in partnership with nongovernmental organizations—including patient and disease advocacy groups, academic clinical investigators, and biopharmaceutical companies—have an opportunity to better collaborate on approaches to include pediatric populations as early as possible in rare disease clinical trials.

During an open session held by the committee on February 7, 2024, senior representatives from CDER, CBER, and OCE all stated the agency’s view concerning the inclusion of pediatric participants early in clinical trials is “evolving.” This sentiment has been echoed by FDA in other venues. On FDA Rare Disease Day, February 27, 2023, Martha Donoghue, the associate director for pediatric oncology and rare cancers in OCE, stated that “over the past decade, this tendency to think about protecting pediatric patients from clinical trials has shifted to thinking that we can best protect pediatric patients with cancer through more timely and thoughtful conduct of pediatric clinical trials. In essence, to give them a chance to benefit through participation in clinical trials as soon as it is scientifically justified and feasible, with the ultimate goal of providing increased access to new, safe, and effective treatment that are approved for pediatric patients with cancer” (FDA, 2023g).

Dr. Nicole Verdun, director, Office of Therapeutic Products, CBER, FDA, stated publicly on March 8, 2024, “…traditionally, the thought has been that you should try things in adults before children…what I hear from patient communities is that we have diseases, especially in the rare disease space, that affect children from birth, and we want to prevent those conditions from happening. We do not want to wait to have to enroll a young child in a trial…we have to pivot a little in mindset and be comfortable with starting sometimes in areas where there is some uncertainty… it really depends on the program, but we are looking for ways to enroll pediatric patients earlier in the development process” (The Alliance for a Stronger FDA, 2024).

Such sentiments have been reiterated in other public meetings, including a 2024 Roundtable on Effective Inclusion of Children Early in Clinical Trials hosted by Leavitt Partners and the Friedreich’s Ataxia Research Alliance, during which senior FDA leadership at the office, division, and center level discussed the need to pivot toward earlier inclusion of pediatric populations in clinical trials. The committee recognizes the need to focus on protecting children living with rare diseases and conditions through clinical trials, so they have access to safe and effective therapies.

RECOMMENDATION 2-1: Congressional action is needed to encourage and incentivize more studies that provide information about the use of rare disease drug products in pediatric populations. To that end, Congress should remove the Pediatric Research Equity Act orphan exemption and require an assessment of additional incentives needed to spur the development of drugs to treat rare diseases or conditions.³⁴

Additionally, the U.S. Food and Drug Administration (FDA) and the National Institutes of Health in partnership with nongovernmental organizations, including patient groups, clinical investigators, and biopharmaceutical companies, should work to provide clarity regarding the evolving regulatory policies and practices for the inclusion of pediatric populations as early as possible in rare disease clinical trials. Actions should include, but are not limited to the following:

• FDA should convene a series of meetings with relevant stakeholders and participate in relevant meetings convened by others to clarify what data are required to support the early inclusion of pediatric populations in clinical trials for rare diseases as well as other key considerations.
• Publish or revise guidance for industry on pediatric study plans for rare disease drug development programs.

Patient Engagement

FDA has made important strides to engage people with lived experience throughout the regulatory review process. Guidance documents, patient focused drug development (PFDD) meeting summaries, direct interaction with patients, and other resources have helped to bridge the gaps among regulators, sponsors, and people with lived experience.

An FDA guidance for industry, Rare Diseases: Considerations for the Development of Drugs and Biological Products, encourages sponsors to discuss trial design with patients and caregivers early in the planning stages, and to consider modifying designs to address patient and family concerns (FDA, 2023l). For example, the guidance notes that endpoint selection can be informed by understanding what aspects of the disease are meaningful to patients and caregivers. In addition, the guidance emphasizes the importance of centering patients in the process. Patient engagement is a critical aspect of the regulatory review process as it provides decision makers with information on lived experience, meaningful outcome measures, therapeutic context, and benefits and risks.

Patients and caregivers are experts in their own experience of living with or caring for someone with a disease or condition and their perspectives and insights should be valued alongside those of regulators, sponsors, and researchers when it comes to informing the development of drugs to meet their needs. A 2015 JAMA article by Hunter, O’Callaghan, and Califf (Hunter et al., 2015) stated that “the FDA is working to give patients a greater voice in medical product development and evaluation” (p. 2500). FDA has several avenues for patient and caregiver input to inform regulatory decision-making. These include the PFDD initiative, the FDA Patient Listening Session program, the FDA Patient Representative Program, and the FDA–Clinical Trials Transformation Initiative (CTTI) Patient Engagement Collaborative (PEC). Information shared via these avenues can provide key insights on disease course and variability, disease outcomes, patient preferences, desired benefits, and acceptable risks and has increasingly become a component of regulatory science at FDA (Kuehn, 2018).

Patient-Focused Drug Development

FDA’s PFDD initiative, which was established under the fifth authorization of the Prescription Drug User Fee Act (PDUFA), is a “systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are meaningfully incorporated into drug development and evaluation” (FDA, 2024d) (see Box 2-5). PFDD initially included a series of FDA-hosted disease-specific meetings, which were held between 2012 and 2017, in which FDA and other key stakeholders, including medical product developers, health care providers, and federal partners, heard directly from patients, their families, caregivers, and patient advocates about the symptoms that matter most to them, the impact the disease has on patients’ daily lives, and patients’ experiences with currently available treatments. Following each meeting, FDA published a summary of the input shared by meeting participants (FDA, 2024f).

BOX 2-5

What is Patient-Focused Drug Development?

PFDD has since expanded to include externally-led PFDD meetings (FDA, 2022e), the development of guidance documents, and other initiatives to facilitate the incorporation of patient input into medical product decision making. Patient listening sessions, similar to PFDD meetings, serve to inform FDA on the concerns of the patient community. However, patient listening sessions are nonpublic, only FDA, patients, caregivers, advocates, and community representatives can participate in the sessions, and they are non-interactive in that the agency participants are listening but not conversing with other participants (FDA, 2024h). There have been over 35 rare disease-specific patient listening sessions since they began in October 2018 (FDA, 2024e) (see Appendix F for a full list of rare disease-specific PFDD meetings and patient listening sessions).

During a series of qualitative interviews with industry representatives, interviewees suggested that PFDD meetings are an adequate mechanism for FDA to gather patient input on disease-specific drug development (see Appendix E for full methodology and results). At the same time, during committee meeting open sessions, a few speakers suggested that the one-way nature of PFDD meetings and patient listening sessions makes it hard for participants to understand the value of their contributions during these convenings. The committee did not find adequate evidence to assess the impact of PFDD meetings and patient listening sessions one way or the other.

PFDD meetings and patient listening sessions provide a pathway for patient input to be considered during the review process, but patient groups often face barriers to effectively leverage these opportunities. Challenges cited in a study by Kuehn (2018) include “resources capacity, . . . policy knowledge, and regulatory culture [at FDA]” (p. 663). There is a perception that well-funded patient groups are more capable than smaller groups of generating data that meet FDA regulatory standards. Smaller advocacy groups may have limited resources to host PFDD meetings and lack full knowledge of regulatory processes and data requirements for decision making.

A broader issue raised by Kuehn (2018) was a perception on the part of interviewees that FDA did not give adequate weight to patient experience data (PED) and should put in place more practical conflict of interest policies for patient groups, which often depend on industry engagement and funding support.³⁶

Conclusion 2-2: FDA is using available mechanisms to gather patient input. However, there are opportunities to better ensure that patient input informs the development of treatments for rare diseases as well as the design and conduct of clinical trials for rare diseases. More clarity is needed on the part of patient groups and people with lived experience on how the agency is using patient input to inform regulatory decision-making and what types of patient input are most relevant.

Patient Experience Data

Patient experience data³⁸ provide information about the experiences, perspectives, needs, and priorities of people living with a disease or condition. These data can be used to inform clinical trial design, endpoint selection, and regulatory review, including benefit–risk assessments (FDA, n.d.-b).

An analysis of NMEs approved by FDA in 2018 found that of the 59 NMEs approved, 48 contained a patient experience data table within the review documentation and 34 reported using patient experience data in the drug review process. Within this group of NMEs, 28 had received an orphan designation. However, only 17 of the 28 (60.7 percent) orphan designated NMEs used PED in the review. In comparison, 17 of the other 20 (85 percent) non-orphan reviews used PED. Sponsor-submitted patient-reported outcomes (PROs) were the most significant source of patient experience data and were used in over half of approved drug reviews. Non-PRO patient experience data used in reviews were qualitative studies, PFDD meeting summary reports, observational survey studies, natural history studies, and patient preference studies (Kieffer et al., 2019).

The 21st Century Cures Act directs FDA to report on the use of patient experience data in regulatory decision-making. A 2021 report by Eastern Research Group (ERG) showed that while patient experience data play an important role in FDA decisions about when to use PROs or other types of clinical outcome assessments, they “generally provide supporting information in situations where the condition is not well characterized, as with some rare diseases” (Eastern Research Group Inc., 2021). The report included interviews with external stakeholders, including patients and their caregivers, clinicians, and representatives of patient and disease advocacy organizations, which indicated a lack of understanding about how FDA uses patient experience data. Similar statements were made by Kara Berasi, the chief executive officer of the Haystack Project, at a committee meeting open session. The ERG report offered recommendations for FDA and other stakeholders to provide more clarity and consistency on whether and how FDA uses patient experience data in regulatory decision-making (see Box 2-6).

BOX 2-6

Select Eastern Research Group Report Findings and Recommendations.

Opportunity to Enhance Patient Input

Taken together, FDA has demonstrated a commitment to engaging people with lived experience. While there are numerous programs, collaborations, and partnerships in place that value the experience and perspectives of people living with rare diseases and conditions and their caregivers, more is needed to fully implement Section 1137 of FDASIA. This is particularly the case for patient groups that are small and under resourced. Strategies are needed to better solicit input from people no matter their race, ethnicity, ability, socio-economic level, or geography with particular consideration for enabling the participation of those who come from marginalized communities.

FDA advisory committees offer independent expert advice and recommendations on scientific, technical, and policy matters related to FDA-regulated products. In addition to including a patient representative who provides lived experience with a particular disease, condition, or medical product, all advisory committee meetings include an open public hearing session during which patients and their caregivers have an opportunity to share relevant information about a given drug and disease or condition.³⁹ In principle, open public hearing sessions should inform the advisory committee on the particular drug product under consideration. In practice, information shared may not be relevant or balanced.

Given limited time, speakers are typically allotted 5–10 minutes each to share their perspective with the advisory committee. Selection of the speakers is typically done on a lottery basis, which means that anyone may have the opportunity to share a point of view whether or not they have relevant experience with a given disease or the drug product being discussed (FDA, 2013b). For example, at the advisory committee meeting for Elevidys for Duchenne muscular dystrophy (DMD), of the 18 public commenters, 8 were not patients or their caregivers (FDA, 2023a). For rare disease patients and their families who have worked hard to reach this point and who depend on the expertise and evidence-based consideration of advisory committees, it can be defeating to share equal time with people who do not have relevant experience or expertise.

In keeping with patient focused drug development, FDA has an opportunity to shape open public hearings so that they provide better input from patients on clinically meaningful benefit and risk tolerance. This is particularly the case for drug development for rare diseases and conditions—patients are often the experts on the disease because, so little is known. Providing a more structured format for selecting speakers who have lived experience with a rare disease or condition or have experience with a given treatment and managing the session to ensure that speakers are contributing valuable information that is relevant to the marketing authorization application may enable a more focused and streamlined approach for seeking public input. Furthermore, better engagement and inclusion of people with lived experience throughout the regulatory lifecycle could help to ensure that the regulatory process is meeting the needs of patients with rare diseases.

A 2013 guidance for the public, FDA advisory committee members, and FDA staff specifies information that speaker requests should include name and affiliation, contact information, and a general description of the nature of the presentation (FDA, 2013b). It does not indicate that speakers should have firsthand experience with a given disease or condition or with the product under consideration. For rare disease patients and caregivers with lived experience, FDA should provide materials on the types of insights and perspectives that would be most beneficial for the advisory committee. This may include reference to relevant PFDD listening sessions or data relevant to the disease indication. For example, speakers could be asked to demonstrate how the primary or secondary outcomes relate to their ability to perform activities of daily living or other challenges or limitations they perceive of these measures.

Advisory committees should be well informed by the community of people most affected by the disease, and they need to listen to the patient voice when making evaluations about a drug to treat a rare disease or condition. In addition to speaking at an open hearing sessions, there are opportunities for patients and caregivers to submit written or electronic comments through the Federal Register. Taken together, these mechanisms are insufficient compared to the opportunity that FDA and the applicant have to speak with the advisory committee, each of which are guaranteed time on the agenda for formal presentation, including a question-and-answer period. Patients and their caregivers should have this dedicated allotted time as well, so their insights and perspectives can be weighted similarly to those of other key stakeholders at the table.

Conclusion 2-3: The strategic engagement of people who have rare diseases and their caregivers with lived experience throughout the drug review and approval process can help regulatory agencies facilitate the development of drug products that meet the needs of patients living with rare diseases and conditions.

RECOMMENDATION 2-2: The U.S. Food and Drug Administration (FDA) should strengthen mechanisms to integrate input from people living with a rare disease or condition, their caregivers, and patient representatives, especially patient groups that are small and under-resourced, throughout the full continuum of the drug development process. To that end, FDA should take the steps necessary to fully implement Section 1137 of the Food and Drug Administration Safety and Innovation Act (Public Law 112-144), which directs the Secretary of Health and Human Services to develop and implement strategies to solicit the views of rare disease patients during the full range of regulatory review discussions. This should include but not be limited to:

• Implementing strategies to meaningfully engage people living with a rare disease or condition, their caregivers, and patient representatives throughout the review process, from initial review discussions to final regulatory decision.
• Ensuring equitable representation of people living with a rare disease or condition, their caregivers, and patient representatives throughout the review process by actively recruiting and supporting participation from underrepresented and under-resourced patient groups, providing necessary support and accommodations to enable their full participation.
• Developing a structured approach to directly engage people with lived experience (those living with or caring for someone living with a rare disease or condition), including in all open public hearing sessions of advisory committee meetings by establishing a mechanism to prioritize and provide speaking opportunities for people with lived experience, particularly patients and caregivers, to inform advisory committees on how primary or secondary outcome measures relate to functional status and quality of life.
• Developing in-person and hybrid education and training programs to assist rare disease patient groups in creating and maintaining tools (e.g., patient registry, natural history data, translational tools) that can contribute to research and development.

Sponsor Engagement

Sponsors developing new drugs must navigate a range of complex challenges when designing and conducting a study for regulatory submission. Clinical trials for regulatory submission require a combination of clinical, safety, biostatistical, and regulatory expertise, as well an understanding of the patient populations a drug is intended to treat to maximize the likelihood that study results meet regulatory requirements to gain market approval (FDA, 2017a). These challenges are heightened when it comes to rare diseases and conditions. Additionally, many companies developing rare disease drugs are small and medium-sized enterprises, which may have fewer resources and less in-house expertise than large pharmaceutical companies. For these reasons it is critically important for sponsors developing rare disease drug products to engage with the agency early and often.

Sponsors may request a meeting with FDA at any time during drug development; FDA may communicate with a sponsor at any time during the process about the need for more data or information. Regulatory project managers (RPMs) located within the clinical review divisions serve an important role as the main point of contact between FDA and sponsors, while nonclinical review division RPMs focus on specific issues (e.g., proprietary names, manufacturing, and controls) (FDA, 2017a).

Sponsors are encouraged to contact FDA through the appropriate RPM, and they are strongly discouraged from directly contacting reviewers assigned to their IND. The 2017 guidance for industry and review staff, Best Practices for Communication Between IND Sponsors and FDA During Drug Development, states, “CDER and CBER strive to provide timely and accurate advice and feedback to sponsors that represent the review teams’ current thinking on the issue, and this is best accomplished by adhering to the communication procedures described above and throughout this guidance” (FDA, 2017a). When appropriate, sponsors may solicit advice on issues including regulatory, clinical and statistical, safety, pharmacology and pharmacokinetics, toxicology, and product quality. In addition to communications between the sponsor and the RPM, sponsors may also request a formal meeting; these can be particularly useful at critical junctures or “milestone meetings” (FDA, 2017a).

Conclusion 2-4: FDA engagement with rare disease drug development sponsors is of particular importance because compared with common diseases, rare diseases are less well understood, more often do not have regulatory precedent, and more commonly lack validated endpoints and outcome measures and involve small patient populations which limit the size and number of clinical trials that can be conducted.

As discussed above, there are opportunities to better ensure that sponsors and other stakeholders, particularly small companies, have access to the knowledge, expertise, and tools to advance new drugs for the treatment of rare diseases and conditions.

RECOMMENDATION 2-3: The U.S. Food and Drug Administration and the National Institutes of Health in collaboration with the European Medicines Agency, nongovernmental organizations, patient groups, and biopharmaceutical sponsors, should implement a sponsor, investigator, and patient group navigation service to support the development of drugs to treat rare diseases and conditions (1) by advising on the range of available regulatory pathways and flexibilities and (2) by providing clarity on how to comply with regulatory policies, apply guidances, and meet requirements in rare disease drug development. Actions should include:

• Facilitation including, but not limited to, consultation, referral to other organizations, services to identify and overcome regulatory barriers, needs assessment, and regular follow-up; and
• The development of educational materials and tools.

The Rare Disease Innovation Hub

In 2024, FDA announced a plan to establish a Rare Disease Innovation Hub (the Hub) to establish a new model for FDA to leverage cross-agency expertise and enhance shared learnings to spur drug development for rare diseases and conditions (FDA, 2024i). The Hub, which will be co-led by the director of CDER and the director of CBER, will provide services across all rare diseases with a special focus on treatments of smaller populations where natural history and disease progression is not fully understood (FDA, 2024i). This will include three primary functions:

• “Serve as a single point of connection and engagement with the rare disease community, including patient and caregiver groups, trade organizations, and scientific/academic organizations, for matters that intersect CDER and CBER. The Hub will help the larger rare disease community navigate important intersections across FDA that affect patients with rare diseases, such as medical devices, including diagnostic tests, and combination products.
• “Enhance intercenter collaboration to address common scientific, clinical and policy issues related to rare disease product development, including relevant cross-disciplinary approaches related to product review, and promote consistency across offices and Centers.
• “Advance regulatory science with dedicated workstreams for consideration of novel endpoints, biomarker development and assays, innovative trial design, real world evidence, and statistical methods” (FDA, 2024i).

In addition to enabling more collaboration across ongoing FDA rare disease programs, the Hub will seek to expand collaborative opportunities with patient groups, sponsors, researchers, and other interested parties (FDA, 2024i). Patients will have an opportunity to shape the Hub’s priorities through and open public meeting that will take place in the fall of 2024.

Accelerating Rare Disease Cures Program

CDER launched the Accelerating Rare disease Cures (ARC) Program in 2022; its mission is “to drive scientific and regulatory innovation and engagement to accelerate the availability of treatments for patients with rare diseases” (FDA, 2024c). The program is governed by senior leaders from the Office of New Drugs, the Office of the Center Director, and the Office of Translational Science and managed by CDER’s Rare Diseases Team; the Rare Diseases Team, established after the fifth reauthorization of PDUFA, is committed in the sixth and seventh reauthorizations of PDUFA to connect rare disease initiatives and programs across CDER. In addition to these groups that lead the ARC program, many other offices, divisions, and programs within FDA contribute and are connected to the work.

In the first year since its inception, ARC focused on stakeholder outreach and education, including FDA patient listening sessions, quarterly newsletters, and new initiatives aimed at gathering stakeholder input and making the rare disease drug approval process more transparent (FDA, 2023b). ARC launched its Learning and Education to Advance and Empower Rare Disease Drug Developers (LEADER 3D) initiative in 2023. Through LEADER 3D, FDA seeks input from stakeholders who design and conduct rare disease drug development programs in order to identify gaps in knowledge about the regulatory process. Input is curated and documented in a public report by FDA (FDA, 2024j) and will be used to create or expand educational resources for stakeholders. Also in 2023, ARC added two new filters to CDER’s Drugs and Biologics Dashboard hosted on FDA-TRACK (FDA, 2024a). This dashboard serves as a management program to report on performance measures and key projects at FDA. The new filters, “Original Rare Disease Application Approval” and “Novel Rare Disease Drugs Approval,” allow users to view information about the development and approval of products for rare diseases (FDA, 2023b).

In addition to these stakeholder-focused efforts, the ARC program has also supported scientific and regulatory initiatives, including the development of platforms to facilitate natural history studies, exploring methodologies to construct novel endpoints, the expansion of the use of drug/disease modeling; establishing efficient approaches to dose-selection for drugs for small population diseases, exploring innovative methodologies to trial design and interpretation for very small populations, and expanding efforts to support in translational medicine approaches for individual rare disease programs (FDA, 2023b).

Rare Disease Endpoint Advancement Pilot Program

The Rare Disease Endpoint Advancement (RDEA) Pilot Program is a joint CDER and CBER program that is intended to advance rare disease drug development by providing a mechanism for sponsors to collaborate with FDA throughout the efficacy endpoint development process. Sponsors submit a proposal for development of a novel efficacy endpoint for consideration to the RDEA pilot program; proposed endpoints are eligible for selection into the program if:

• The associated drug or biological product development program is active and addresses a rare disease (or a common disease where the endpoint or methodology could be applicable to a rare disease);
• The associated drug or biological product has an active IND or pre-IND for this treatment (with the exception of the endpoint being studied through natural history studies); and
• The proposed endpoint is a novel efficacy endpoint intended to establish substantial evidence of effectiveness for rare disease treatment. A novel endpoint is one that has never been used to support drug development or one that has been modified from its prior use (FDA, 2024p).

Announced in October 2022, the RDEA pilot will accept proposals through fiscal year 2027. When a proposal is admitted into the RDEA pilot program, FDA conducts an initial meeting and up to three followup meetings with the sponsor. At these meetings, sponsors can engage in focused discussion with interdisciplinary FDA experts and talk through the development of novel efficacy endpoints intended to establish evidence of effectiveness (FDA, 2023k). The RDEA meetings are in addition to other interactions with FDA that are conducted through the IND submission process.

The RDEA pilot program is intended to serve an educational purpose and encourage transparency and collaboration among the rare disease community (Lee et al., 2023). To this end, FDA conducts public workshops to discuss topics related to endpoint development for rare disease and can share information about the novel endpoints developed through the RDEA pilot program in various public-facing materials, such as in guidance documents and on the RDEA pilot program webpage. Sponsors who submit proposals to the RDEA pilot program for novel endpoints must agree to disclose certain elements of their endpoint development program prior to a product’s approval.

Support for clinical Trials Advancing Rare disease Therapeutics

Support for clinical Trials Advancing Rare disease Therapeutics (START) is a joint CBER and CDER pilot program that was launched in late 2023. It augments currently available formal meetings by addressing issues through more rapid, ad hoc communication mechanisms (FDA, 2023o; Lee et al., 2023). To be eligible, a drug development program must be under an active IND that is in electronic common technical document (eCTD) format, unless the IND is of a type granted a waiver from eCTD format and must have a chemistry manufacturing and controls development strategy that aligns with clinical development plans. For CBER-regulated products, the product must be a cell or gene therapy under IND being developed toward a BLA and must be intended to address an unmet medical need as a treatment for a rare disease or serious condition that is likely to lead to significant disability or death within the first decade of life. For CDER-regulated products, the product must be intended to treat rare neurodegenerative conditions, including those of rare genetic metabolic etiology (FDA, 2023o).

Sponsors who are selected to participate in START will receive enhanced communications with FDA review staff, including an initial meeting to review features of the pilot, discuss a pathway to support a marketing application, and to identify specific issues about which the sponsor would like further communication (FDA, 2023o). Additional communications may be conducted via email or teleconference, which will be scheduled or held as needed as agreed upon by the sponsor and FDA. The program is designed to be milestone-driven; that is, it is intended to help a product reach a significant regulatory milestone, such as initiation of a pivotal clinical study stage or the pre-BLA or pre-NDA meeting stage (FDA, 2023o). The additional communication provided to sponsors is intended to address issues that would otherwise delay or prevent a promising product from progressing along the pathway toward approval (FDA, 2023o).

Complex Innovative Trial Design Meeting Program

Due to the complex biology underpinning rare diseases and conditions, low disease prevalence, and patient heterogeneity, it is often challenging to design traditional randomized controlled trials for studying drugs that treat rare diseases or conditions. As such, clinical trials for rare diseases and conditions are often smaller than for other more prevalent conditions and may require the use of novel design elements to meet evidentiary standards. To assist sponsors, FDA’s Complex Innovative Trial Design Meeting program (also referred to as the Complex Innovative Trial Paired Meeting Program) offers sponsors up to two meetings with FDA to discuss their proposed complex innovative design elements during late-stage clinical development. In guidance, FDA explains that there is no fixed definition of a complex innovative design because what is considered innovative may change over time, and that the determination of whether a specific novel design is appropriate for regulatory use is made on a case-by-case basis (FDA, 2020a). The guidance provides examples of innovative design approaches (e.g., adaptive designs, Bayesian inference), and gives sponsors suggestions on common elements that should be included in a proposal for this program (FDA, 2020a). Like RDEA, the Complex Innovative Trial Design (CID) meeting program has educational components and requires sponsors to sign a disclosure agreement so that certain information can be shared publicly. FDA held several meetings on CIDs on diseases during which FDA and sponsors discussed trial design elements such as:

• Use of information from historical studies to increase the study power;
• Use of an active-controlled non-inferiority design;
• Model-based extrapolation from adults to the pediatric population; and
• Use of Bayesian methods and response adaptive randomization (FDA, 2023d).

In the first year of its existence, the CID meeting program selected five meeting requests, all of which were related to the use of Bayesian methods. Two of the requests were from sponsors developing products for rare diseases: Duchenne muscular dystrophy and pediatric multiple sclerosis (Price and Scott, 2021). Other CID meetings that supported rare disease drug product development focused on pediatric multiple sclerosis, lupus, epilepsy with myoclonic-atonic seizures (FDA, 2023d).

Bespoke Gene Therapy Consortium

FDA serves an advisory role in the Accelerating Medicines Partnership® Program Bespoke Gene Therapy Consortium, which is a public–private partnership aimed at facilitating the development of adeno-associated virus (AAV) gene therapies for individuals or small populations with very rare diseases.⁴⁰ The consortium is involved in two concurrent and interrelated projects aimed at making AAV technology more broadly applicable and advancing scientific and regulatory approaches to AAV gene therapies:

1.

Further the understanding of AAV technology for gene therapy by supporting research in areas including enhancing vector generation and transgene expression for AAV gene therapies. Though AAV has been successfully used to treat genetic diseases, there is a need to better understand the underlying biology and how to best leverage this tool.

2.

Develop a standard operational playbook for developing these “bespoke” gene therapies for very rare diseases. The playbook will contain approaches to streamlining product development and navigating the regulatory pathway and standardized submission package templates to create a repeatable process for the development and regulatory approval of AAV gene therapies.

The first version of the playbook was released in February 2024 and focused on potential for streamlining pre-clinical and product testing, navigating the regulatory pathway, and standardized regulatory submissions (Bespoke Gene Therapy Consortium, 2024). The playbook serves as a guide for developers, with notes about best practices, decision trees to guide the submission process, and templates for submission requirements.

Opportunities for Expanding FDA Rare Disease Programs

Although the programs described above are welcome developments, most remain limited in scope and scale compared with the vastness of need in rare disease drug development. Some programs have existed for enough time to assess their effectiveness and strengths and weaknesses. Several programs are still early on in their implementation, making it difficult to assess their impact on orphan product development. For instance, the RDEA pilot as conceived will address only an exceedingly small fraction of the endpoint challenges that exist in rare disease development. Furthermore, while the START pilot program holds great promise, participant selection was only just publicly announced earlier this year, and, as such, the committee was unable to assess the program’s effectiveness or impact on orphan approvals.

Each of these special programs is intended to strengthen the overall orphan drug development and review, but their recency and proliferation present analytical challenges for program assessment. The lack of a track record makes it challenging for sponsors to choose the best path forward, increasing the complexity of designing an orphan drug development program.

Recommendation 2-4: The U.S. Food and Drug Administration (FDA) should assess the impact of new and ongoing programs and approaches that support drug development for rare diseases and conditions to improve the regulatory decision-making process; publicly share the results of these assessments in a timely manner; take steps to ensure that lessons learned across different programs are disseminated throughout FDA centers and divisions, including a summary of regulatory flexibilities and novel innovative approaches that were considered acceptable; scale up and expand successful programs across therapeutic areas; and modify or sunset programs that are not improving the regulatory decision-making process. Programs and regulatory approaches should include, but not be limited to:

• Rare Disease Endpoint Advancement Pilot Program
• Support for clinical Trials Advancing Rare disease Therapeutics pilot program
• Complex Innovative Trial Design meeting program
• FDA-NIH Bespoke Gene Therapy Consortium
• Programs and pilots led by the Oncology Center of Excellence (e.g., real-time oncology review, Project Orbis);
• Flexibility and leadership in the review and oversight of genetically-targeted advanced therapeutics (e.g., genetic therapies), especially for very low-prevalence patient populations;
• Adoption and support of master protocols, particularly basket trials, to support mutationally defined product approvals;
• Guidance development on cutting-edge topics to support drug research and development, such as the use of accelerated approval in tissue-agnostic drug development (i.e., drugs that target specific molecular alterations) and master protocols, among others.