Revised FDA Guidance on Developing Rare Disease Therapies

Rare diseases, defined as conditions affecting fewer than 200,000 people in the United States, pose a significant health care concern.There are approximately 7,000 rare diseases that cumulatively affect more than 25 million Americans, half of which are children.2 In addition, most rare diseases are serious or life-threatening disorders with unmet medical needs. Due to the small patient populations and complexity of rare diseases, many sponsors were previously reluctant to develop treatments for these conditions. However, this changed with the passage of the Orphan Drug Act (ODA) of 1983, which offers sponsors incentives, such as the waiver of user fees and a 7-year market exclusivity period, to make drug development for rare diseases financially viable.1 The ODA resulted in a significant increase in the number of approvals of rare disease therapies, with more than 750 orphan drug products approved since the enactment of the ODA and 90 products approved in 2018 alone.3 Despite the dramatic increase in the number of approvals, sponsors continue to face challenges when developing therapeutics for rare diseases. These challenges stem from an incomplete understanding of the natural history and pathophysiology of the disease, the limited number of patients available for clinical trials, and the pediatric populations that are often affected. To address these issues, the Food and Drug Administration (FDA) released a draft guidance in 2015, Rare Diseases: Common Issues in Drug Development, which aimed to assist sponsors in conducting more efficient and successful drug development programs for rare diseases. On 16 January 2019, the FDA issued an update to its 2015 guidance. The revisions include the following:

  1. An updated Natural History Studies section

The FDA highlights the importance of evaluating natural history knowledge early to inform drug development programs. Because the natural history of rare diseases is often limited, conducting natural history studies can provide a sponsor with a greater understanding of the disease and aid in defining the disease population, selecting clinical endpoints, or identifying new biomarkers. According to the guidance, natural history study designs can be characterized as (1) retrospective or prospective and (2) cross-sectional or longitudinal, with each study type possessing advantages and disadvantages. It is important to carefully evaluate these during drug development planning stages as a natural history study may also be used as an external control group for interventional trials.

  1. Inclusion of issues for surrogate biomarkers

Because the knowledge about a rare disease’s pathophysiology and clinical manifestations is often incomplete, efficacy endpoints are not always available. This guidance indicates that sponsors can use biomarkers as surrogate endpoints in some cases. However, the use of a surrogate endpoint requires demonstration of analytical and clinical validation of the biomarker test, and analytical validity should be confirmed before starting the clinical trial.

  1. Nonclinical flexibility

Regulations state that the FDA may exercise flexibility in applying regulatory standards for drugs that treat serious and life-threatening diseases, as long as safety and effectiveness are preserved. When determining nonclinical flexibility, the FDA evaluates several factors, including the pharmacological and chemical characteristics of the drug, the design and objectives of the proposed clinical investigations, the anticipated risks to humans, and the existing accumulated nonclinical toxicology and human data.

  1. Additional information on external controls and early randomization

For rare diseases with an unmet medical need, a single-arm trial, in which all enrolled patients receive the investigational drug, with an external control may be used when there is a highly predictable disease course and a large, self-evident expected drug effect. However, randomized, controlled trials are often the most efficient way to determine the clinical effect of a drug. When a randomized trial is feasible, randomization should also be carried out as early as possible. Importantly, sponsors should address any concerns about control arms with patients and other stakeholder groups early to avoid undermining trial recruitment and retention.

  1. Addition of a Safety section

To evaluate safety, the sponsor should characterize the drug’s safety profile in a reasonable number of patients over a reasonable duration of time. For rare diseases, the term reasonable must take into account certain feasibility challenges, including the limited number of patients with the disease and the patients’ tolerance for risk in an unmet medical need setting. For example, a smaller number of patients may be acceptable when the intended treatment population is small.

  1. Additional information on changes to drug substance or manufacturing process

The FDA may also exercise flexibility on the manufacturing information needed for submission. When determining manufacturing flexibility, the FDA will consider factors such as product characteristics, seriousness of the condition and medical need, manufacturing processes, the robustness of the sponsor’s quality system, and the strength of the sponsor’s risk-based quality assessment.

  1. Inclusion of an Additional Considerations section

Information on patient participation, expedited programs, and pediatric considerations is also included in the revised guidance. The FDA encourages the participation of patients, caregivers, and advocates in rare disease drug development programs because their perspectives and experiences may provide meaningful information for the drug review process.  Because most rare diseases are serious or life-threatening with unmet medical needs, the FDA also encourages sponsors to consider fast track designation, breakthrough therapy designation, priority review, and accelerated approval for their drug development programs. Finally, given that about half of the people affected by rare diseases are children, the FDA strongly encourages sponsors to study the drug in all relevant pediatric populations so that it may be labeled for pediatric use. References 1Public Law 97-414, 96 Stat. 2049 (1983). Amended by Public Law 98-551 (1984) to add a numeric prevalence threshold to the definition of rare diseases. 2NIH National Center for Advancing Translational Sciences. Genetic and Rare Disease Information Center. FAQs about Rare Diseases. Updated 30 Nov 2017. Available from: 3FDA. Search Orphan Drug Designations and Approvals. 28 Jan 2019. Available from:

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