NATIONAL HARBOR, Maryland — Rare disease product development is challenging, requiring interdisciplinary collaboration and multiple strategies to produce viable solutions and treatments, officials said at a session presented at the 2021 World Orphan Drug Congress.

Janet Maynard, MD, deputy director of the US Food and Drug Administration’s Office of Rare Diseases

To streamline the drug development process, the US Food and Drug Administration (FDA) has reorganized the Office of New Drugs within the Center for Drug Evaluation and Research (CDER). A new rare disease hub is charged with advancing drugs for rare diseases, explained Janet Maynard, MD, deputy director of the Office of Rare Diseases. The division evaluates novel trial designs, approves orphan drugs and biologics for rare diseases, and assists in patient outreach and engagement.

According to Dr. Maynard, the number of orphan drug approvals has increased over the past decade, with 58% of all new drug approvals in the CDER falling in the orphan drug category. Compared to nonorphan new molecular entities (NME), 89% of orphan NMEs utilized expedited programs through the CDER and New Biologics Approvals to prioritize resources and accelerate approval timelines.

Dr. Maynard said many challenges exist in the field of rare disease drug development, including:

  • Small (sometimes extremely small) patient populations
  • Genotypic and phenotypic heterogeneity within a disease
  • Poorly understood natural history
  • Serious, often life-threatening, progressive childhood onset of many rare diseases
  • Patient reluctance to participate in randomization into placebo arms of clinical trials
  • Lack of or limited regulatory precedents
  • Lack of drug development tools
  • Need to uphold regulatory standards while allowing for regulatory flexibility.

The FDA has also established the Rare Disease Drug Development Council (RDDDC), a forum to discuss cross-cutting rare disease topics. This council, composed of 15 representatives from the CDER, serves in an advisory capacity.

Additionally, in December 2018, the FDA drafted the framework to establish a program to consider the potential of real-world evidence (RWE) as a basis for drug approval. RWE is defined by the FDA as “clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of real-world data (RWD).”

RWD is defined by the FDA as “data relating to patient health status and/or delivery of health care routinely collected from a variety of resources.” These resources include electronic medical records, medical claims data, disease and product registries, and wearable devices, among others.

Dr. Maynard suggested that “well-designed, noninterventional studies relying on fit-for-purpose RWD when compared to a suitable control can be considered adequate and well-controlled under FDA regulations.”

The FDA has also undertaken an initiative called Patient-Focused Drug Development (PFDD), in which the perspectives of patients are considered when guiding treatment development. Patients can speak of the impact that disease symptoms have on their daily lives, as well as their current management of the disease using available treatments.

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The FDA is currently establishing 4 guidances in which patient organizations may collaborate with the FDA on collecting and submitting patient data to guide product development.

Guidance 1, finalized in 2020, sets forth the methods with which to collect comprehensive and representative input. Guidance 2, drafted in 2019, details methods to identify what is most important to patients. Guidance 3, currently in progress, will discuss ways to select, develop, or modify fit-for-purpose clinical outcome assessments. Lastly, Guidance 4, also currently in progress, will discuss the incorporation of clinical outcome assessments into endpoints for regulatory decision-making.

The FDA has also initiated the Rare Disease Cures Accelerator (RDCA), which has funded $10 million in grants to the Critical Path Institute in collaboration with the National Organization for Rare Disorders (NORD) for investment and innovation in rare disease. The RDCA considers patient perspective in assessing clinical outcomes and standardization of data and analysis platforms to better characterize rare diseases.

Lastly, the FDA has created the CDER Pilot Grant Program to develop standard core clinical outcome assessments, which measure disease and treatment burdens and their related endpoints. These outcome measures are to be made available to the public at little to no cost.


Updates on clinical development for rare diseases: endpoints, real world evidence, patient voice. Presented at: World Orphan Drug Congress USA 2021; August 25, 2021; National Harbor, MD.