Rare Diseases: Common Issues in Drug Development (Draft Guidance for Industry)

The Policy

What it does

Provides non-binding guidance for industry to assist the development of drugs and biological products to treat or prevent rare diseases. 


The FDA released an updated Draft Guidance for Rare Diseases to provide their current views and opinions on issues that may occur during drug development and that can be more difficult in the case of rare disease drug development. The guidance has specifically been released for industry stakeholders that are involved in rare disease research and drug development. While called a guidance for industry, the guidance will also be relevant to university and other not-for-profit medical research organizations. While the guidance is not legally enforceable, it still holds weight in the drug development process by providing developers with a framework in which to successfully create safe, effective therapies for rare diseases. Depending on the therapy developed, sponsors will submit new drug or new biologic approvals to the Centers for Drug or Biologics Evaluation and Research (CDER or CBER), respectively. These two organizations within the FDA have specific oversight for these two classes of therapies.

The process of drug development has many nuances and difficulties; the success rate for approving a new therapy is only around 14%. The out of pocket costs for rare-disease drug development are estimated to be $166 million. To garner FDA new drug approval, new therapies must pass preclinical tests in animal (in vivo) and cell (in vitro) models before passing multiple clinical trials.

The updates to Rare Diseases: Common Issues in Drug Development include revisions specific to rare diseases:

  • Disease natural history: due to the nature of rare diseases, one set of natural history studies will likely be insufficient. This guidance makes suggestions and provides guiding principles for natural history studies in cases of rare diseases.
  • Outcome assessments and endpoints: due to the inherently smaller population of rare disease patients, more disease stages may be necessary to include for outcome assessment and determining useful clinical endpoints.
  • Safety and efficacy: safety measures are determined with the understanding that the number of patients in rare disease groups is lower than typically expected.

The 2019 guidance includes suggestions on involving patients, their families, and their advocates in the drug development process. According to the FDA, the involvement of these individuals may provide clinicians with key information on patients’ needs, experiences, and perspectives that can impact the approval process.


The Orphan Drug Act (ODA) was passed in 1983 to facilitate the development of drugs for “orphan diseases,” a term synonymous with rare diseases. In this act, an orphan disease was characterized as a disease that affects less than 200,000 people per year. Facilitation of new drug approvals in the ODA included financial incentives and more time with market exclusivity.

The NIH currently reports that there may be as many as 7,000 different rare diseases. In the US alone, an estimated 20-30 million people are living with a rare disease.

In the decade prior to the ODA, only 10 new drugs had been approved for rare diseases. In 2018 alone, 35 new drugs were approved for rare diseases and the FDA has approved over 350 products since the ODA was passed. The FDA issued its first draft guidance for drug development specifically regarding rare diseases in 2015. While this first guidance was well received as a good first step, there have been comments calling for enhanced clarity in the document, which led to the current draft guidance.

The Science

Science Synopsis

A rare disease is any disease that affects less than 200,000 people in the United States. There are almost 7,000 estimated rare diseases, and each one presents its own challenges for drug development, making it challenging to provide a one-size-fits-all approach to drug and biologics development. This draft guidance aims to provide general suggestions and address key points to be aware of in the development of drugs for rare diseases. While not providing a specific answer for any specific rare disease, the guidance provides an outline to follow in order to facilitate productive sponsorship of drug approvals. Drug development costs are currently estimated to be approximately $2.6 billion per drug.

Scientific Assumptions

  • It is more difficult to develop a therapy for rare diseases compared to more common diseases (Page 1 lines 19-23). According to MIT’s Analytics for Life-Sciences Professionals and Healthcare Advocates (ALPHA) 2019 study, the estimated probability of a new drug’s overall success through 3 phases of clinical trials is 12.1%, while the estimated probability of overall success in drugs for rare diseases is 12.6%.

The Debate

Scientific Controversies / Uncertainties

As comments on the guidance suggest, there are no apparent controversies regarding the guidance for industry on drug development in rare diseases; however, there are suggestions for improvements in clarity.

Endorsements & Opposition

Many major pharmaceutical companies, who are most likely to be influenced by this guidance, have provided comments on the 2019 draft. While most were positive regarding the importance of a rare-disease specific guidance, there were suggestions from most large pharmaceutical companies for enhanced clarity.

  • Regeneron Pharmaceuticals submitted a positive comment with additional suggestions for the updated guidance: “Overall, the recommendations in this guidance are consistent with current industry practice for the development of studies designed for adults/adolescents with rare diseases.”
  • Takeda: “These topics [covered in the guidance] are paramount to rare disease drug development; while greatly improved, Takeda believes they would benefit from additional elaboration and refinement.”
  • Roche/Genentech: “The draft guidance is well-constructed and helpful… there are, however, several points on which Roche/Genentech requests further consideration or elaboration…”
  • IQVIA: “IQVIA supports the agency’s approach and views this guidance document as clear and informative, providing helpful explanation of FDA’s current thinking with regards to common issues in development of drugs for rare diseases.

Other large organizations (not-for-profits and professional organizations) have provided comments as well, including:

  • American Society of Gene & Cell Therapy (ASGCT): “ASCGT specifically commends the inclusion of information in this draft guidance that the Society previously recommended…”
  • Muscular Dystrophy Association (MDA): “MDA previously provided comment on the 2015 Draft Guidance that FDA should encourage greater emphasis on patient perspective as it relates to efficacy endpoints. Patient input is critical to the development process and we appreciate that the latest version of the Draft Guidance reflects the concerns we shared previously.”
  • National Organization for Rare Disorders (NORD): “FDA’s expanded flexibility in the use of non-placebo controls, coupled with its encouragement of the use of broader and more representative inclusion/exclusion criteria, will further focus rare disease clinical trials on the needs of the rare disease patient.”

Potential Impacts

This is a nonbinding FDA guidance, that is, it is unlikely to have any major effects per se on drug development. However, it is helpful for clarification with the end goal being to improve the approval process for therapies for rare diseases.