FDA Releases Draft Guidance on Treatments for Rare Diseases

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The U.S. Food and Drug Administration (FDA) released new draft guidance to assist sponsors of  treatments for rare diseases in planning and conducting more efficient and productive pre-investigational new drug application (pre-IND) meetings. The guidance was announced at the NORD (National Organization for Rare Diseases) Summit in Washington, D.C.

The agency states that while issues discussed at pre-IND meetings may vary depending on the drug, development stage, and targeted disease, sponsors should consider quality, nonclinical evaluation, clinical pharmacology, early phase study designs, and statistical analysis plans when preparing a pre-IND meeting package. In addition to these topics, the guidance also addresses expedited programs for serious conditions, companion diagnostics, orphan drug product incentives, pediatric studies, and data standards and electronic submissions.


The Federal Food, Drug, and Cosmetic Act defines a rare disease as a disease or condition that affects fewer than 200,000 people in the United States. During drug development, sponsors can request formal meetings with FDA. These meetings may be particularly helpful for sponsors of drugs being developed for rare disease indications. A pre-IND meeting is often the first regulatory communication between the sponsor and FDA regarding the development program for an investigational drug or a new indication for an approved drug. During pre-IND meetings, sponsors can discuss with FDA the unique challenges of rare disease drug development and where regulatory flexibility can be justified.


At the pre-IND meeting for a rare disease drug development program, the sponsor should clearly summarize the type and amount of chemistry, manufacturing, and controls information to be submitted in the IND and justify the appropriateness of the information in supporting the proposed clinical trials (e.g., 73 number of patients in the proposed trials, trial durations, and a safety risk assessment). In addition to providing standard meeting background material, sponsors should include additional detailed information to enable meaningful discussion of the specific questions posed to FDA.

Nonclinical studies are also important. They provide information used to assess whether conducting human clinical trials with the investigational drug would be reasonably safe. The types of studies needed for an investigational drug depend on the drug’s intended use, the proposed clinical trial population (e.g., healthy volunteers versus patients with the indicated disease, anticipated age group), and the proposed treatment regimen. FDA can exercise flexibility in nonclinical programs where the proposed clinical indications are for treatment of rare diseases, particularly diseases that are serious and life threatening.

Furthermore, clinical pharmacology studies provide critical information on a drug’s mechanism of action, pharmacokinetic and pharmacodynamic properties, potential for clinical benefit, safety profile, and dose- or exposure-response relationship. These studies also enable therapeutic individualization based on assessment of the impact of intrinsic factors (e.g., renal and hepatic function, weight, race, sex, genetics) and extrinsic factors (e.g., concomitant drug use, food intake) on drug response.

Although studies in healthy subjects may determine which factors influence a drug’s disposition or pharmacodynamic effects, dedicated clinical trials that inform dosing and usage instructions in the target population with a rare disease may be limited. Therefore, careful planning of the clinical pharmacology aspects of the drug development plan for a rare disease is important, because information from such studies and analyses can inform trial design and serve as supportive evidence of effectiveness. Data generated from such studies and analyses can efficiently optimize conditions for drug use (e.g., dose, schedule, patient selection).

Finally, although FDA has no specified minimum number of patients needed to establish drug safety and efficacy, the number of patients should be adequate to assess benefit and risk. While the approval standard for drugs treating rare diseases is the same as that for drugs treating nonrare diseases, it is appropriate for FDA to exercise the broadest possible scientific judgment in applying the evidentiary standard in the rare disease setting. To that end, FDA will consider: (1) benefits and risks of the drug; (2) seriousness of the disease; and (3) if there is an unmet medical need. This approach reflects FDA’s recognition that patients and physicians are generally willing to accept greater risks and side effects from treatment of life-threatening and severely debilitating diseases than they would for other diseases.

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