From the regulatory/legislative perspective, there are special challenges associated with Food and Drug Administration (FDA) review and approval of products to treat rare diseases. The majority of New Drug Applications (NDAs) for orphan drugs are based on small clinical trials, some with as few as 20 patients. As noted by Coté earlier in the workshop, the Orphan Drug Act provides for predominantly financial incentives for orphan drug development. Orphan drugs are not held to different or less stringent standards than other drugs. Marketing approval for all drugs requires, by law, “substantial evidence of effectiveness” (21 CFR § 314.50). But exactly how that evidence is provided is negotiable, and communications with FDA can help ensure the most effective use of the sponsor’s limited financial and human (i.e., patient) resources.

Regulatory Tools

The Orphan Drug Act has been successfully implemented, resulting in the approval of 326 products to treat rare and neglected diseases over the past 25 years.4 There are additional tools pertaining to the regulation of nonorphan drugs, such as the Prescription Drug User Fee Act (PDUFA) and the FDA Modernization Act of 1997 (FDAMA), that can also help advance the development of orphan products (see Box 7-2). For example:

  • Fast-track designation can be given to a drug product that is both intended to treat a serious/life-threatening condition and claimed to address an unmet medical need. Fast-track designation allows for more involvement with FDA through scheduled meetings and permits rolling review, whereby the NDA can be submitted in sections.

  • Accelerated approval is based on a surrogate end point rather than a clinical outcome. For example, a surrogate end point for treatment of HIV could be a decrease in viral titers rather than demonstration of clinical improvement or extension of patient life span. Proof of a clinically meaningful benefit, which can take a


This section is based on the presentation of Anne Pariser, M.D., Medical Team Leader, Inborn Errors of Metabolism Team, Division of Gastroenterology Products, Center for Drug Evaluation and Research, FDA.


Dr. Pariser’s presentation focused on conducting clinical trials for drugs to treat rare diseases and drugs that have been designated as orphan products. It is important to note that some of the discussion may not apply to drugs for neglected diseases.


The Orphan Drug Act is discussed in detail in Chapter 3.

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