The Orphan Drug Act aims to incentivize treatment of rare disorders or conditions affecting fewer than 200,000 persons in the United States through: (1) federal funding of grants and contracts to perform clinical trials of orphan products; (2) a tax credit of 50 percent of clinical testing costs; and (3) an exclusive right to market the orphan drug for approved orphan indications for 7 years from the date of marketing approval. While these financial incentives certainly make the business decision to engage in orphan drug development more palatable, the FDA does not approve orphan drugs on a separate pathway, despite the limited understanding of the diseases in question that presents developers of these drugs with problems stemming from small sample size and lack of well-defined efficacy endpoints.

These issues are especially vexing in the pediatric context, which comprises about 26 percent of the total orphan product approvals since the program’s inception. Those drugs are subject to pediatric regulation as well, giving pediatric treatment providers less reason for hope that the Orphan Drug Act provides them with an avenue for solutions to their problems. The FDA has now promulgated draft guidance to address drug development and study design for orphan drugs that includes several suggestions that might improve the odds of a successful development program.

At the outset, the FDA stated that it “acknowledges that certain aspects of drug development that are feasible for common diseases may not be feasible for rare diseases.” Based on this understanding, the FDA appears willing to be flexible in its approach to approving orphan drugs, provided that the applicant can show both the necessity and safety of a unique development program. The FDA provided the following suggestions to IND and NDA filers wishing to create a unique development program:

Applicants should conduct natural history studies so the FDA can better understand unique elements of study design. Applicants should, if possible, have a full understanding of the pathophysiology of the disease in question before conducing trials so that studies can be designed with meaningful endpoints and the identification of informative biomarkers. Nonclinical (g. animal or in vitro) studies should be conducted early on to determine safety monitoring procedures and initial dosing regimens. Efficacy endpoints should be identified as early as possible to guide study design. While initial production quantities may be small, applicants should discuss CMC development plans at pre-IND meetings to avoid delays later in the process.

The overarching tenor of the FDA’s new draft guidance seems to suggest applicants should not necessarily view the complications stemming from small sample size to make drug development impossible. These problems of small sample size are especially true in the pediatric context, where both the parent and the child may object to study participation. Safety and efficacy studies should mirror standard study designs as closely as possible, and the adequacy of those studies will be analyzed by FDA on a case-by-case basis taking into account the quality of the data, the benefit of the treatment, the length of exposure, the patient population, and the potential for harm from the treatment. As long as the FDA is provided a proper scientific rational for deviations from the norm, it appears willing to consider bolder approaches to drug development for orphan drugs.