The U.S. Food and Drug Administration (FDA) has recently reaffirmed its commitment to spurring the development for rare conditions with a Draft Guidance that appears to offer a more flexible approach to rare disease drug development.
Since the passage of the 1983 Orphan Drug Act, drug manufacturers in the U.S. have been provided with incentives to develop drugs used to treat rare diseases which affect fewer than 200,000 people, referred to as “orphan drugs.” These incentives include longer period of marketing exclusivity, user fee waivers, tax credits, and federal funding of grants and contracts to perform clinical trials of orphan products. Still, the FDA approves orphan drugs on the same pathway as other new drug applications (NDAs). This is problematic, as there is a general limited understanding of rare diseases and drug developers remained plagued by challenges stemming from small sample sizes and lack of well-defined efficacy endpoints when studying rare diseases.
In August 2015, the FDA released a Draft Guidance intended to assist drug manufacturers in the development of drugs to treat rare diseases. In the Draft Guidance, the FDA expressed flexibility in its approach to reviewing and approving orphan drugs applications when the manufacturer can demonstrate the necessity and safety of a unique development program. The Draft Guidance advises manufacturers in developing clinical trials, selecting trial participants, and creating of metrics for evaluating the effectiveness of an experimental drug when evaluating rare diseases
Through the Draft Guidance, the FDA acknowledged the typical drug development pathway may not be feasible for rare diseases. In response, the FDA offers greater flexibility in the NDA approval pathway to drug manufactures developing orphan drugs. For example, the FDA notes that there is “no specific minimum number of patients” who must be studied in a rare disease clinical trial. Rather, the appropriate number of study participants will be evaluated on a case-by-case basis by considering the persuasiveness of findings, expected benefits, potential harm and the size of the population that could gain a new treatment option.
The FDA Draft Guidance also counsels drugs sponsors working in the rare disease space to gain a better understanding of the natural history of the disease to inform the design and analysis of clinical trials. Although prospective longitudinal natural history studies are not required, FDA recommends that, for an orphan drug, “a well-designed natural history study may help in designing an efficient drug development program.” Natural history studies aid in defining the disease population, developing outcome measures, and developing optimized biomarkers that may provide for early recognition of safety concerns and provide supportive evidence of efficacy.
Generally, safety and efficacy studies for rare diseases should aim to mirror standard study designs. However, certain limitations are unavoidable due to the limited patient-population of rare diseases. The Draft Guidance also discusses considerations to support the proposed clinical investigation or investigations, reliable endpoints and outcome assessment, standard of evidence to establish safety and effectiveness, and drug manufacturing considerations during drug development for rare diseases. The adequacy of rare disease studies will be analyzed by FDA on a case-by-case basis with reasonable flexibility, taking into consideration the quality of the data, the length of exposure, the benefit of the treatment, the patient population, and the potential for harm from the treatment. Drug manufacturers engaging in research and development of rare diseases should provide a sufficient scientific rational for any deviations from the expected clinical trial standards.
Financial incentives associated with the development of orphan drugs, accompanied by a slightly more flexible FDA-approval pathway, make the development of drugs for rare conditions more viable for drug companies. These incentives and flexibility spur orphan drug development that may otherwise be overlooked by pharmaceutical manufacturers. Moreover, they provide underserved patients with serious and life-threatening rare diseases greater access to promising therapies.
For assistance in developing new drug applications for orphan drugs in compliance with the FDA draft guidance, contact Frier Levitt.
