The FDA has published a draft guidance for industry entitled “Rare Diseases: Common Issues in Drug Development.”

The purpose of this draft guidance (January 2019) is to assist sponsors of drug and biological products for the treatment or prevention of rare diseases in conducting more efficient and successful drug development programs. Although the statutory requirements for marketing approval for drugs to treat rare and common diseases are the same and issues discussed in this guidance are encountered in other drug development programs, these issues are frequently more difficult to address in the context of a rare disease for which there is often limited medical and scientific knowledge, natural history data, and drug development experience.  This guidance revises and replaces the draft guidance for industry Rare Diseases: Common Issues in Drug Development issued in August 2015. This revision includes the following:

  • Updates to the Natural History Studies section
  • Inclusion of issues for evaluation and validation of surrogate biomarkers
  • Description of nonclinical flexibility
  • Additional information on external controls and early randomization
  • Addition of a safety section
  • Retitled Chemistry, Manufacturing, and Controls section to Pharmaceutical Quality Considerations
  • Additional information on changes to drug substance or manufacturing process with clarification on areas of flexibility
  • Inclusion of an Additional Considerations section addressing several topics: participation of patients, caretakers, and advocates; consideration of pediatric issues; and interactions with FDA

This guidance addresses the importance of the following elements in development programs for rare diseases:

  • Adequate description and understanding of the disease’s natural history
  • Adequate understanding of the pathophysiology of the disease and the drug’s mechanism of action
  • Nonclinical-pharmacotoxicology and human toxicology considerations to support the proposed clinical investigation or investigations
  • Selection or development of outcome assessments and endpoints
  • Evidence to establish safety and effectiveness
  • Drug manufacturing considerations during drug development (e.g., pharmaceutical quality system considerations)4
  • Participation of patients, caretakers, and advocates in development programs Interactions with the Agency

Early consideration of these issues gives sponsors the opportunity to efficiently and effectively address the issues and to have productive meetings with FDA. These and other issues, as they apply to all drug development programs, are also considered in FDA and International Council for Harmonisation (ICH) guidances for industry