The draft guidance for industry, Rare Diseases: Common Issues in Drug Development Guidance for Industry, provides specific recommendations for developing drugs for rare diseases. This guidance was issued in the hope of alleviating the unmet need for pharmaceuticals to treat many rare diseases, as designated by the Orphan Drug Act. The guidance addresses the obstacles that pharmaceutical companies face regarding the collecting of medical and scientific data needed for drug development. This 2019 version updates the previous draft guidance of the same name released in 2015. In the current version, the Food and Drug Administration (FDA) revised the use of the natural history studies and updated guidance regarding the selection of biomarkers, clinical endpoints, nonclinical studies, evidence for safety and effectiveness, and considerations for pharmaceutical quality.
A rare disease is defined as a disease that affects fewer than 200,000 people at any given time. Rare diseases can result from a rare genetic mutation in an individual’s DNA. For example, the rare genetic disease Alkapturnia has an incidence rate of one out of every 250,000 - 1,000,000 people, and occurs when there is a mutation in the HGD gene. This gene codes for an enzyme that breaks down certain amino acids; the accumulation of these amino acids can lead to symptoms like dark urine, arthritis, and discoloration of connective tissue.
First, the FDA guidance recommends studying the natural history of rare diseases; this history can provide insight into the disease population and how to design the clinical trial. The FDA suggests that drug companies can use a variety of experimental designs for natural history studies (e.g., retrospective, prospective, cross-sectional, or longitudinal).
The FDA guidance also suggests that sponsors select relevant biomarkers or identify new biomarkers to set dosages for trials to maximize understanding the effects of interventions and ultimately to improve efficiency of the drug. Likewise, the FDA reiterates the importance of properly selecting clinical endpoints based on the objective of the trial.
Along with providing recommendations on trial methodologies, the FDA issues guidance on nonclinical studies. These studies demonstrate that potential treatments will be safe to conduct in humans including by providing insight into how the drug is absorbed, how fast it can react, and how it functions.
When developing drugs, the FDA requires sponsors to demonstrate the drug’s effectiveness and safety for labeling. However, rare diseases have a limited number of patients which makes it harder to get the amount of data necessary to uncover potential low chance risks associated with the drug. The FDA emphasizes that — regardless of whether treatment is being developed for a rare or common disease — companies must all show substantial evidence for the drug’s claimed effect.