Blog Post

Overcoming statistical challenges in rare disease drug development

June 17, 2024

The statutory standard for approval of orphan drugs is not different from that of common diseases now and in the foreseeable future. Regulatory agencies like the FDA require substantial evidence of the drug’s effectiveness for its intended use and sufficient information to conclude that the drug is safe. However, flexibility is given in how the standard can be met given the challenges associated with the limited number of subjects available in rare disease.

Below are 3 keys to overcome the statistical challenges faced in this setting.

  • Communicate early and often with regulatory authorities. Given that novel statistical approaches are often used, plans should be discussed with regulatory authorities in advance at meetings such as a pre-investigational new drug application (pre-IND) meeting.  Sponsors are encouraged to engage with regulatory authorities as early as possible once a well thought out plan has been drafted. In addition, guidance documents should be referenced during planning such as FDA’s Rare Diseases: Considerations for the Development of Drugs and Biological Products (, Rare Diseases: Early Drug Development and the Role of Pre-IND Meetings Guidance for Industry (, and Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence (
  • Consider use of innovative statistical endpoints, designs, and analysis methods. Traditional methods that rely on large sample statistics often cannot be used due to the small sample size. Based on knowledge of the indication, a composite endpoint or multiple primary endpoints can be used to fully capture all the clinically relevant outcomes often present in rare disease indications while increasing power. Global tests can then be applied which combine tests at the patient level or across endpoints. Additional strategies such as Bayesian methods that maximize use of external data, crossover designs, n-of-1 trial designs, and master protocols can also be considered.
  • Although innovation is encouraged, do not recreate the wheel if not needed. Creating a novel endpoint or approach should be a final alternative when no other options are available. A comprehensive search of examples of approvals in the rare disease setting should be the initial step.  As in common diseases, even if in a different indication, one may be able identify a statistical approach that may be relevant to the current development program. Regulatory authorities recognize the challenges, encourage use of such innovative methods, and have initiated programs to further support their development. Sponsors can take advantage of initiatives such as CDER’s Critical Path Innovation Meetings (CPIM), Accelerating Rare disease Cures (ARC), and Disease Endpoint Advancement (RDEA) Pilot programs.

Rho has experts that can provide guidance in choice of endpoints, statistical design, and optimal approaches to support the success of your rare disease development program. Contact us for more information.

patricia stephensonPatricia Stephenson, Sc.D., Associate Director, Biostatistics is a Harvard graduate with over 10 years of experience working in oncology, including working with researchers at the Dana-Farber Cancer Institute. Dr. Stephenson has served as the lead statistician for multiple oncology studies, including a Phase 1 study pivotal for an NDA submission for accelerated approval. As a result, she was involved in several submission activities including supporting the statistical preparation and review for the Summary of Clinical Efficacy (SCE) and Summary of Clinical Safety (SCS) as well as preparation for a FDA Advisory Committee Meeting.  Previously, Dr. Stephenson also served as the lead statistician for multiple Phase 1 and 2 studies in ovarian cancer, renal cell carcinoma, gastrointestinal stromal tumors, and non-small cell lung cancer