Strategies for Successful Rare Disease Clinical Trials

1. NIAMS Extramural Scientific Planning Retreat 2013April 4, 2013Session 1: Strategies for Successful Rare Disease Clinical Trials

2. Strategies for Successful Rare Disease Clinical Trials • Goal / Objective: • Identify strategies that NIAMS can use to enhance the likelihood of success of Clinical Trials in Rare Diseases • Provide NIAMS attendees with an understanding of practices that will enhance a trial’s likelihood of being informative and impactful, as well as insights into how to avoid potential pitfalls associated with studies of rare diseases • Rationale: • Rare diseases collectively affect millions of people • Clinical trials of rare diseases present unique challenges • Rare diseases are a significant component of the NIAMS mission • Guest Speakers: • Dr. Katherine Mathews, University of Iowa • Dr. Keith Hull, U.S. Food and Drug Administration • Dr. David Eckstein, National Center for Advancing Translational Sciences (NCATS)

3. Strategies for Successful Rare Disease Clinical Trials–Session Structure Small Group Discussion Large Group Discussion Summary of Small Group Deliberations Guest Speaker Presentations General Discussion • 2 Hypothetical Scenarios • Single principal investigator with late translation research finding • A network considering a study that might leverage Foundation for NIH resources • 4 Questions • Obstacles in planning/conducting • Barriers to access resources • Issues specific for each case • Strategies for assessing future impact and current priority

4. Strategies for Successful Rare Disease Clinical Trials—Common Obstacles • Limited number of patients eligible and available to participate in trials • Limited quantitative data of disease status over time (from natural history studies) • Limited availability of validated or established outcome measures, surrogate endpoints, biomarkers, etc. • Limited clinical research workforce and trial infrastructure • Drug readiness – strength of preclinical data, access to drug/placebo, investigational new drug (IND) applications • Understanding of regulatory requirements • Competing trials and off-label use of drugs

5. Strategies for Successful Rare Disease Clinical Trials—Overcoming Obstacles • Partnering with private voluntary organizations (PVOs) and Industry • Accessing registries • Adapting outcome measures, biomarkers, or surrogate endpoints from common diseases [e.g., NIH-funded Patient Reported Outcomes Measurement Information System (PROMIS)] • Leveraging existing clinical research infrastructure from other rare or common diseases • Using innovative trial designs

6. Strategies for Successful Rare Disease Clinical Trials—Innovative Trial Designs • Baseline control, crossover, and n-of-1 • Historical controls • Adaptive designs • Responsive-adaptive randomization • Ranking and selection • Internal pilot • Sequential analysis • Bayesian analysis • Prognostic and predictive enrichment

7. Strategies for Successful Rare Disease Clinical Trials—Success vs. Impact • Success relates to the degree to which the trial achieves the stated aims • Impact is a subjective measure of the degree to which the study influences the field of research, informs clinical practice, changes public perceptions, or other positive and durable outcomes Trials can be successful without necessarily being impactful. Clinical trial grants can be impactful without the trials being successful.

8. Strategies for Successful Rare Disease Clinical Trials—Looking Ahead • Explore ways in which NIAMS can play a greater role in helping investigators who have less experience learn from successful clinical trials’ researchers • Consider strategies for evaluation and dissemination of information regarding clinical trials’ designs • Identify NIH and FDA resources that could be beneficial in the design and conduct of rare disease trials and facilitate access to them • Work with other organizations at NIH to leverage resources • Further analysis of NIAMS-funded clinical trials may provide additional insights