As clinical trials grow more complex, confidence in trial data is eroding. As a result, Sponsors are rethinking how they work with biostatistics and data partners.

In a recent industry survey, only 46% of life sciences leaders said they are fully confident their organization’s trial data are consistently available and accurate. That confidence gap becomes greater as advanced analytics and adaptive designs increasingly influence regulatory decisions.

With more than 30 years of experience supporting regulatory-facing trials, IDDI founder and CEO Dr. Marc Buyse shares insight on what three decades of regulatory submissions reveal about where data confidence breaks down.

Contract Pharma: Why is trial complexity becoming a regulatory risk?

Dr. Marc Buyse: Trials are becoming more complex in terms of their statistical design, methods of analysis, and even conduct, such as when safety and/or efficacy data are monitored by an Indepenent Data Monitoring Committee (IDMC). In complex trials, design is inherently harder and even the smallest details and mistakes can make a significant difference — introducing significant regulatory risk. 

Complexity and risk are effectively managed, however, when trials are correctly designed from the start. In practice, this means: 

• All difficulties and risks are discussed and addressed from a methodological point of view at the design stage
• A statistician with strong theoretical background and regulatory experience is involved in all discussions with regulatory agencies (FDA, EMA, and others)

Contract Pharma: How are sponsor expectations of CROs and data partners quietly changing?

Dr. Buyse: Beyond increased regulatory risk, the rise of complex trials also means sponsors are expecting more from their designs than ever before. For example, it’s not unusual for sponsors to come prepared with an AI-driven sample size. What they don’t come prepared with, however, is the expertise necessary to address the difficult questions that come with such designs. 

Functional CROs with deep biostatistics and regulatory expertise are increasingly involved in clinical development programs because they can address those difficult questions, providing much-needed guidance on: 

• Complex, innovative designs and modeling techniques
• Measurements and adjudication of outcomes
• Use of biomarkers or surrogate endpoints
• Handling of protocol deviations and missing data
• Bayesian approaches
• And beyond 

Contract Pharma: What do three decades of regulatory submissions reveal about where data confidence breaks down?

Dr. Buyse: Data confidence breaks down when communication with the FDA, EMA, or other regulatory bodies breaks down. The worst thing a sponsor can do is avoid discussion about difficult methodological issues with the agency. The best course of action is to let an expert statistician representing the sponsor discuss the issue and find resolution with the agency statisticians, who may at times be unfamiliar with some of the techniques proposed. Statistical consultants who support a regulatory submission must behave as colleagues with the FDA or EMA and must be prepared to engage in professional conversations with them whenever a difficulty arises regarding trial design, conduct, or analysis. Raise it, discuss it, and find a resolution. 

Marc Buyse, Sc.D., Founder, Chief Executive Officer, and Chief Scientific Officer, IDDI. Marc was president of the International Society for Clinical Biostatistics, president of the Quetelet Society, and fellow of the Society for Clinical Trials. He worked at the EORTC in Brussels and the Dana Farber Cancer Institute in Boston prior to founding IDDI, CluePoints, and One2Treat. He has published extensively in the fields of clinical trial methodology, meta-analysis, statistical detection of fraud, validation of biomarkers and surrogate endpoints, multiple prioritized outcome analyses, and drug clinical development in general.