Califf Makes Improving Trial Designs a High Priority
FDA commissioner nominee Robert Califf says improving clinical trial designs to understand the effects of new drugs and devices in patient subpopulations is a high priority for the agency and it will “require a comprehensive, multifaceted approach using a concept known as ‘quality by design.’” Responding to follow-up questions related to his confirmation hearing late last year from Senate HELP Committee ranking member Patty Murray (D-WA), Califf says the “general tools consist of small focused trials in people with common characteristics using clinical and molecular markers and, on the other extreme, very large trials using electronic health records and quality registries to provide a low cost data system. Each circumstance is somewhat different and carefully planned trials to most efficiently answer the important questions are needed. All of this needs to occur in the context of more efficient networks of research sites with standard procedures and common data standards and terminology.”
Califf states that a major new advance is the “direct involvement of patients, their caregivers, and advocates in every aspect of the clinical trials, including prioritization of questions, protocol design, quality oversight and analysis and dissemination. FDA is already committed to more inclusion of patients in the effort, and as it evolves, it is already clear that trials are improving as result. The rapid advance of social media is enabling inclusion of patients in a direct and interactive manner, which has the potential for enormous improvement in generalizable enrollment into studies.”
Using biomarkers and other patient characteristics can enable small, focused trials to evaluate particular populations, he says, adding that when viewed in the “overall context of product development this approach will be a critical tool, and the Precision Medicine Initiative will accelerate the potential. On the other hand, the use of integrated health systems, community clinics, and community engaged research in combination with electronic health records and registries built on informed consent and developed to improve quality offer the realistic opportunity to do much larger trials with more generalizability at a dramatically lower cost. Considerable work on this approach is already underway at FDA and it will accelerate in the upcoming year.
“Before joining FDA,” he continues, “I was the PI [principal investigator] of the NIH-funded Healthcare Systems Research Collaboratory and Co-PI of the (PCORnet), both of which are developing the concepts and operations for this transformation of the clinical trials system (see https://www.nihcollaboratory.org/about-us/Pages/default.aspx). In conjunction with industry for drugs and biologics, there is agreement to submit data using common data standard over the next several years. This will enable FDA to look at inclusion of relevant populations much more effectively. Similar approaches are underway for devices.”
Answering Murray’s questions about a controversial study (Rocket–AF) overseen by him while leading the Duke Clinical Research Institute (see earlier story), Califf appears to dismiss the concerns with Janssen Pharmaceuticals’ blood thinner Xarelto (rivaroxaban). “Over 190 clinical trials are now registered in www.ClinicalTrials.gov involving rivaroxaban,” he says. “In addition, numerous registries and observational studies have been undertaken. Finally, FDA uses post-marketing surveillance, including its Sentinel Initiative, to monitor the safety of marketed drugs, but as noted in the article by Dr. Ellis Unger (Atrial fibrillation, oral anticoagulant drugs, and their reversal agents http://www.fda.gov/Drugs/NewsEvents/ucm467203.htm), the safety of rivaroxaban has been a special area of interest. No signals have been announced by FDA, and the article offers reassurance.”