FDA, Sponsors Seek Study Endpoints Earlier in Development

As payers demand more evidence documenting medical product value, biopharma companies are responding by moving sooner to decide key clinical outcomes to measure. While clinical trials still have to document product safety, efficacy, and quality, sponsors also look to demonstrate suitability for formulary placement and reimbursement. Food and Drug Administration officials support these strategies to help pharmaceutical companies develop more relevant early trials, which requires adjustments in regulatory policies, as well as corporate development programs and marketing strategies.  

The challenge for industry is to identify clinically relevant endpoints early enough to ensure that trials produce data that will support commercialization. Sponsors are adopting an “endpoint mode” to R&D that entails deciding which endpoints are clinically relevant and meaningful even before launching Phase II trials, explained Debra Silberg, Senior Director of Clinical Development at Shire Pharmaceuticals. She noted at a recent Drug Information Association (DIA) conference on “Beginning with the End in Mind” that relevant endpoints should be important to physicians, patients, and payers.

Commercial staff should be included on company development teams to ensure that clinical trials measure outcomes that will be recognized by payers and support product launch, advised Consultant Joseph Caminiti. Payers want to see comparative studies and how a new drug affects specific patient groups, he noted:  “Tumor shrinkage,” he added, “doesn’t demonstrate anything.”

Our commercial colleagues can’t make all the calls based on commercial data, said Janssen R&D Vice President, Francisco Leon, but he also supported input from commercial operations to be sure that clinical studies fill the gaps and enroll an appropriate patient population.

Early analysis of endpoints should support faster development, Leon added. Starting with a target product profile (TPP) in Phase I can help identify relevant endpoints and patient reported outcomes (PROs) needed for successful development—or indicate that a program should be killed early. Mohan Bala, head of oncology value and access at Sanofi, similarly emphasized the importance of designing clinical trials that can demonstrate the added value of a new therapy against a comparative product. He noted that there are differences in clinical study populations and outcomes to meet regulatory and reimbursement requirements. Effective study designs should weigh inclusion/exclusion criteria, choose clinically relevant comparators, limit crossover designs, and select endpoints that are similar to what is observed in clinical practice. Long-term patient follow-up also is important to better understand the impact of treatment and magnitude of benefit.

FDA wants to talk
To support earlier agreement of study endpoints, reviewers in the Center for Drug Evaluation and Research (CDER) are encouraging sponsors to open the discussion on innovative study plans before launching Phase II studies to gain agreement on the validity of the planned endpoints and study design. CDER’s Study Endpoints and Labeling Development staff (SEALD), which works with review divisions to assess proposals for clinical trial design and outcomes assessments, has developed a “wheel-and-spokes” clinical outcome assessment (COA) tool that provides a framework for sponsors to devise and evaluate PROs and other assessment measures that will be “meaningful and interpretable,” and support labeling claims. The initiative reflects FDA’s efforts to incorporate patient perspectives more clearly into the drug development process and to ensure that COAs reflect relevant populations and realistic treatment benefits.

More than 30 COAs are in various stages of qualification, noted Electra Papadopoulos of SEALD at the DIA conference, and a recent guidance on qualification of drug development tools should generate more assessments. Sponsors are encouraged by FDA’s offer of advice in designing valid early trials, but complain that it’s difficult to schedule timely meetings with relevant agency personnel.

Meanwhile CDER’s Office of Prescription Drug Promotion (OPDP) continues to examine closely whether clinical outcomes claims in marketing materials reflect approved labeling. OPDP Senior Regulatory Review Officer, Elaine Hu Cunningham, identified a number of promotional pieces containing overly broad claims of improved patient function, reduced pain, enhanced adherence, and less fatigue that were not supported by valid COAs, PROs, or other assessments. OPDP consults with CDER review divisions and with SEALD, Cunningham added, to help sponsors devise studies that will support desired promotional claims.