ACR-FDA Summit Focuses on Study Design, Safety Considerations

2022 ACR-FDA SUMMIT—A better understanding of premarketing safety of treatments through dose exploration and controlled studies, as well as long-term safety in post-marketing studies, could assist rheumatoid arthritis (RA), psoriatic arthritis and other rheumatology programs in the future, according to Nadia Habal, MD, Division of Rheumatology and Transplant Medicine, Office of New Drugs, U.S. Food & Drug Administration (FDA).

Dr. Habal

Dr. Habal and other experts addressed regulatory considerations for long-term safety assessment in clinical studies during the 2022 ACR-FDA Summit held virtually in May.

The availability of multiple, highly effective disease-modifying anti-rheumatic drugs that can help patients achieve remission or lower disease activity raises questions about the utility of long-term, placebo-controlled trials. Having patients receive suboptimal treatment for long time periods in studies is no longer appropriate, Dr. Habal said.

Traditional Study Design

Historically, treatments have been evaluated with short proof-of-concept and dose-ranging studies, followed by phase 3, confirmatory, controlled studies with 6- or even 12-month placebo-controlled periods. Studies have evolved to incorporate provisions for rescue when patients’ conditions devolve; they are transferred to alternative therapies or the active drug instead of placebo. These studies may be followed by long-term extension studies, which are often open-label and uncontrolled.

This development paradigm presents challenges for the accurate assessment of long-term safety and efficacy of the investigational treatment, Dr. Habal explained.

“While randomized comparisons are generally reliable for assessment of short-term safety, a study design with rescue and crossover between treatment arms, and uncontrolled extension studies, complicates the longer term safety assessment,” she said.

Evaluating patients at later time points is important in these studies given the unique and latent toxicities of chronic immunosuppressives, including serious and opportunistic infections, tuberculosis, malignancy, cardiovascular morbidity and mortality.

The typical RA study program has included 3,000 to 4,000 patients. However, most of the treatment exposure in these programs is during the uncontrolled portion of the study, making it difficult to evaluate whether adverse events are attributable to study drugs or other factors.

Clinical programs in RA can be optimized to help address these challenges without increasing the size of the study population or the length of exposure, Dr. Habal said. For example, robust dose exploration can better inform the risk–benefit profile of a product and the doses to be studied in the larger phase 3 program. In addition, study design should address the importance of a controlled long-term assessment, such as using an active comparator that allows for meaningful interpretation of the long-term safety and efficacy of the investigational product.