Safety signal detection and evaluation in clinical development programs: A case study of tofacitinib.

Adverse events are anticipated during a clinical development program. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We describe here the process undertaken by Pfizer to investigate a safety signal for pancreatic cancer with tofacitinib. Potential cases of pancreatic cancer across indications from Pfizer's clinical trials and safety databases were identified and underwent in-depth case review and external expert consultation. The magnitude of the signal was quantified. The feasibility of formal signal evaluation via a hypothesis-testing study was explored. As of July 2016, 14 cases of potential pancreatic cancer were identified: eight cases in clinical development trials (psoriasis n = 6; RA n = 1; psoriatic arthritis n = 1), four cases in a postmarketing study in RA patients in Japan, and two spontaneous reports. Incidence rates (95% confidence intervals) per 100 patient-years ranged from 0 (0, 0.02) to 0.14 in RA, 0.05 (0.01, 0.15) to 0.07 (0.02, 0.16) in psoriasis, and 0.25 (0.01, 1.37) in psoriatic arthritis. The majority of patients had established risk factors for pancreatic cancer. The pharmaceutical industry's rapid and transparent response to safety signals is essential for ensuring patient safety and enabling physicians and patients to adequately assess a drug's risk:benefit. Safety signals emerging through pharmacovigilance may be true or false indicators of a causative association with drug exposure. In this example, it was determined that tofacitinib exposure was unlikely to be related to induction and promotion of pancreatic cancer; however, a relationship with pancreatic cancer promotion could not be excluded.