Postmarketing requirements reveal important efficacy, safety data following accelerated approvals

All oncology drug products granted accelerated approval by the FDA between 2011 and 2016 were on schedule to fulfill their postmarketing requirements, according to a research letter published in JAMA Oncology.

However, three agents that failed to meet primary efficacy endpoints had not yet been pulled from the market. Also, postmarketing requirements revealed serious safety concerns in two agents that prompted label changes.

“The rapidity of approving novel agents in oncology allows patients access to potentially lifesaving therapies and incentivizes investigators in academia and pharmaceutical industries to continue clinical research efforts,” Marjorie Zettler, PhD, MPH, senior scientist at Cardinal Health Specialty Solutions in Ohio, and Chadi Nabhan, MD, MBA, FACP, chief medical officer at Cardinal Health Specialty Solutions, wrote in the letter.

“Recently, the FDA has been criticized for its oversight of postmarketing requirement clinical studies,” Zettler and Nabhan added. “The agency has come under fire for failure to penalize sponsors for postmarketing requirement clinical studies completed late.”

Postmarketing requirement clinical trials and commitment studies occur after a drug or biological product has been approved by the FDA. Because most accelerated approvals are based on surrogate or intermediate endpoints that have been shown to predict clinical benefit, postmarketing requirements ensure efficacy and safety with longer follow-up.

Zettler and Nabhan evaluated attainment of postmarketing requirements associated with agents granted accelerated approval for oncology indications over 6 years.

Researchers reviewed the Novel New Drug Summaries for all new drug applications and biologic license applications approved between 2011 and 2016. Approved products included generic drugs, reformulations, combinations of two or more non-novel agents, and diagnostic or contrast agents.

Researchers also evaluated the FDA’s Postmarket Requirements and Commitments database to determine requirements, projected dates of completion, and status of studies and clinical trials.

During the 6-year timeframe, 49 agents received approval for oncology indications, of which 23 received accelerated approval.

Among the agents granted accelerated approval, 17 had postmarketing requirements to complete, including 34 clinical trials.

At the time of the report, 15 of these trials had been completed, 14 remained ongoing, two had been terminated and three were pending.

Twelve of the completed trials met efficacy endpoints, whereas three trials — intended as confirmatory trials for atezolizumab (Tecentriq, Genentech), nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) — failed to meet their efficacy endpoints.

Researchers noted these three agents remain on the market.

The two terminated studies — both for idelalisib (Zydelig, Gilead) — were discontinued due to safety concerns.

Ponatinib (Iclusig, Takeda Oncology) was temporarily removed from the market because the FDA required further studies and a risk evaluation and mitigation strategy; the postmarketing requirement study was eventually completed.

Labeling of idelalisib and ponatinib changed after recognition of serious safety concerns.

An ongoing clinical trial of olaparib (Lynparza, AstraZeneca) was released as a postmarketing requirement by the FDA.

“Our own review of postmarketing requirement clinical studies for novel oncology drug products granted accelerated approval within the last 6 years found that no studies were behind their original schedules,” the researchers wrote.

“These examples underscore the importance of collecting the additional clinical safety and efficacy data outlined in postmarketing requirements and the need for collaborative efforts between the FDA, sponsors and investigators,” they added. – by Melinda Stevens

Disclosure s : Zettler and Nabhan are employed by Cardinal Health, Inc.