Fulfillment of Postmarketing Requirements to the FDA for Therapies Granted Oncology Indications Between 2011 and 2016

The US Food and Drug Administration (FDA) attempts to strike a balance between approving newer therapies expeditiously while assuring that patients consuming these products are not harmed with unrecognized adverse events.¹ The rapidity of approving novel agents in oncology allows patients access to potentially lifesaving therapies and incentivizes investigators in academic and pharmaceutical industries to continue clinical research efforts. The FDA strives to mitigate the risk of early market entry through the use of an accelerated approval (AA) program by requiring postmarketing studies.

The data used to support AA may rely on surrogate or intermediate clinical end points that have been determined to reasonably predict clinical benefit. We aimed to examine the fulfillment of postmarketing requirements (PMRs) associated with drugs granted AA for oncology indications in the past 6 years.

We reviewed the FDA’s published Novel New Drug Summaries for all new drug applications and biologic license applications approved between January 2011 and December 2016 to identify products approved for oncology indications. Our sample excluded generic drugs, reformulations, combination products composed of 2 or more non-novel agents, and diagnostic or contrast agents. The Novel New Drug Summary reports also provided information regarding the use of expedited programs. The FDA’s PMR and Commitments database was subsequently searched for those products granted AA to identify postmarketing clinical study requirements, their projected completion dates, and current status. Moreover, the ClinicalTrials.gov website and sponsor websites were searched for information regarding the status of studies matching the description of those outlined in the FDA’s database. In cases where information derived from ClinicalTrials.gov or sponsor websites did not align with the FDA database, the most recent data was presumed correct. Finally, the Drugs@FDA database (https://www.accessdata.fda.gov/scripts/cder/daf/) was accessed to review drug approval packages and subsequent changes to labeling, where applicable.

A total of 49 novel drugs were approved for oncology indications between January 2011 and December 2016, of which 23 (47%) were granted AA. Of these, 17 (74%) had PMRs including 34 clinical trials to complete (Table). Of these 34 clinical studies, 15 (44%) have been completed, 14 (41%) are ongoing, 2 (6%) have been terminated, and 3 (9%) are pending. Of the 15 completed trials, 3 (20%) have failed, all of which were intended as confirmatory trials (for atezolizumab, nivolumab, and pembrolizumab). The 2 terminated studies (both for idelalisib) were stopped owing to significant safety concerns. One product (ponatinib) was temporarily pulled from the market, with the FDA requiring further studies, and a risk evaluation and mitigation strategy; however, the PMR clinical study eventually resumed and was completed. One ongoing trial (for olaparib) was released as a PMR by the FDA. None of the pending or ongoing studies are behind their original schedules as posted in the FDA’s PMR database.

Recently, the FDA has been criticized for its oversight of PMR clinical studies.^2,3 The agency has come under fire for failure to penalize sponsors for PMR clinical studies completed late. Our own review of PMR clinical studies for novel oncology drug products granted AA within the last 6 years found that no studies were behind their original schedules. However, PMR studies identified serious safety concerns in 2 incidents that resulted in changes to the labeling for both products (idelalisib and ponatinib). In addition, our analysis identified 3 instances (20%) where confirmatory PMR clinical studies for drugs granted AA failed to meet their primary efficacy end points. To date, none of these 3 drugs have been pulled from the market. These examples underscore the importance of collecting the additional clinical safety and efficacy data outlined in the PMRs and the need for collaborative efforts between the FDA, sponsors, and investigators.

Corresponding Author: Chadi Nabhan, MD, MBA, Cardinal Health Specialty Solutions, 3651 Birchwood Dr, Waukegan, IL 60085 (chadi.nabhan@cardinalhealth.com).

Accepted for Publication: February 8, 2018.

Published Online: May 10, 2018. doi:10.1001/jamaoncol.2018.0610

Author Contributions: Drs Zettler and Nabhan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Both authors.

Acquisition, analysis, or interpretation of data: Both authors.

Drafting of the manuscript: Both authors.

Critical revision of the manuscript for important intellectual content: Both authors.

Statistical analysis: Both authors.

Obtained funding: Nabhan.

Administrative, technical, or material support: Nabhan.

Study supervision: Nabhan.

Conflict of Interest Disclosures: Drs Zettler and Nabhan are both employed by Cardinal Health, Inc.

Meeting Presentation: Portions of this work was presented as a poster at the 52nd Annual Meeting of the American Society of Hematology; December 7-12, 2017; Atlanta, Georgia.