Characteristics of Trials and Regulatory Pathways Leading to US Approval of Innovative vs. Non-Innovative Oncology Drugs

Abstract

Background: Successful first-generation drugs can be updated or copied with small alterations to make drugs, which are less expensive to develop and carry less financial risk for manufacturers, since the mechanism of action has been validated and a well-defined consumer market exists. We compared the pivotal clinical trials and FDA approval pathways for first- and second-generation cancer drugs. Methods: Among cancer drugs approved in the US from 1994-2014, we found four classes of oncology drugs in which second-generation products followed many years after the first-generation agents: BCR-ABL tyrosine kinase inhibitors for treatment of chronic myelogenous leukemia, ALK tyrosine kinase inhibitors for non-small cell lung cancer, CD20 monoclonal antibodies for chronic lymphocytic leukemia and HER2 monoclonal antibodies for breast cancer. From information on these 13 drugs available in documents published by FDA at the time of approval, we extracted the following characteristics: approval pathway, pivotal trial design, number of participants, efficacy endpoints, and outcomes. Findings: The first-generation and 3 out of 4 second-generation BCR-ABL tyrosine kinase inhibitor drugs were granted expedited approval, while all 4 drugs were approved based on single-arm pivotal trials. Both ALK tyrosine kinase inhibitor drugs were based on single-arm trials and expedited regulatory review. The first-generation CD20 monoclonal antibody drug was approved based on single-arm trials, and 1 of the 2 second-generation drugs had pivotal trials that were randomized. All benefited from expedited approval. All 3 HER2 monoclonal antibodies in the sample were based on randomized trials and expedited pathways. Interpretation: Second-generation tyrosine kinase inhibitors and monoclonal antibodies used in cancer treatment were often approved through expedited approval pathways and studied in single-arm trials. Such pathways help facilitate the approval of these products for earlier use by patients, but are also associated with greater risk of post-approval safety-related labeling changes or unanticipated adverse events. Funding Statement: Dr. Kesselheim's work is funded by the Laura and John Arnold Foundation, with additional support from the Harvard Program in Therapeutic Science and the Engelberg Foundation. Dr. Vokinger's work is funded by the Swiss National Foundation. Declaration of Interest: The authors have declared no conflicts of interest.