Abstract
ImportanceIt is unknown whether and to what degree trials submitted to the US FDA to support drug approval adhere to NCCN guideline-recommended care in their baseline and surveillance CNS imaging protocols.ObjectiveWe sought to characterize the frequency with which the trials cited in US FDA drug approvals for first line advanced NSCLC between 2015 and 2020 deviated from NCCN guideline-recommended care for baseline and surveillance CNS imaging.Design, setting, and participantsRetrospective observational analysis using publicly available data of (1) list of trials cited by the FDA in drug approvals for first line advanced NSCLC from 2015 to 2020 (2) individual trial protocols (3) published trial data and supplementary appendices (4) archived versions of the NCCN guidelines for NSCLC from 2009 to 2018 (the years during which the trials were enrolling).Main outcomes and measuresEstimated percentage of trials for first line advanced NSCLC leading to FDA approval which deviated from NCCN guideline-recommended care with regards to CNS baseline and surveillance imaging.ResultsA total of 14 studies that had been cited in FDA drug approvals for first line advanced NSCLC met our inclusion criteria between January 1, 2015 and September 30, 2020. Of these trials, 8 (57.1%) deviated from NCCN guidelines in their baseline CNS imaging requirement. The frequency of re-assessment of CNS disease was variable amongst trials as well, with 9 (64.3%) deviating from NCCN recommendations.Conclusions and relevanceThe trials supporting US FDA drug approvals in first line advanced NSCLC often have CNS imaging requirements that do not adhere to NCCN guidelines. Many trials permit alternative, substandard methods and the proportion of patients undergoing each modality is uniformly not reported. Nonstandard CNS surveillance protocols are common. To best serve patients with advanced NSCLC in the US, drug approvals by the FDA must be based on trials that mirror clinical practice and have imaging requirements consistent with current US standard of care.
Highlights
Over 228,000 people will be diagnosed with lung cancer each year in the United States and the vast majority will present with non-small cell lung cancer (NSCLC) [1]
The trials supporting US Food and Drug Administration (FDA) drug approvals in first line advanced NSCLC often have central nervous system (CNS) imaging requirements that do not adhere to National Comprehensive Cancer Network (NCCN) guidelines
To best serve patients with advanced NSCLC in the US, drug approvals by the FDA must be based on trials that mirror clinical practice and have imaging requirements consistent with current US standard of care
Summary
Over 228,000 people will be diagnosed with lung cancer each year in the United States and the vast majority will present with non-small cell lung cancer (NSCLC) [1]. Lung cancer is the leading cause of cancer-related mortality in the United States and 5-year survival rates remain below 25%. A 1995 BMJ meta-analysis of 8 clinical trials comparing platinum-based chemotherapy to best supportive care demonstrated the most effective chemotherapy regimens of the day increased the one-year survival rate from 5 to 15% [2]. New therapeutic options have improved patient outcomes, with the average one-year survival for advanced forms of the disease exceeding 25% [1]. Continued improvement in patient outcomes relies upon well-designed clinical trials comparing novel therapeutic agents to the current best standard of care. A reliance on surrogate endpoints and the inappropriate use of post-protocol therapies (or crossover) have been cited as deficiencies in pivotal registration studies submitted to the US FDA [5]
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