National Comprehensive Cancer Network Guideline Recommendations of Cancer Drugs With Accelerated Approval

Abstract

ImportanceMany cancer drugs are approved under the US Food and Drug Administration (FDA) accelerated approval pathway based on preliminary evidence. It is unclear how this limited evidence is integrated into the National Comprehensive Cancer Network (NCCN) guidelines, which are common references for clinicians and are used by public and private payers to determine reimbursement for oncology treatments.ObjectiveTo analyze the NCCN guidelines’ assessments for cancer drug indications that received FDA accelerated approval compared with cancer drug indications that received FDA regular approval.Design, Setting, and ParticipantsThis cross-sectional study analyzes FDA-approved indications for cancer drugs that were granted accelerated approval from program inception in 1992 to June 30, 2022. For each drug, the FDA-approved labeling was reviewed to identify all indications. All analyses were performed at the drug-indication level.ExposureThe exposure was FDA regulatory status as of October 2022, including regular approval, accelerated approval, accelerated approval converted to regular approval, and withdrawn accelerated approval.Main Outcomes and MeasuresThe level of evidence and consensus (category 1, 2A, 2B, and 3) and treatment preference (preferred, alternative preferred, other recommended, and useful in certain circumstances) ratings assigned by NCCN committees as of February 2023.ResultsA total of 315 oncology indications for 100 drugs were analyzed. These indications included 156 (50%) with regular approval, 60 (38%) with accelerated approval, 78 (49%) with accelerated approval that was converted to regular approval, and 21 (13%) with withdrawn accelerated approvals. Among all indications, 105 (33%) were rated by the NCCN as having category 1 evidence, 185 (59%) with category 2A, 6 (2%) with category 2B, and 2 (1%) with category 3 evidence. Compared with indications with regular approval, those with accelerated approval were less frequently assigned category 1 evidence (47% vs 3%; P < .001) and were less often listed as preferred treatment options (58% vs 40%; P = .008). Among the 21 withdrawn accelerated approval indications, 8 (38%) remained in the NCCN guidelines, with most having level 2A evidence ratings.Conclusions and RelevanceThis study found that cancer drug indications with accelerated approval were less likely to be assigned high-level evidence ratings and preferred status in the NCCN guidelines compared with indications with regular approval; most accelerated and regular approval drugs had low-quality evidence ratings but high levels of consensus among oncologists on NCCN committees. Greater clarity on the thresholds and definitions of evidence levels would make the NCCN guidelines more useful to clinicians, patients, and payers.

Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval

“…While the FDA has requested withdrawal of 27 cancer drug indications approved via accelerated approval (including 17 since 2021 alone), it rarely requests withdrawal of indications that have received regular approval. Furthermore, once a cancer drug is granted accelerated approval by the FDA, it is generally placed on treatment guidelines (though it is less likely to be “preferred” compared with regular approvals) and covered by insurance providers. This results in clinical availability, but is accompanied by patient exposure to the high prices and out-of-pocket costs of many cancer therapies .…”

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway

“…If confirmatory trials also use surrogate endpoints, clinical benefit may never be verified (Gyawali et al, 2019 ). When lack of clinical benefit is confirmed, withdrawal processes are prolonged (Aaron et al, 2022 ; Chang et al, 2020 ) or withdrawal after evidence of lack of benefit may not happen at all (Cliff et al, 2023 ; Gyawali, Rome, et al, 2021 ). Withdrawals themselves may not be indicative of the pathway failing (Woodcock, 2018 ), since higher risk approvals are part of the intention of the pathway.…”