A study examining indications for 129 cancer drugs accelerated approved by the FDA from 2013 to 2023 found that among 46 indications followed up for over 5 years, 43% of confirmatory trials failed to demonstrate improvements in patients' overall survival or quality of life, with an additional 15% of trial results remaining undisclosed. The FDA established the Accelerated Approval pathway in 1992 to expedite the entry of drugs for diseases with unmet needs, initially in response to the HIV epidemic of the 1980s, gradually extending its application to other conditions.
At the core of Accelerated Approval is the allowance for expedited drug approval based on surrogate or intermediate endpoints for diseases with unmet therapeutic needs. Following Accelerated Approval, mandatory confirmatory trials are required by drug companies to substantiate patient benefits, either leading to full approval or withdrawal from the market.
Research indicates that as of March 1, 2023, the FDA granted 294 Accelerated Approvals, with 180 (61%) targeting oncology indications, with over 83% of Accelerated Approvals from 2012 to 2022 targeting oncology indications.
Published on April 7, 2024, in the Journal of the American Medical Association (JAMA), a study assessed indications for 129 cancer drugs accelerated approved by the FDA from 2013 to 2023. Among 46 indications followed up for over 5 years, 43% of confirmatory trials failed to demonstrate improvements in patients' overall survival or quality of life, with an additional 15% of trial results remaining undisclosed.
Nearly half of the drugs evaluated in this study received Accelerated Approval based on patient response rates. However, a study by FDA researchers in 2023 suggested that patient response rates and progression-free survival are often unrelated to overall survival.
Publicly available data indicate that overall survival refers to the time from the initiation of a treatment regimen to death from any cause, considered the "gold standard" primary endpoint in clinical trials of anticancer drugs. Progression-free survival refers to the time from the initiation of a treatment regimen to tumor progression or death from any cause. Patient response rate refers to the proportion of patients with tumor volume reduction reaching a predefined threshold and maintained for a minimum duration.
Edward Cliff, one of the study's authors and a hematologist, stated that this is a reasonable surrogate endpoint, as tumors rarely shrink on their own.
In some cases, the absence of demonstrated clinical benefits does not prevent the FDA from converting Accelerated Approval to full approval. The authors of the aforementioned study argue that the evidence base for FDA's conversion decisions is becoming less stringent.
The study found that among drugs ultimately receiving full approval, 60% were based on surrogate endpoints. There has been a shift in the evidence for converting Accelerated Approval to full approval. From 2013 to 2020, all conversion decisions were based on progression-free survival or overall survival. However, from 2021 to 2023, 7 out of 19 conversions (37%) were based on patient response rates. The authors believe that this measure does not capture whether the treatment helps patients live longer and provides information on drug toxicity.
"It doesn't tell you net clinical benefit; it tells you that there is imaging evidence that the drug is beneficial. Some people have tumor shrinkage on imaging but have malignant neuropathies, and things are actually worse. People can also die from infections, which we often see in hematological malignancies," said Cliff.
The authors of the study stated that their findings do not oppose the use of drugs approved through Accelerated Approval but emphasize the importance of conveying the potential benefits and uncertainties of these products to patients. They urge pharmaceutical companies to collect patient quality of life data more regularly during confirmatory studies and urge the FDA to encourage companies to collect stronger evidence of clinical benefit to support full approval of drugs.
Cliff pointed out that their study does not directly address the question of whether Accelerated Approval is too frequent.
In response to this issue, Reshma Ramachandran, a family physician and health services researcher at Yale University, expressed concern over these findings.
Ramachandran's team's research suggests that the National Comprehensive Cancer Network guidelines, which provide information for healthcare coverage decisions, do not always include information on the accelerated approval status of drugs, and guidelines do not continue to be updated when confirmatory trials fail to show clinical benefits. She believes that physicians should not only pay close attention to whether drugs have been FDA-approved but also to the strength of evidence behind the approval.
"Many clinical physicians do not pay attention to the level of clinical trial behind the drug's approval. They usually only care about the outcome—Is it FDA-approved?" said Ramachandran.
The pros and cons of the FDA's Accelerated Approval system can provide insights for relevant systems in China. China first proposed accelerated review regulations in 1999 and formally implemented the "Conditional Approval System" on July 1, 2020. During the COVID-19 pandemic, the first domestically produced recombinant COVID-19 protein vaccine was approved for market through the Conditional Approval System.
Research shows that as of June 2023, China has approved 80 conditional approvals, with 6 already converted to regular approvals. Among the conditional approvals for oncology, 76 (95%) have been granted, with 5 successfully converted to regular approvals and no withdrawals reported.
