Cancer drugs that are granted accelerated approval by FDA often do not show clear outcomes benefits when more rigorous clinical trials are conducted, according to a study published last month in JAMA Internal Medicine.
About FDA's accelerated approval process
Under FDA's accelerated approvals process, drugmakers can receive FDA approval to sell their products in the United States if preliminary studies suggest they improve so-called "surrogate measures" of a disease, such as by shrinking the size of a tumor. In exchange for early entry into the marketplace, FDA requires drugmakers to conduct follow-up clinical trials to determine whether the drug presents a clinical benefit to patient, such as improving overall survival or quality of life.
FDA in 2018 examined 93 cancer drugs granted accelerated approval, and it concluded that the process had been largely successful because just five of the drugs were later pulled from the market. However, researchers at Harvard Medical School's Program on Regulation, Therapeutics and Law, also known as PORTAL Research, wanted to determine whether the drugs that remained on the market had ultimately proven effective.
Among the 93 oncology drugs, the researchers found only 19 met primary endpoints and showed they clearly extended patients' lives in confirmatory clinical trials. The majority of the oncology drugs failed to show real clinical benefits in follow-up studies, the researchers found.
In fact, even in the cases of follow-up studies that FDA said had confirmed a drug's clinical benefit, the researchers determined that many studies have not truly evaluated clinical outcomes. For 19 of the drugs, researchers relied on the same surrogate endpoint used in the preapproval trial, while 20 were based on a different surrogate endpoint than the one used in the preapproval trial.
Bishal Gyawali, the study's lead author and researcher at Brigham and Women's Hospital in Boston, said, "So the confirmatory trials were not confirming clinical benefit but actually confirming benefit in a surrogate endpoint."
The researchers also found three drugs failed to meet their primary endpoints in confirmatory clinical trials. Even so, FDA granted one of the three drugs, Roche's brain cancer glioblastoma drug Avastin, full approval in 2017. The researchers found FDA approved Avastin based on the drug's ability to increase the time cancer patients survive without their tumors growing larger, which is called progression-free survival.
Gyawali in an email to MedCity News wrote, "The success of the [accelerated approval] pathway lies in the fact that confirmatory studies are duly conducted in time and use clinical endpoints such as overall survival or quality of life to actually confirm benefit rather than test another surrogate measure. When drugs fail in confirmatory studies, quick and decisive steps must be taken to withdraw the drug from the market to prevent undue harm from unhelpful drugs."
To ensure the program's success, the researchers recommended a number of policy changes. For instance, they suggested FDA reduce the length of time between an accelerated approval and the release of confirmatory data showing a drug's real clinical benefits by requiring drugmakers to have confirmatory trials underway by the time they receive an accelerated approval.
In a commentary, Ezekiel Emanuel, an oncologist and senior fellow at the Center for American Progress, and colleagues at the University of Pennsylvania, similarly called on FDA to re-evaluate its approach. "Drugs with unproven effectiveness sell false hope to desperate patients, who are likely paying thousands of dollars out of pocket for them," they wrote, adding, "Approval of ineffective drugs also crowds out innovation that might produce effective treatment."
FDA spokesperson Amanda Turney said, "FDA only approves drugs when the data received in a drug application demonstrate a favorable risk-benefit profile." She added, "Patients with refractory diseases often have few or no therapeutic options and we take that into account when examining the risk-benefit profile of these drugs" (Harris, "Shots," NPR, 4/28; Lawrence, Medpage Today, 5/28; Dearment, MedCity News, 5/29; Gyawali et al., JAMA Internal Medicine, 5/28).
June 13 webconference: Learn key strategies to manage oncology drug costs
The cost of oncology drugs is one of the hottest topics in health care and a major concern for patients and providers.
Join us on Thursday, June 13 at 3 pm ET to learn strategies to get a handle on drug costs and ensure the financial sustainability of your cancer program.