Cancer drugs evaluated through the Food and Drug Administration’s (FDA) accelerated approval process do not always offer substantial clinical improvement or survival benefit when evaluated over a longer period of time using traditional criteria, according to pair of reports published this week in JAMA Internal Medicine.

The FDA has various procedures in place—including accelerated approval, fast track and breakthrough therapy designation—to speed up review and approval of new therapies for serious diseases that address an unmet medical need.

In the 1980s and 1990s, AIDS activists and other patient advocates pushed the government to approve experimental therapies more quickly on the basis of surrogate endpoints—biomarkers or early events that are thought to predict longer-term outcomes—rather than waiting for enough patients to die to determine whether a treatment improves survival. In the case of HIV, for example, drugs must show that they reduce the amount of virus in the blood.

Oncology clinical trials use a plethora of response criteria, including response rates (complete or partial tumor shrinkage) and progression-free survival (how long patients live without their disease worsening). But the ultimate goal is to offer clinical benefit and prolong overall survival.

In the first study, Bishal Gyawali, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues assessed how 93 cancer drugs that received accelerated approval between December 1992 and May 2017 fared in confirmatory trials.

Drugs that receive accelerated approval based on surrogate or interim criteria are supposed to continue to be evaluated—either in post-marketing (Phase IV) trials or ongoing follow-up in pivotal Phase III trials—until clinical and survival data are mature. At that point, the FDA may either grant regular full approval or rescind approval if a drug does not continue to measure up. In an analysis last year, the agency concluded that the pathway is successful because only 5% of drugs had been withdrawn or revoked over the past 25 years.

Gyawali’s team, however, found that just 20% of the rapidly approved drugs led to an improvement in survival, 21% showed an improvement in a different surrogate measure than the one used as a basis for initial approval and 20% continued to show improvement in the same surrogate measure in confirmatory trials. In addition, five confirmatory trials were delayed, 10 were pending and nine were ongoing. Three drugs did not meet their primary endpoints in confirmatory trials, but one received full approval anyway.

“Few cancer drugs approved via the accelerated FDA approval pathway were judged to have verified benefits based on improvement in survival reported in confirmatory trials,” the study authors concluded. They added that the FDA may need to reassess its requirements for confirmatory trials in order to obtain “more clinically meaningful information” for patients and providers about the real benefits and drawbacks of new therapies.

In the second study, Emerson Chen, MD, of the Knight Cancer Institute at Oregon Health and Science University in Portland, and colleagues looked at response rates in clinical trials that led to the approval of 85 indications for 59 cancer drugs based on this surrogate measure between 2006 and 2018.

About a third of new cancer medications are approved based on response rate, usually in single-arm trials that do not compare them against existing standard therapies or a placebo, the authors noted. Typically, tumor shrinkage of 30% or more is used as a threshold for partial response, but this does not necessarily correlate with real clinical improvement. Drugs are usually tested and approved for one type of cancer at a time, so a single drug may receive approvals for multiple indications.

Of the 85 indications approved based on response rate, 38% received regular full approval, and 62% received accelerated approval; 55% of the latter were later converted to regular approval. Of the 29 indications that were upgraded from accelerated to regular approval, six (21%) later showed an overall survival benefit, 16 (55%) later showed a progression-free survival benefit and seven (24%) continued to use only response rates.

Looking at all 85 approved indications, the median overall response rate was 41%; the median complete response rate, meaning full tumor regression, was much lower, at 6%. Chen’s team found that 16% had response rates below 20%, a third had response rates of less than 30% and 47% had response rates below 40%. They also noted that the median number of participants in studies leading to approval was 117, with a sample size range of 18 to 1,052.

Based on these findings, the study authors concluded, “Many cancer drugs are approved on the basis of low or modest response rates, typically in single-arm studies.” They added that these lower response rates did not correlate well with overall survival—meaning they are not a good surrogate measure—but high response rates (seen in about a fifth of the indications) can justify accelerated approval.

Some of these drugs, the authors noted, “could potentially be tested in premarket randomized clinical trials measuring directly endpoints that demonstrate clinical benefit.” In fact, because many medications are being tested in people with advanced or metastatic cancer, improvements in survival could be seen in the short term.

“Response rate is not itself a meaningful clinical outcome; the size of a tumor does not matter if patients’ lives are not extended or if their quality of life is not improved,” Sarah DiMagno, of Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues wrote in an accompany commentary. “Response rate is useful only if it reliably predicts these outcomes.”

The commenters noted that because the FDA is tasked with rescinding approval of drugs that don’t ultimately show clinical or survival benefit—and “is very reluctant and slow to do so”—the low number of withdrawals is not a valid measure of the success of the accelerated approval pathway.

“The reliance on surrogate endpoints has real costs for patients and society. Drugs with unproven effectiveness sell false hope to desperate patients, who are likely paying thousands of dollars out of pocket for them,” DiMagno and coauthors concluded. “Private insurance companies, Medicare and Medicaid pay millions—maybe billions—of dollars for drugs for which we do not know the real benefits and risks. This raises insurance premiums and wastes tax dollars. Exorbitant drug prices are bad enough for treatments that work. Charging vulnerable patients for drugs without evidence that they actually improve patients’ survival and quality of life is unconscionable.”

Click here to read the Gyawali abstract.

Click here to read the Chen abstract.