Surrogates Speed Cancer Drug Approvals, but Only by 11 Months

Using surrogate endpoints in trials to get cancer drugs to market faster shaves 11 months (12%) off the average 7.3-year development time, investigators have calculated in new research.

Lead author Emerson Chen, MD, Knight Cancer Institute, Oregon Health and Science University (OHSU), Portland, and colleagues question whether trading the certainty of overall survival (OS) to shorten trials by only that much is worth it.

Coauthor Vinay Prasad, MD, MPH, also from OHSU, told Medscape Medical News, "We are tolerating massive uncertainty for limited speed."

The analysis was published online on April 1 in JAMA Internal Medicine.

First to Calculate the Reduction in Time

Rather than indicating how people with cancer feel or how long they live, surrogate markers represent other outcomes, including tumor size.

Chen and colleagues write that although much research has been done on the uncertainty of clinical benefit associated with the use of surrogate markers, they knew of no calculations as to how much clinical trial time was saved by using surrogates, such as progression-free survival (PFS) and response rate (RR).

They analyzed all original and updated clinical trials that led to the US Food and Drug Administration's accelerated or regular approval of cancer drugs from 2006 to 2017 and identified 188 indications among 107 drugs approved for treating solid tumors and hematologic malignant neoplasms.

The authors found that compared with using OS as the endpoint, using PFS was associated with average study time reductions of 11 months (95% confidence interval [CI], 5 – 17 months). Using RR was linked to an average reduction in clinical trial time of 19 months (95% CI, 13 – 25 months).

According to the article, 38% of cancer drugs approved in the United States during the study period were approved on the basis of RR; for 34%, approvals were based on PFS; and for 28%, approvals were based on OS and patient-reported outcomes.

Surrogate endpoints may be met sooner, which benefits patients when drugs are eventually proven to benefit survival.

However, in some cases, drugs approved on the basis of surrogate endpoints later fail to show a survival benefit.

The authors write, "In addition to high-profile examples in which surrogate end points failed to determine survival benefit, such as bevacizumab in metastatic breast cancer, an umbrella meta-analysis of oncology clinical trials demonstrated a weak association between commonly used surrogate end points and OS in most cancer types."

Prasad added, "Recall, recently pembrolizumab [Keytruda, Merck] failed to improve survival of liver cancer patients in a phase 3 trial conducted after the drug gained an accelerated approval based on a surrogate endpoint. Same with palbociclib [Ibrance, Pfizer] in breast cancer; the phase 3 trial completed after approval failed to confirm the benefit inferred from a surrogate endpoint."

Scientist Says 11-Month Reduction Is Significant

Asked by Medscape Medical News to comment on the findings, Ivo Abraham, PhD, RN, professor of pharmacy practice and science at the University of Arizona in Tucson, said that with respect to weighing risk, the cost savings of shorter trials and potential benefit to patients and the healthcare system are substantial.

Eleven months of expensive trials burden the healthcare system, pharmaceutical companies, payers, patients, and taxpayers, he noted.

He pointed out that the range of time savings listed in the article when PFS is used as the endpoint is between 5 months and 17 months and said the high end of that range is particularly noteworthy.

"In some situations, this could really translate into significant savings," Abraham said.

He said he agrees with the authors that response rate is not an optimal marker and doesn't indicate how long the tumor shrinkage will last.

As for PFS, he acknowledged that there will always be cases in which it is later found that PFS did not correlate with OS, but he said the marker should not be discounted.

"The nice thing about PFS is that it is strictly related to the tumor," he said, whereas OS is affected by other factors lumped into all-cause mortality.

It's also important to consider the patient's choice, he said. "If we focus on OS only, we forget that PFS for a lot of people is very meaningful and probably more meaningful.

"It may be that a patient is happy if progression of the cancer can be delayed by a certain amount of time," he added. "Somewhere in these discussions, the patient perspective gets a little bit lost."

The study was supported by the Oregon Clinical and Translational Research Institute. Prasad receives royalties from his book Ending Medical Reversal; funding from the Laura and John Arnold Foundation; and payments for editorial contributions to Medscape. The other author have disclosed no relevant financial relationships. Abraham is an employee of Matrix45 and owns stock in Matrix45, Belgamis, and ExAnte International. Matrix45 has received funding from Amgen.

JAMA Intern Med. Published online April 1, 2019. Abstract

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