Current Drug Evaluation System 'Holds Drugs Hostage' from Patients Who May Benefit

Food and Drug Administration (FDA) approvals are typically based on positive phase 3 clinical trials that show a drug can improve overall survival (OS) of a certain group of patients compared with standard of care. However, OS should not be the sole factor in determining whether a drug gets approved, according to Maurie Markman, M.D., president of medicine and science at Cancer Treatment Centers of America.

“We are not talking about patients who might live two or three months after they finish a trial. We have patients who are living one to three years longer,” Markman said. “Therefore, holding that drug or combination — a patient would have received the drug two or three years ago — hostage to a survival endpoint, when all of the things that might have happened to the patient population during the interim is not controlled, simply makes no sense.”

Markman argued that using OS as the only endpoint is no longer rational. Instead, other measures should also be considered, such as overall response rates and duration of response. Another idea involves examining each patient’s natural history of disease and characterizes their time to progression.

“There are a variety of ways we could look at this, but the point is that we need to come up with strategies that are acceptable to the regulatory agencies, insurers and, ultimately, the patients,” he said.

Finding alternative ways to measure treatment success is particularly important in patients with ovarian cancer, a rarer disease, where the likelihood of completing a phase 3 trial is low. Not to mention, ovarian cancer is not always and easily measured disease.

But, luckily, some trials are beginning to look at these other endpoints, Markman said.

“The extraordinary poster child for that is the approval of the checkpoint inhibitor based on robust phase 2 trial data with microsatellite instability-high (MSI-H) tumors, and I applaud the FDA for this. What they have done is extraordinary for patients,” he said.

The drug he referred to is Keytruda (pembrolizumab) and is efficacious in patients with ovarian cancer whose tumor is MSI-H — a group that makes up only about 2 percent of the ovarian cancer population, according to Markman.

Since the number of patients with MSI-H ovarian cancer is so small, it potentially would have taken decades to complete a trial looking at OS. Instead, researchers saw that there was more than a 40 percent response rate, with many of the responses lasting six months to a year.

“If a patient has ovarian cancer and their tumor is MSI-H, they now have the potential benefit from this therapy because of the FDA’s action,” Markman said. “The FDA needs to be encouraged for these kinds of events.”

Moving forward, Markman hopes that more trial leaders will look beyond OS as the primary endpoint, and that the FDA does, too.

“We have to figure out this trial issue,” Markman said. “We have to learn how to do trials, gather information and decide whether these strategies are of value. There are opportunities today in terms of understanding the biology. There are hundreds of drugs out there and we have to test them to find their impact.”