Researchers Question FDA's Use of Surrogate Endpoints for Cancer Drug Approvals

Regulatory NewsRegulatory News | 19 October 2015 |  By 

Two researchers are questioning the US Food and Drug Administration's (FDA) use of surrogate endpoints in approving new oncology drugs and the agency's failure to more strictly enforce postmarketing study requirements for these drugs, according to a letter appearing in JAMA Internal Medicine.

Drugmakers have increasingly relied on surrogate endpoints to support the approval for new cancer drugs. Instead of demonstrating improvements in overall survival, often called "the 'gold standard' among endpoints in oncology trials," sponsors are looking at other outcomes, such as tumor response rate, progression-free survival or disease free survival to demonstrate their products' efficacy.

The authors of the letter – Chul Kim, MD, MPH of the National Cancer Institute and Vinay Prasad, MD, MPH of the Knight Cancer Center – looked at cancer drugs approved from 2008 through 2012 to determine if surrogate endpoints were able to demonstrate improvements in overall survival once on the market.

Oncology Drugs Approved from 2008-2012
Oncology Approvals
Total approvals54
Approvals with surrogate endpoint36
Surrogate Endpoints
Endpoint: response rate19 approvals, 14 accelerated approvals, 5 traditional
Endpoint: progression free survival, disease free survival17 approvals, 1 accelerated approval, 16 traditional

Of the cancer drugs approved during that timeframe, two-thirds (67%) relied on a surrogate endpoint for approval. After conducting a review of medical literature, the researchers found only 5 of the 36 drugs which relied on a surrogate endpoint had demonstrated an improvement in overall survival by August 2015. The authors also found that 18 drugs failed to improve overall survival, while 13 drugs continue to have unknown survival effects.

The authors of the letter conclude that "FDA may be approving many costly, toxic drugs that do not improve overall survival."

FDA defended its practice of approving drugs using surrogate endpoints to Focus, emphasizing the importance of getting new treatments to patients suffering from life threatening diseases quickly:

"We have a longstanding commitment to regulatory flexibility regarding the evidence required to support approval of treatments for serious conditions for which there is unmet medical need … FDA recognizes the importance of approving these medications as soon as the sponsor has shown that a drug meets the scientific and legal standards for safety and effectiveness."

Speaking to Focus, Prasad called on FDA to "set a reasonable period of time – and we can debate what that might be – by which drugs must show they either improve how long patients live or how well they live."

But FDA spokeswoman Sarah Peddicord seemed more confident in the agency's approval history, noting: "We have had multiple discussions over a number of years within the global scientific and patient community, including with the Oncologic Drugs Advisory Committee, to gain consensus of the use of progression-free survival and response rate as endpoints to support approval of drugs that treat cancer. It has been widely accepted that the benefit of a drug can be demonstrated by a variety of endpoints, not just overall survival."

This is not the first time FDA has been called out for its oversight of postmarketing studies for drugs that relied on a surrogate endpoint for approval. In 2009, a US Government Accountability Office (GAO) Report found that many drugs approved using surrogate endpoints between 1992 and 2008 did not complete required postmarketing studies. The GAO report found that postmarketing studies had been closed for only two-thirds of the drugs for which FDA required them during that time, with the remaining third either delayed, terminated, pending, ongoing or submitted to FDA, but not yet reviewed.

JAMA Internal Medicine


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