UD FDA criticised for rush to approve cancer drugs
The US Food and Drug Administration FDA has been slammed for its “indefensible” accelerated approval of cancer drugs that have no “no true survival benefit” in a report published in Mayo Clinic Proceedings. The paper studied 25 drugs that received accelerated approval between 2009 and 2014, and found 14 had “no supporting evidence” when it came to overall survival. The report criticised the use of surrogate endpoints - including response rate and disease-free survival - which were not required to be linked to overall survival.

A new study has called into question the standards used by the U.S. Food and Drug Administration to approve new cancer drugs and whether those drugs are helping patients live longer.

The paper, which was published in Mayo Clinic Proceedings, assessed 25 drugs approved under the agency's accelerated approval program between 2009 and 2014. The authors found that 14 of those drugs -- 56% -- did not have supporting evidence backing the correlation between the surrogate measure used for approval and actual overall survival. Among 30 drugs approved under traditional approval, 11, or 37% were similarly lacking evidence of survival benefit.

Surrogates include objective response rate, time to progression, and disease free survival. None of these surrogates are required to align with overall survival, thus a drug that improves disease free survival may demonstrate no true survival benefit.

"I think that is indefensible," said senior author Vinay Prasad, MD, an oncologist and assistant professor of medicine at Oregon Health and Science University. "The FDA sets its own rules for when to use a surrogate. In a large percent of these approvals, the surrogate has never been studied. They just take it for granted."

An oncologist who was not involved in the study said the findings highlighted an important concern: While the fundamental goal should be to help patients live longer and better, most clinical trials that lead to new cancer drugs don't evaluate either. Christopher Booth, MD, of Queen's University in Kingston, Canada said many of the new cancer drugs that are heralded as "breakthrough treatments" provide only modest benefit.

"Oncologists, investigators, and regulatory approval bodies should set the bar higher by requiring evidence of surrogacy before approving drugs that do not evaluate overall survival or quality of life," he said in email.

In an email, FDA spokesperson, Sarah Peddicord, said the agency will review the new paper as part of its ongoing assessment of this issue.

In general, the FDA believes that progression-free survival is adequate for approving new cancer drugs.

"Depending on the circumstances, an improvement in PFS may provide substantial evidence supporting either traditional approval or accelerated approval," she said.

She said the FDA has had multiple discussions over a number of years within the global scientific and patient community to gain a consensus that progression-free survival and another common surrogate known as response rate are acceptable 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," she said.

Progression-free survival or PFS is one of the most common surrogates cites in accelerated approval decisions and it is also one of the most common measures found in a 2014 Journal Sentinel/MedPage Today investigation showing that between 2003 and 2014, 74% of 54 new cancer drugs approved by the FDA were based on surrogates. Seldom was there proof of improved quality of life, either.

On average, the treatment cost of those drugs cost is about $10,000 a month.

Last year, a separate Journal Sentinel/MedPage Today investigation found that the drug, Afinitor, had come before the FDA five times in the previous 6 years, and each time won approval for a new use -- for three types of cancer and two types of nonmalignant tumors. On none of those occasions did the drug show an improvement in actual survival or quality of life.

But the drug comes with a long list of serious side effects -- mouth sores, infections, fatigue, diarrhea, abdominal pain, fever, cough, headache, and decreased appetite. In clinical trials, each occurred in at least 30% of patients.

In the trial for advanced breast cancer, 63% of those taking Afinitor had to reduce dose or temporarily stop treatment, compared with 14% who got a placebo.

Another drug, Avastin(bevacizumab), received accelerated approval for breast cancer in 2008 after a study showed it improved the surrogate measure progression-free survival by 5.5 months over chemotherapy. However, in subsequent studies that benefit disappeared -- and no breast cancer survival or quality-of-life benefit was found.

But the drug was inked to life-threatening side effects, including hemorrhage, heart attacks, heart failure, and perforations in the nose, stomach and intestines. In 2011, the FDA revoked Avastin's breast cancer indication.

The Avastin debacle showed that surrogates don't always lead to improvements in survival, said Daniel Goldstein, MD, an oncologist in Israel, who a frequent critic of the cost of cancer therapy.

"The problem today is that we have a plethora of drugs that were approved based on similar surrogate endpoints but follow-up data has not been appropriately obtained and published," Goldstein said in an email. "We therefore may be harming patients, by giving drugs that don't work and have significant side-effects. Furthermore, it is a waste of money to be using drugs that may not actually be of any use."

Goldstein, who also has an affiliation with Emory University in Atlanta, said the FDA needs to create and enforce policies that show that follow-up survival studies are performed and published.

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