The FDA’s epic regulatory failure


A new study in JAMA Internal Medicine finds that two-thirds of cancer drugs considered by the U.S. Food and Drug Administration (FDA) over the past five years were approved without evidence that they improve health outcomes or length of life. (This study closely corroborates and acknowledges the findings published last year by John Fauber of the Milwaukee Journal Sentinel and Elbert Chu of MedPage Today.)

Follow-up studies showed that 86 percent of the drugs approved with surrogate endpoints (or measures) and more than half (57 percent) of the cancer drugs approved by the FDA “have unknown effects on overall survival or fail to show gains in survival.” In other words, the authors write, “most cancer drug approvals have not been shown to, or do not, improve clinically relevant end points.”

The use of surrogate endpoints in the approval process is at the heart of this issue. Drug companies argue that these alternative measures permit smaller, cheaper and faster clinical trials, allowing desperately needed drugs to get to market faster. Demonstrating efficacy with “harder” measures like overall survival — whether someone actually lives longer as a result of the drug — is a higher bar that requires more time and resources.

Many drug company representatives argue that the shortcut is not only acceptable but desirable. A 2011 Genentech white paper on oncology endpoints opens with this headline:

… such surrogate endpoints as objective response rate and progression-free survival have been employed because they can be reached faster and may offer important benefits in evaluating therapies.

“May offer important benefits” is the operative phrase here. The problem arises when positive surrogate measure performance is not reflected in better health outcomes or longer life. A common example is progression-free survival (PFS), a widely used surrogate measure of how long the tumor remains dormant before beginning to grow again. While many studies of drug performance use PFS to measure impact, there typically is only spotty correlation between longer PFS and health or survival improvements. Surrogate measures can also mask complications that detract from improved results. So, as the FDA data show, positive performance on a surrogate measure may have no bearing on whether the drug works meaningfully for patients, and using surrogate measures may, in fact, be detrimental to patient care.

Of course, once FDA approval has been achieved, drug companies benefit. There is no discount associated with the compromise of using surrogate measures. The Journal Sentinel/MedPage Today investigation found that drugs approved by the FDA during the study period averaged about $10,000 per month. Four were priced at $20,000 per month, and one was $40,000 per month.

This revelation — that most FDA cancer drug approvals lack evidence and don’t work — begs whether the FDA is so deeply influenced by pharma that it has abrogated its mission of ensuring safe, effective drugs for the American people. Some part of the move away from rigor and toward haste can probably also be assigned to trying to accommodate patient advocacy groups, who campaign for rapid new drug development.

Most importantly, the Kim-Prasad article raises hugely important questions of safety, credibility, and trust for health care regulators. Even with follow-up, almost 9 of 10 drugs using surrogate endpoints approved by the FDA don’t or haven’t been shown to improve clinical results. FDA approval wrongly conveys that products work when they don’t, greenlighting them for use (to little or no positive effect) by American cancer patients, paid for at exorbitant rates by governmental, corporate and individual purchasers.

This is an epic regulatory failure. An inability to address this would be open acknowledgment that, at least with respect to cancer drugs, the FDA has been fully captured by the interests it is intended to regulate.

Brian Klepper is a health care analyst and principal, Health Value Direct.  This article originally appeared in the Health Care Blog.


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