It’s possible that the medicine you’re taking isn’t helping—even if it’s been approved by the Food and Drug Administration. That’s the upshot of a pair of studies in the latest issue of JAMA Internal Medicine. Not good. As an invited commentary in the same issue says, “Charging vulnerable patients for drugs without evidence that they actually improve patients’ survival and quality of life is unconscionable.”
One study examines 93 cancer drug uses that were granted accelerated approval by the FDA between 1992 and 2017. Of those, only 19 showed improvement in overall survival. Another 39 showed improvement by a surrogate measure, such as tumor shrinkage. The problem with surrogates is that they aren’t always accurate measures—drugs that shrink tumors don’t necessarily make people live longer. Some of the other drug uses that got accelerated approval were still in a gray area as of 2017 because their confirmatory trials were delayed, pending, or ongoing. Five of the 93 were withdrawn or had their approvals revoked.
The second study in the journal zeroed in on cases where the FDA approves drugs based on the response rate—the percentage of patients whose tumors shrink by a certain amount. It found that the threshold for approval can be quite low. Of 85 cancer drug uses approved on the basis of response rate, 40 shrank tumors by less than 40 percent. The authors suggest that some of the drugs could be tested before they hit the market by “measuring directly end points that demonstrate clinical benefit,” not just tumor shrinkage.
To be fair to the FDA, it’s under intense pressure to accelerate approval of drugs that appear to have the potential to save lives. In an email, FDA spokeswoman Amanda Turney wrote, “The FDA only approves drugs when the data received in a drug application demonstrate a favorable risk-benefit profile. Patients with refractory diseases often have few or no therapeutic options and we take that into account when examining the risk-benefit profile of these drugs.” (A refractory disease is one that doesn’t respond to conventional treatments.) Turney’s email also says that survival rate isn’t the only valid endpoint to consider when deciding whether to approve a drug.
But the invited commentary by Dr. Ezekiel Emanuel of the University of Pennsylvania’s Perelman School of Medicine and two co-authors says that the FDA is leaning too far toward approving drugs without proven efficacy. It cites for example the FDA’s approval of bevacizumab for progressive glioblastoma, an aggressive brain cancer. According to the commentary, “the confirmatory trial, with more than 400 patients, reported no improvement in terms of overall survival, quality-of-life end points, or neurocognitive functioning.” What’s more, almost two-thirds of the patients on bevacizumab had severe to life-threatening side effects.
“Drugs with unproven effectiveness sell false hope to desperate patients, who are likely paying thousands of dollars out of pocket for them,” the commentary says. “Private insurance companies, Medicare, and Medicaid pay millions—maybe billions—of dollars for drugs for which we do not know the real benefits and risks. This raises insurance premiums and wastes tax dollars.”
By coincidence I just finished reading a book on this theme, published in 2015, called Ending Medical Reversal: Improving Outcomes, Saving Lives, by Dr. Vinayak Prasad of Oregon Health and Science University and Dr. Adam Cifu of the University of Chicago. Prasad was the lead author on the response rate paper in the latest JAMA Internal Medicine.
Ending Medical Reversal argues that drugs, surgeries, and other treatments shouldn’t be approved without proof of their value from the gold standard of evidence: randomized controlled trials. In such trials, some patients are randomly chosen to get the treatment while the others get a placebo. A placebo isn’t always a sugar pill; it can be a sham surgery that looks and feels to the patient like the real thing.
The book’s appendix features 146 medical interventions that were once accepted practice but were ultimately reversed. Estrogen replacement for postmenopausal women and stents for stable coronary-artery disease are two. Another example from the introduction: “In one decade, doctors recommend an aggressive treatment of high-dose chemotherapy and stem-cell transplantation for women with breast cancer, promising that it will give a woman her best chance of a cure. Then, over the next decade, doctors report that all of that enthusiasm was misguided; the aggressive treatment was no better than a less aggressive course of therapy, which, incidentally, was what we had been doing previously.”
For another perspective on accelerated drug approval, the FDA referred me to Dr. Brian Druker, an oncologist at Oregon Health and Science University who helped develop Gleevec for treatment of chronic myeloid leukemia. (The costly compound was patented before it reached his lab so he never earned royalties.) Druker said it would be a mistake to end the FDA’s accelerated approval process. Drugs that may not work for everybody could still be lifesavers for certain diseases and certain populations, he said.
Still, Druker says the JAMA Internal Medicine papers raise important points. “It becomes a really difficult debate,” Druker says, “but one that’s worth having.”
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