In a letter posted on Twitter, Woodcock said an independent review and assessment should consider interactions between Biogen, the company that makes Aduhelm, and the FDA during the process that led to the June approval of the drug.
Woodcock wrote she has "tremendous confidence in the integrity of the staff and leadership" in the FDA's Center for Drug Evaluation and Research involved in the review of the drug, aducanumab, and sold as Aduhelm.
"There continue to be concerns raised, however, regarding contacts between representatives from Biogen and FDA during the review process, including some that may have occurred outside of the form correspondence process," Woodcock wrote to to OIG Acting Inspector Christi Grimm.
"To the extent these concerns could undermine the public's confidence in FDA's decision, I believe that it is critical that the events at issue be reviewed by an independent body such as the Office of the Inspector General in order to determine whether any interactions that occurred between Biogen and FDA review staff were inconsistent with FDA policies and procedures."
On Twitter, Woodcock said that if HHS OIG decides to conduct the review, the agency will "fully cooperate" and review any recommendations it might provide.
Between 2010 and 2015, drug companies submitted data to the U.S. Food and Drug Administration (FDA) for three different drugs for Alzheimer’s disease, a devastating condition that afflicts six million Americans. The FDA rejected all three because the manufacturers failed to provide convincing evidence that their drugs actually improved symptoms of Alzheimer’s much less cured the disease. How times change. Last month, when biotech company Biogen came to the FDA with data on aducanumab, yet another Alzheimer’s drug, the evidence the company brought once again failed to show that the drug could slow or stop Alzheimer’s cognitive decline. This time, however, the FDA gave the drug a green light, prompting Michel Vounatsos, CEO of Biogen, to pronounce the decision “historic.”
It was historic all right, but not in the way Vounatsos probably meant it. The scientific data for aducanumab is so flimsy and contradictory, ten of 11 members of the FDA’s advisory committee of outside experts voted against approving the drug (the eleventh abstained). Even the FDA’s own statistician recommended the drug be rejected. When higher ups at the agency went ahead and approved it, three advisory committee members quit in protest. In a scathing resignation letter to the FDA, committee member Aaron Kesselheim called it “probably the worst drug approval decision in recent U.S. history.”
In addition to aducanumab’s failure to improve symptoms, the drug also packs some nasty side effects. Patients in Biogen’s clinical trials who were given the dose of the drug that was ultimately approved by the FDA were three times as likely to suffer brain swelling and hemorrhages as patients given placebo. They were also more likely to have painful headaches, vision loss, disorientation and falls—exactly the kinds of symptoms Alzheimer’s patients don’t need. The public safety advocacy group, Public Citizen, has called for an investigation into the process that led to aducanumab’s approval and for FDA officials overseeing it to be fired. That won’t be nearly enough to fix what ails the FDA.
Aducanumab, whose trade name is Aduhelm, was approved through what’s known as an accelerated pathway, an approval process originally intended for life-threatening diseases for which there are few remedies. The fast-track process requires a lower level of evidence to gain FDA approval than the normal pathway. Once the drug is approved, companies are supposed to conduct confirmatory trials, studies designed to tell for sure if the drug is, in fact, safe and effective.
Biogen got aducanumab on the accelerated pathway after it had already tested the drug in two large randomized controlled trials. Neither trial showed the drug had any effect on memory loss, personality changes, or cognitive decline. In fact, the studies proved futile and were stopped because patients who were on the drug did no better than those on the placebo.
On the accelerated pathway, the company was permitted to test the drug’s effect on a “surrogate endpoint.” These are things that can be measured in the body, like the presence of a protein in the blood or tumor size. A drug’s effect on a surrogate endpoint is much easier to demonstrate than its effect on a “clinical endpoint,” such as improved survival or quality of life. That means drugs can get approved faster using fewer patients and at far lower cost.
Cheaper and faster might seem like a good thing, except that surrogate endpoints often prove to have little or no connection to a drug’s more important clinical effects. In the case of aducanumab, Biogen’s surrogate endpoint was the development of amyloid plaques, clumps of protein commonly found in the brains of patients with Alzheimer’s. However, more than two dozen prior studies of amyloid reducing drugs failed to show any connection between slowing amyloid protein and improved cognition. Some showed worse outcomes. And Biogen already had two failed trials with clinical endpoints, like cognitive decline, memory loss, and death.
The FDA has given Biogen until 2030 to conduct yet another trial to determine whether or not aducanumab actually works on Alzheimer’s symptoms that really matter. For the next nine years patients can take a drug with unknown (and unlikely) benefits and substantial risks of harm. At $56,000 a year per patient, aducanumab also threatens to bankrupt Medicare, which is compelled by law to cover any drug approved by the FDA.
This is not the first time the FDA has given a drug the go ahead on the basis of a shaky surrogate endpoint. Companies now apply for accelerated approval more often than not for all kinds of drugs, not just those treating life-threatening diseases—and the FDA is increasingly likely to let them on the market. In 2020, nearly three quarters (73 percent) of new drugs received fast-track approval compared to less than 40 percent a decade ago.
Most drugs approved on the basis of a surrogate endpoint remain on the market because confirmatory studies are either delayed or not conducted–some for more than a decade and in one case for 24 years. Now, under a new category that Richard Pazdur, FDA’s head of the oncology (cancer) division, has dubbed “dangling” approvals, the agency is ignoring even completed confirmatory studies that fail to show benefit or that showed excessive harms.
Last May, for example, the FDA reviewed the confirmatory trials for a set of drugs used to treat six different kinds of cancer. All of the drugs were approved on the basis of surrogate endpoints, such as the degree to which the drug shrank tumors or the time it took after treatment for a cancer to return. Not one of the confirmatory trials showed an improvement in patients’ quality of life or survival. In some cases, they made quality of life worse. Yet the FDA quietly left four on the market. Two others were withdrawn voluntarily by the manufacturers.
The agency defends its increasing use of surrogate endpoints by pointing to a handful of success stories, such as Gleevec to treat leukemia, which went through accelerated approval has proved highly effective. However, it is the very hit-and-miss nature of surrogates that caused the agency in the past to insist on studies of clinical benefit before releasing drugs onto the market.
By ignoring negative clinical outcomes in favor of a surrogate endpoint, the FDA has turned the scientific process on its head, if not the point of having a regulatory agency entrusted with ensuring the drugs that doctors prescribe, and patients take, are both safe and effective. “Dying with a smaller cancer rather than a bigger cancer is no consolation because you’re still dead,” says Ezekiel Emanuel, a breast cancer specialist and professor at the University of Pennsylvania. Meanwhile, patients and taxpayers get to fork over tens of thousands of dollars a year for the privilege of taking drugs that don’t work.