In June 2021, the US Food and Drug Administration (FDA) approved aducanumab, a monoclonal antibody, for the treatment of Alzheimer’s disease, even though the data remain “incomplete and contradictory,” as one commentator put it.
Although one member of the FDA’s independent advisory committee called the approval “a dangerous precedent,” sadly, the approval of aducanumab doesn’t establish a “precedent.” A similar, less public process of drug approval, to which I was a central witness, unfolded 10 years ago in 2011.
First, a few words about aducanumab. The FDA approved it based on a “surrogate” marker: a measurement that may (or may not) predict an outcome of interest, but which provides no evidence of clinical benefit. The surrogate marker was the reduction, during treatment with aducanumab, of plaques of the protein “amyloid” in the brains of individuals with Alzheimer’s disease. The FDA claimed in its official press release that this reduction is “reasonably likely to predict a clinical benefit.” However, while amyloid plaques are generally assumed to cause cognitive decline, there is uncertainty as to whether reducing amyloid plaques in the brain protects patients from cognitive decline. Previous trials of drugs which reduce amyloid plaques in the brain have shown no clinical benefit. Aducanumab is associated with potentially harmful side effects. Notwithstanding all this, the FDA granted “accelerated approval” for Aducanumab. Biogen now has to do a post approval trial to confirm any clinical benefit, which could take years. This means profits will be reaped before Biogen is called upon to show evidence that Aducanumab has a positive effect on cognitive decline in patients with Alzheimer’s.
In licensing aducanumab, the FDA ignored the advice of its own independent advisory committee. To date, three of the committee members have resigned in protest.
But as controversial as all this is, it doesn’t set a “precedent.” One was established over 10 years ago, with the approval of a drug aimed at treatment for thalassemia, a common blood disorder affecting hundreds of thousands of children in the world’s poorest countries.
In 1989, I began clinical trials of an experimental drug, deferiprone, to treat children with thalassemia. My publicly funded trials were later supplemented by funding from Apotex, a pharmaceutical company, whose CEO was Barry Sherman. Two years later, while continuing the trials, I recognized problems with the drug’s safety. Sherman threatened me with legal action should I inform patients or publish my concerns, and prematurely and abruptly terminated both clinical trials, thereby avoiding generation of further data potentially adverse to his interests. I nonetheless proceeded to inform my patients and publish my concerns. This 25 year saga became arguably Canada’s most publicized—and certainly its most enduring—biomedical research scandal. It even went on to form the basis of a John Le Carré thriller.
Over years, those threats of legal action from Sherman ultimately led to lawsuits. In 2009, he applied for approval of deferiprone from the FDA. In his application Sherman urged the FDA, as he had to the European Medicines Agency 10 years before, to ignore my concerns about the drug’s safety, because according to Sherman, not only had I allegedly falsified trial data, but I’d committed thousands of “protocol violations” in the conduct of the trial.
The FDA commissioned its Department of Scientific Investigation to conduct an inspection of my original trials. Over a week, the FDA inspector conducted a painstaking inspection of all my clinical data, confirmed concerns about the safety of deferiprone that I’d been struggling to raise for years and showed that Sherman’s allegations were unfounded. After examining all the data, the inspector reported that with respect to my trials’ primary (non-surrogate) endpoint of effectiveness, liver iron concentration, Sherman had submitted data to the FDA that had excluded 45% of subjects.
The most immediate outcome of this conclusion was that the FDA rejected Sherman’s application. The FDA also informed Sherman that, given that my trials had been terminated prematurely, there existed no adequate studies of effectiveness for deferiprone. The FDA therefore demanded at least one additional prospective, randomized, controlled clinical study to verify the effectiveness of deferiprone.
Sherman demanded that the FDA approve the drug based on selected data from older studies which, as in the case of aducanumab, had used a surrogate marker of “effectiveness.” Ignoring its own written findings, the FDA issued “accelerated approval” for deferiprone (albeit as “last resort” therapy.) Asked whether the FDA had ever issued approval based on data of such poor quality, an FDA official responded as follows: “Not that I am aware of. I want to make sure this doesn’t establish a precedent.”
Despite this chapter in the FDA’s history, when I discuss the approval of aducanumab with colleagues or patients, I often hear: “But it must be safe and effective because the FDA approved it.” This is troubling to anyone who has borne witness to what an FDA approval means, and what it doesn’t mean.
Some readers might be surprised that the FDA is paid by Pharma—that the very industry the FDA has a duty to regulate supplies 65% of its budget used for the drug approval process. Or that pharma employees, “consultants,” and “independent patient voices” press hard and successfully for drug approvals.
The stories of aducanumab and deferiprone are not the only ones leading many sensible people to an inevitable question: what function does the FDA now serve?
More questions are being asked: in September 2021, US Congress issued its first public request to the FDA for data and documents related to the approval process of aducanumab.
Now, more than ever, we need regulatory agencies that don’t simply conjure up profit-generating hope, but approve products as safe and effective, because they are safe and effective.
Nancy Olivieri, a physician and a professor of pediatrics, medicine and public health sciences at the University of Toronto. Twitter: @DrNancyOlivieri