The FDA has a difficult job. It is understaffed and underfunded. It has to walk a very fine line between prematurely approving a new drug that may turn out to be useless or even harmful and rejecting or delaying approval of a drug when earlier approval might have been saving lives. On the whole, I have always thought they did a pretty good job, considering. But I was shocked and disappointed at their recent approval of a drug for Alzheimer’s disease.
Aduhelm (aducanumab) was approved on June 7, 2021, using the accelerated approval pathway. That pathway was intended for drugs that treat serious or life-threatening illness and provide a meaningful therapeutic advantage over existing treatments. Alzheimer’s disease qualifies as a serious and life-threatening illness, but does the new drug provide a meaningful therapeutic advantage? Does it even work? That remains doubtful.
Approval of a new drug is usually based on two positive studies. Here we have one positive and one negative. There were two phase 3 clinical trials, both double-blind studies. One showed reduction in clinical decline; the other didn’t. In the positive trial, the high dose of medication slowed cognitive decline only slightly, by about four months over an eighteen-month period.
But both showed a reduction in amyloid plaques. The FDA website says, “there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients.”
There is a problem with that reasoning. While amyloid plaques have been associated with symptomatic Alzheimer’s disease, we still don’t know whether they are a cause or a result of the disease. And there is no evidence that decreasing the number of those plaques is effective for improving the symptoms. The one positive study found a correlation with reduced symptoms; it did not constitute evidence for causation. The FDA requires the manufacturer to do further studies, and if those studies are negative, approval will be withdrawn.
There was dissension in the FDA ranks. The advisory committee recommended against approval. Three members of the FDA advisory committee resigned in protest over the approval. Office of New Drugs Director Peter Stein supported approval but wrote in a memo that the drug would most likely benefit people in early stages of the disease. He appeared to assume that the FDA approval would limit the medicine’s use to those patients. It didn’t; there are no restrictions.
Meanwhile, the drug is approved, and some headlines are touting it as a cure for the disease, which it absolutely is not.
Concerns have been raised by many experts. The drug is given monthly by IV infusion and patients are required to get regular MRI scans, because 40 percent of patients in the trials had brain swelling or hemorrhages. Many of those were mild or asymptomatic, but one expert estimates that 1 in 200–300 patients will have serious side effects requiring hospitalization. The FDA doesn’t list any contraindications, but experts recommend avoiding the drug if a patient has a history of brain hemorrhages, stroke, or unstable medical conditions or if they are on blood thinners. And because the studies were done on patients with mild Alzheimer’s disease and high levels of amyloid, treatment should be limited to patients whose status matches those of patients in the trials. There is no evidence that it is effective for patients with more advanced disease, but I predict there will be a temptation to give it to the patients who are most affected.
Another big concern is the price: $56,000 a year.
In my opinion, the FDA should not have approved the drug until they had more evidence. Why did they violate their usual careful procedures? What were they thinking?