In a Reversal, F.D.A. Calls for Limits on Who Gets Alzheimer’s Drug

The agency faced criticism for approving Aduhelm for all Alzheimer’s patients. The new label recommends that the drug be given only to patients with mild symptoms.,


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Facing sharp criticism for approving a controversial drug for all Alzheimer’s patients, the Food and Drug Administration has greatly narrowed its recommendation, suggesting that only those with mild memory or thinking problems should receive it.

The F.D.A.’s turnabout, highly unusual for a drug that has only been available for a few weeks, could considerably reduce the number of eligible patients. The initial label, saying the drug could be appropriate for anyone with Alzheimer’s, encompassed about six million Americans. Under the revised label, as many as two million Americans would likely be eligible.

Medicare and private insurers may use the new label to restrict coverage of the drug, called Aduhelm. That could alleviate the drug’s financial burden, particularly on Medicare, which is expected to shoulder the bulk of costs of the treatment, a monthly intravenous infusion. The drug’s maker, Biogen, is charging $56,000 annually for the drug, and costs for diagnostics and safety monitoring could add tens of thousands of dollars to the bill.

“Since the agency approved Aduhelm, prescribers and other stakeholders have expressed confusion regarding the intended population for treatment,” said Michael Felberbaum, a spokesman for the F.D.A. The agency’s new position is that “it is appropriate to initiate treatment in patients with the mild cognitive impairment or mild dementia stages of Alzheimer’s disease,” he said. This is the population who were entered into the clinical trials.

The approval of Aduhelm has been one of the most contentious F.D.A. decisions in recent years, largely because many scientists, and the F.D.A.’s own independent advisory committee, say the evidence does not convincingly show that the drug works. And in addition to the approval itself, the agency’s surprisingly broad label caused a storm of concern among many Alzheimer’s experts, even those who had supported the drug’s approval.

The revision to the label does not forbid patients with moderate or severe Alzheimer’s from receiving the treatment; as with other drugs, physicians can still prescribe it off-label. But the change sends a strong message to doctors and insurers about who should receive the drug.

The F.D.A. initiated the labeling change, and Biogen agreed to submit revised language. Biogen had said in recent weeks that it intended to market the use of the drug to patients who resembled those in the clinical trials.

In one late-stage clinical trial, the highest dose of the drug appeared to slow patients’ cognitive decline by a fraction of a point on an 18-point scale rating memory, problem-solving skills and function. But in a second identically designed clinical trial, the drug showed no benefit at all.

The agency approved the drug under a pathway known as accelerated approval, more commonly used for cancer drugs, based on the drug’s ability to reduce levels of a protein, amyloid, that clumps into plaques in the brains of Alzheimer’s patients and is considered a biomarker of the disease. But many Alzheimer’s experts say there is not yet convincing evidence that reducing levels of amyloid can produce any effect on people’s memory and thinking problems.

When the F.D.A. approved Aduhelm a month ago, its original label had said that the drug is “for the treatment of Alzheimer’s disease.” The surprisingly broad label caused a storm of concern among many Alzheimer’s experts, even those who had supported the drug’s approval.

At a forum last month sponsored by the Alzheimer’s Association, which had pushed for approval of Aduhelm, a panel of Alzheimer’s clinicians with varying views of whether the drug should have been approved were nonetheless united in saying that its use should be sharply limited.

Many experts say that the drug’s label should not only narrow the use of Aduhelm to mild stages of the disease, but should also require two other strict conditions of the clinical trials: that eligible patients have evidence of high levels of a key protein, amyloid, in their brains, and that people with certain medical conditions (called “contraindications”) should be prevented from taking the drug, or at least designated as a high-risk group, because it can cause brain swelling and brain bleeding.

At the forum, Dr. Stephen Salloway, director of the Memory and Aging Program at Butler Hospital in Providence, R.I., who helped conduct the Aduhelm trials and is one of the drug’s most passionate medical champions, said that when he saw that the label included no contraindications, his reaction was “oy.”

On Thursday, Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California, who also worked on one of the Aduhelm trials and has opposed approval of the drug, said the new labeling fell short.

Among other things, the label should have stated, he said, that people with diabetes, high blood pressure and those taking blood thinners were not allowed to participate in the clinical trials and that, as a result, “we don’t know any extent of increased risk” for those patients.

Dr. Jason Karlawish, a co-director of the University of Pennsylvania’s Penn Memory Center, said the new label hews more closely to what he and other Alzheimer’s experts believe should have been written in the first place. But the abrupt revision of the label so soon after a widely criticized approval decision is concerning, he said.

“The revision of this label is yet another piece of evidence that should cause the American public to be concerned about how F.D.A. is practicing its regulatory science,” said Dr. Karlawish, who is a site investigator on Biogen-sponsored studies.

Mr. Felberbaum of the F.D.A. said that because Alzheimer’s is a progressive illness, “some patients may benefit from ongoing treatment even if they progress from mild cognitive impairment or mild dementia to later stages of the disease during treatment with aducanumab,” referring to the scientific name of the drug.

But the agency’s new label makes it clear that such a decision would be made without any scientific evidence. “There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied,” the revised label says.

In Congress, two House committees last month announced an investigation into the drug’s approval and its price. Lawmakers including Senator Elizabeth Warren, Democrat of Massachusetts, Senator Bill Cassidy, Republican of Louisiana and Rep. Katie Porter, Democrat of California, have also called for scrutiny of the drug.

“This event only adds to the importance of having those congressional hearings to figure out what’s going on at F.D.A. and why they’re doing this,” Dr. Karlawish said.

The first patient to get the drug outside of a clinical trial, a 70-year-old Rhode Island man, received his first infusion three weeks ago at Butler Hospital. Biogen has not yet announced how many patients have received the drug so far, but its distribution is expected to be slow in the first months, because of challenges administering it.

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