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The road to Aduhelm: What one ex-FDA adviser called 'probably the worst drug approval decision in recent US history' for an Alzheimer's treatment - CNN
Sep 27, 2021 6 mins, 36 secs
Aduhelm, if effective, would address one of the most pressing needs in modern medicine: to slow the symptoms of Alzheimer's disease.

"There was a strange dynamic, compared to the other advisory committee meetings I've attended," Kesselheim said.

"The discussion at the committee related to the clinical benefits of the drug" -- that is, whether it slowed the cognitive decline of Alzheimer's patients, he said.

(Aduhelm, which is injected intravenously, also caused significant side effects, including brain swelling in about a third of patients. Brain swelling, at a minimum, can produce painful headaches as well as more serious problems, including, in rare cases, death.)

In light of this, the advisory committee voted, with one member voting uncertain but no one dissenting, to recommend that the FDA reject the drug.

Seven months later, in June, the FDA gave Biogen final approval to treat patients with Aduhelm in all stages of Alzheimer's disease.

In his letter of resignation, Kesselheim called the Aduhelm process "probably the worst drug approval decision in recent US history."

Of course, an advisory committee's recommendations are just that -- advisory.

"The approval has already renewed investment activity in Alzheimer's disease research and development, and we are optimistic that other innovative treatments will soon join Aduhelm," said Allison Parks, a spokeswoman for Biogen.

At its core, though, the controversy about Aduhelm raises a fundamental question: Did the FDA approve a drug that doesn't help people -- and if so, why?

'What's going on here?'

"Alzheimer's is really like nothing else in chronic disease because it is so devastating to the family and caregivers as well as the people who have it," said Harry Johns, the president of the Alzheimer's Association, the nation's largest advocacy group for victims of the disease.

As Courtney Rhodes, an FDA spokeswoman, said, "Given the unmet needs for patients with Alzheimer's disease -- a serious, progressive and ultimately fatal disease -- the agency chose to use the accelerated approval pathway to allow earlier access to patients while we continue to acquire data on the drug's benefit." The FDA will continue to collect data on the effectiveness of Aduhelm for the next nine years.

But other parts of the FDA's explanation for its decision surprised and angered advisory committee members.

Aduhelm is designed to address a surrogate end point for Alzheimer's disease, just like cholesterol medication addresses a surrogate end point for heart disease.

As the FDA said in its original statement on Aduhelm, "While the specific causes of Alzheimer's disease are not fully known, it is characterized by changes in the brain—including amyloid plaques and neurofibrillary, or tau, tangles—that result in loss of neurons and their connections." Aduhelm is designed to remove some of the plaques, and thus, the theory goes, slow the progress of symptoms of Alzheimer's disease.

In other words, reducing amyloid has not meant that anyone is actually getting better."

Still, when the FDA approved Aduhelm in June, it did so because the drug reduced plaque.

As the agency said in its announcement of the approval, three studies involving more than 3,000 patients in total showed that "patients receiving the treatment had significant dose-and time-dependent reduction of amyloid beta plaque, while patients in the control arm of the studies had no reduction of amyloid beta plaque." The logic was straightforward for a surrogate medication: Less plaque meant less disease meant fewer symptoms.

As Rhodes, the FDA spokeswoman, said, the FDA "concluded that it is reasonably likely that this reduction in amyloid plaque will result in meaningful clinical benefit to patients."

But that reasoning immediately came under attack from the members of the advisory committee.

David Knopman, a neurologist at the Mayo Clinic, wrote in his email of resignation from the advisory committee, "Biomarker justification for approval in the absence of consistent clinical benefit after 18 months of treatment is indefensible."

But committee members were surprised by more than the FDA's decision to use what they regard as a flawed surrogate measure to approve the drug.

They were especially offended because the issue of amyloid plaque hadn't really been raised at the committee meeting in November.

"The whole focus of the advisory committee meeting was whether the medication affected cognitive function -- which it didn't improve -- but not whether it affected some surrogate for cognitive function," said Kesselheim.

Worse yet, according to the critics, the FDA gave Aduhelm accelerated approval in June, another possibility that had not been raised before the committee.

(In notable contrast, the FDA did not act in an accelerated fashion when it finally approved the Pfizer/BionTech vaccine for Covid-19 in August.)

The FDA remains adamant that both the process and the result of the review of Aduhelm were correct.

"We appreciate the perspective of the members of the advisory committee and value their input," the FDA's Rhodes said, "The advisory committee's view was that there was insufficient evidence that the drug provided clinical benefit.

Taking the advisory committee's input into account, we considered the application further and determined that although there was residual uncertainty about clinical benefit, as the committee told us, Aduhelm does reduce amyloid plaque."

Still, the contested medical evidence, plus the apparent coziness of the FDA and Biogen representatives, raised questions about whether the agency was taking the advisory committee seriously at all.

In the face of all this, why did the FDA approve the drug?"

Should the market decide?

Supporters of the FDA's decision, which include the Alzheimer's Association, have a simple answer to this question.

According to minutes of the meeting of approximately 15 government scientists, the vast majority questioned whether the evidence met the threshold for "instilling public confidence in the usefulness of the drug." One member of the committee said, according to the minutes, approval could "result in millions of patients taking aducanumab without any indication of actually receiving any benefit, or worse, cause harm."

What was more, the FDA's statistical analysis unit produced a study of the Aduhelm results that concluded "there is no compelling substantial evidence of treatment effect or disease slowing."

The question, then, is what happened between April and June, when the drug was approved, to turn things around.

"We believe that the FDA, starting back in 2019, worked in inappropriately close collaboration with Biogen," said Carome, who testified at the advisory committee meeting against FDA approval of Aduhelm.

Over more than a decade, we at Biogen engaged in rigorous and science-driven research and development that assessed whether Aduhelm could help patients worldwide who suffer from Alzheimer's disease.

We are proud of the work our dedicated team has done to develop Aduhelm, and of the potential it brings to Alzheimer's patients.

Michael Greicius, a professor and clinician who treats Alzheimer's patients at Stanford's medical school, "The idea at the FDA increasingly seems to be if a drug is potentially effective and not clearly harmful, the market should decide whether patients should use it."

This idea is reflected in what's known as the "right to try" movement, which aims to allow patients greater latitude to try drugs that have not received full FDA approval outside of a clinical trial.

When pharmaceutical companies can sell almost anything they want, with no oversight from government, that's not a situation that's good for patients."

The question for families

Soon after Aduhelm was approved in June, Biogen began a sophisticated marketing campaign in support of the drug, starting with advertisements on the internet.

Manchin said the Aduhelm approval process "brings into question the current interim leadership of Dr.

(Lilly, another major pharmaceutical company, has a similar product in the approval process at the FDA, and has sought to receive approval on the same grounds.)

All of which leaves perhaps the most important question: What should Alzheimer's patients and their families do?

"Once the FDA approved it, I've been faced with the real-world possibility of prescribing it to this person sitting in front of me," said Greicius, who studies the disease and treats patients at Stanford.

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