The regulatory coverage of the FDA


This week, three members of an 11-person FDA advisory council resigned in protest at the FDA’s approval of Aduhelm (aducanumab) for the treatment of Alzheimer’s disease. These resignations are extremely unusual, but understandable in this case.

Aduhelm was approved by the agency even though both pivotal trials were prematurely stopped because they were judged useless, the FDA’s own statistical evaluator did not support the approval, and the FDA advisory committee that considered the application overwhelmingly rejected it. In addition, in a poll by Endpoint News, whose readership is heavily influenced by employees and executives in the biopharmaceutical industry, approve of a bad idea. So how did Aduhelm get approved on June 7th? Two words: regulatory coverage.

Regulatory coverage is defined when a supposedly objective regulatory authority ultimately promotes the goals of the industries it regulates. The FDA has been trapped for quite some time. In a 2016 study published in the British Medical Journal, the majority of the FDA’s hematology-oncology reviewers who left the agency ended up working or advising for the biopharmaceutical industry. In another study by science Magazine, 11 of 16 FDA reviewers who worked on 28 drug approvals and then left the agency, work or advise for the companies that recently regulated them.

For example, Dr. Thomas Laughren, a former director of psychiatric products at the FDA who had a history of less objective action while serving with the FDA in 2012 and formed a consulting firm to help companies focused on psychiatric products Navigate through the regulatory authority’s approval process. One of these companies is AstraZeneca, manufacturer of Seroquel. He was instrumental in the wider approval of Seroquel in 2009 and even went as far as personally minimizing cardiac risk-related questions related to the drug at a meeting of the FDA advisory committee. However, once approved, there was no hiding from these side effects and the drug had to be given a warning in 2011.

In 2016, there was a great deal of controversy surrounding the actions of Dr. Janet Woodcock, the current FDA commissioner while she was director of the Center for Drug Evaluation and Research (CDER). The FDA, acting on Woodcock’s behest, overruled significant internal disagreements to approve Exondys, a therapy for Duchenne muscular dystrophy (DMD), a rare and serious disease that currently has an annual treatment cost of around $ 1 million per patient per year. Fortunately for the public, the FDA released the internal disagreement with its regulatory documents.

One of the loudest objections came from Dr. Ellis Unger, who was director of the Office of Drug Evaluation at CDER. According to Unger, Woodcock was heavily involved in the review of Exondys from the start and decided to get the drug approved before the actual review team made its own recommendation. Interfering aside, Unger was very vocal in his belief that Exondys was ineffective, even calling it a “scientifically elegant placebo.” Exondys was approved for its action on dystrophin, which is considered a biomarker of effectiveness. Unger pointed out that the effect on dystrophin is so small that the effect of the drug would be 1/32 of an inch in 10 inches of snow on the sidewalk. In addition, Dr. John Jenkins, the agency’s director of new drugs, also opposed approval and retired shortly afterwards.

Why did Woodcock fight so fiercely for Exondys recognition? Worst of all, arguably, concerns about the share price of Sarepta, the maker of Exondys. In her presentation to the Agency’s Scientific Dispute Process Review Board (SDR Board), Woodcock noted that Sarepta “needed to be capitalized” and mentioned how the stock reacted to various FDA actions. She also suggested that if Sarepta isn’t approved, the company may not have enough capital to continue its study of Exondys and other drugs in the company’s pipeline. Or, in essence, we need to approve this drug for them to study.

And of course we mustn’t forget the political pressure. In the regulatory documents, it was noted that both Unger and Woodcock received extensive correspondence from Congress and the public urging approval of the drug. It was probably no coincidence that Sarepta significantly increased its lobbying expenses before and during the approval process. Lobbying still has a fantastic return on investment as Exondys ‘revenues are currently over $ 400 million per year (after spending one patient per year’ s earnings for less than a year).

Now let’s get back to Aduhelm. In March 2019, Biogen’s two identical randomized controlled trials investigating Aduhelm in patients with mild Alzheimer’s disease (Trials 301 and 302) were halted because the Data Security Monitoring Panel judged them to be pointless and unlikely to provide a clinically meaningful benefit. In October of this year, Biogen announced that after receiving additional data from one of the studies, it had decided to apply to the FDA for approval of the high dose tested (10 mg / kg). This despite the fact that the benefit was only seen in Study 302, while in Study 301, patients on the high dose actually did worse than patients on placebo. Even the pooled data from both studies showed no significant benefit for the high dose.

After Biogen made the decision to move on, the company got down to work on the narrative. At the Clinical Trials on Alzheimer’s Disease conference in December 2019, during a session to discuss the data, no skeptics or even statisticians were given a platform to speak. In addition, no open question-and-answer segment was allowed and all microphones were removed from the room. That was very unusual, especially since question-and-answer sessions are the norm at a doctors’ conference. Even more shocking, Biogen and the FDA released joint briefings for the meeting of the FDA Advisory Committee (a panel of experts convened prior to a drug’s approval) to discuss the drug’s safety and efficacy. In my 22 years in biotechnology, I can’t remember this ever happening. Usually the FDA has one set of briefing documents discussing the data from their point of view and the company has a different set.

Despite this questionable level of collaboration, if not consultation, the meeting did not go well for Biogen. Statisticians usually don’t like the acrobatics it takes to turn a negative study into a positive, and the FDA statistician at the meeting, Dr. Tristan Massie was no different. It concluded that the evidence was contradicting itself and that approval could indeed negatively impact the development of more effective treatments, both in terms of future trial design and recruitment (patients in clinical trials would often prefer one approved drug to another ). . The Advisory Committee shared their view and the key question was whether Study 302 provided evidence of the drug’s effectiveness; not a single committee member voted yes and 10 voted no with one abstention. Quite an overwhelmingly negative reaction.

And yet the FDA approved it anyway. Worse, the actual drug label that doctors and patients check when considering a drug reads like it was written by Biogen’s marketing team. First, the label indicates that it is approved for the treatment of all stages of Alzheimer’s disease, although it has only been tested in light patients and had little effectiveness there either. This inflates the addressable market size significantly, as all six million Americans with Alzheimer’s are now eligible for therapy. Given that the company decided to price the drug well ahead of any forecast, at $ 56,000 per patient per year (the Institute for Clinical and Economic Review calculated a fair price of between $ 2,500 and $ 8,300), it could this drug can be a real budget buster. And that estimate of six million patients only includes people over the age of 65, so Medicare covers them (especially Medicare Part B since it is an infusion). In 2019, the total Medicare Part B spending was $ 37 billion. If only 15 percent of Alzheimer’s patients choose Aduhelm, it would be spending $ 50 billion.

The FDA also stated that it approved Aduhelm for reducing amyloid plaques – misfolded proteins between nerve cells – although that wasn’t the primary endpoint of the two studies and there is actually no evidence that reducing plaques improves anything . In the case of Aduhelm, too, both studies showed a significant reduction in plaques and yet one of the studies showed that a placebo exceeded the high dose. We have already seen a similar scenario. Merck’s Verubecestat was able to reduce plaques by 60 to 80 percent and still had no clinical benefit (and was even worse than placebo for several key measures).

There were a few additional imperfections in the label that Biogen seems to benefit from. Attempt 301 was the “bad”, attempt 302 was the “good”. The label reverses the numbering so that the “good” experiment is labeled “Study 1,” which allows you to talk about this data first and foremost. In discussing Study 2, the label excludes any presentation of clinical data showing that placebo patients outperformed patients receiving the approved dose, despite the fact that they did for the study’s primary endpoint . This is very important information that would be important to patients and doctors when considering therapy and whether the benefits outweigh the risk of side effects such as cerebral microhemorrhage (19 percent of patients who received the high dose) and cerebral edema (35 Percent of patients).

Why did the FDA do all of this? Alongside the usual post-FDA career incentives, political considerations were likely at work, as in the case of Sarepta (and remember Janet Woodcock, who heavily influenced that decision and is currently the FDA commissioner). Less than two weeks before approval, President Joe Biden said, “If we don’t do something about Alzheimer’s in America … [hospital bed] will be dealing with an Alzheimer’s patient for the next 15 years. ”Guess which 2020 candidate was by far the largest recipient of campaign money from Biogen and related parties? Joe Biden for $ 76,241. And like Sarepta, Biogen also significantly stepped up its lobbying work in the run-up to the FDA decision, with 2020 being a record year and 2021 a record quarter. The FDA didn’t publish the internal deliberations like it did with Sarepta, but I suspect they wouldn’t necessarily be that different and would indicate similar pressures.

I have great respect for the FDA and think the vast majority of reviewers are trying to do the right thing, but the system is broken and there needs to be more firewalls to protect the FDA from tampering. A 2006 survey of FDA scientists found that 18.4 percent of them were “asked for non-scientific reasons to inappropriately exclude or change technical information or its conclusions in an FDA scientific document.” I have to imagine that a similar survey would not produce better results today.

Maxim Jacobs is Managing Partner and Director of Research for North America for the Edison Group, an investment research, investor relations and advisory firm. Follow him on Twitter @MaxJacobsEdison

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