FDA review of new Alzheimer drug

 The FDA is currently seeking a review of their very recent recommendations approving the new Biogen drug aducanumab, which purportedly helps treat Alzheimer’s disease. This FDA review request was engendered by a STAT analysis suggesting significant drug company shenanigans (see https://edition.pagesuite.com/popovers/dynamic_article_popover.aspx?artguid=a5dc1cb2-8885-45ed-97ed-c0736cd1d87f&appid=1165 ) 

 

Details: 

-- acting FDA Commissioner Janet Woodcock just asked the independent Office of Inspector General (OIG) for an investigation into the approval of aducanumab by the FDA, within just one month of its approval 

-- the OIG does have broad power to subpoena internal documents and conduct interviews under oath as well as pursue potential criminal violations through the Department of Justice 

-- this current potential investigation is quite unusual in the FDA, though the OIG is currently assessing the monitoring of the safety of medical devices (though a less serious investigation than above)

 

-- STAT, an important organization that investigates potential conflicts of interest and underhanded practices/malfeasance of drug and medical device companies, published their concerns about the whole approval process

    -- there had been a close relationship between Billy Dunn, head of the FDA’s neuroscience division, and Biogen executives 

        -- there was an off-the-books Biogen meeting with Dunn in May 2019, which STAT reported as enlisting his support for the medication 

        -- one month later Dunn and FDA colleagues push for “accelerated approval”, a regulatory shortcut (though the FDA claimed that this option was only considered this past March, about 2 years later...) 

            -- there was information inside Biogen in 2019 that the drug approval was inevitable 

-- this drug was approved expansively, even though only one of the two large clinical trials done showed there was some slowing of the progression of Alzheimer’s vs placebo; the other study actually found that those on the highest doses did worse than those on placebo. And the studies were done only in patients with early Alzheimer's, though the initial approval was for all with Alzheimer’s 

    -- neither of these two studies have been published in peer-reviewed journals 

-- 3 members of the advisory committee involved in the FDA initial approval process resigned, one noting the approval to be "the worst approval decision" he could remember (see https://www.nytimes.com/2021/07/08/health/aduhelm-alzheimers-fda.html )

 

Commentary: 

-- to me, there was never a clear imperative to approve this drug in an accelerated fashion: 

    -- aducanumab is apparently quite efficient in removing amyloid plaques from the brain 

    -- as noted in https://www.bmj.com/content/374/bmj.n1682 : 

        -- in the two identical phase 3 trials (preapproval), early analyses suggested the medication was “futile”, though further data were collected, the data were reanalyzed in March 2019, and one of the two studies suggested some cognitive benefit. Such an approval with such a potential applicability to huge number of people, seems like it should have had a more rigorous evaluation than simply two preprint pre-peer reviewed articles with conflicting results 

    -- though amyloid plaques are associated with Alzheimer’s, it is unclear what the causative mechanisms for dementia are, and prior studies have found specific anti-amyloid agents to be ineffective (ie, maybe amyloid is not such a great surrogate marker....)

    -- and, in general, surrogate endpoints (such as amyloid plaques) need to be assessed with much more rigor than clear-cut clinical endpoints (such as actual cognitive decline).

        -- as noted in this BMJ article: “the FDA concluded that there were ‘residual uncertainties regarding clinical benefit’” but that “it be granted a license under its ‘accelerated approval’ pathway for drugs that “’may provide meaningful therapeutic benefit’ based on a surrogate endpoint ‘that is reasonably likely to predict a clinical benefit’”  (ie: in this case, the argument largely hinged on how effective the drug was in decreasing the plaques)

    -- and, at $56,000 per person per year, this drug would certainly augment the coffers of Biogen. By a lot.....since >6 million Americans have Alzheimer's

--the FDA did modify their approval on July 8 to be limited to those with mild disease (which was the group of patients actually studied, and generalization to all patients was completely and utterly not evidence-based), based on the huge outcry against their initial recommendation.

    -- which would decrease the target to about 1.5 million Americans...

 

so, what are the big issues here??

--this process was accelerated for a very expensive medication with potentially a huge market, with "Alzheimer's Disease" evoking huge fear in the population, likely on the order of "cancer", and a real driver for many consumers to do whatever is necessary to get their clinicians to prescribe the med

    --and all of this will make it hard for clinicians to resist with a "I don't think this is a great drug, or will even be effective" retort

-- there seems to have been significant shenanigans in the approval process, with apparent huge manipulations and conflicts of interest within an agency entrusted to protect the population, leading to this apparent egregious FDA approval

    -- and, this will likely undercut the general credibility of this really important agency

    --the whole issue shows the FDA in bad light, likely heightening the current anti-federal government, anti-federal agency, anti-public health ideology which has significant popular support

    --and, this anti-government rage, no doubt augmented by this current FDA controversy, further reinforces those who are already somewhat fearful of the Covid vaccines (even in the non-Trumpers who just don't trust the government), leaving the general population at increased risk for covid-related morbidity, mortality, and increased likelihood of the evolution of non-vaccine sensitive SARS-CoV-2 variants

--though, on a positive note, this increased scrutiny might lead to another area where there has been remarkably little in the past: medical devices 

    --see http://gmodestmedblogs.blogspot.com/2018/12/physician-conflicts-of-interest-not.html for prior blog on physician conflicts of interest in drug and medical device companies

    --and it reinforces the need for watchdog organizations to monitor agencies like the FDA, to make sure that the “experts” involved are truly independent of conflicts of interest...

 

geoff

 

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