When we take a medication newly approved by the Food and Drug Administration (FDA), we are banking on a number of things. First, we trust that the new medication has been thoroughly tested using rigorously-designed experimental protocols.
Second, we trust that the review of the data is unbiased and objective.
And finally, we trust that decisions about the approval and release of a medication are made in an unbiased manner that puts the health and safety of future patients as a top priority.
It appears that the approval of Aduhelm, a drug targeting the progression of Alzheimer’s disease made by Biogen, shows an ugly side of the FDA, a side that likely violates all of the traditional approval criteria, thereby undermining public trust and confidence in the agency.
In fact, so egregious was the violation of trust by the FDA that it led to the resignations of Dr. Aaron Kesselheim as well as two other members of the FDA’s advisory committee, a group of experts that give external, and therefore unbiased opinions about the efficacy and safety of new drugs. The advisory committee voted overwhelmingly to not approve Aduhelm based on the data of its trials, data that showed the medication was not effective at stopping the progression of Alzheimer’s.
As Dr. Marion Mass writes for realclearhealth.com, “Aduhelm’s trials did not demonstrate ‘certain’ clinical benefits, but ‘suggested’ clinical benefits and ‘convincingly and consistently show safety and reduction of amyloid plaque in the brain, a defining pathological characteristic of Alzheimer’s disease.’” However, the evidence is far from clear-cut or convincing if you peel back the proverbial onion.
To begin with, Aduhelm was approved as a drug that showed surrogate measures of improvement, not clinical benefits. A surrogate measure takes into account when certain biological indicators are present, rather than clinical presentations, such as a reduction in symptomatology and signs. For example, the reduction of cholesterol by statins is a surrogate measure correlated with improved cardiac outcomes.
Similarly, with Alzheimer’s disease, a surrogate measure would be the reduction of amyloid plaques, protein fragments that are normally broken down and eliminated in healthy brains but tend to accumulate in people with Alzheimer’s. The thinking goes that by reducing the accumulation of amyloid plaques, the cognitive declines associated with Alzheimer’s would be slowed down or improved.
Except in the case of Aduhelm, the evidence is not so straightforward. Kesselheim frames it this way:
“The reduction of plaque is a surrogate measure, a lab measurement which stands in for a clinical end point, which is how a patient feels, functions or survives. Amyloid plaque is a protein deposit on the brain that you can observe on a PET scan. Some Alzheimer’s patients have it, and some don’t have it. It’s associated with Alzheimer’s, but it’s not a perfect association. We don’t know what it means to reduce the amyloid plaque. It’s not 100% clear. In contrast, your LDL cholesterol level is a clear surrogate measure. If you change your LDL, then you reduce the number of heart attacks and strokes.”
Furthermore, as Kesselheim points out, “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.” On these measures of clinical improvement of Alzheimer’s symptoms, Aduhelm clearly failed to deliver.
As statnews.com, a website dedicated exclusively to the analysis of biotech, pharma, and the life sciences remarked, “Instead of judging Aduhelm based on its effect on the progression of Alzheimer’s, for which the evidence is debatable, the agency approved the drug based on its ability to remove brain plaques called beta-amyloid, which are believed to contribute to the disease.”
This overreliance on loosely correlated surrogate measures unnecessarily muddies interpretations of efficacy. As the National Library of Medicine writes, “Unfortunately, the use of such surrogates can give rise to paradoxical situations in which the effect of the treatment on the surrogate is positive, the surrogate and outcome are strongly positively correlated, but the effect of the treatment on the outcome is negative.” And while there are protocols for resolving this paradox, the assumption is that the data is robust and that the trials were completed.
Yet, in a feat of what can only be described as circular reasoning, the FDA was undaunted in their approval of the drug. Courtney Rhodes, an FDA spokeswoman, explained, “We appreciate the perspective of the members of the advisory committee and value their input. 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.”
Complicating matters is the fact that not only was Biogen’s own data not definitive in terms of improving medical outcomes, but the data indicated it lacked internal coherency.
As Time magazine reports, “The companies conducted two similar studies, started several months apart, focusing on patients with mild cognitive impairment and evidence of amyloid in the brain, as confirmed by brain imaging. Early results from one study showed no benefit of aducanumab in improving cognitive test scores, while the other trial did. Because of the negative results, the companies decided in March 2019 to stop both studies after statisticians determined that the drug likely would not help patients.”
This lack of trial completion combined with negative results is indicative of a lack of robust control measures and a sloppy approach to experimental execution. These conditions should have been enough to scuttle FDA approval.
Making matter worse is the fact that Biogen’s data also showed that Aduhelm, which is administered intravenously, caused significant and troubling side effects. According to the National Council on Aging, “The most common side effect is painful brain swelling, which occurred in about 35% of patients in the clinical trials. Biogen reports that this side effect is most commonly seen as short-term swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain with the swelling.”
However, Biogen then did an intellectual about-face and stated that a follow-up study provided evidence of Aduhelm’s effectiveness. Company executive Al Sandrock wrote an open letter defending the company’s data and deflecting accusations of malfeasance, arguing, “It is normal for scientists and clinicians to discuss data from experiments and clinical trials, to debate, and to disagree, on the interpretation of data. Recently, however, there has been a turn outside the boundaries of legitimate scientific deliberation.”
And, at a quarterly earnings presentation, Michel Vounatsos, chief executive of the Cambridge biotech, defended the decision to approve Aduhelm, stating,“. . .we are not the ones suffering the most. Whatever the motives of the controversy are, the ones who are potentially misled, confused, denied help are the patients.”
Moreover, it appears that FDA regulators and Biogen may have a tainted relationship, one calling into question issues of a conflict of interest. As Kesselheim, a professor at Harvard Medical School and member of the advisory board for six years, stated, “There was a strange dynamic, compared to the other advisory committee meetings I’ve attended,” adding “Usually there’s some distance between the FDA and the company, but on this one the company and the FDA were fully in line with each other in support of the drug.”
Dr. Michael Carome, a physician who is the director of the Health Research Group for the consumer advocacy nonprofit Public Citizen and who testified at the advisory committee meeting against FDA approval of Aduhelm, has even darker suspicions: “We believe that the FDA, starting back in 2019, worked in inappropriately close collaboration with Biogen. FDA became a partner with Biogen, and they made the decision about whether to approve the drug. They were not objective, unbiased regulators. It seems as if the decision was preordained” argued Carome.
Mayo Clinic neurologist Dr. David Knopman, an FDA advisory member who also resigned as a form of protest, was equally dismayed at the decision of the FDA to reject the findings of the advisory committee, saying, “I was very disappointed at how the advisory committee input was treated by the FDA. I don’t wish to be put in a position like this again.”
Even more troubling than the fact that Aduhelm was approved over the unanimous objections of its advisory committee is its approval for fast-tracking, a process known as “accelrated approval.” As the FDA elaborates, “Aduhelm was approved using the accelerated approval pathway, which can be used for a drug for a serious or life-threatening illness that provides a meaningful therapeutic advantage over existing treatments. Accelerated approval can be based on the drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, with a required post-approval trial to verify that the drug provides the expected clinical benefit.”
To be fair, Alzheimer’s is a horrible disease and a pressing medical issue. Afflicting more than six million people every year, Alzheimer’s causes significant grief for both the victim of the disease and their family members and loved ones.
Jeffrey Kluger, a senior writer at Time magazine, makes the following eloquent observation: “Suffering is always hard to quantify – especially when the pain is caused by as cruel a disease as Alzheimer’s. Most illnesses attack the body; Alzheimer’s destroys the mind – and in the process, annihilates the very self.”
This underlying desperation, the very loss of the self, may be the precipitating dynamic that allowed an unproven drug such as Aduhelm to be not only approved, but also have its path to market expedited, despite evidence that it won’t be helpful to people suffering from Alzheimer’s.
Harry Johns, president of the Alzheimers’s Association put it this way: “We strongly advocated approval on the basis of the available science, knowing full well that this is no cure. It is a really marginal advantage, but that marginal difference can make a real difference for people who have a great need.”
Still, a sense of desperation should not be substituted for a rigorous approach to drug development because relying on shaky data is not aligned to accepted practices that use widely established standards and parameters to judge the effectiveness of a medication.
Dr. Caleb Alexander, an epidemiologist at Johns Hopkins, vehemently disagrees with taking such a slipshod approach to treating people with Alzheimer’s, saying, “To make the case that something is better than nothing is not the law of the land in the United States. That’s not the evidentiary basis for market access. They have to show substantial evidence of efficacy, and they didn’t. You can argue that, theoretically, that this drug should work, but we don’t approve drugs on that basis in the United States. We do it based on data, not based on theory.”
Furthermore, there are real-world consequences to such decisions beyond the side effects. At the very least, people will have their hopes unrealistically raised only to likely be unmet because of the lack of effectiveness of Aduhelm.
As Kesselheim contends, “There’s this libertarian idea that people should have the opportunity to choose what they put into their own bodies. But that sort of free market is what led the FDA to start weighing the costs and benefits of drugs in the first place during the early 1960s. When pharmaceutical companies can sell almost anything they want, with no oversight from government, that’s not a situation that’s good for patients.”
There are also significant financial costs associated with Aduhelm. A recent analysis by the Kaiser Family Foundation (KFF) concluded, “If just one-quarter of these beneficiaries are prescribed Aduhelm, or 500,000 beneficiaries, and Medicare pays 103% of $56,000 in the near term, total spending for Aduhelm in one year alone would be nearly $29 billion, paid by Medicare and the patients who use this drug – an amount that far exceeds spending on any other drug covered under Medicare Part B or Part D, based on 2019 spending.”
Additionally, KKF found that there would be significant out-of-pocket expenses for patients and their families, stating, “. . . beneficiaries would face about $11,500 in coinsurance for one year of Aduhelm treatment, which represents nearly 40% of the $29,650 in median annual income per Medicare beneficiary in 2019,” adding “Because Aduhelm is not a cure for Alzheimer’s disease, patients could incur these annual out-of-pocket costs over multiple years.”
Of course, finances alone are not a valid argument for not allowing a medical intervention that could possibly ameliorate one of the most devastating and pervasive diseases of our times. We should be sympathetic to allowing people to take measures that might improve their quality of life.
But, that decision should be made on clear, objective, robust data. It should be made in light of benefits clearly outweighing risks. And, it should not be tainted by what appears to be a form of dirty inside baseball. On all those measures, Aduhelm falls woefully and pitifully short, leading Kesselheim to rightfully conclude that Aduhelm is “’probably the worst drug approval decision in recent US history.”
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