The pharmaceutical giant Biogen’s designer drug for Alzheimer’s disease, aducanumab (Aduhelm), was granted accelerated approval from the FDA earlier this year with support from patient advocacy groups. Approval was granted despite the premature termination of clinical trials and the near-unanimous objections of the FDA’s own scientific advisory panel. Perhaps most remarkably, the FDA extended the approval to all patients with Alzheimer’s disease, instead of the limited range of patients with early-stage disease who have undergone extensive testing to prove they have Alzheimer’s disease.
The ensuing controversy has forced the FDA to edit the label of the drug to be approved for patients with mild cognitive impairment and early Alzheimer’s disease. This move has significantly reduced the number of patients who will qualify for the more than $50,000/year treatment. Federal investigations have been launched into the process leading to approval and the pricing structure. Substantial doubt remains as to whether the drug works at all.
To counter the outcry of criticism, Biogen rolled out a slick new marketing package including an extended advertisement in The New York Times and a website that purports to help patients identify symptoms of mild cognitive impairment. They tell readers “about 1 in 12 Americans over age 50 has mild cognitive impairment due to Alzheimer’s disease” – equating to nearly 10 million people. It is a preposterous statistic since the total number of patients currently diagnosed with any stage of Alzheimer’s disease in the United States is about 6 million.
Biogen’s website ‘It’s Time We Know’ offers consumers a quiz that looks like a clinical screening tool to test for symptoms of mild cognitive impairment. A high percentage of people will screen positive for symptoms; in fact, nearly every person in my research group had symptoms of mild cognitive impairment according to this quiz and all would be instructed by Biogen to discuss the issue with their doctor or call Biogen’s Alzheimer’s Learning Line. The fine print accompanying the quiz reveals that it isn’t a validated clinical tool, even though it was designed to look like one. This calculated series of falsehoods make common human experiences of normal aging or absent-mindedness seem like an illness that is much more prevalent than it is.
This is flagrant misinformation that seems like predatory marketing. In actuality, mild cognitive impairment is a complex clinical diagnosis. While a fraction of patients with mild cognitive impairment have the initial changes of Alzheimer’s disease in their brains (nowhere near the 75% claimed by Biogen), many have other illnesses including depression, sleep apnea, medication side effects, small blood vessel disease, or the early stages of other forms of dementia. Some simply have normal age-related memory loss and live full, normal lives.
Here are some real facts. There is more than one way to define mild cognitive impairment, but by any measure, it is rare among people in their 50s. Mild cognitive impairment is also much less likely to represent the beginning stages of Alzheimer’s disease in people’s 50s than it is later in life. Up to half of the patients in this age range with mild cognitive impairment return to cognitively normal status on subsequent testing. Around 50% of patients diagnosed with mild cognitive impairment in later life (60+) do have evidence of abnormal β-amyloid accumulation based on PET scans, which is the main component of the amyloid plaques found in the brains of people with Alzheimer’s disease. However, this alone is not enough to establish that the cognitive symptoms are due to Alzheimer’s disease.
Diagnosing Alzheimer’s disease requires demonstrating that, in addition to β-amyloid plaques, there are also changes in a protein called tau. Only about 20% of patients with mild cognitive impairment will be diagnosed with Alzheimer’s disease within three years, and most won’t progress to dementia in 10 years. The potential for symptoms to worsen is obviously important, but patients and families need to know that a diagnosis of mild cognitive impairment is not the same as a diagnosis of Alzheimer’s disease.
A Biogen representative claimed the primary source of the statistic that 1 in 12 Americans over age 50 had mild cognitive impairment due to Alzheimer’s Disease was a 2018 article in the journal Neurology. That Neurology article did not study people in their 50s and the prevalences were for all forms of mild cognitive impairment, not “mild cognitive impairment due to Alzheimer’s disease,” which is the very specific language Biogen uses.
The criteria Biogen used in their trials for “mild cognitive impairment due to Alzheimer’s disease” was patients had to have objective evidence of memory problems, a particular range of scores on cognitive tests, and a PET-scan showing the accumulation of β-amyloid in the brain above a pre-specified threshold. As a board-certified neurologist, I am not aware of any published evidence that 1 in 12 adults over age 50 fit these criteria.
Monday morning, Biogen provided me with a more detailed explanation of the sourcing behind their claims, which contradicts their initial public explanation in some respects. The additional data they claim to have used still did not include patients as young as age 50 and is vulnerable to important biases. For instance, the claim that 75% of patients with mild cognitive impairment have underlying Alzheimer’s disease came from a study that did not use modern diagnostic testing, but rather simply asked physicians for their best guess. And the patients in that study were between ages 69 and 88. The conceptualization of mild cognitive impairment Biogen is using in their marketing of aducanumab is totally different from the rigorous definition they use in their clinical trials, which is a dubious tactic.
This issue fits into a pattern of cherry-picking data to fit a narrative favorable to the company. Why would Biogen obscure the source of the data behind this central claim? It is because most patients with mild cognitive impairment in their 50s simply do not have underlying Alzheimer’s disease. Treating patients in this age range without using modern biomarkers, as the FDA currently allows, will result in a high percentage of patients being treated, potentially for many years, without any potential for benefit.
Ironically, this week Biogen’s head of research and development, Alfred Sandrock, released an open letter to the “Alzheimer’s disease community”, accusing concerned scientists and clinicians of spreading “extensive misinformation and misunderstanding” about aducanumab. He suggested the ongoing controversies were “outside the boundaries of legitimate scientific deliberation.”
Of course, the controversy is legitimate. Biogen bungled the clinical trials resulting in conflicting findings, and then politicized the approval process by leveraging their relationships with patient advocacy organizations and an overly collaborative relationship with the FDA. These relationships have raised concerns about whether the process was unbiased. If Biogen wants to settle this controversy, they should produce higher quality data instead of antagonizing concerned physicians and scientists.
Although the new Biogen ad campaign doesn’t directly mention aducanumab, the obvious intention is to expand the number of patients diagnosed with mild cognitive impairment to increase the population meeting criteria for Biogen’s new and massively expensive drug. Because the FDA approval did not require that patients be tested for the presence of β-amyloid before treatment, most patients in their 50s and early 60s considering treatment with aducanumab won’t have β-amyloid plaques in their brains.
One of our roles as physicians caring for patients with Alzheimer’s disease is to help them spot and avoid the all-too-common con-artists who try to exploit patients’ and families’ fears and desperation. In the United States, fortunately, most of these con artists are on the fringes of medical practice. Emboldened by a stamp of approval from the FDA and patient advocacy organizations, Biogen and its misinformation campaign are in an unprecedented position to cause harm to patients. It is time for patient advocacy organizations to work to restrain the excesses of Biogen’s roll-out of aducanumab. Narrowing the label was an important step, but we must insist that the marketing of this drug is honest, pricing is fair, patient selection is cautious and additional clinical trials are completed in a reasonable timeframe to demonstrate conclusively whether the drug is effective.