The FDA approval of an anti-amyloid antibody made waves, and let to a shake-up of it´s expert committee. Here´s a sequel to the analysis on the events as they unfolded. You can check part I of the blog article on this story here.
The US Food and Drug Administration (FDA) gave the new Alzheimer's drug aducanumab the green light at the beginning of June 2021 - surprisingly, against the recommendation of its expert committee, which supported not to approve the drug.
The aforementioned statement sums up the view of Prof. Jason Karlawish, an Alzheimer's expert at the University of Pennsylvania's Perelman School of Medicine. He agrees with another independent analysis of the data done by the Institute for Clinical and Economic Review1 and has indicated that he "will not prescribe the drug to his patients"2. He sees the contradiction impacting the drug on the data, which for him are incomplete and contradictory, and on the other hand in decisions that were not scientifically but economically motivated.
The Phase III trials ('EMERGE' and 'ENGAGE') were started immediately after a small Phase I trial, thus omitting Phase II trials, an essential step that would have allowed for more informed hypotheses and decisions. "Skipping the learning and confirmation phase and then doing an interim (futility) analysis, set in motion a frustrating series of events, none of which have benefited the discovery of better therapies for Alzheimer's disease."2
Many voices also criticise the use of retrospective analyses as unscientific. Although post hoc analyses can provide helpful insights for the design of future prospective studies, they are so burdened with statistical bias that they are unsuitable as evidence of the effectiveness of a therapy, according to Prof. Perlmutter.3 He is one of the three (of a total of 11) experts who have left the advisory board in the wake of the events.
He also points out that the FDA's decision was only based on a surrogate endpoint: after retrospective evaluation of further data (which had been added after the interim analysis), a reduction of beta-amyloid plaques in PET had been shown in some subgroups, which the participants in the control group did not show.
However, it has not yet been proven that this also results in a clinical benefit. One thinks of the many previous studies on various active substances that break down amyloid and which were all negative with regard to the clinical result. In the meantime, it has been questioned again and again whether a sole targeting of amyloid can be effective at all.
The approval of a drug that is not effective also has serious potential to hinder subsequent trials, as it has been warned by both Prof. Perlmutter and Prof. Karlawish.3 A risk-taking patient will now prefer to choose the guarantee of getting the verum instead of participating in a trial. In addition, it could happen that in the future new active substances will no longer have to be compared with placebo, but with aducanumab. The billions that the use of the drug will cost would be better invested in further research.
Public Citizen's Health Research Group not only agreed with the external advisory committee's verdict, but also criticised the FDA for its collaboration with the drug's manufacturers on briefing documents and more. In a letter to the US Secretary of Health and Human Services in April, they called for the temporary suspension of the FDA's head of neuroscience, Dr. Bill Dunn.4 But other formations also threw their weight behind the issue, with the Alzheimer's Association, for example, pushing for approval.4,5
This was the statement of another renowned expert, Prof. Vinay Prasad.6 Besides patient care, his focus is on meta-research, i.e. he analyses the quality of medical evidence, drug development, clinical trial design and health policy.
In addition to more than 280 scientific articles, he is the author of books such as Malignant: How bad evidence and bad policy work against cancer patients (2020) or Ending Medical Reversal - Improving Outcomes, Saving Lives (2015). "Medical reversal happens when a new therapy or diagnostic procedure is started without a solid evidence base - and only abandoned afterwards when it turns out not to help or even harm patients. The opposite of progress, in other words.
The FDA is failing in its task, he sadly concludes. Aducanumab is not the only one to be mentioned here. As recently as April 2021, the FDA had six accelerated (i.e. actually conditional) approvals of cancer immunotherapies up for re-evaluation. Although clinical trials could not show any improvement in survival or quality of life, the approvals were not withdrawn in four of the six cases.
Many other examples of questionable therapies remaining in circulation for a long time in this way can be found in oncology and neurology, among others. All of this even tops the odyssey of the drug memantine, which was approved some 18 years ago, as highlighted by a colleague in a reader commentary on Medscape.4 In it, he laments not only its limited medical benefit (which is why, for example, the reimbursement claim was withdrawn in France at some point), but above all the fact that the application of the drug has continued until today.
In 2014, shortly before the patent expired, the manufacturer developed an extended release formulation to obtain a new patent. Then it wanted to withdraw the marketing authorisation for the old (now generically available) preparation, which would have undermined competition and forced buyers to switch to the new, more expensive product.7 The manufacturer was sued and lost, but eventually a combination pill of donepezil (whose patent had also expired in the meantime) and memantine was created and again received a new patent that remains valid until 2026 (Namzaric). In the USA, a monthly pack now costs just under $600.
In an article worth reading about the financial aspects of the aducanumab issue, the authors, two American law professors, write: "Because of how our health care system is structured, this FDA decision will de facto shift many billions of dollars in public funds and patient money to a single drug manufacturer."
They estimate that if the drug is prescribed to only a third of eligible patients, it would cost Medicare $112 billion a year - a huge figure that dwarfs any other drug. "Whether this is a good use of our collective resources is not a question that the FDA has considered. But it is a question that may haunt the health care system for many years to come."8
References:
1. Lin GA et al. Aducanumab for Alzheimer’s Disease: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review, May 5, 2021. https://icer.org/wp-content/uploads/2020/10/ICER_ALZ_Draft_Evidence_Report_050521.pdf.
2. If the FDA approves aducanumab, I won’t prescribe it. STAT https://www.statnews.com/2021/05/30/if-the-fda-approves-biogens-alzheimers-treatment-i-wont-prescribe-it/ (2021).
3. Two FDA Panel Members Resign Over Alzheimer’s Drug Approval. Medscape http://www.medscape.com/viewarticle/952802.
4. FDA Approves Controversial Alzheimer’s Drug. Medscape http://www.medscape.com/viewarticle/952502.
5. The FDA Has Approved A New Alzheimer’s Drug — Here’s Why That’s Controversial. NPR.org https://www.npr.org/2021/06/07/1003964235/fda-approves-controversial-alzheimers-drug-aducanumab.
6. The FDA Is Failing the American People. https://www.medpagetoday.com/opinion/vinay-prasad/93136 (2021).
7. Actavis, Others Plotted To Delay Generic Namenda, Suit Says - Law360. https://www.law360.com/articles/665234/actavis-others-plotted-to-delay-generic-namenda-suit-says.
8. Sachs, N. B., Rachel. The Drug That Could Break American Health Care. The Atlantic https://www.theatlantic.com/ideas/archive/2021/06/aduhelm-drug-alzheimers-cost-medicare/619169/ (2021).