It is difficult to know where exactly to begin this commentary regarding the FDA approval to permit commer-cial sales of the Alzheimer disease drug aducanumab-avwa.
It is difficult to know where exactly to begin this commentary regarding the FDA approval to permit commer-cial sales of the Alzheimer disease drug aducanumab-avwa (Aduhelm). There are so many disturbing features of this story, with likely more to be told in the near future.
A reasonable starting point is to acknowledge that similari-ties of the regulatory process used to move this agent from the realm of objectively monitored investigative efforts designed to demonstrate both the safety and efficacy of the drug to the arena of sales and marketing to those increasingly and most often employed to permit quicker access of novel antican-cer pharmaceutical agents.1,2 Therefore, it is not inconceivable that the serious deficiencies associated with the aducanumab approval process may be used in the future by critics of the accelerated approval pathway to deter use of this strat-egy in oncology.
In fact, the objective parameter of progression-free survival, commonly employed as a primary end point in many clini-cal trials, recognizes that cancer is increasingly viewed as a chronic illness in several settings. As a result, patients may appropriately follow multiple therapeutic strategies after they have progressed on a specific regimen in a trial. This makes it difficult if not impossible to conclude whether a particu-lar investigative treatment delivered months or even years before a patient’s death was responsible for the overall survival outcome. This surrogate end point directly related to extending the time until a patient’s disease progresses is widely recog-nized as being clinically meaningful; however, many prominent academics still fail to appreciate, or simply refuse to consider, this critical point. For example, authors of a recent commentary on anticancer agents argued that “paying full price for products that have not been shown through randomized clinical trials to improve cancer survival or patients’ quality of life constitutes inefficient care.”2
What are the specific concerns surrounding regulatory approval of aducanumab? The first to be highlighted is the use of a particular surrogate end point that was claimed by the company and advocates within the FDA to likely predict for a favorable clinical outcome. In this situation the FDA “based its decision on the effects of aducanumab on brain β-amyloid levels as a surrogate marker of reasonably likely clinical bene-fit.”1 Unfortunately, there remains considerable controversy regarding the relationship between this biological marker and specific disease-related symptoms or evidence of progression of Alzheimer disease. As a result, the relevance of this factor as a reliable and accurate clinically meaningful end point is highly questionable.
In fact, of the 11 members of the FDA advisory committee who were asked to consider approval of this agent for commer-cial use based on the presented data, 10 voted no and 1 voted uncertain regarding whether it was appropriate to conclude that this agent favorably affected the characteristic decline in cognitive function observed in this devastating neurological condition.1 The FDA’s subsequent approval of the agent despite the overwhelming vote to not support this action led to the unprecedented resignation of several members of the regula-tory agency’s advisory committee.
The second concern with the approval regarded the over-all safety findings of aducanumab, which demonstrated questionable clinical activity. Of the 3285 participants in registration-quality clinical trials evaluating aducanumab in patients with early Alzheimer disease, approximately one-third of patients experienced brain edema and one-quarter experienced distressing symptoms, including headache, confusion, nausea, and dizziness.3 Subjective and objective toxic effects are commonly observed with anticancer agents, and their potential effect on a patient’s quality of life must be balanced against meaningful evidence of efficacy. Based on the data presented publicly to date, it is quite difficult to argue aducanumab satisfied this critical evaluation.
The next issue to be highlighted is the apparent lack of appropriate representation within the clinical trials of individuals who would potentially be eligible in the real world to receive aducanumab once commercially available. The authors of one report that examined the medical claims from the Centers for Medicare & Medicaid Services (CMS) found that rather remarkably the clinical trials of aducanumab would have excluded 92.2% of individuals with Alzheimer-related disorders, 91% with mild dementia due to Alzheimer disease, and 85.5% with mild cognitive impairment or mild dementia based on a single exclusion criterion. Further findings noted that most patients would meet multiple exclusion criteria.4 For example, individuals would have been excluded for the presence of common medical conditions, including cardiovascular disease, receiving anticoagulation, chronic kidney disease, and age greater than 85 years. In addition, the studies included a low percentage of Hispanic, Black, and Native American participants.5
How relevant would the clinical trial data concerning both safety and efficacy leading to regulatory approval be for this agent when employed in the large population of individuals in the United States with Alzheimer disease and other forms of dementia?
Finally, it is important to note the cost of aducanumab as set by the manufacturer: $56,000 per year.1 This does not include the price for tests (eg, brain MRI) to routinely monitor for associated toxicities of the agent, physician interactions, or required hospitalizations/emergency department visits associated with adverse effects. It should also be noted that the nonprofit Institute for Clinical and Economic Review suggested a value-based price of between $2500 and $8300 per year based on the available efficacy and toxicity data.6
Concern by Medicare administrators was so great for the effect of the cost of this agent to the entire program that they have raised the cost of premiums for Medicare participants by 13% for 2022, despite the fact CMS has yet to determine whether it will agree to pay for this agent.7
Clearly, there are serious issues to be considered here, and members of the cancer community can only hope this serious FDA misadventure will not negatively affect future access of patients with cancer to novel pharmaceutical agents.