FDA Approves Failed Alzheimer’s Drug

The Food and Drug Administration has approved the first new drug for Alzheimer’s disease in nearly two decades. The “treatment,” aducanumab (ADU), has not been shown to be effective, and the FDA’s own advisory panel voted 10 to 0 (with 1 uncertain) against its approval in November. The same panel accused the agency of demonstrating a bias in favor of Biogen, the company behind ADU, throughout the process.

Members of the panel also wrote an article in JAMA detailing how the drug failed and how the FDA collaborated with Biogen to re-analyze the data, which they wrote “potentially compromised the FDA’s objectivity.”

Following the drug’s approval, three members of the FDA’s advisory committee resigned. Aaron Kesselheim, who had served on the committee since 2015, wrote that the approval of ADU “was probably the worst drug approval decision in recent U.S. history.”

The drug received “accelerated approval,” meaning that its approval is conditional on future studies showing efficacy. Proponents argue that a new treatment for Alzheimer’s is desperately needed, and that the conditional approval, often used for cancer treatments, is appropriate for the disease. Others have expressed concerns that a dangerous precedent has been set in lowering the threshold of scientific evidence needed before going to market.

The accelerated approval pathway requires the use of surrogate endpoints, which are believed to predict success in the overall endpoint of interest. For instance, the outcome of a new cancer treatment might take an unreasonably long time to assess when patients are waiting to have access to it. Instead, reduction of tumor size can be used as a much faster endpoint to measure, given the confidence of beneficial outcome based on the reduced size of the tumors.

However, there isn’t a clear parallel with Alzheimer’s. Instead of tumors, the surrogate endpoint for ADU is its ability to clear beta-amyloid plaques that build up in the brain. These are believed by many to be the cause of the disease, yet the theory remains highly controversial and has yet to produce effective treatments despite decades of developing medicines that reduce these plaques.

Therefore, while ADU has demonstrated its ability to clear some of the buildup, there’s little reason to believe that it will translate into clinical improvements in cognitive function. Indeed, the cherry-picked data offered by Biogen showed only a fraction of a point of improvement on an 18-point scale.

Additionally, the FDA has lowered its thresholds by abandoning the scientific process. In order to be valid, evidence must come from clinical trials that predict an outcome and set prespecified targets. It’s the scientific equivalent of shooting arrows at a bullseye: the real test of ability comes in painting the bullseye before, not after, the arrows land.

In March of 2019, Biogen halted a pair of phase III trials for ADU (dubbed EMERGE and ENGAGE) after they failed to meet their performance targets. According to their interim analyses, EMERGE was “trending positive” and ENGAGE was unlikely to meet its outcomes. And both trials found a high rate of adverse effects, including fluid buildup in the brain. Thus, both trials were halted in a disappointing day for Alzheimer’s research.

Then, in October of 2019, Biogen issued a press release reversing their position. Their post-hoc analysis (i.e., examining the landed arrows for a pattern after they’ve landed) showed that a subgroup of patients who received a higher dose of ADU did demonstrate statistically significant cognitive improvements relative to a placebo group (who did not receive the drug). Biogen presented this data to the FDA for the drug’s approval.

However, some within the field raised a number of concerns with the process. First, the data presented by Biogen was limited, preventing outside experts from assessing all the information. Furthermore, the data that Biogen did release still failed to prove efficacy, as experts detailed in a paper submitted to the academic journal Alzheimer’s & Dementia. Ultimately, they concluded, “the data from the EMERGE and ENGAGE trials, as presented by Biogen to date, do not support the conclusion that ADU has clinical benefits.”

The authors focused on a number of issues. Among these, they noted that the significant outcome of the high-dose ADU subgroup could just as well be due to a greater decline in that subgroup’s placebo counterpart. In other words, the difference between drug and placebo in this case could either be due to the benefits of high-dose ADU or to the worsening decline of the group it was compared to.

“The key point is this,” they say, “the larger decline in the placebo group in EMERGE is an alternative explanation for statistically significant benefits for high-dose ADU in that trial.”  The only way to find out is to conduct another phase III trial, which Biogen has tried to avoid.

While there’s nothing wrong with the post-hoc analysis conducted by Biogen—it’s a necessary step in finding patterns for further investigation—it cannot prove causation and does not provide scientific evidence for efficacy.

As the aforementioned paper notes, “While it is possible that ADU has cognitive benefits, the data as they exist are clearly insufficient to support a claim of efficacy…even overlooking the distortions introduced by the premature termination of the trials, the finding of one positive and one negative result is a statement of inconclusiveness.”

While the conditions of approval stipulate that further evidence must be collected in postmarket trials, the collection of this data often proves problematic. According to the FDA, the trial must be carried out with “due diligence,” leaving much ambiguity in how quickly they have to be conducted. Exondys 51, a drug approved for muscular dystrophy in 2016, still hasn’t completed its postmarket trials. As with ADU, the FDA’s advisory panel voted (though much more narrowly) against the drug. The panel’s decision was overruled by Janet Woodcock, who now serves as acting commissioner of the FDA.

A company like Biogen has, at best, only a chance of confirming the efficacy of what they’re already selling. If results aren’t favorable, they stand to lose a major source of revenue. Meanwhile, it can be difficult to enroll individuals for the postmarket trial, given that they stand the chance of receiving a placebo instead of a drug that’s already on the market.

With a wholesale price of $56,000 per year, Biogen may have a strong incentive to delay as long as possible. Here, too, the drug has been criticized by experts. According to the Institute for Clinical and Economic Review, ADU would be cost-effective if priced from $2,500 to $8,300, which could lead many private and public insurers unwilling to cover the drug. Others have asked what a reasonable price would be for a drug that actually shows a significant impact on Alzheimer’s, if ADU is already priced so high.

One such contender may be Eli Lilly’s donanemab. The company recently released data from a phase II trial that showed mixed results on par with ADU’s, though without the extensive data manipulations that were needed to support the latter. Furthermore, a larger phase III trial, which is better able to detect drug effects, might show a significant impact of donanemab. Beyond the question of drug pricing, the standard set by the approval of ADU raises the question of whether Eli Lilly could decide to apply for FDA approval through the same mechanism, given the data they’ve already obtained.

Ultimately, the FDA’s decision on ADU will have far-reaching impacts on future research. As another member of its advisory panel said, “if we approve something where the data is not strong we have a risk of delaying good treatment and effective treatment for more than a couple years.”

Moreover, with their disinterest in acquiring basic evidence for the drug, their controversial use of the accelerated approval pathway, and their overruling of a nearly unanimous advisory board vote against the drug, the FDA sets a precedent that could facilitate the approval of more ineffective and harmful drugs in the future.