CAMBRIDGE, Mass. — Biogen's surprise decision last month to file for approval of its experimental Alzheimer's drug aducanumab will put the Food and Drug Administration in an unenviable position.
By Biogen's telling, one of two identical Phase 3 studies of aducanumab succeeded, showing treatment significantly reduced cognitive decline. That was a striking change from March, when the drugmaker decided to shutter the trial based on an early prediction it would not meet its goal.
But the FDA typically requires two positive, randomized studies for approval. And Biogen still remains one short, as the other Phase 3 test found aducanumab no better, or perhaps even less beneficial, than placebo. That raises the possibility that Biogen has stumbled into a false positive result, a question that the company's top scientist rejected Thursday at the STAT Summit.
"I do think that there are times when a single positive trial is enough for approval," said Chief Medical Officer Al Sandrock. "It is up to the FDA to determine whether this is one of those circumstances."
Sandrock would not reveal, however, whether the company intends to seek a full or accelerated OK from the FDA.
If it's the latter, Biogen would likely be called upon to run another study of aducanumab to confirm the result of the one positive trial, known as EMERGE.
Biogen isn't opposed to doing so, Sandrock said at the meeting, but he cautioned that "it's going to be hard to maintain a placebo-controlled trial if there is a drug approved."
Prospective study participants would certainly have less incentive to consent to receiving placebo if they knew they could take an approved drug for their disease.
Such difficulty, coupled with the statistical uncertainty of trusting data from a single trial, could push the FDA to ask Biogen conduct a second randomized study before any approval.
A decision to do so would be fraught for other reasons, however. No disease-modifying therapies currently exist for the millions of Americans with Alzheimer's disease, likely putting some pressure on the FDA to allow a drug through to market after the first Phase 3 success the field's seen for an amyloid-targeting therapy.
"Here's the decision the FDA is going to have to make," said Sandrock. "Do we believe there is enough evidence to approve it now? Or do we ask the company to do another trial, wait five years and how many people have to get demented in that time period?"
From a less favorable point of view for Biogen, the FDA would run the risk of clearing a treatment that doesn't work, and could end up costing the healthcare system billions of dollars for little or no real benefit. Waiting would allow the FDA to determine more conclusively whether aducanumab is worthy of such expense in money and patient lives.
"Expect a lot of statistical arguments from every side, but we think at the end of the day a marginal benefit, potentially impactful safety effects, numerous conflicting data points and an overall statistical mish-mash is unlikely to lead to regulatory validation," wrote Brian Skorney, an equity analyst at Baird, in a note to investors in October.
The drugmaker has yet to actually submit aducanumab to the FDA, which could decline to review the drug and short-circuit the biotech's unusual bid to win approval. More data from both studies will be disclosed in December at the Clinical Trials on Alzheimer's Disease conference in San Diego.
In selling its decision to investors, Biogen has emphasized that it only decided to file aducanumab following two meetings with the FDA, one in July and another in October. At that second meeting, regulators told Biogen that it would be "reasonable" to submit aducanumab, according to Sandrock.
"I believe the drug works," he said. "This kind of data has never been seen before to my knowledge — in the full data set, all patients, not sub-group, pre-specified primary and secondary endpoints — I don't think you get that just by chance."
Results from the other, negative study, by contrast, follow a pattern of dozens of failed trials testing the same therapeutic hypothesis Biogen was testing with aducanumab. Whether that data outweigh the success of EMERGE will be one of the more consequential regulatory decisions the FDA could make.