Biogen, fresh off coveted FDA nod for Aduhelm, must now navigate ethics minefield for phase 4 trial

In the confirmatory study, Biogen will need to show that Aduhelm can not only clear beta-amyloid from the brain, but also that this reduction in amyloid correlates with a slowing down of cognitive decline.(kor_el_ya / Pixabay)

After the Aduhelm approval set a precedent for FDA clearance based on surrogate endpoints, all eyes will be on Biogen as it conducts a new trial to prove the therapy is effective in treating Alzheimer's disease in a post-approval environment.

The biotech, luckily, has plenty of time to figure things out.

The FDA green-lighted aducanumab, to be sold as Aduhelm, through the accelerated approval pathway, which allows the agency to base approvals on surrogate endpoints, such as protein levels or tumor shrinkage, rather than a demonstrated clinical benefit, like extending patients’ lives. It’s an option often used to get drugs for cancer and rare diseases to patients sooner, with the requirement that companies conduct a confirmatory study after approval to show their drug actually helps patients. 

In the confirmatory study, also known as a phase 4, Biogen will need to show that Aduhelm can not only clear beta-amyloid—the sticky plaques that are a hallmark of Alzheimer’s—from the brain, but also that this reduction in amyloid correlates with a slowing down of cognitive decline. But that could be easier said than done. 

The confirmatory study is crucial: If Biogen can't prove Aduhelm is effective, the FDA could yank the product from the market.

RELATED: Editor's Corner—The FDA's decision on aducanumab will drag down innovation for years to come 

“The challenges are on both sides, on the pharmaceutical company trying to design a clinical trial and also on the patients,” said Rabi Hanna, M.D., co-founder and chief medical officer of Lamassu Pharma and director of Pediatric Bone Transplantation at Cleveland Clinic Children's Hospital. “How will you design the trial? Will it be a randomized study? And what’s going to be different between this and the phase 3 study that you have done?” 

In a letter approving the application for Aduhelm, the FDA told Biogen to “conduct a randomized, controlled trial to evaluate the efficacy of aducanumab-avwa compared to an appropriate control for the treatment of Alzheimer’s disease.” The trial should be long enough to see changes on an “acceptable endpoint” in the patients participating in the trial, though the agency did not elaborate on what that endpoint might be. 

“Randomization is quite challenging, especially if it’s a life-threatening disease. Patients will say: ‘this is FDA-approved, I have the right to try it, why do I need to enroll in a study that would offer me placebo?” Hanna said. 

One solution might be to conduct that study overseas, where the drug is not yet available. It’s an idea that arose when the FDA authorized COVID-19 vaccines and clinical trial participants who had received placebo became eligible to receive the shots outside of the study.

RELATED: Biogen's aducanumab crosses FDA finish line just in time to save its business 

“Participants [in future trials] might have to be in groups that are not currently eligible for a vaccine or who live in other parts of the world where vaccines simply aren't available,” NPR reported in February. 

That approach may assuage ethics concerns around giving people a placebo when they could be getting a potentially effective treatment, but opens a whole other ethics can of worms around the quick approval of drugs in the U.S. on less-than-solid evidence and pushing the burden of proving they work onto other countries. 

“When you’re running a trial in places outside the U.S. for a drug that is primarily going to be developed and marketed in the U.S., you have to be very concerned about protecting vulnerable populations,” said Charles Binkley, M.D., director of Bioethics at the Markkula Center for Applied Ethics at Santa Clara University. 

“If people in the U.S. refuse to participate because they believe the risk-benefit ratio is too great, [and you find] a group of people who, for other reasons, may not feel that way, you have to be even more careful to protect them and that you’re not exploiting their vulnerability,” Binkley said. 

RELATED: Investor interest in Alzheimer's 'changed on the dime' following FDA's decision on Biogen's aducanumab 

An alternative that would keep the phase 4 trial at home is to use each patient as their own placebo. This would require knowing each patient’s medical history very well and establishing a baseline of cognitive function, Hanna said. Once the patient starts taking Aduhelm, investigators could compare results from tests of cognitive function to this baseline. 

“I see that as more realistic in a medication like this that addresses neurological degeneration than doing it in placebo, which has been the gold standard in the past,” Hanna said. 

Whatever Biogen ends up doing, it has close to nine years to do it. The company has until August 2022 to finalize the trial design and until August 2029 to complete the study, according to the FDA’s letter. The agency expects the final study report by February 2030.

Meanwhile, Biogen plans to sell the drug for roughly $56,000 per patient per year the whole time it’s carrying out this trial, a figure that has drawn fierce criticism even from supporters of the approval. Analysts predict the drug could bring in as much as $10 billion per year for Biogen at peak sales, and will amount to "one of the biggest launches in biopharma history."

RELATED: Biogen's $56K price on Aduhelm 'simply unacceptable,' Alzheimer's Association says after vouching for FDA approval

“We are putting resources and plans in place to complete the post-approval clinical trial as quickly as possible, consistent with FDA guidelines, scientific rigor and our high standards for patient care,” said a Biogen spokesperson in an email. “We’ve started this work with great urgency already. We are committed to completing this trial as soon as possible.”

If you’re feeling déjà vu, it’s likely because we already saw this with Sarepta Therapeutics and the Duchenne muscular dystrophy treatment Exondys 51. In 2016, the drug scored an accelerated approval based on a study with a surrogate endpoint: an increase in patients’ levels of dystrophin protein. As with Aduhelm, the FDA went against an expert panel’s recommendation to reject the drug, though the vote was much closer for Exondys 51. 

The study did not show that the drug improved patients’ motor function or otherwise provided a clinical benefit. Six years down the line, Sarepta still hasn’t completed a phase 4 study confirming that benefit.

Offering patients a drug that is still being studied muddies the line between clinical trial participants and consumers choosing to take—and pay for—the drug.

RELATED: Biogen's high price for Aduhelm—plus the drug's broad label—could trigger drug pricing reform, analysts say

“[Aducaumab has] been approved under the accelerated process but it’s not clear to me that we actually moved these patients from being trial subjects to being actual patients, which has interesting repercussions for ethics in terms of research informed consent,” Binkley said. “Is there going to be a higher standard that physicians are going to need to comply with when prescribing this drug?” 

How doctors prescribe Aduhelm isn’t the only thing Biogen and the FDA will need to keep track of over the next several years.

“My own criticism or wish for that is to be more specific with [a clear] timeline,” Hanna said. “Nine years can be very, very long, so it would be helpful to have a more specific timeline and restrictions on how the drug is being marketed and to be able to have drug monitoring while [the study] is being done.”