Dan Gorenstein: Any day now, the Food and Drug Administration will decide the fate of a hotly debated, highly anticipated new Alzheimer’s drug.

The stakes are high.  

Nearly 6 million Americans are affected by this devastating disease.

Drug maker Biogen stands to make billions…with taxpayers footing much of that tab.

And then there’s the FDA’s reputation as the nation’s watchdog on drug safety and effectiveness.

It’s all on the line with this new drug.

Today, our 100th episode, the costly and controversial medication that’s got the FDA under fire from all sides, and the crisis it could cause. 

From the studio at the Leonard Davis Institute at the University of Pennsylvania, I’m Dan Gorenstein, and this is Tradeoffs.

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DG: The FDA has until June 7th to decide whether to green light the new drug known as aducanumab. An approval would bring the first novel Alzheimer’s medication to market in nearly two decades. And it would also shock, even disappoint, many experts, including Caleb Alexander.

Caleb Alexander: Professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health

DG: Caleb studies drug safety and efficacy, and he serves on the FDA advisory committee that’s reviewed this controversial new treatment.

Okay. So alright, Caleb, catch us up to speed. This company, Biogen, set out to test a new drug for Alzheimer’s. What was Biogen hoping this drug would do?

CA: Well, like any company bringing a new product to market, Biogen was hoping for good news. And in this instance, that means evidence that the product aducanumab results in significant improvement in the severity of symptoms of dementia among individuals with Alzheimer’s disease. It’s been remarkably difficult to identify treatments that significantly stall, let alone halt the progressive, inexorable decline that we see in individuals with this particular type of what’s called neurodementia.

DG: And so Biogen is dreaming big here, thinking they potentially are on the cusp of a groundbreaking treatment for a devastating disease. And the company puts the drug to a test in two randomized trials. At a super high level, Caleb, what did Biogen find from these two trials?

CA: Well, the first trial suggested that there was no benefit of the drug and the second trial raised the possibility that there might be some benefit of the drug. So the trials yielded conflicting evidence. There was some suggestion of benefit. And the key question for regulators such as the FDA is, you know, are the trials convincing? Are the trials enough to move this forward, to move this product forward to market?

DG: How is it possible for two trials of the same drug to have two different results?

CA: Well, that’s a great question and it does seem a little perplexing that one trial would suggest that the drug doesn’t work and the other trial might provide some evidence that it may work. So if the trials were conducted in different populations or using highly different exposures or different levels of the drug or different length of follow up or different methods of assessing the outcomes, it might make sense that the results are conflicting. But what’s more curious in this instance is that the trials were very, very similar.

DG: It’s worth noting here that the conflicting evidence isn’t the only unusual thing about these trials. Biogen halted the trials midway through — back in March 2019 — because the drug had failed to significantly delay cognitive decline.

Six months later, the company made an eyebrow raising U-turn, announcing they had analyzed additional data indicating the drug might actually work. But in November 2020, the FDA advisory committee Caleb sits on found that new evidence insufficient by a vote of 10 to nothing, with 1 person uncertain.

How far away is the evidence from aducanumab from the FDA’s usual bar? Is it close or are we talking, like, radically insufficient here?

CA: Well, I don’t think this is a tough call, if that’s what you’re asking. I mean, you know, I’ve sat on many of these committees and I can tell you, this is not a typical, ‘You know, this part looks good. There’s some questions here.’ I mean, we are not sitting right on the fence. I can assure you that. And frankly, that was reflected by the near unanimity of the advisory committee that I sat on. There simply is a big, big distance between the typical evidentiary threshold that’s met and the totality of evidence for this product.

DG: So it is not clear that this drug aducanumab works. However, one of the two randomized controlled trials suggests that there is some positive benefit here. Going off the results from that, how much of a clinical benefit is there, Caleb, to this drug, if it in fact does work? 

CA: What we know from this one clinical trial where one of the two treatment arms did show a statistically significant effect, is that if the drug works, its effect in slowing the inevitable progression of Alzheimer’s disease is actually quite modest. In other words, we’re not talking about reversing Alzheimer’s. We’re not talking about halting Alzheimer’s. We’re talking about very modestly slowing the decline of Alzheimer’s relative to what may have occurred without treatment.

DG: Biogen said the drug may preserve certain abilities for some people by about seven months. Experts, including Caleb, say the benefit looks even smaller when cognitive decline is assessed in another way.

After the break, the case for approving this drug even if it offers little help…and the major costs that it could carry.

MIDROLL

DG: The FDA is under immense pressure from all sides in advance of its June 7 deadline to approve or reject aducanumab, a drug that could help millions of Americans with mild Alzheimer’s and other cognitive problems.

Some of the loudest voices pushing for the drug’s approval, despite its mixed evidence, are Alzheimer’s patient and caregiver advocacy groups. It’s a case they made passionately in November 2020 at a meeting of experts advising the FDA on this decision…

Montage of patient advocate testimony from November 2020 FDA meeting: We are asking you from the bottom of our hearts to consider bringing aducanumab to market. // Those who are eligible must be given the chance to buy time. The unmet need is obvious. Please take every measure to bring this therapy forward. // After years of great disappointment and drug trials, for those in the throes of urgency as our minds decline, please offer us some hope. // I urge you to vote for hope over despair. I urge you to recommend approval of aducanumab.

DG: Among the experts on that committee was our guest today, Johns Hopkins professor Caleb Alexander.

Many advocates who testified at that meeting argued that Alzheimer’s is such a bad disease with so few promising drugs, why not try? Caleb, I’m curious, what are the risks and benefits of that approach? 

CA: I understand the appeal of saying, ‘Let’s just get this thing out there, people are desperate. We don’t need the government to come in heavy-handed and decide what drug, you know, my mom or dad or grandmother and grandfather should be able to access.’ There are many individuals who would be willing to assume the risks, presumably well-informed. And there could be, I presume, potential real benefits in terms of the, you know, market effects in terms of just putting wind in the sails for further investment and so on and so forth. But that’s not our system of drug regulation. And it’s not the one that I would want to live in, although I understand fully the desperation and urgency that is felt so palpably by millions of Americans. But, you know, at the end of the day, there’s a bar that products have to be able to get over before they’re allowed to be sold on the market.

DG: And what are the risks to this approach, the like, let’s just give it a shot, people are desperate out there?

CA: Well, I think that there are enormous risks. The first and most fundamental is that it would undermine or threaten to undermine our system of drug regulation in the United States. So I think there’s enormous risk in terms of the precedent that it would set for what constitutes enough evidence to bring a product to market. There are also risks with respect to how it might disrupt further research to develop treatments that clearly are safe and effective. So, for example, individuals who are offered this treatment may be less likely to participate in clinical trials of the next potential treatment. There would also be risks in terms of the risks that patients and caregivers would take in using this product.

DG: Now, it’s up to the FDA to decide by June 7th whether the fact that November no vote from its advisory panel, which is nonbinding, or go against that recommendation. But it’s not just a simple yes-no decision, right? Can you lay out the possible scenarios?

CA: Well, the FDA could allow the product to be approved, they could approve it with conditions. If the FDA were to kick the can down the road further, they could do so stipulating the sort of additional information that they would like to see. Or they could reject the application altogether. 

DG: Caleb, at a higher level, this decision is about a lot more than just this one drug. It could have a ripple effect on how both pharma and the FDA approach drug development going forward. There are some people who are supporting the approval of the drug that say if the FDA doesn’t approve it, it’s going to have a chilling effect on drug makers who are going after hard diseases like Alzheimer’s, like certain cancers. On a personal level, that strikes me as a little bit hard to believe because Alzheimer’s is such an important medical problem, I mean, if they land this big fish, it’s going to be worth a lot of money.

CA: Well, I don’t disagree, I don’t disagree. Listen, I mean, an approval here, would be a grand slam for Biogen. And it simply, you know, manufacturers aren’t naive. They expect to fail some and many of them fail often. And it’s not as if failure isn’t an integral part of our drug development system. Of course it is! So I simply don’t buy it. I mean, most folks that I’ve spoken with from pharma on the commercial side agree with me that the evidence simply isn’t there at this time for this product. I see it as terribly consequential. I don’t see it as terribly controversial in that I think that the evidence is actually quite clear.

DG: There are, of course, massive financial stakes here for Biogen, Medicare and patients. And the confusing clinical data clouds this picture too, right? I mean, we’ve seen estimates of a fair price range anywhere from $2,500 to $50,000 a year. 

CA: Right. 

DG: But that’s not the only cost if the drug is approved. I mean, there’s potentially expensive PET scans and monitoring that goes into this…

CA: So I think it is very important to think about, you know, there’ll be both the direct costs of the product, which, as you point out, estimates of what a fair price is, quote unquote, vary enormously, which I think reflects some of the sort of murkiness of the evidence around the product, and then all the potential indirect costs. If the coverage and reimbursement is limited or if the product is treated in such a way that there are high copayments or high rates of coinsurance, or if patients ultimately or their caregivers shoulder the burdens of the downstream costs there could very well be high levels of financial toxicity. 

DG: Aducanumab hitting the market could be a significant stress on federal health spending. 

In a JAMA Health Forum editorial, insurance executives from Humana estimated…with many caveats…the drug’s total costs, including tests and everything else, could run up to $360B per year. That is more than a third of Medicare’s total spending.

At the same time, other estimates suggest that Alzheimer’s costs the country about $500 billion a year, a toll that will just keep climbing.

How much of a dent aducanumab would make in that is unclear…a fact the drug price analysis group ICER emphasized in their recent report using the words “uncertain” or “uncertainty” 32 times.

I’d like to go back to the FDA advisory committee meeting that you were at. It featured some very emotional testimony from people affected by Alzheimer’s…

Montage of patient advocate testimony  from November 2020 FDA meeting: Simply put, Alzheimer’s has turned life upside down for me. // I have lived deep inside the cruel labyrinth of this disease // The disease took my maternal grandfather, my mother, paternal uncle, Then it came for me. // My diagnosis of Alzheimer’s has shattered my world, taken away my freedom and my ability to work, and it will eventually rob me of my ability to think or to remember // For us, waiting for perfection is not an option. We’re losing the ability to recognize our family members now. We are losing ourselves now. We simply can’t wait.

DG: Here you are. You’re looking at the evidence. That’s why you’re there. That’s why you’re sitting on this panel. And it’s very clear to you, overwhelmingly, this drug is not ready for prime time. Simultaneously, you were hearing these stories. How did it feel staring at the data that you have very real, serious qualms about?

CA: Well…when I’m in an advisory committee meeting, I am trying to be of service to the US Food and Drug Administration and the constituents that that the FDA serves. And so my North Star is always the science and the evidence and the totality of evidence. And so, you know, it can be difficult to to to hear testimony, especially testimony that’s so candid about the ways that a disease has affected one’s life or that of a loved one, or to hear such heartfelt requests to suggest that the FDA approve a product when I may not feel that it’s ready that the evidence is there. But it’s helpful to me to keep in mind my role, which is as a consultant to the FDA, to assist them with the regulatory decision that they face.

DG: How would you make the case to the widow, the 70 year old with early onset Alzheimer’s, it’s for the best to dash the hope today and that dashing hope today promises a better tomorrow? How do you make that case?

CA: Well, what I would say is that there are enormous efforts being undertaken to identify safe and effective treatments and I also think that we’ll get there. And when products come before the FDA, we have to be sure that they meet a certain threshold of safety and effectiveness. That’s a fundamental part of our system of drug regulation. I think it’s also important to note that these types of treatments, certainly aducanumab, if we assume it has the effects that it could possibly have based on, you know, this partially successful clinical trial, that these are only one small piece of improving the lives of those with Alzheimer’s disease, and we need to be sure that in pursuing these treatments, we don’t lose the forest for the trees. And we recognize the importance and the value of many, many other dimensions of care that are important for aging individuals and their loved ones.

DG: Thank you very much for taking the time to talk to us on Tradeoffs, Caleb. I appreciate it very much. 

CA: Thank you.

DG: A quick note before we sign off today. 

This is Tradeoffs 100th episode. We’ve come a long way since those first few stories in October 2019, and on behalf of the team, I just want to say thanks for listening. And we’re excited to commemorate the next 100!

I’m Dan Gorenstein…and this is Tradeoffs.