BIOtechNOW delves into the current state of Alzheimer’s disease research with today’s feature on regulatory challenges. Tomorrow, we cover the first Alzheimer’s prevention trial, and on Wednesday, we will explore the societal and economic impact of this devastating disease.
The therapies currently approved for Alzheimer’s disease work by treating the patients’ symptoms, improving their cognitive and overall functions. Increasingly, however, experts are intent on slowing or halting the disease process—before it has ravaged patients’ brains. In February, the U.S. Food and Drug Administration (FDA), released draft guidelines summarizing the agency’s current thinking on identifying and evaluating patients with very early Alzheimer’s disease (AD) in clinical trials, who may not be showing symptoms. The draft guidance also discusses how a treatment might be able to be shown to slow the progression of AD, as opposed to just having an effect on symptoms.
BIOtechNOW Event Daily asked Russell Katz, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research more about the guidelines. Here’s (an edited transcript of) what he said.
Q:What are the major regulatory challenges facing Alzheimer’s research, and how do these new guidelines help?
Now, we believe we are able to identify patients with AD so early in their course that they have no, or very little, impairment in their functioning. This raises the question of what the standard should be, then, for approving a drug for these patients. That’s the primary regulatory challenge that the guideline was designed to address. In the guideline, we say that in patients who have very mild cognitive impairment, we might be able to approve a treatment based on its effect just on a cognitive measure and not on a functional measure. For those patients who have very mild impairment of function, a single measure that combines aspects of cognition and function would be acceptable.
The other regulatory challenge in AD and other degenerative diseases, is how do you distinguish an effect on symptoms from an effect on modifying the disease itself. The guidelines talk a bit about that. One approach is a randomized-start or randomized-withdrawal design. We think the design itself—although complicated to do—could distinguish between a symptomatic and disease-modifying effect.
The other approach is the combination of change on a clinical outcome and a change on some biomarkers, whether it’s imaging of amyloid in the patient’s brain or spinal fluid biochemistry changes, or perhaps something else. So we said we’d entertain that as possibly showing an effect on disease modification.
Q:Have the advances in biomarkers caught up
to this new guidance?
A lot of data is being generated on changes in imaging biomarkers before patients really become clinically significantly impaired, and there are many ways people will use these findings. For example,
there’s been a lot of great work done in identifying patients early based on these biomarkers. We tell sponsors, ‘You should be enrolling those people who have these changes in your trials.’ The field has several proposals that include clinical findings and biomarker findings as research criteria to identify these patients early.
That, at the moment, is the primary use for these biomarkers. We also say in the guidelines that we are not prepared at this point to rely on a drug’s effects on those biomarkers alone as supporting a drug’s approval, because we don’t know the relationship between a drug-induced change on any of these biomarkers and the patient’s clinical status.
Q:What does a “valid” biomarker mean to you
in the context of disease modification and these
A valid biomarker is one for which we have evidence that a drug-induced change in the biomarker will be reflected in a clinical benefit to the patient. If a treatment were to decrease the amount of amyloid in the patient’s brain, for example, and also be shown to have a clinical effect that was meaningful, then that would be part of the process of validation.
It would be very useful to have a lot of different treatments show that when they make the biomarker better then the patient gets better. That’s true validation, and we’re not there yet.
The law permits us to approve a drug based on an effect on a biomarker that’s what’s called “reasonably likely” to predict a clinical benefit. In other words, we could approve a drug based on an effect on an unvalidated biomarker, but we don’t believe we’re there yet either. Let’s say we improved the amyloid imaging biomarker — we don’t believe we know enough to say that that’s reasonably likely to make the patients better clinically. That’s what the [draft] guidance says, and maybe people will have something to say about that.
Q:What does “reasonably likely” mean? What sort of evidence would you need?
I think we’d have to have some evidence, maybe in one study for one drug, but not definitive evidence—at least—that shows that when you made the biomarker improve you also made the patients better. Until we have that information, or until we learn enough about the disease to say, ‘Yes, we know anything you do that improves this particular biomarker is very likely to make patients better,’ until we have that kind of understanding of the disease, which at the moment we do not have, we’d be reluctant to approve a drug just on the effect on a biomarker.
Q:The draft guidelines also note that a traditional parallel-arm study might not be the best way to show a disease-modifying effect of a treatment and that a randomized-start trial would instead be better. What are the challenges of this alternative design?
If a sponsor could do a randomized start design trial, we think more or less the only reasonable interpretation would be that the drug was having an effect on the underlying disease and not just symptoms. But it’s a complicated design to do. It’s typically long. People drop out, and that’s a particular problem for a study like this. The study has to be of a sufficient duration to be able to tease out the symptomatic effect from the underlying disease progression
We still think if such a trial could be done the right way, it would be a useful design. We have to admit, though, that we don’t have a track record of these studies having been done. However, if we had an example of a drug that made the biomarker better and also the patients better clinically we would entertain that as possibly showing disease modification.
Q: What are your thoughts for the future of Alzheimer’s disease treatment? What about prevention?
We’re much further along in understanding the disease and coming up with drugs that we think are actually targeting the underlying disease. When will we have a treatment that slows the progression of the disease? It’s hard to say. I’m certainly optimistic. But I don’t think it’s going to happen tomorrow. But as you know, the National Plan calls for the availability of such a treatment by 2025, and we hope it can happen sooner. But we’ll need the evidence.
Prevention is a tricky matter. It’s not clear how you would design a trial that would actually prove prevention. But of course it’s what everybody wants. We would love to have a drug that delayed the onset of the disease. That would be fantastic. But that’s not the same thing as prevention.