Everyone agrees that Alzheimer’s Disease is one of the most important areas of unmet need in medicine. No one doubts that a therapy that slows or halts the progression of the disease would have profound positive benefits for society.

Where some people disagree is on exactly what FDA should be doing about it. Within industry, Alzheimer’s is often cited as an example where the agency should be more proactive, creative and flexible in its regulatory standards, and do everything in its power to work with sponsors to approve new therapies based on any glimmer of efficacy.

That is not how Center for Drug Evaluation & Research Deputy Director for Clinical Science Robert Temple sees it. “You just need a drug that works,” he says.

During The RPM Report’s FDA/CMS Summit for Biopharma executives December 11, Temple offered a view that an effective Alzheimer’s therapy should be relatively easy to identify under traditional regulatory pathways—and by implication that recent failed studies suggest that the drugs in question just don’t work, not that there needs to be some rethinking of the regulatory model to create a path to approval.

Temple’s comments were made in the context of a discussion of proposals that cite the challenges in Alzheimer’s drug development as a case where FDA should apply different standards in the approval process, either by being more flexible in using tools like Accelerated Approval or via legislative changes like “Progressive Approval.” ([A#00121224015])

Temple made several important points.

It is not hard to detect very small signs of benefit in Alzheimer’s. In fact, he said, “we are so good at detecting effects of drugs in Alzheimer’s disease, we can approve drugs that hardly work at all. We have, repeatedly”. That reflects the nature of the disease: “Unfortunately for the people who have it, it’s an easy disease to study. It’s progressive. It doesn’t bounce around like depression does very much. It mostly goes downhill and it has been historically easy to detect drugs that work.”
He is skeptical of the idea that an effective drug will not be effective in advanced disease. Temple acknowledged that it is certainly possible that a drug would only work in patients who are not yet symptomatic or at least not severely so—but he noted that in cardiovascular disease, cancer and other drug classes, efficacy has generally been easiest to show in very sick patients. “A lot depends on your belief system. There are people who believe that once the disease is present, you can’t do anything about it anymore. Whether that’s true or not remains to be seen.” The level of benefit may not make much of a clinical difference in patients who have extremely advanced disease, he acknowledged, but it easy to show a treatment effect. In most cases, “it turns out the best people to study are the sickest people.”
A study to show an early effect is relatively easy to design and conduct. Temple suggested that a “takeaway” design would be appropriate, with one group randomized to drug and one given placebo for a period of time (say 12 months) before switching to drug. “If you had a drug that took people with minimal cognitive impairment and lowered the rate of overt dementia at one year from 10% to something lower, it’d be very easy to know that if you could do that.” Also see "Invaluable Guidance: FDA’s Dean of Drug Reviews on “Enrichment Strategies”" - Pink Sheet, 4 January, 2013.
There are not good surrogate markers at this time. The recent clinical trial failures in the space likely make that a non-controversial view.
It is appropriate for FDA to be cautious about approving a drug that would be taking in an “at risk” population with the goal of preventing or delaying the onset of symptoms. Temple noted that calls for the agency to be more flexible about surrogate markers have to be weighed against the likelihood that a drug could in theory be taken by “tens—maybe more—of millions” of asymptomatic people who have a perceived risk of developing Alzheimer’s over a long period of time. “You want to know it is doing more harm than good,” he said. “That is not trivial.”

Temple is not directly responsible for Alzheimer’s drug reviews. However, as the widely acknowledged “dean” of the FDA drug review team, his views have considerable influence inside the agency.

The announcement by Lilly on December 12 that it will proceed with a new Phase III trial for its Alzheimer’s agent solanezumab rather than file based on a secondary analysis from early trials that failed to hit the primary endpoint suggests that Temple’s viewpoint aligns with what sponsors are hearing. Temple’s comments at the conference in effect amounted to a declaration that if Lilly’s drug actually does work, a prospective trial should be able to show it in a convincing fashion. Also see "Lilly Antibody Proves Ineffective In Rheumatoid Arthritis, But Lupus Trials Continue" - Pink Sheet, 14 December, 2012.

A Skeptical Take on Current Alzheimer’s Therapy: FDA’s Temple Says Problem Is Drugs, Not Endpoints

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