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Alzheimer's Guidance Shows Challenges Facing FDA, Industry

By Mari Serebrov
Washington Editor

Much to-do has been made about the FDA's draft guidance on developing drugs for early stage Alzheimer's disease (AD), but some people are missing the point, especially if they think the agency is "loosening" its standards for Alzheimer's treatments, according to an FDA official.

First off, the agency has no standard to loosen for drugs targeting the early stages of the disease, Russell Katz, director of the Office of Drug Evaluation I in the FDA's division of neurology products, said at a webinar last week on the draft that was released in February. So far, all clinical development has focused on patients with more advanced forms of the disease.

Secondly, the key messages of the guidance are the FDA's unofficial endorsement of new diagnostic criteria for identifying patients with early stage AD and the agency's search for ways to assess clinical meaningfulness in patients who exhibit little cognitive impairment, Katz said.

Intended as a conversation starter, the draft lays out a potential approach to select subjects with early AD and those at risk of developing the disease for enrollment in clinical trials. It also addresses possible outcome measures. (See BioWorld Today, March 15, 2013.)

Both elements are critical to designing trials for patients in the early Alzheimer's population, and they both pose challenges to the FDA.

To approve a drug for Alzheimer's, the agency wants to know it's been evaluated in patients who truly have the disease. Mild cognitive impairment (MCI), without an assessment of underlying pathology, has been used to diagnose early stages of Alzheimer's, even though many patients with MCI never move on to the dementia associated with the late stage of the disease.

While Europe recently adopted early diagnostic criteria for AD, the FDA stopped short of officially endorsing specific criteria in its draft guidance. Instead, it urged sponsors to use, on a case-by-case basis, various biomarker-based criteria developed by such groups as the International Working Group for New Research Criteria for the Diagnosis of AD and the National Institute on Aging – Alzheimer's Association working group.

According to the guidance, the FDA can't formally endorse specific diagnostic frameworks yet because of "the need for an assessment of sensitivity and specificity in identifying patients who do have actual AD in clinical trials."

Just as challenging is proposing clinically meaningful endpoints for early stage trials. Drugs tested in patients with dementia have to use a co-primary outcome measure, demonstrating efficacy on both a cognitive and a functional or global assessment scale. However, the results, for the most part, have been disappointing.

"It was too late in the disease process," said Nicholas Kozauer, the acting clinical team leader in the FDA's division of neurology products. "The damage was done."

But moving the co-primary outcome to the MCI stage won't work because patients at that stage have no functional impairment yet, Kozauer said.

A single primary outcome that assesses both cognition and function – such as the Clinical Dementia Ratings-Sum of Boxes – could work for MCI patients approaching dementia, Kozauer said, adding that the agency is open to using other scales.

Because of the evolving nature of the science, the FDA will consider other potential outcomes, including a time-to-event endpoint for a drug intended to modify the disease. The goal is to make sure an approved drug has a clinically meaningful effect on a patient's global functioning. That would be more than remembering an extra word or two from a list, Katz said.

Much of the work done in the Alzheimer's space to date has focused on treating the symptoms, but there is a major shift toward drugs with the potential to modify the disease, Katz said. That shift raises questions about trial designs for such drugs.

A "disease-modification claim would be an extraordinary claim. . . . We're looking for a design that forces that conclusion so we don't have to assume a disease-modifying effect," Katz said.

The guidance also raised the possibility of using accelerated approval for early stage AD drugs. Katz and Kozauer agreed that accelerated approval would most likely be reserved for disease-modifying drugs, as it would be difficult to justify using a surrogate endpoint for symptomatic treatments.

To grant accelerated approval, Kozauer said the FDA would require accurate identification of patients with early AD.

The agency is accepting comments on the draft through April 9, and it could be awhile after that before a final draft is issued, Katz said.