UPDATED: FDA proposes to dramatically lower the bar on Alzheimer's drugs

Just weeks after pointing R&D groups engaged in Alzheimer's drug research to early-stage patients, the FDA is proposing to lower the bar biotechs will have to clear in order to gain an approval. And faced with a string of blockbuster collapses in Phase III, regulators are signaling a greater willingness to offer early, accelerated approvals for the most promising therapies that come out of the pipeline.

Up to now, the FDA has required drug developers to demonstrate improvements in both cognition and function in order for a drug developer to gain an approval. Simply put, patients in the study would not only have to demonstrate improved memory and acuity compared to a placebo group, they would also have to do better at simple daily chores like dressing themselves.

That's proven a devilishly hard target, eluding Big Pharma groups which have poured billions of dollars into new drugs only to come up short on late-stage development. But there's been a growing belief that patients diagnosed with the disease are often too damaged to benefit from therapies. As a result, the FDA has been urging drug developers to move their target to early-stage or high-risk patients, and the agency is now looking to adopt new guidances to assist the biopharma companies on trial designs that can use a new standard focused on cognitive improvements alone or preventive measures proven with biomarkers.

These new standards--initially addressed in a new draft guidance last month--could radically alter the R&D landscape for Alzheimer's drugs, widely perceived as a golden ticket to instant blockbuster status. They could also open a pathway to new therapies that could help millions of patients grapple with a mysterious and terrible disease.

"This is really a huge advance," Dr. Eric Siemers, senior medical director for the Alzheimer's disease team at Eli Lilly ($LLY), tells The New York Times. "Kudos to the FDA."

Lilly ($LLY) is in a position to know. Its drug solanezumab tripped a signal for improved cognition, which investigators found in a secondary analysis of the data. The drug completely failed to hit its endpoints, though, and secondary analysis has always been an unreliable tool to find measures of efficacy. So Lilly was pointed back to the clinic to do another Phase III study. 

But this new proposal from the FDA could make it much easier for Lilly and many others to gather the data needed for an approval.

Andrea Pfeifer

Andrea Pfeifer, the CEO of AC Immune, which is collaborating with Genentech on an ambitious early-stage program, tells FierceBiotech that she applauded "the FDA's  commitment and efforts to target patients at an early stage of Alzheimer's disease which should lead to innovative trial design; it is also a big step forward towards much needed prevention and early stage treatment. The agency recognizes the regulatory hurdles in the absence of valid biomarkers in that early patient population. Now global efforts across industry, government and academia are needed to identify validated biomarkers in this early stage population and translate those biomarkers into functional endpoints."

Writing in the New England Journal of Medicine, the FDA noted that "the premise that effective cognitive improvement will be manifested in the functional assessment of patients is untenable in the case of early-stage Alzheimer's disease, which is increasingly the target of drug-development efforts. We simply do not yet have drug-development tools that are validated to provide measures of function in patients with Alzheimer's disease before the onset of overt dementia."

"For patients whose disease is at an even earlier clinical stage, so that functional impairment would be more difficult to assess, it might be feasible to approve a drug through the FDA's accelerated approval pathway on the basis of assessment of cognitive outcome alone.The accelerated-approval mechanism allows drugs that address an unmet medical need to be approved on the basis of a surrogate end point or an intermediate clinical end point (e.g., a sensitive cognitive measure), with the stipulation that postapproval studies will be conducted to verify the clinical benefit. Such a regulatory process may hold promise for facilitating the approval of treatments that appear to be effective in early Alzheimer's disease, when patients might be expected to derive the greatest benefit."

- here's the column from JAMA
- read the report from The New York Times

Special Reports: The Top Phase III Disasters of 2012 | The Alzheimer's pipeline: What's next?

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