A new draft guidance document released by the US Food and Drug Administration (FDA) seeks to provide sponsors with a better understanding of how it intends to regulate drug products that treat a disease that manufacturers and patients alike have long sought better treatments for: Alzheimer's disease (AD).
The guidance, Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease, was released on 7 February 2013.
FDA explained that even diagnosing AD, which is marked by a steady cognitive decline and loss of brain function, can be extraordinarily challenging. At present, most clinical evaluation criteria, such as those developed by the National Institute of Neurologic and Communicative Disorders and Stroke's (NINCDS) Alzheimer's Association, can only detect the disease in the presence of cognitive impairments-too late to prevent much of the disease's onset.
While autopsy or brain biopsy are currently the only two methods capable of showing definitive proof of the effects of AD, FDA noted that a number of biomarkers-levels of f β-amyloid, tau proteins and markers of neuronal degeneration-"have shown some promise" in being able to accurately detect the presence of AD.
These limitations, FDA said, have consequences for the development of new and promising therapies, and in particular ones focused on preventing the onset of overt dementia to begin with.
"The underlying anatomical and pathophysiologic changes in AD begin many years before clinical symptoms emerge," FDA explained. "We recognize that the standard approaches to the selection of outcome measures historically used in the development of treatments for dementia of the Alzheimer's type have major limitations when applied to clinical trials enrolling patients in the early clinical stages of the disease, or before clinical impairment has emerged at all."
FDA said its guidance is intended to showcase some of the ways sponsors might adapt the current standards for the development of most drugs to ones that would "appear more appropriate" for early-stage AD.
Those early stages are often marked by mild cognitive impairment (MCI), though regulators noted that not all patients who have MCI will develop Alzheimer's. FDA took note of several emerging diagnostic tools, and said it "support[s] the concept of enriching trial populations with patients most likely to progress to more overt dementia, using both clinical and biomarker-based criteria."
At this time, however, it said it was unable to specifically endorse the use of any diagnostic frameworks.
Clinical outcomes measures should use a "co-primary outcomes measure approach," FDA said, in which the drug is able to show its efficacy at improving cognitive function and meaningful functional or global assessment measures.
Why the latter, paired measures? "Before the onset of overt dementia … milder functional and/or global impairments become more challenging to assess accurately, especially for patients early in the spectrum of the illness," FDA explained. Regulators conceded that while the "principle" of this outcomes measures holds, its application in practice may be "impractical," particularly if patients were not at a state of MCI closest to overt dementia.
In milder cases of MCI, the former measure-preventing cognitive decline-may be sufficient to show evidence of effectiveness, FDA said.
For patients with advanced MCI, FDA said it recommends evaluation using the Clinical Dementia Rating - Sum of Boxes (CDR-SB) score, which it said was a well-validated tool.
For patients with the earliest clinical stages of AD-and FDA makes the assumption that they are or will be able to be reliably identified-the difficulties of establishing a product's benefits over the course of a trial of "reasonable duration" may be too much to surmount. Regulators said in such cases, it is prepared to use "the accelerated approval mechanism (21 CFR 149 314.510) to consider an effect on a valid and reliable cognitive assessment used as a single primary efficacy measure as support for a marketing approval." Follow-up studies would be required of the sponsor, FDA said.
Regulators added that perhaps the most appealing endpoint for all studies might be the time-to-dementia metric, which would ideally show that a treatment has successfully delayed the onset of AD by a meaningful amount of time.
Sponsors may use a composite scale to show that a product successfully improves cognitive and global functions, which it said would likely allow sponsors to conduct clinical trials that are shorter in duration. "The composite approach also circumvents the inherent challenges of applying a dichotomous time-to-event analysis to two disease stages that in actuality exist on a continuum," observed FDA.
Endpoints: Outstanding Questions
But if sponsors are tempted to use surrogate endpoints-and FDA admitted it's a tempting proposition-regulators urged caution, noting they have concerns that such effects could be reversible. Sponsors will need to take care to show the lasting effects of the product on the progression of AD.
FDA said it will consider drugs tested using only a single primary outcome measured by a biomarker under its accelerated approval program, but said to date, "No reliable evidence exists … that any observed treatment effect on such a measure is reasonably likely to predict ultimate clinical benefit."
" Until there is widespread evidence-based agreement in the research community that an effect on a particular biomarker is reasonably likely to predict clinical benefit, we will not be in a position to consider an approval based on the use of a biomarker as a surrogate outcome measure in AD (at any stage of the illness)," it explained.
Secondary, supportive outcome measures might also be used in combination with these primary measures, it said, though they, too, will need to be validated and appropriate. Other alternative trial designs could also come to be used, but FDA said a randomized-start or randomized-withdrawal trial design appears to be the "more convincing means of demonstrating such an effect" and would be the most ethical trial design as well.
"In this study design, patients are randomized to drug and placebo, and at some point, placebo patients are crossed over to active treatment," FDA explained. "If patients in the trial who were initially on placebo then assigned to active treatment fail to catch up (after a reasonable period of time) to patients who received active treatment for the entire duration of the trial, a disease modifying effect of treatment would have been shown."
Comments on the draft guidance are due by 9 April 2013.