On February 5, 2013, FDA announced the availability of Draft Guidance relating to the development of drugs for the treatment of early stage Alzheimer’s disease. The Draft Guidance, titled, “Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease” addresses: (1) diagnostic criteria for early stage Alzheimer’s disease; (2) appropriate clinical outcome measures; and (3) ways to demonstrate disease modification. Addressing these issues in early stage Alzheimer’s disease poses unique difficulties, because patients may have little to no impairment of global functioning. FDA is seeking public comment on the Draft Guidance within sixty days.
The Draft Guidance provides FDA’s current thinking on useful diagnostic criteria for early Alzheimer’s disease. FDA cited useful research in developing diagnostic criteria, such as the research criteria for prodromal Alzheimer’s disease and preclinical Alzheimer’s disease. Specifically, FDA also cited as useful efforts by the research community to incorporate biomarkers into the diagnostic criteria. FDA concluded that, “we support the concept of enriching trial populations with patients most likely to progress to more overt dementia, using both clinical biomarker-based criteria.” FDA also indicated, however, that FDA could not formally endorse any specific diagnostic framework, because more work was necessary to assess the specificity and sensitivity of these criteria, as well as the validation of these methodologies.
The Draft Guidance also provides FDA’s current thinking on ways to establish clinical efficacy in trials involving patients suffering from early stage Alzheimer’s disease. While FDA requires a co-primary outcome measure to demonstrate efficacy on both cognitive and functional levels for clinical trials on the dementia stage of Alzheimer’s disease, in the draft guidance, FDA acknowledged that these endpoints may be impractical for patients suffering from early stage disease. Therefore, FDA indicated that for early stage disease “clear evidence of an effect on delaying cognitive impairment may provide sufficient evidence of effectiveness.”
Specifically, FDA indicated that it would be appropriate to use a composite scale, such as the Clinical Dementia Rating – Sum of Boxes score (CDR – SB), which assesses both cognition and function as a single primary efficacy outcome measure. FDA also indicated that it would use the accelerated approval mechanism (followed by additional post-approval studies) because, for patients suffering from only subtle cognitive effects (but no functional impairment), “it would be difficult to establish a clinical consequence of any cognitive benefit during the course of a trial of reasonable duration.” Finally, FDA stated that a time-to-dementia diagnosis approach was “particularly appealing” but that a single composite scale assessing cognition and function may be “more attractive,” because it would allow for shorter and smaller trials.
FDA also described its current thinking for evaluating claims of disease modification. While FDA recognized the appeal of using divergence of slopes between treatment arms as evidence of disease modification, FDA remained concerned that this would not distinguish pharmacologically reversible effects that increase over time. FDA recognized that biomarkers for Alzheimer’s disease have been the subject of intense study, but nevertheless there was no consensus that any particular biomarker was reasonably likely to predict an ultimate clinical outcome. That being said, FDA indicated that disease modification claims could be supported by: (1) evidence of meaningful effect on a biomarker coupled with clinical benefit, or (2) clinical demonstration of lasting effect on the disease course.