Shifting paradigms in Alzheimer’s disease clinical trial methodology

February 7, 2014 John Harrison
describe the imageThe past few months have witnessed some very interesting developments in the sphere of Alzheimer’s disease clinical drug trial design. A very significant development was the publication of a concept paper for discussion by the European Medicines Agency.  The paper raises three key areas for consideration and discussion:
  1. New research diagnostic criteria  used in clinical trials for different stages of AD
  2. The potential use of several biomarkers in the different stages of drug development
  3. The use of appropriate outcome measures with adequate clinical relevance to be used at any stage of the disease continuum

Items 1 and 3 are clearly of critical interest to those of us concerned with cognition testing, but after recent presentations at other Alzheimer’s disease events, so too is item 2.

Diagnostic criteria for Alzheimer’s disease have routinely specified evidence of impaired cognition. Impaired performance on a standard measure of episodic memory was a requirement of the 1984 NINCDS-ADRDA criteria and more recently a feature of the ‘Dubois criteria’. Efficacy measures for detecting cognitive effects have tended for the past 20 years to be limited to use of traditional measures such as the ADAS-cog.  A number of commentators have been critical of its use, but it is only recently that its inadequacy has been highlighted.  The event that caused this revaluation has been the desire of opinion leaders and sponsors to treat patients earlier in the disease course, and if possible whilst at risk of progressing to meet diagnostic criteria for Alzheimer’s disease.  The thesis under examination is that amyloid is a key cause of Alzheimer’s disease but that patients in the mild-to-moderate stages of the disease (the typical drug trial cohort for investigation) are too far progressed to benefit from anti-amyloid treatments.  The solution therefore is to look to secondary prevention by dosing individuals in the prodrome of the disease.  The problem with using the ADAS-cog in a prodromal cohort is that of the 12 most popularly used subtests, the vast majority of a prodromal cohort will perform at ceiling on 9 of them. This has induced sponsors to consider alternative assessments, such as the Neuropsychological Test Battery (NTB) and novel cognitive composite scores, such as the one employed by EnVivo Pharmaceuticals in their recent trial.

A number of possible composite measures were presented and considered at the recent Clinical Trials for Alzheimer’s Disease held in San Diego.  The proposed measures were a blend of traditional measures used in novel combination, traditional measures augmented with previously unused tests and, on occasion, computerised tests used across the internet or delivered by local computer hardware. However, no clear candidate measure has emerged as the preferred or even most sensitive measure.

A further interesting facet of the CTAD meeting was the remarkable key note presentation by Prof. Paul Aisen entitled ‘Toward Effective Alzheimer’s Therapy: Progress and Collaboration’.  Prof. Aisen is a highly respected opinion leader in the field of Alzheimer’s disease and a key theme of his presentation was the potentially useful role and importance of cognition as a biomarker in Alzheimer’s disease. Biomarkers have traditionally been thought of measures of brain size or function, and as ‘wet’ assays of biology, such as CSF levels of amyloid protein.  Professor Aisen’s widening of the biomarker category to include cognition was to many of us a very welcome development. An issue with many of the biomarkers we consider in Alzheimer’s disease is whether the observed change has clinically meaningful impact.  Changes in cognition are much more clearly linked to functional changes, and are consequently a potentially far more relevant marker. 

So, all three components of the problem statement included in the EMA concept paper include reference to cognitive assessment.  I’ll be suggesting a focus on the cognitive domains of episodic verbal memory, working memory and executive function, in line with the proposals made at the European Task Force meeting back in 2008. I’ll also be suggesting that the agency permit the use of any test that meets best practice requirements, rather than specifying the use of particular test. After all, what we do in clinical trials of new compounds for Alzheimer’s disease is actually fairly straightforward.  Our hypothesis is that the compound either rescues cognition, or prevents further decline.  All that science requires we do thereafter is to pick a good measure of cognition with which to test our hypothesis.

A good deal of cognition testing is now carried out using either computerised testing or computer-assisted technology, both in the detection of cognitive deficits and in studies of putative new compounds. Such technology can significantly reduce the burden placed on patients and study teams alike, simplifying the site visit process and improving the quality of data captured while guiding patients through complex questionnaires.

Best Regards, 

John Harrison, PhD
Scientific Consultant, CRF Health

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