Q&A session with Dr. John Harrison
This is the beginning of a series of blog posts written following a Q&A session with Dr. John Harrison. During our conversation with Dr. Harrison we discussed the current problems with Alzheimer's Clinical Trials and the reasons behind the very low success rates for treatments. We then talked about some of the better instruments that can be used and how technology will help to turn the situation around in the future.
Part 1: Current problems in Alzheimer's clinical drug trials
Q: What is your assessment of the current testing environment for Alzheimer’s clinical drug trials?
Harrison: To be candid, we seem to be saddled with several outcome measures that are used more based on tradition, rather than having any significant effectiveness attached to them. There seems to be a belief that we have to use these scales simply because they have always been used. Yet the reality is very few drugs have been registered to treat Alzheimer’s using these outcome measures. When we have a new drug for Alzheimer’s we assume it will either rescue or prevent declining cognition -- and almost always that is focused on memory. So all we have to do after that is find a way to test memory and see if we are right. Yet largely because of the limitations of these common outcome measures, that is not how it has worked. We have measures that were really designed for other purposes that we are trying to shoehorn into clinical drug trials, this has been a very unsuccessful ambition. Likely one of the major drivers toward new instruments will be that an appetite for new measures will grow as current or future trials continue to fail. I think the community will end up using these new instruments just because everything else has failed them.
Q: One key issue appears to be coverage – the types of cognitive function that are measured by these commonly used tests. What is your perspective on that challenge?
Harrison: There really is a significant gap in terms of the breadth of coverage with the current tools. With Alzheimer’s the problem that most patients or caregivers notice first is their poor memory. That’s the likely reason that most come to the clinic, so we traditionally have viewed Alzheimer’s as a disorder of memory. Yet we now know it is much more than that. It is not just memory that is impaired with Alzheimer’s, it is a full range of functions including: response time, executive function, how well a patient pays attention, his or her ability to organize their time or to make plans. These functions and capabilities are not measured by the ADAS-Cog, which was designed as a measure of memory, praxis and language. So you may have a really good drug with potential to help people pay attention, help them concentrate better, or help their executive skills but the tests we are using are not providing coverage in those areas. If a drug could have even a modest effect on those skills it would be significant, but that hasn't been measured. We are missing out on considerable opportunity to help address some of these issues. Consider this: We had a Europe Task Force for Alzheimer’s and when we discussed what areas of cognition we should look at with Alzheimer’s we had an easy consensus -- working memory, episodic memory, and executive function. Well, only one of those – episodic memory -- is measured by the most common clinical trial test, ADAS-Cog. The assessment I recommend actually takes less time than the ADAS-Cog and gives you much better breadth of coverage. It’s all very doable; you just have to fish outside of the usual box and get better tests.
Q: So then what particular instruments do you feel should no longer be used in Alzheimer’s Disease trials?
Harrison: The ADAS-Cog and the MMSE for sure. Also we should consider doing away with other tests for which we don’t have or can’t find qualified and experienced raters, such as the Clinical Dementia Rating Sum of Boxes (CDR-SB). With respect to the ADAS-Cog, we are, as a community, mostly convinced that is not the test we should be using. The MMSE is also not very useful. It was designed in 1975 as a bedside test of cognition that junior interns could administer. It is designed very purposely to be fabulously brief, and it is very insensitive. It really doesn’t meet any of the usual standard criteria we would ask of an instrument like this. More by accident than by purpose, it started being used as a way of grading Alzheimer’s patients and in nearly everyone’s view, it does so very badly.
Stay tuned for part two of this four-part series - please feel free to share your comments.
Associate Director of Marketing, CRF Health
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