Part 2 - Q&A Session with Dr. John Harrison
This is the second part in the 4-part series 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.
Dr. John Harrison is Honorary Senior Lecturer in the Dept. of Medicine at Imperial College London and Principal Consultant at Metis Cognition Ltd. Metis currently advises more than 40 pharmaceutical companies with the selection and successful integration of cognitive testing into their development programs.
John is a member of the American Psychological Association, holds Chartered Psychologist status with the British Psychological Society, and Chartered Scientist status with the Science Council. He has authored/co-authored more than 60 books and scientific articles, including a popular neuroscience book ‘Synaesthesia: The Strangest Thing’.
In case you missed it, read Part I of this Q&A.
Q: How important is it to start trials in earlier stages of Alzheimer’s disease?
Harrison: It’s absolutely critical, and the entire thrust of disease-modifying drugs is seeking to address Alzheimer’s in the very earliest stages. The big issue at moment is recruiting the right patients, and efficiently administering the work-up that is required to get them in the study. We currently face a situation in which as much as 90 percent of patients that are initially identified as potential candidates are not eligible for the trial. That can get very expensive for a sponsor. This is an area where I see an excellent opportunity for electronic delivery of remote testing. I am convinced the idea of conducting the screening and testing offsite offers a clear opportunity for electronic testing and more efficiently identifying those eligible for the trial.
Q: So in your view what is the path to better, more accurate testing in clinical drug trials?
Harrison: In order to get the very best test we probably need to start from first principles, as the best possible test probably is not yet in existence. I don’t think there is any such thing as a 'magical' test currently for Alzheimer’s. Good tests exist; they just don’t tend to be used for Alzheimer’s drug trials. My advice to sponsors is always to focus on picking a really good test and then quite simply see if it rescues cognition, or at least prevents or reduces any further decline. We know which areas of people’s thinking are compromised in Alzheimer’s so we should pick tests that are focused on those areas of thinking, and then use them to see if we are right in our assumptions about the effect of a certain compound. In the current environment to come up with that ideal test would be a significant challenge – it would be expensive; it would take time; and currently there is not a large appetite for that to occur. The next best move is to make the best of what we have. There are a whole group of established tests for cognition that are not perfect, but they are better than what is being used currently. In the last couple years in particular there has been an enthusiasm to use these tests, which are already validated. So currently we are in a transition phase from using the old, not very helpful tests and transitioning to at least slightly better ones.
Q: And what key measures would a successful Alzheimer’s Disease instrument cover?
Harrison: The important issue is to develop an approach that measures cognition in a way that addresses clinical relevance. We need a validated measure that allows us to reach conclusions about function, as well as cognition. This would avoid the current need for co-primary measures of both cognition and function. One of things we are, as a community, quite good at doing is using cognitive tests to show positive effects of treatment in Proof of Concept studies. If you use sensitive measures, there are instances in which you can measure statistically significant effects, but those are not often particularly big effects. For instance, we might have a trial that yields a statistically significant benefit of treatment, but that might be a .2 or a .3 effect size. In the mind of fair-minded third parties, it is not clear that such a small difference is actually clinically relevant. Specifically, regulators want to see, beyond statistical significance - that the treatment is capable of actually making a difference that is clinically relevant. Today, what we have to do in an Alzheimer's drug trial is show a positive cognitive effect of treatment and then have another metric to show that the benefit of treatment is actually clinically relevant. The Holy Grail for quite a long time has been to find a measure that effectively gauges cognition, but can also demonstrate clinical relevance. We’re not there yet, but if we could achieve this we could move to a single primary measure, which would be beneficial to all involved.
Q: What are some newer or less frequently used tests that currently exist and hold promise as being better measures for Alzheimer’s clinical drug trials?
Harrison: One example is The Free and Cued Selective Reminding Test, in which subjects match certain common items with specific category cues and then are tested on recall. There’s also the Hopkins Verbal Learning Test and the California Verbal Learning Test. These are good measures of cognition and they are the ones coming from what I would call good-old paper-and-pencil clinical psychology. These tests exist; it is just a matter of developing consensus and a willingness to use them in this context. Then there are also significant offerings from the commercial space with at least six companies I know of offering computerized tests that take less time to administer and, I believe, are typically more reliable than some traditional tests. The system offered by Cogstate measures a number of key cognitive functions and is part of three major academic initiatives that I know of. There is real potential here.
Q: The tests you mentioned as possibilities for the future, are they available electronically? If not, do you think they would work in this format?
Harrison: Many of the better cognitive tests are computerized already and many of the current ‘paper-and-pencil’ scales could at least benefit from being computerized. There is a whole host of vendors that already provide rather traditional psychological paradigms as computerized tests. Yet what we have never really done is to use tests that are computer assisted. For instance, with some of these tests we might ask a patient to state as many words he or she can think of that begin with the letter F in the next minute. Currently, the person administering the test gives those instructions, starts the stopwatch, and writes down what is said. Right now, there is no way to do that with a computer, but certainly a test like that would benefit from being computer assisted in terms of ease of administration and accuracy of the results. You could envision other tests benefitting from computer assistance in terms of efficiency. For instance, with word recall tests we typically send people large boxes with white cards and easels with which to administer the tests. This would be so much easier on an iPad. It is remarkable that after 20 years of the ADAS-Cog most people still use flip charts.
Stay tuned for part three of this series.
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