Continuing the ADAGIO discussion and its impact on clinical trial strategies

Dr. Schwarzschild's analysis is very interesting and raises in my mind another key issue with interpreting these kinds of clinical trials results. How do you define clinically meaningful benefit from a statistical effect size? The 5-8 point change in ELLDOPA vs. 1-2 point change in ADAGIO that Michael mentions seems certainly a big difference, but what did that mean for overall subject well being? I'm curious if the same analysis shows similar differences if you looked, say, at Activities of Daily Living or other quality of life-type scales?

Michael also points to an issue that I raised in my question #4: if clinicians do start giving drugs like rasagiline (and even levodopa?) earlier in the disease course, this will clearly impact the kind of subject that can be used in clinical trials. Inclusion criteria for trials may have to take this into account as it will become harder and harder to find these early 'untreated' subjects that to date have been so valuable for testing novel disease-modifying drugs. The MJFF is currently providing funding support to the clinical trial being run by Dr. Schwarzschild to test a urate-elevating strategy (inosine) in people with PD as well as another 'neuroprotective' agent, isradipine, in a trial being coordinated by Dr. Tanya Simuni at Northwestern University. These two trials, along with the ongoing Phase III trial of Coenzyme Q10, will likely all be impacted by potential challenges of finding early PD subjects who have not yet begun PD treatments.

And in the absence of a 'home run' therapeutic that basically stops progression in its tracks, realistically we will likely see more and more therapeutics that meet statistical thresholds for showing a disease-modifying effect in current clinical trial designs even if the clinical benefit is uncertain. So again the question appears to be: How do we deal with that reality? It's hard to deny people a drug (so long as it is safe) that 'might' have disease-modifying potential, but if the danger is that you will then squash future attempts to develop and test even better drugs, we will need to come up with strategies to deal with this in how clinical trials are designed and run.

Again, I invite the community, including those of you involved in running or designing PD trials, to add your thoughts to this discussion.