If you’ve been disappointed with the long intervals between my posts over the past few months (and I hope you are), there’s a reason.  I’ve been using much of my discretionary sitting-at-the-computer time writing a long review article on clinical trial design in PSP.

The editor of the journal Alzheimer’s and Dementia: Translational Research and Clinical Interventions invited me to write something on PSP for a special issue on a trial outcome measure called “minimum clinically important difference.”  The MCID is the smallest change in an existing, validated, accepted clinical rating scale that can be perceived by the patient as making a difference to their everyday level of disability or quality of life.  An alternative definition I’ve seen is the smallest difference that would prompt the clinician to recommend a change in treatment. The MCID has never to my knowledge been used in PSP trials, though for over a decade it has served at least as a secondary measure in trials in other conditions, including Parkinson’s disease. 

The most widely accepted outcome measure for PSP clinical trials is still the original, 28-item version of the PSP Rating Scale, which uses a point scale of 0 (best) to 100 (worst). But the original PSPRS been criticized, most prominently by the FDA, as too dependent on the neurological examination, with insufficient attention to the patient’s daily life. The European Union’s equivalent of the FDA, the European Medicines Agency (EMA), still prefers the original PSPRS. (Disclosure: I developed the PSPRS and receive a share of its licensing fees from Rutgers University, the scale’s official owner.)

I collaborated in this writing project with Ronald G. Thomas, PhD, a biostatistician at UC San Diego.  We calculated an MCID for PSP using data from the placebo groups of five published, 12-month double-blind clinical trials.  I won’t get into more details lest I plagiarize myself or invite scoops, as the manuscript was submitted only a couple of weeks ago and has not yet cleared peer review.  But I can tell you that the MCID is only a small part of our paper, which discusses many aspects of PSP trial design with an eye toward allowing trials to enroll participants faster and to become smaller, cheaper, shorter, and easier for the patient and caregiver.

Aside from obvious the patient/caregiver consideration, why is all this so important?  Because we need to lower the bar for small pharma or biotech companies to try their new drugs in PSP. One obstacle is the cost – fewer patients and shorter trial durations are simply cheaper.  Another is that during a trial, the clock is ticking on the drug’s patent protection.

A very interesting outcome of the calculations Dr. Thomas performed for our paper (again, provisional pending peer review) relates to the number of participants required for a PSP “futility trial.”  That kind of trial typically uses controls from previously published sources, thereby reducing recruitment time and costs.  It is designed to determine relatively cheaply if a drug should be abandoned or it’s worth testing in a formal, expensive, traditional trial meeting government requirements for potential approval.  A small company whose futility trial “rules out futility” (to use the formal, statistical term for success in this context) could find it easy to license or sell that drug to a larger company or to attract venture capital for a large trial of its own.

Dr. Thomas found that a futility trial needs only 100 participants on the active drug, assuming it uses placebo data from 200 people from previous trials, and has 80% power to detect a 35% slowing of progression with a statistical significance of .05. That’s not really huge news, as futility trials have been performed in PSP before, albeit using different statistical parameters than these. 

The take-home is that the unsuccessful double-blind PSP trials of the past have provided a valuable resource in the form of their placebo groups’ data, which can allow futility trials and permit many other improvement to our current clinical trial designs in PSP. That could make the clinical trial pipeline easier, faster, cheaper and less of an obstacle to small, start-up pharma companies.