Go Green, Recycle your Patients

Euthymics, a small Massachusetts-based biotech, recently announced the start of the TRIADE trial, which they describe as “Phase 2b/3a”. I am guessing that that somewhat-rare designation means they’re hoping that this will count as a pivotal trial, but have not yet had formal agreement from FDA on that topic. Part of this may be due to the trial’s design – per the press release, they’re using a Sequential Parallel Comparison Design (SPCD).

This is an intriguing trial design because it takes one of the benefits of traditional crossover designs – increasing statistical power by “reusing” patients in multiple treatments – while avoiding many of the problems, most notably any concerns about the persistence of treatment effect. This is because only a select but key subset of patients – those who were in the control arm but showed no response – are re-randomized to both arms. This group clearly has no treatment effect to persist, so they make an excellent population to further test with. (It’s important to note that all patients are continued on treatment in order to preserve blinding.)

In essence, we have a placebo run-in phase embedded within a traditional trial. It seems worth asking how this trial design compares against a simpler trial that includes such a run-in – I do not see any information on the website to help answer that.

And that points to the major drawback of the SPCD: it’s patented, and therefore not freely available to study and use. As far as I can tell, the design has not been through an FDA Special Protocol Assessment yet, which would certainly be a critical rite of passage towards greater acceptance. While I can appreciate the inventors’ desire to be rewarded for their creative breakthrough in devising the SPCD (and wish them nothing but good fortune for it), it appears that keeping the design proprietary may slow down efforts to validate and promote its use.

From Russia with (3 to 20 times more) Love

“Russia’s Clinical Trials are a Thriving Business”, trumpeted the news release that came to my inbox the other day. Inside was a rather startling – and ever-so-slightly odd – claim:

NPR Marketplace Health Desk Reporter Gregory Warner uncovers the truths about clinical trials in Russia; namely, the ability for biopharmaceutical companies to enroll patients 3 to 20 times faster than in the more established regions of North America and Western Europe.

Of course, as you might expect, the NPR reporter does not “uncover” that – rather, the 3 to 20 times faster “truth” is simply a verbatim statement from the CEO of ClinStar, a CRO specializing in running trials in Russia and Eastern Europe. There is no explanation of the 3-to-20 number, or why there is such a wide confidence interval (if that’s what that is).

The full NPR story goes on to hint that the business of Russian clinical trials may be a bit on the ethically cloudy side by associating it with past practices of lavishing gifts and attention on leading physicians (no direct tie is made – the reporter however not so subtly notes the fact that one person who used to work in Russia as a drug rep now works in clinical trials). I think the implication here is that Russia gets results by any means necessary, and the pharma industry is excitedly queuing up to get its trials done faster.

However, this speed factor is coupled with the extremely modest claim that clinical trial business in Russia is “growing at 15% a years.” While this is certainly not a bad rate of growth, it’s hardly explosive. It’s in fact comparable to the revenue growth of the overall CRO market for the few years preceding the current downturn, estimated at 12.2%, and dwarfed by the estimated 34% annual growth of the industry in India.

From my perspective, the industry seems very hesitant to put too many eggs in Eastern Europe’s basket just yet. We need faster trials, certainly, but we need reliable and clean data even more. Recent troubling research experience with Russia -- most notably the dimebon fiasco, where overwhelming positive data in Russian phase 2 trials have turned out to be completely irreproducible in larger western trials –has left the industry wary about the region. And wink-and-nod publicity about incredible speed gains probably will ultimately hurt wider acceptance of Eastern European trials more than it will help.

1st-Person Accounts of Trial Participation

Two intriguing articles on participation in clinical trials were published this week. Both happen to be about breast cancer, but both touch squarely on some universal points:

ABC News features patient Haralee Weintraub, who has enrolled in 5 trials in the past 10 years. While she is unusual for having participated in so many studies, Weintraub’s offers great insights into the barriers and benefits of being in the trial, including the fact that many benefits – such as close follow-up and attention from the treatment team -- are not obvious at first.

Meanwhile, the New York Times’ recurring column from Dr Peter Bach on his wife’s breast cancer offers a moving description of her consent into a trial. His essay focuses mainly on the incremental, slow pace of cancer research (“this arduous slog”) and how it is both incredibly frustrating and absolutely necessary for long-term improvements in treatment.