Via @AndyBiotech on Twitter, here’s a story on some very troubling developments in offshore clinical trials. That Cardiobrief article is referring to this letter in NEJM, and the subject is the NIH’s trial of spironolactone in heart failure patients. The TOPCAT trial enrolled 3445 participants in 6 countries (1151 in the US, 326 in Canada, 167 in Brazil, 123 in Argentina, 1066 in Russia, and 612 in the Republic of Georgia). These were supposed to be patients who had heart failure with preserved ejection fraction (HFpEF), a group that makes up about half the population that have congestive heart failure.
The problems with the trial were apparent rather quickly. There was a significant regional variation in its results, and attempts to iron those out by looking into differences in diagnosis and patient classification didn’t explain them. Spirononlactone showed statistically significant benefits (not huge, but real) in the North and South American patient cohort, but no difference at all in the Russia/Georgia group, and the event rate was much higher in the former as well.
This new letter advances the least welcome explanation for these discrepancies. The authors have gone back to the repository of blood samples taken from patients during the trial and analyzed them for canrenone, the main metabolite of spironolactone. It’s present in 97% of the blood samples from the patients in the Americas, and in a dose-responsive manner when compared to patient status. But in the Russia/Georgia samples, 30% of them show no metabolite at all, and there is no overall dose-response relationship. The authors conclude that “Our findings suggest that the trial results obtained in Russia do not reflect the true therapeutic response to spironolactone“, and that’s the sort of statement that’s made through clenched teeth.
These numbers back up an earlier article which drew what has to be the most likely conclusion: that a significant number of patients in Russia and Georgia never ever got the drug. The Cardiobrief piece goes further, airing out the speculation that the spironolactone was, in fact, sold off on the open market by trial personnel rather than actually used as intended. That’s the first thought that occurred to me, too – it had to go somewhere, right?
The whole debacle brings to mind a paper by John Ioannidis and co-authors a few years ago that looked at clinical studies in various countries. There were significant differences noted in the trials conducted in less-developed countries without a tradition of clinical research, and the paper suggested that these factors needed to be taken into account. As clinical trials become more globalized, it looks like these conclusions are more noteworthy than ever. It’s hard enough to get solid numbers out of human clinical data as it is. Trial design and patient selection are issues that any clinical team wrestles with extensively before the first patient is even dosed. But if all this time, effort, care, and money is then wasted by people who don’t even bother to give the drug to the study group, well. . .
So if you’re thinking of running a big clinical trial in Russia or perhaps one of the former Soviet republics, you might want to consider the example of TOPCAT. This warning goes for a number of other countries as well, but I suspect that the NIH investigators expected better when they chose Russia and Georgia for their own study. I have worked with a number of excellent Russian scientists during my career, and I’m very sad for their sake that their country’s reputation has ended up where it is. But if you don’t believe that this is what things have come to, go try to find some spironolactone metabolites.