How to best design RCTs for new transplant immunosuppressives

The ability to adequately suppress the immune system and prevent allograft rejection has been a true success story over the past several decades.  With the advent of drugs such as calcineurin inhibitors, induction agents such as thymoglobulin, azathioprine and later MMF, the vast majority of patients who undergo kidney transplant can count on long-term graft function, especially when compared to the early days of transplant. 

Despite this success, however, there are many transplant nephrologists who feel that we could do better.  One of the great ironies of transplant nephrology, of course, is that the very drugs which have been instrumental in preventing immune-mediated allograft rejection, the calcineurin inhibitors, are themselves nephrotoxic.  Ideally, we should be able to develop drugs which are just as successful as immunosuppressants as the CNIs but which lack the nephrotoxic side effects.  

However, according to this 2008 American Journal of Transplantation editorial by Vincenti et al, a significant barrier towards achieving this goal is created by the current policies of the Food & Drug Administration (FDA), which insists on using outdated regimens for immunosuppression in the control arms of any new transplant RCTs.  The authors point out the fact that in 2005, over 70% of current kidney transplant recipients are sent out of the hospital with a combination of tacrolimus and MMF; however, only about 11% of all patients are treated with the "FDA-approved" regimen of cyclosporine and MMF.  In order to obtain eventual FDA approval, many current RCTs for new immunosuppressants are therefore tested against the cyclosporine + MMF. Negative consequences of this approach include (a) a reluctance of many transplant centers to subject their patients to the perceived suboptimal control arm of cyclosporine + MMF (rather than tacrolimus + MMF), and (b) a concern that any RCTs are being compared to a suboptimal, seldom-used regimen not comparable to what is currently considered standard-of-care.

Finally, another aspect of transplant trials under scrutiny is which clinical end-point to follow. Traditionally end-points such as "# of episodes of acute rejection" have been considered appropriate; there is now a move towards using harder end-points such as long-term graft survival or estimated GFR which are more relevant. As an example of this, recent results from the BENEFIT trial, comparing belatacept versus cyclosporine, show that although belatacept is associated with a higher rate of acute rejection than cyclosporine, it demonstrates improved renal structure and function at one year.