No robust conclusions to be drawn from clinical trials in the absence of an adequate control group

It is not difficult to agree with Tedesco et al. that important strategies for immunosuppression at this time include the reduction of calcineurin inhibitors (CNIs) to minimize nephrotoxicity and maximize graft function and survival. However, in their report of two studies on ‘everolimus with reduced exposure cyclosporine’ in this issue of Transplant International [1], we find a number of concerns that warrant some comments. The focus of interest is nephrotoxicity. Although, everolimus may be a non-nephrotoxic alternative, it is a wellknown fact that target of rapamycin (TOR) inhibitors like everolimus and sirolimus may potentiate the nephrotoxicity of CNIs and, in particular, cyclosporine A (CsA). Sirolimus combined with CsA was found in earlier studies to be associated with worse renal function compared with CsA combined with mycophenolate mofetil (MMF), and the same combination was later shown to have worse graft survival compared with standard regimens in both randomized prospective and large retrospective studies. Consequently, in the United States, the use of the sirolimus and CsA combination in renal transplantation has declined in clinical practice [2]. It is therefore unclear how these studies, in the absence of a suitable control group, can address concerns about the combined nephrotoxicity of everolimus and CsA. In the absence of an adequate control group, conclusions about efficacy, but more importantly about safety of the protocol, are impossible. The declaration of Helsinki formulated and periodically updated by the World Medical Association [3] clearly states that ‘The benefits, risks, burdens, and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists’. This stands to reason because the same association also states that ‘Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research’, and even if at inception of a clinical trial there is consensus that the tested regimen might benefit the population, this assumption has to be monitored throughout the trial by a safety monitoring board comparing the accumulating data with a control group that is receiving ‘the best current prophylactic, diagnostic, and therapeutic methods’. It is therefore unclear why the design of the two studies reported by Tedesco et al. did not include an appropriate control group, for example, with CsA and MMF. Uncontrolled trials are of the lowest caliber or quality because of the biases and lack of rigor that are inherent in such studies. Moreover, the inability to compare one group with another means that the study results are of no value in the assessment of a drug’s effectiveness and comparative safety. For these reasons, the ‘safety and efficacy of everolimus with reduced exposure cyclosporine’ advocated in the title of the report by Tedesco et al. cannot be established by the two trials described. The title of the report by Tedesco et al. claims that the exposure of CsA was reduced. In Table 3 of their report [1], the CsA dose, concentration 2 h after dosing (C2) and trough levels from month 4 to 12 are presented. Admittedly, the mean trough levels of CsA during this Transplant International ISSN 0934-0874