Empirical Use of Fluconazole in Critically Ill Patients: Good Study, but What Was the Hold-up?

IN RESPONSE:

We appreciate the readers' interest in our study. Dr. Shelburne and Dr. Lee bring up the very important issue of publication delay. Some of the delays that occurred in the reporting of this trial—and in other, similarly complex, multicentered clinical trials conducted in critically ill patient populations—are invariably due to the difficulties in completing the data set after the final patient is enrolled. Performance of quality assurance, data cleaning, site answers to data queries, and review of each individual case by a busy data review committee can be cumbersome and time-intensive processes, which clearly took too long in our study. A study such as ours is a joint venture between the investigators and the sponsor. Although there was an element of initial disappointment with a trial yielding negative results and although the focus of many involved may have been diverted at times during the long process, there was no intentional delay in the publication of these results. Efforts to improve the speed of publication and promote the publication of important clinical trials with negative findings are critical to the dissemination of data that may affect clinical practice. Policies that may speed the publication of clinical trial results include the assignment of dedicated clinical monitors to each study site and the formation of a publication committee and timeline at the onset of the project. In September 2004, an editorial published by the International Committee of Medical Journal Editors (1) stated that, beginning in September 2005, clinical trials could only be considered for publication if they had been publicly registered before patient enrollment. This policy will help promote the reporting of all clinical trials.

With regard to the current yield of routine blood cultures for the growth of Candida species, although the rate of false-negative results for the detection of candidemia is lessened with current blood culture systems, the high attributable mortality rate due to candidemia still makes empirical or prophylactic therapy attractive. Dr. Lee notes correctly that there has been a shift from C. albicans to non-albicans species, including C. glabrata, and that echinocandins may have activity against fluconazole-resistant isolates. Given the substantially higher cost of echinocandins, and the fact that most Candida species remain susceptible to fluconazole (2), it remains to be seen whether empirical therapy with an echinocandin will be beneficial and cost-effective. Dr. Lee also questions the large number of patients enrolled in the trial despite the fact that the trial was terminated at the interim analysis for lack of efficacy. The interim analysis looked at completed patients, and enrollment was not paused but was rapid and ongoing at the time of the analysis. Patients already in the trial at the time of the decision were allowed to complete the study, and thus, 270 patients were ultimately enrolled.