Reply:
Authors: Tahany Awad, Kristian Thorlund, Goran Hauser, Davor Stimac, Mahasen Mabrouk, Christian Gluud
Journal: Hepatology (2011)

We thank Schulze zur Wiesch and colleagues for their comments. In the design of randomized clinical trials (RCTs) lies the inevitable trade-off between being an exploratory trial or a management trial.1 Exploratory trials are concerned with what might be the "truth" under certain controlled clinical settings whereas management trials are typically concerned with efficacy of some intervention(s) in real-life clinical settings and/or improving the management of some intervention(s). Most RCT designs meet somewhere in the middle between the two categories. The extent to which the RCTs included in a systematic review are exploratory or management trials will strongly affect the extent to which the drawn inferences about effectiveness can be extrapolated to real-life clinical settings. In the RCTs included in our systematic review, patients were treated with peginterferon plus ribavirin in accordance with what is considered to be standard of care.2 However, little emphasis was put on management issues such as the handling of syringes. Additional management RCTs or observational studies are therefore valuable for informing whether the two peginterferon treatments yield different degrees of benefit in real-life clinical settings. The study by Schulze zur Wiesch et al. constitutes an important first step in this enterprise.3 However, it does come with a number of potential limitations, and we wish to offer caution about the interpretation of their results. In the study by Schulze zur Wiesch et al., the personnel received specific training for the handling of syringes for peginterferon 2b.3 Although this approach is indeed valuable for informing effectiveness of management of peginterferon 2b, an absence of similar training for management of peginterferon 2a may create an unfair comparison. That is, because physicians and nurses received training in management of peginterferon 2b, they are likely to be more attentive to issues pertaining to management of peginterferon 2b than issues pertaining to management of peginterferon 2a. Thus, when they are administering both treatments, it is likely that they unintentionally may end up providing better care (e.g., stay with patient longer, monitor clinical markers more thoroughly, and so forth) to patients who receive peginterferon 2b than those who receive peginterferon 2a. An additional serious problem in this vein is that study participants were not allocated randomly to the two peginterferon treatments. Thus, one can speculate that having recently received training in the management of peginterferon 2b, physicians might have been likely to administer peginterferon 2a to patients to whom they believed administering peginterferon 2b might be problematic. The numbers certainly point toward this tendency. The study by Schulze zur Wiesch et al. was conducted between 2002 and 2008, a time when equipoise existed between the two peginterferon treatments.3 Yet, the majority of patients received peginterferon 2a (304 received peginterferon 2a, but only 182 patients received peginterferon 2b). The research question that Schulze zur Wiesch et al. is actually answering is then "is peginterferon 2b, when preceded by special training in management of syringes, as effective as peginterferon 2a?" Putting this finding in the context of our systematic review, one must seemingly be willing to allocate the resources needed to train personnel in the proper management of syringes when treating patients with peginterferon 2b in order to achieve similar sustained virological response (SVR) corresponding to that of peginterferon 2a treatment without preceding management training. Although this information is certainly useful in countries where the governments and health care entities are willing to allocate such resources, it it doubtful that third-world countries will derive value from the findings by Schulze zur Wiesch et al. Further, one must also wonder what benefits could potentially be achieved with peginterferon 2a if the same resources instead were directed to proper management training preceding this intervention. Schulze zur Wiesch et al. also commit a cardinal error in their statistical analysis. They infer that there is no difference between the two peginterferons because they do not achieve a statistically significant different result. However, the statistical test they employ is based on the null hypothesis (at least we assume) and can therefore only be used to test whether there is a difference, not whether there is equivalence. To test if the two treatments are the same, the authors should have employed equivalence or a noninferiority test in which a hypothesis that the difference between the two treatments is no greater than some "important" threshold is tested. It is worth noting that if, for example, we assume a 5% absolute difference in SVR (which is approximately the estimate from our systematic review) would constitute an important difference, such a test would not be statistically significant. In other words, there is insufficient statistical evidence to support that the two treatments yield the same SVR in real-life clinical practice. In summary, the study by Schulze zur Wiesch et al. suffers from a number of important limitations that call for confirmation in larger observational studies, management RCTs, and/or systematic reviews of such studies. Tahany Awad M.D.*, Kristian Thorlund B.Sc. , Goran Hauser M.D. , Davor Stimac M.D. , Mahasen Mabrouk M.D.§, Christian Gluud M.D. , * Cochrane Hepato-Biliary Group, Rigshospitalet Copenhagen, Copenhagen, Denmark, Copenhagen Trial Unit, Center for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark, Clinics of Internal Medicine, Clinical Hospital Center of Rijeka, Rijeka, Croatia, § Department of Endemic Medicine, Cairo University, Cairo, Egypt.