Letter: the ethics of using inferior regimens in H. pylori randomised trials

Sirs, Recently, Kim et al. published a randomised comparison of sequential and ‘legacy’ triple therapy (containing clarithromycin or metronidazole, amoxicillin and a proton pump inhibitor) for Helicobacter pylori infection in Korea.1 They showed that sequential therapy was superior to triple therapy (85.9% vs. 75.0%). Numerous prior studies have shown that triple therapy yields unacceptably low results in Korea.2–8 Patient care differs fundamentally from clinical research. Physicians choose (in his/her opinion and hopefully evidence-based), the best therapy for a particular patient, taking into account all the variables unique to that patient. In clinical research trials, the primary goal is to seek to obtain new knowledge; in this instance, regarding the efficacy and safety of therapies for H. pylori infection. For patient care, the choice of therapy is patient specific, whereas research often involves randomisation to different therapies and comparisons of relevant clinical outcomes. The critical element that defines whether a clinical trial is ethical is the presence of an ‘honest null hypothesis’ that requires clinical equipoise9–11 (i.e. a genuine uncertainty regarding the merits of one treatment compared to another in relation to that particular population).10 Research subjects should never be exposed to the risks of valueless research (i.e. the answer is already known or the question is trivial), nor should they be knowingly be assigned (randomly or not) to a known inferior treatment.10–12 By definition, a trial is unethical if it includes a therapy known (at the time) to be inferior. An honest null hypothesis requires that the investigator critically analyse the information currently available and attempt to discover information before and during the trial that would be relevant to the treatment decisions.9–11 If the question was whether sequential therapy was useful in Korea, the investigators should have examined whether they could obtain the targeted 100% eradication, rather than seek to prove that it was better than a known ineffective regimen.13 The internationally accepted ethical guidelines contained in the Declaration of Helsinki include the following: ‘the benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods.14 ‘Approved’ and ‘recommended’ differ from ‘effective’. Investigators must be held to high standards and cannot rely on a so-called standard-of-care guidelines published by various groups or even Food and Drug Administration marketing approval (e.g. Ellenberg and Temple from the US Food and Drug Administration15 noted ‘marketing approval does not establish treatment as ‘standard-of-care’ even in the United States and certainly not in other countries’). Approximately, a dozen similar randomised trials using a legacy comparator regimen were published in 2011. We believe all could be considered unethical, if legacy therapy had previously been shown to be ineffective in the populations where the studies were conducted. As authors (including Kim et al.1) typically acknowledge knowledge of unacceptably poor results for legacy therapy prior to their studies (in their background section, as part of their sample size calculations, etc), it is arguable that there was nothing to be gained by confirming that knowledge. In the spirit of disclosure, we published a study in asymptomatic H. pylori-infected children where placebo was used.16 Superficially, the use of a placebo in a treatment trial with H. pylori-infected subjects would appear unethical. A superficial reader (e.g. having only read the title and abstract) might believe that this is the case in our trial as well. Our population-based trial was not a treatment trial, but was designed to examine the important question of the role of H. pylori in iron deficiency in children (see companion article).17 Prior to our trial, funded by the Trasher foundation, there was uncertainty whether H. pylori eradication improved iron stores in children. As we stated in those papers, ‘there is consensus against screening and treatment of H. pylori infection in asymptomatic children.’ Reasons for not treating asymptomatic children include adverse events, the introduction of antimicrobial resistance,18H. pylori could be a transient infection in children (which had been studied in the population where our study was conducted), etc.19 Therefore, H. pylori eradication treatments have been primarily been limited to infected, symptomatic children with a relevant diagnosed gastrointestinal disease. Our results showed all groups to yield unacceptable low eradication, and we thought it important to bring that to the world’s attention, in that there is considerable interest in sequential therapy. Everyone involved in research, whether they are actually involved in carrying out the research as an investigator or reviewing the study as a member of an IRB committee, a reviewer or journal editor, has a responsibility to maintain high ethical standards and ensure that the welfare of human subjects is the first priority. Unethical trials should not be conducted, and those that are conducted should not be published. Declaration of personal interests: Dr. Graham is an unpaid consultant for Novartis in relation to vaccine development for treatment or prevention of H. pylori infection. Dr. Graham is also a paid consultant for Otsuka Pharmaceuticals. Dr. Graham has received royalties on the Baylor College of Medicine patent covering materials related to 13C-urea breath test. Dr. Fischbach has nothing to declare. Declaration of funding interests: This material is based upon work supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs. Dr. Graham is supported in part by Public Health Service grant DK56338 that funds the Texas Medical Center Digestive Diseases Center. DK067366 and CA116845. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the VA or NIH.