Perspective
Helicobacter pylori Eradication Therapy Research: Ethical Issues and Description of Results

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As an infectious disease, the approach to anti–Helicobacter pylori therapy differs from other common gastrointestinal conditions because treatment success of more than 90% to 95% should be expected and the reasons for treatment failure can always be understood. Neither comparisons with another regimen nor randomization are required to identify a highly successful therapy. Treatment success should be judged first in relation to outcome (ie, ≥95% or grade A). Inclusion of a known inferior regimen in a clinical trial is generally unethical. If the use of a known inferior drug is required by a regulatory agency, subjects must be given full and accurate information regarding expectations with each regimen; there can be no deceptions. Comparative trials should be restricted to highly successful treatments (ie, comparisons of different doses, durations, compliance, cost, and so forth). Success should be judged as ordered categories such as <85%, 85%–89%, 90%–94%, or ≥95% and statistically equivalent regimens with the same grade success (ie, 90%–94% [Grade B]) are inferior to those higher category (ie, ≥95% [Grade A]) regimens. Only grade A or B regimens should be prescribed. Here we discuss anti–H pylori eradication studies from the prospective of an infectious disease with the goal of providing recommendations regarding changes in approach and in reporting that should help resolve the ethical issues and make the results of clinical trials more useful to clinicians.

Section snippets

Clinical Research Regarding Treatment of Common Bacterial Infections

Medical research fundamentally differs from medical practice. The obligation of the physician in clinical practice is to provide optimal care to the individual patient. In contrast, clinical trials are scientific experiments designed to increase generalizable scientific knowledge so as to promote the medical good of future patients. Although patients may derive benefit from the treatment offered as part of clinical research, such benefit is not the primary goal of the research.4

Fundamentally,

Infectious Disease Research Versus Other Clinical Research in Gastroenterology

Many human conditions have variable and often unpredictable responses to therapy, and the effects of treatment are often small. In many conditions there is also a high rate of spontaneous improvement such that a placebo may be required to determine whether the therapy has any benefit. For treatments in which the effect is reliably superior to placebo, one generally prefers an active control rather than a placebo. The active control is typically the best currently available therapy with the goal

Factors Responsible for H pylori Treatment Failures

Most factors that influence outcome in H pylori treatment studies are known and can be controlled for (Table 2). The most important cause for poor outcome in optimized regimens is the presence of antimicrobial resistance. None of the factors in Table 1 is random, unknown, or not measurable, such that the reason for a poor outcome almost always can be identified. Thus, the approach to treatment studies with H pylori as an infectious disease is markedly different than with other common

Ethical Issues With Anti–H pylori Therapy

We will focus on 2 issues: the requirement for an honest null hypothesis and the need for fully informed consent. As noted earlier, by definition, a trial is unethical if it compares a known (at the time) inferior therapy with a known superior therapy because there can be no honest null hypothesis.

By 2001, 2 meta-analyses encompassing more than 53,000 subjects showed that the success with triple therapies (a proton pump inhibitor [PPI], amoxicillin, and either clarithromycin or metronidazole)

Informed Consent

Informed consent is one of the basic principles of clinical research. The Helsinki accord states that in medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests. By definition, the subject must receive any information that the investigator has that might affect his or her decision to enter a trial or to continue in an ongoing trial. The (at least) annual review of ongoing trials should include a question

H pylori Treatment Trials Since 2003–2004

Because the investigators in subsequent Italian sequential-triple therapy comparisons also typically were investigators in the pivotal study, it is clear that those results were well known to them17 and the fact that legacy triple therapy was inferior therapy was used to reduce the sample sizes to accommodate the expected larger differences.24, 25, 26 How to handle the informed consent was more difficult. In the Vaira et al24 study, the subjects and institutional boards were told that the

A Paradigm Shift Is Required for Design of Studies for the Evaluation of H pylori Eradication Therapy

Although, up to this point, we have focused here on studies comparing legacy triple therapy and sequential therapy, there are many other examples of clinical trials in which known inferior therapies were given to subjects and many meta-analyses of the results of these trials.3, 29

H pylori infection is possibly the only common disease in gastroenterology in which the treatment success of experimental therapy is expected to be 95% or greater and in which the causes of treatment failure are easily

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    Conflicts of interest The authors disclose the following: Dr Graham is an unpaid consultant for Novartis in relation to vaccine development for treatment or prevention of Helicobacter pylori infection. Dr Graham is also a paid consultant for Otsuka Pharmaceuticals regarding diagnostic testing and until July 2007 was a member of the Board of Directors of Meretek Diagnostics, the manufacturer of the 13C-urea breath test. Until November 2009, Dr Graham received royalties on the Baylor College of Medicine patent covering materials related to the 13C-urea breath test.

    Funding This material is based on 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, which funds the Texas Medical Center Digestive Diseases Center and R21DK067366. The contents are solely the responsibility of the author and do not necessarily represent the official views of the VA or the National Institutes of Health.

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