There are several misstatements in Drs. Graham and Yamaoka's letter. There was no sponsor for our study, and triple therapy is a legacy therapy solely in a fantasy world. Triple therapy was recently reaffirmed by an international consensus group as the principal therapy to be used worldwide and by U.S. and Japanese guidelines (1–3). It is, therefore, an appropriate control group for any new therapy. Our study began in 2003, when it was uncertain whether sequential therapy was truly effective in large cohorts. A fundamental question remained unanswered until now: Was sequential therapy the answer to clarithromycin resistance? An expert international consensus group reviewed the data on sequential therapy in 2005 and concluded that it was promising but that more data were needed, particularly with regard to clarithromycin resistance (1). Because there were no safety issues with either treatment in our study and because the consensus group felt that more data were needed, it was imperative that we continue the trial. We have already demonstrated that triple-drug therapy with levofloxacin is an effective salvage therapy for patients in whom sequential therapy fails (4). Therefore, a perfectly satisfactory alternative therapy of proven efficacy was available for patients with treatment failure; data on those patients will be reported elsewhere.

Ethical trial designs minimize risk to patients and maximize the likelihood of a meaningful outcome for patients and society. Early termination of a trial requires the demonstration of a serious unanticipated side effect or an unanticipated difference between treatments that is much larger than expected (5). Researchers deciding to terminate a trial early have a heavy responsibility both to those who have taken part in the trial already and to society (5). The results of our study were within the anticipated treatment estimates and there were no safety issues; therefore, our responsibility to the patients who volunteered, to society, and to the scientific community was to continue. The suggestion that we should not have had a control group is inappropriate. No serious investigator would contemplate a treatment efficacy trial without a control group (in this case, the current gold standard for treatment). The limitations of uncontrolled studies are well known to all researchers. Underpowered, uncontrolled trials —sometimes of unsafe agents—continue to be published. These studies yield biased results with wide CIs that mislead rather than illuminate and place patients at risk for drug toxicity and resistant organisms. They should be deplored rather than encouraged. We hope that the benefits of our study to individual patients and to society in general are apparent.