Evaluation of the Trial to Assess Chelation Therapy (TACT): the scientific process, peer review, and editorial scrutiny.

IN THIS ISSUE OF JAMA, LAMAS AND COLLEAGUES 1 report the results of the Trial to Assess Chelation Therapy (TACT). In this multicenter clinical trial, 1708 patients with previous myocardial infarction (MI) were randomized to receive 40 infusions of chelation solution vs placebo. After a median follow-up of 55 months, the primary end point (a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina) occurred in 222 patients (26%) in the chelation group and in 261 patients (30%) in the placebo group, with the major between-group difference involving fewer coronary revascularization procedures in the chelation group (15%) than in the placebo group (18%). The authors conclude that although chelation therapy modestly reduced the risk of a composite of adverse cardiovascular outcomes, the results “are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.” This 10-year, $31 million, National Institutes of Health (NIH)–funded study conducted under the auspices of the National Heart, Lung, and Blood Institute and the National Center for Complementary and Alternative Medicine was intended to provide a rigorous evaluation of the use of chelation therapy, thereby providing evidence to inform patients who may be seeking an as yet unproven therapy for prevention and treatment of coronary artery disease. However, the study has generated controversy since its inception, with concerns that have included ethical issues involving an investigation by the Office for Human Research Protections (OHRP) regarding allegations of noncompliance with federal regulations for the protection of research participants; study conduct issues involving allegations about the research capabilities and professional credentials of some study sites and site investigators, as well as temporary suspension of trial enrollment; and fundamental scientific issues, involving concerns ranging from the safety of the chelating agent being studied to modification of the prespecified sample size and alteration of the prespecified statistical significance levels because of multiple interim analyses. In light of these and other concerns, the editorial assessment of TACT, like other studies with complex interrelated issues, was extensive and comprehensive because the evaluation extends beyond assessment of scientific validity and clinical relevance. Accordingly, the editorial review and scientific assessment involved not only JAMA’s usual level of scrutiny and diligence in evaluating the research report, including careful review of the study protocols, statistical analysis plans, and methods papers—it also involved assessment of OHRP reports, other documents related to the ethical and regulatory aspects of trial conduct, and reports of professional and public reaction about the study. In addition, the manuscript was extensively reviewed by independent peer reviewers with expertise in vascular medicine, study design, and statistical analysis; by several members of the JAMA editorial board; and by the JAMA cardiology contributing editors and senior editorial staff. The authors’ revisions to the manuscript and their responses to the extensive critiques and concerns raised by this assessment were scholarly and thorough and directly addressed the issues and concerns, as evident in their extensive explanations about the statistical analysis (included in the online supplement with the article) and their forthright explanations and responses related to the editors’ concerns about study ethics and trial conduct (included in the eAppendix to this Editorial at http://www.jama.com). As with all manuscripts, the final decision to publish the TACT report was made by the Editor in Chief and Executive Editor in consultation with the senior editorial staff. Because articles published in journals like JAMA can influence the practice of medicine, this level of scrutiny of TACT reflects our commitment to fulfilling the responsibility to try to ensure that every article published in JAMA is valid and is reported accurately. This includes conducting a detailed methodological evaluation, presenting scientific information objectively and clearly, and making certain that study inferences and interpretations are communicated appropriately. Although peer review and editorial evaluation are not perfect for guaranteeing validity, these approaches provide for expert review, scientific assessment,