Lessons learned from recent cardiovascular clinical trials: Part II.

Structural Issues in the Conduct of Trials The present structure for administering multicenter clinical trials funded by the government was established by the Greenberg Report1 and first implemented by the Coronary Drug Project.2 Referred to as the National Institutes of Health (NIH) clinical trial model (Figure 1), this example became the standard for trials sponsored by the National Heart, Lung and Blood Institute (NHLBI) and by many other NIH institutes.3 Key components of this model include the sponsoring agency, steering committee, data coordinating center, and data monitoring committee (DMC). The steering committee usually is made up of a study chair and other selected (or elected) representatives from the investigators and sponsor. Steering committee members develop the protocol, lead the trial, and publish the results when the trial is completed. The data coordination center is responsible for the management and quality control of the trial data, as well as for interim or final analyses of the baseline, safety, and efficacy data. The DMC monitors the trial for evidence of relative harm or convincing evidence of benefit. Most DMCs also track the trial’s progress, adherence to protocol, and the quality of the data.4 Although outright fraudulent data are rare, the responsibility of assuring high-quality trial operations is widely shared but falls directly into the oversight mantle of the DMC and the institutional review board (IRB). Definitive largescale, randomized trials with an irreversible outcome (death) and a serious morbidity outcome (myocardial infarction or stroke) are most likely to appoint a DMC. The US Secretary of Health and Human Services recently announced that all trials must have a monitoring plan and all supported the use of DMCs when a concern exists about irreversible outcomes.5 The US Food and Drug Administration (FDA) also recently published a draft guidance on DMC structure and function.6 IRBs are appointed by each research institution to review the ethics, the protocol’s scientific soundness, the relevance of the intervention, and the patient consent process. IRBs also provide local oversight of the safety of patients. Recently, the US system of IRBs has been heavily criticized by the Inspector General,7 and several individual institutions have been sanctioned by the Office of Health Research Policies.8,9 The concerns initially centered on failure to adhere to established standards of review, and attention has recently shifted to redefining these standards so that sound quantitative principles of quality and trial design can be incorporated into ethical review.4 Over the past decade, most noncardiovascular trials sponsored by the medical products industry have not used the NIH clinical trial model. Instead, some have appointed company employees to oversee the trial. In other cases, they have hired a contract research organization, with little participation in or influence from representatives of clinical practice or the academic community, and often without an independent DMC. Cardiovascular disease trials have a much stronger tradition of independent input by the steering committee and DMC than trials investigating most other diseases. In fact, a modified version of the NIH clinical trial model is used frequently in cardiovascular trials sponsored by industry (Figure 2).10 The Swedish metoprolol trial in heart attack patients11 and the Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial of milrinone in congestive heart failure patients12 were two of the first to use this model. Many other industry-sponsored trials have followed their lead13–15 because of the model’s many benefits. First, academic investigators can provide, through the steering committee, considerable input into the design of the protocol and the leadership of the trial. Second, an independent DMC is essential for a trial to be kept masked to those involved in its conduct, thereby minimizing bias until convincing evidence for benefit or harm has emerged. Another benefit of this model is the independent statistical analysis center’s role: to provide support to the DMC during the trial and to the steering committee after the trial is completed, allowing the sponsor’s statisticians to remain