TABLE 2.

MINIMIZING RISK IN INTENSIVE CARE UNIT INTERVENTION TRIALS

1. Both interventional strategies in a two-arm trial should have a well-grounded pathophysiologic rationale to benefit all eligible patients. Determination of nonlinear treatment responses is best done with relatively fixed treatments along the range of treatments rather than fixed treatments bracketing variable, unexplained usual-care practices.

2. Experts in the field should develop the experimental treatment strategies, much as consensus recommendations for practice are developed when high-level clinical evidence is lacking. Both treatments must be considered to be good or competent care.

3. Experimental interventions should be guided by explicit guidelines or protocols so that the results of the clinical trials can be clearly communicated. This allows for use of superior arms to serve as control for future trials and for clinicians to fully understand the intervention when they consider changing their practices.

4. Intervention protocols should, when possible, titrate or customize the intervention to meet individual patient needs. Many dynamic protocols do this: one example is the titration of tidal volume to plateau airway pressures (or dyspnea) in the ARDSnet tidal volume protocols (8). Such protocols meet changing patient needs, thus providing individualized care within the given treatment objective.

5. Treatment protocols and guidelines should be designed to minimize risks in comparison to anticipated benefits. Treatment protocols should also consider incorporating elements that minimize risk in comparison to usual care. One example is the addition of protocolized weaning in trials of lung protection.

6. If there has been limited clinical experience with one of the clinical approaches under consideration, then phase II assessments of the approach should be done before proceeding with phase III.

7. Sequential stopping rules should be carefully designed to stop the trial as soon as its goals are reached, while still controlling the error rate and maintaining power. Any continuation of a trial beyond the point where the results can be ascertained with certainty exposes the patients to unnecessary risk. It should be realized, however, that trials that stop early for futility will provide weaker evidence for equivalence in comparison to a trial that continues to its full accrual.

8. Independent and qualified protocol review committees and/or DSMBs should undertake review of the research protocols.

9. DSMBs should review as close to real-time data as possible in ICU studies of rapidly fatal diseases. When possible, outcomes in otherwise comparable historical controls should be provided to DSMBs as an additional safety measure.

Definition of abbreviations: DSMB = data safety monitoring board; ICU = intensive care unit.