Trial design and monitoring

An understanding of the principles and different types of trial design is important. Observational studies are particularly affected by issues of bias and confounding that cast doubts about their validity. Indeed, randomisation is one of the major factors that has increased the relevance of clinical trials. Even then, all attempts must still be made to reduce bias at the time of randomisation. The randomisation process may include stratification for key baseline descriptor(s), but in very large scale studies it is often assumed that baseline risks should be matched between the two groups assigned different therapeutic approaches.

The importance of an adequate (ideally placebo) control group has been demonstrated repeatedly. As one example, without inclusion of a contemporary, placebo group, the important proarrhythmic effect of class 1c anti-arrhythmic drugs may not have been recognised in the CAST (cardiac arrhythmia suppression trial) study,8 as event rates in those randomised to active treatment were similar to those from previous individual patient usage data held by the pharmaceutical company.

A placebo limb may be unethical in certain circumstances—for example, thrombolysis in acute myocardial infarction. In such a context, different "active" treatments should be compared. Because of decreasing mortality rates with general improvements in management, trials which attempt to show superiority of newer agents above standard treatments are increasingly more difficult. The large number of patients needed can be a major problem. As an extension to this, trials designed to demonstrate "equivalence" with narrow confidence intervals actually require more rather than fewer patients compared with "superiority" studies.9 Because of this, the latest shift has been to "non-inferiority" trials. Then the clinical value of demonstrating that there is no clinically significant difference in outcomes between a new agent and conventional treatment may lie in the lower cost, greater ease of administration, or greater safety of the new agent. These analyses are often undertaken in conjunction with the main trial.

Other design strategies which may be incorporated to increase power in comparative studies are not only to increase the sample size, but to randomise unevenly by including fewer patients in "control" groups, and to deliberately enrol patients at higher risk so as to increase the number of end points.

A further relatively new development has been the possible use of a "cluster" design which allows randomisation of groups of people. This technique is used when the intervention is administered to and can affect entire clusters of people rather than individuals within the cluster, or when the intervention, although given to individuals, may "contaminate" others in the control group so as to weaken any estimate of treatment difference.10 The methodology can be particularly applied to studies of methods of care. An example could be a telephone based support system for patients when compared to usual outpatient care.

Factorial design (and simplicity) are other methodological approaches that may increase the efficiency of randomised controlled trials. Factorial design not only allows more than one hypothesis to be tested simultaneously, but allows large scale evaluation of some treatments such as dietary supplements that might not otherwise be possible because of difficulty in attracting the necessary funding.

Very large scale clinical trials should have an independent data and safety monitoring board. Their role should be clearly stated. Typically, the board will operate with pre-specified general stopping rules but they should usually be encouraged not to terminate a trial too early. This is because the reliability of data is greater with an increasing number of end points, perhaps euphemistically termed "regression to the truth". Accordingly, the mathematical functions which determine stopping often require more extreme evidence of effect earlier compared with later in the trial. Particularly, trials should rarely be terminated very early on the basis of "futility" because this deduction is unreliable when there are relatively few end points.

One major end point should be clearly specified and used as the basis for power calculations, the estimate of the "reliability" of the result. These power calculations should be presented.

All cause mortality is the hardest end point and allows for inaccuracies in the certification of the cause of death.11 It usually requires inclusion of a very large number of patients in the study. Increasingly, an expanded end point which is a composite of a number of outcomes is the primary end point. An expanded end point could be a composite of cause specific death, related non-fatal events, and perhaps an index of cost benefit such as a measure of hospitalisation. Each component should be biologically plausible and there should be an attempt to minimise any possibility of "double counting".

Care is prudent before there is wide extrapolation from the results of secondary end point data from smaller trials. As an example, data from the ELITE II study12 failed to confirm a mortality benefit of an angiotensin receptor antagonist compared to an angiotensin converting enzyme (ACE) inhibitor in heart failure patients, although this had previously been demonstrated in the smaller ELITE I study. The primary end point in ELITE I was renal function rather than mortality, but the somewhat dramatic effect on survival had been sufficient to convince a number of regulatory authorities throughout the world to liberalise indications for angiotensin receptor antagonism.

Trial acronyms

ELITE: Evaluation of Losartan In The Elderly

FRISC: Fragmin during Instability in Coronary artery disease HOPE: Heart Outcomes Prevention Evaluation

TIMI: Thrombolysis In Myocardial Infarction

VANQWISH: Veterans Affairs Non-Q Wave Infarction Strategies in Hospital graphy and, possibly, revascularisation with a "conservative" approach based on medical treatment. In the TIMI Illb, VANQWISH, and FRISC II studies, from 14-57% and 48-73%, respectively, of those patients assigned to a conservative therapeutic approach had cardiac catheterisation while an inpatient or within 12 months.13 These intervention rates translated to revascularisation approaches by 12 months in 33-49% in those assigned initial conservative treatment compared to 44-78% of those assigned to an initial invasive strategy. This made meaningful conclusions concerning the role of early revascularisation very difficult.

The examples also suggest the potential value of additional presentation of "on-treatment" analyses when this is appropriate.

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