American College of Cardiology -- Anaheim, California

The Strengths and Limitations of Large Multicentre Trials


According to Dr. Elliott Rappaport, speaking at the American College of Cardiology 46th Annual Scientific Session, large-scale randomised, double-blind, placebo-controlled clinical trials offer the "best scientific approach currently available to establish whether a particular diagnostic preventive or therapeutic choice alters a specific outcome." Megatrials offer hard evidence as to whether or not a benefit is seen and also help establish the quantitative degree of benefit likely to be achieved in the predefined endpoint(s). When meticulously carried out, they can provide the unbiased evidence upon which sound medical decisions must be based, and offer physicians an opportunity for augmenting their own personal experience. Guidelines are increasingly being set by international bodies of experts based on their collective analysis of clinical trials. The more clear cut the evidence, the stronger the recommendation made regarding appropriate therapy.

Generalisation
A number of factors influence the degree to which results of a clinical trial may be generalised to the population at large. For example, the more restricted the use of concomitant therapy during the trial, the greater the likelihood that the results will be reproducible in other patients with the same disorder. The enhanced compliance generated by the close scrutiny, as well as greater access to ancillary testing and follow-up and a sometimes reduced incidence of comorbid conditions within the confines of a clinical trial may make for more favourable outcomes than might be seen in the general population. Teaching hospitals or large medical centres are disproportionately represented in megatrials and their populations may be substantially different from those seen in the general community or in private practice. These and other variables such as socioeconomics, nutrition, language barriers, hygiene, etc. are often not taken into consideration and may have a substantial impact on outcome and/or generality of results.

Limitations
Not all clinical trials are created equal, and it may be imprudent to assume that publication in a well-respected journal automatically confers wholesale validity. Sometimes

the conclusions may be unduly influenced by overly enthusiastic or optimistic interpretation of the results. Misinterpretation may stem from the investigators' own preconceived notions or biases and could lead to selective use of data. One means of reducing distorted results due to latent bias is to ensure that trials are conducted in double-blind fashion whenever possible.

The megatrial can have significant problems, in particular if there are no restrictions of nontrial treatments. Poor study design and nonrepresentative study cohorts also weaken the impact of clinical trials on medical practice. Randomisation is the key to a successful trial if unbiased comparison groups are to be generated, but the quality of randomisation can vary greatly from trial to trial. The problem of crossovers from one trial arm to another, or using additional nonprotocol interventions has been problematic in some megatrials and has limited acceptability of the conclusions reached from the results, especially in analyses using the intention-to-treat principle.

Meta-analyses and Smaller Trials
In contrast, small trials which engender less time and cost can also be important, especially when consistent trends lead to meta-analyses that can help provide a means of estimating the likelihood of benefit from the interventions under investigation. However, differences in entry and exclusion criteria, especially in meta-analyses, can significantly hamper the purity of the results and the authenticity of the conclusions. Dr. Rappaport offered a caveat in this regard: Especially where decisions that may affect mortality or serious morbidity are involved, meta-analyses are insufficient to conclude definitively that the intervention is beneficial. He stressed that a megatrial for purposes of conformity is desirable since, often, results of such trials fail to reach the conclusions of a meta-analysis of earlier smaller trials.

Evaluating the Clinical Trial
Dr. Rappaport concluded by exhorting physicians to incorporate trial results into their armamentaria of treatment according to their own preferences and the needs of their individual patients.