Strengths and Limitations of Clinical Trials

Large randomized clinical trials can provide strong evidence of the true effect of a treatment or intervention, because they provide excellent control of confounding, but they also have some limitations:

Strengths of Intervention Studies (Clinical Trials) They provide the best means of minimizing the effect of confounding They avoid bias in allocation to exposure groups Large randomized clinical trials are the best design for detecting small to moderate effects that may be clinically important

 

Limitations Ethical issues need to be considered Risks to subjects versus potential benefits Does equipoise exist? Some questions cannot be answered ethically with a clinical trial. They are usually time consuming and costly Lengthy trials run the risk of loss to follow up (LTF), and if LTF is different for one of the exposure-outcome categories, the measure of association will be biased, just as with prospective cohort studies(see the module on Bias). Invariably, some subjects will fail to adhere to the protocol, and non-adherence will cause an underestimated measure of association (see below).

Non-adherence

Ideally, the investigators want to compare exposed subjects to non-exposed in groups that are similar with respect to confounding factors. The true benefit of a new drug will be underestimated if subjects given the active medication fail to take it, causing subjects who were actually not exposed to be mixed in with the exposed subjects who were actually taking the medication. This mixing of the exposure groups dilutes the apparent benefit causing underestimates of association. The same thing occurs if people in the placebo group begin taking the active medication. This occurred in the Physicians' Health Study in which follow up questionnaires estimated that about 15% of the subjects assigned to the aspirin group did not take it, and a similar proportion of subjects in the placebo group used aspirin fairly regularly. This would cause an underestimate of the true benefit. In this case, in which the exposure was preventive with an observed risk ratio = 0.59, the true risk ratio would have been even smaller. In other words, non-adherence caused a "bias toward the null," an underestimate of the true benefit.

Non-compliance can occur due to side effects of the treatment, illness, or loss of interest in the study.

How to Promote Adherence in a Clinical Trial

1. Begin with an interested group of participants
2. Make it easy to participate
   • Present a realistic picture of the protocol during informed consent
   • Exclude participants with pre-existing conditions that make compliance difficult
   • Simplify the protocol as much as possible
   • Conduct a run-in period if necessary
3. Use blinding and placebos
4. Keep in touch
   • Maintain frequent contact with subjects WITHOUT interfering with treatment
   • Provide incentives (free check-ups, transportation, t-shirts, birthday cards)

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