The randomised controlled trial (RCT) is considered the gold standard study design for clinical research, providing the strongest form of evidence available from a single study (40, 41). The strengths of the RCT lie in its design features, most notably randomisation, blinding and allocation concealment. These design features serve to maximise a trial’s internal validity by preventing any biases or confounding, such that any differences between treatment arms in terms of outcome can be directly attributed to treatments (42).
Randomisation prevents the introduction of bias which may occur during the treatment allocation process if, consciously or unconsciously, recruiting clinicians or patients are able to influence choice of treatment, leading to systematic allocation of patients with generally poor or good prognoses to the different treatment groups (40). In order to protect against such biases, randomisation necessarily involves two processes: not only the use of a random allocation sequence (thus preventing any predictability of future treatment allocations given knowledge of previous allocations) but also the concealment of each treatment allocation until it is actually assigned to the trial participant (known as “allocation concealment”).
Assuming sufficient numbers of recruited patients, randomisation will therefore provide baseline comparability between treatment groups, both in terms of known and unknown prognostic factors, ensuring fair group comparisons. Additionally, in providing an ‘ignorable’ assignment mechanism, randomisation provides a valid basis for hypothesis testing (43, 44), allowing the use of probability theory to determine the likelihood that the observed differences between treatment groups have arisen purely by chance (41).
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Allocation concealment may, depending on the trial, be extended beyond the point of randomisation, such that one or more parties (patients, clinicians, assessors or analysts) remain unaware of treatment allocations during the entire trial period, a design feature known as “blinding”. Blinding prevents bias occurring when preconceived ideas or experience of treatments affect judgment or decisions made during the trial. For example, blinding may reduce the probability of co-intervention bias (when additional treatment is given to one treatment group only) or diagnostic-suspicion bias (when the analysis or interpretation of results is influenced by knowledge of treatment). Knowledge of treatment group can also influence decisions made during outcome assessment or statistical analysis, for example, on patient withdrawals, outcomes and time points to analyse and report. Thus, although patient and/or clinician blinding is not always practical, it may be possible to conceal treatment assignment from those evaluating and analysing outcomes in order to avoid measurement bias and ensure objectivity in statistical analyses (44-46).
Blinding may be achieved by use of a placebo, an inert substance which appears identical to the active treatment under study; in the case of active-controlled trials, treatment assignment may be masked using placebos for both treatments, providing a “double dummy”. Use of a placebo is necessary to distinguish the placebo effect (caused by expectation of treatment) from the true effect of treatment (47).
These design features which serve to increase internal validity do so, however, at the expense of a trial’s external validity. In aiming to ensure robust, valid conclusions, such constraints render the trial a somewhat artificial clinical environment, compromising the generalisability of its results to the wider population of interest. In particular, features (such as the nature of the patient-clinician relationship, and their individual preferences)
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which typically influence a patient’s response to treatment or likelihood of compliance may be altered by randomisation and blinding (48).
Thus, although generalisability (external validity) of trial results is generally based on the assumption that the sample is generalisable to the target population, this may not be the case. Trial participants may be typically more motivated and interested in the treatment than others with the same condition, and this greater medical awareness may mean they are more likely to comply with treatment instruction (37). More generally, by influencing their behaviour, trial conditions may also impact on a patient’s likelihood of nonadherence, altering patterns and rates of nonadherence in the trial compared to those that would typically be expected in practice. In general, trial adherence rates are usually considered to be higher than those displayed by the general public, despite the fact that trial participants may face greater barriers to adherence than those being treated in a usual care setting. For example, the trial treatment protocol may be rather more involved or demanding, and may be accompanied by more intense follow-up or invasive assessments than would be experienced in general practice, all of which can hinder participation (11).
Conversely, the extra contact with health care professionals provided by the trial setting may, in itself, provide patients with incentive and encouragement to persevere. Blinding may also help to reduce problems with patient drop out, as knowledge of treatment allocation may cause disappointment and subsequent patient withdrawal, if they perceive their allocation is the inferior treatment. On the other hand, blinding, especially by use of placebo, may mean patients are less likely to persevere with treatment, given the possibility that they are receiving a dummy drug. Furthermore, patients’ uncertainty about the efficacy of a drug being tested in the trial setting may mean that trial
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participants are less likely to persevere with unpleasant side effects of treatment than those who are confident of the efficacy of their treatment.
Patients may fear embarrassment if they report side effects or withdraw from treatment that turns out to be a placebo; indeed, empirical evidence has shown that patients are more likely to report side effects or withdraw from treatment if the trial involves an active control treatment rather than placebo (49). Similarly, a clinician blinded to treatment allocation may proceed more cautiously (for example with dose escalation), perhaps monitoring the patient’s response and symptoms more closely than usual (46). Thus, unnatural trial conditions may affect a trial participant’s behaviour, which is turn may distort their (perceived, reported or actual) trial outcomes, thus potentially limiting the reliability and generalisability of the trial’s overall conclusions.