Withdrawal or drop-out is often used as an outcome measure in trial reports. Review authors should hesitate to interpret such data as surrogate markers for safety or tolerability because of the potential for bias:
The attribution of reason(s) for discontinuation is complex and may be due to mild but irritating side effects, toxicity, lack of efficacy, non-medical reasons, or a combination of causes (Ioannidis 2004);
The pressures on patients and investigators under trial conditions to keep the number of withdrawals and drop-outs low can result in rates that do not reflect the experience of adverse events within the study population;
Unblinding of intervention assignment often precedes the decision to withdraw. This can lead to an over-estimate of the intervention’s effect on patient withdrawal. For example, symptoms of patients in the placebo arm are less likely to lead to discontinuation. Conversely, patients in the active intervention group who complained of symptoms suggesting adverse effects may have been more readily withdrawn.