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Purpose Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long‐term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness. Methods We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps. Results Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences. Conclusion This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

Objectives: To assess the use of asthma drugs by men and women with asthma and to identify sex specific predictors for the use of oral steroids. Design: Cross sectional study. Setting: Six general practicesin East Anglia. Subjects: 103 men and 134 women aged 20-54 with asthma. Main outcome measures: Self reported use of β agonists, inhaled steroids, and oral steroids. Results: No sex difference was found in use of β agonists or inhaled steroids. However a strong association existed between sex and oral steroid use. 40 (30%) women reported using oral steroids compared with nine (9%) men. Women were more than five times (odds ratio=5.5, 95% confidence interval 2.2 to 13.7) more likely to report use of oral steroids than men after asthma symptoms, age, visits to the general practitioner in previous six months, and time since diagnosis of asthma were controlled for. Women who had visited the general practitioner for asthma one or more times in the previous six months were four times (3.9, 1.6 to 9.5) as likely to report use of oral steroids. In addition, more frequent visits to the general practitioner for asthma were related in a dose-response manner to a greater likelihood of using oral steroids among women after asthma symptoms, age, and time since diagnosis were controlled for. This relation was not observed among men. Conclusion: Women used oral steroids more than men. The more frequent consultations with a doctor by women may result in more requests for oral steroids or doctors may preferentially prescribe oral steroids to women.