Ethics of extra-protocol pre-screening in clinical trials

Randomised controlled trials are considered the gold standard for evaluating medical interventions, but their external validity is often undermined by restrictive eligibility criteria. This paper introduces a taxonomy that distinguishes between protocol-based pre-screening and extra-protocol pre-screening and provides a conceptual and ethical analysis of extra-protocol pre-screening in clinical trials. While protocol-based pre-screening excludes individuals who clearly do not meet the trial’s protocol-defined eligibility criteria, extra-protocol pre-screening excludes otherwise eligible participants for reasons external to the trial’s eligibility criteria. The paper finds that extra-protocol pre-screening undermines autonomy by denying individuals the opportunity to decide on participation, contravenes beneficence by restricting access to potentially beneficial interventions, violates justice by exacerbating inequities in research participation and compromises scientific integrity by introducing selection bias that undermines external validity. Extra-protocol pre-screening thus represents a ‘hidden layer’” of participant exclusion that threatens ethical and scientific standards in clinical research, stemming from perverse incentives in clinical trial conduct rather than investigator failings. The paper offers some recommendations for practice to mitigate these ethical issues.