Trial exclusion criteria and their impact on the estimation of antipsychotic drugs effect: A case study using the SOHO database

OBJECTIVES: To explore the impact upon estimation of drug effect as a result of applying exclusion criteria in randomized-controlled trials (RCT) measuring the efficacy of antipsychotics (AP) in schizophrenia. METHODS: Three characteristics which may act as effect-modifiers of AP, while also common exclusion criteria in RCTs, were identified through literature review: schizophrenia duration, substance use disorder and poor adherence. The SOHO cohort was used to estimate the effect of initiating antipsychotic drugs "A", "B" or "C" (pooled) upon symptom evolution at 3months from baseline (CGI-S scale). "Estimated effectiveness" and "estimated efficacy" were drawn from the "SOHO" and "RCT-like" (patients with none of the above-listed exclusion criteria) samples, respectively. Effect-modification and impact of each exclusion criterion on AP effect estimates were explored using non-adjusted statistics. RESULTS: The "SOHO sample" included 8250 patients initiating drug A, B or C at baseline, whose AP "estimated effectiveness" was CGI-S=-0.78 (95% CI=-0.80, -0.76). The "RCT-like" sub-sample included 5348 (65%) patients whose AP "estimated efficacy" was CGI-S=-0.73 (95% CI=-0.75, -0.70). Patients with short illness duration (=3years since first AP; n=2436) experienced significant symptom improvement ( CGI-S=-0.89; 95%CI=-0.93, -0.85) compared to patients with duration >3years (mean CGI-S=-0.73; 95%CI=-0.76, -0.71). Excluding patients with short illness duration led to a change in AP effect estimates but this was not the case for substance use disorder or poor adherence. CONCLUSION: Using certain exclusion criteria in RCTs may impact the drug's effect estimate, particularly when exclusion criteria are AP effect-modifiers representing frequent characteristics among patients with schizophrenia.