Evaluating ADHD medication trial representativeness: a Swedish population-based study comparing hypothetically trial-eligible and ineligible individuals

Abstract

Background: randomised controlled trials (RCTs) evaluating attention-deficit/hyperactivity disorder (ADHD) medications often use strict eligibility criteria, potentially limiting generalisability to patients in real-world clinscal settings. We aimed to 1) determine the proportion of individuals with ADHD who would be ineligible for medication RCTs and 2) evaluate differences in treatment patterns and clinical/functional outcomes between RCT-eligible and ineligible individuals.

Methods: we used Swedish national registries to identify individuals with ADHD, aged 4-68, initiating pharmacological treatment between January 1, 2007, and December 31, 2019, with follow-up through December 31, 2020. Hypothetical RCT ineligibility was determined using exclusion criteria from the international MED-ADHD dataset, including 164 RCTs of ADHD medications. Cox models evaluated differences in medication switching and discontinuation within 1 year between eligible and ineligible individuals. Poisson models compared eligible and ineligible individuals on rates of psychiatric hospitalizations, injuries/accidents, and substance misuse within 1 year of initiating ADHD medications. People with lived experience were not involved in the research and writing process. Ethnicity data were not available.

Outcomes: out of 189,699 individuals (112,153 males [59%] and 77,546 [41%] females; mean age=21[range 4-68] years) initiating ADHD medication, 53% (74% of adults, 35% of adolescents, and 21% of children) would have been ineligible for RCT participation. Ineligible individuals had a higher likelihood of treatment switching (HR=1·15, 95% CI 1·12-1·17), and a decreased likelihood of medication discontinuation (HR=0·96 [0·94-0·98]) compared to eligible individuals. RCT-ineligible individuals had significantly higher rates of psychiatric hospitalizations (IRR=3·76 [3·67-3·85]) and specialist care visits related to substance misuse (IRR=3·42 [3·30-3·54]), depression (IRR=6·00 [5·94-6·06]), and anxiety (IRR=11·63 [11·56-11·69]).

Interpretation: individuals ineligible for ADHD medication trials face higher risks of adverse outcomes. This study provides the first empirical evidence for the limited generalisability of ADHD RCTs to real world clinical populations, by applying eligibility criteria extracted from a comprehensive dataset of RCTs to a large real-world cohort. Triangulating evidence from RCTs and real-world studies is crucial to inform rigorous evidence-based treatment guidelines.

Funding: National Institute of Healthcare and Research (NIHR); European Union’s Horizon 2020, Swedish Research Council.

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Identifiers

ORCID for Miguel Garcia-Argibay: orcid.org/0000-0002-4811-2330

ORCID for Samuele Cortese: orcid.org/0000-0001-5877-8075

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