Assessing trial representativeness using Serious Adverse Events: An observational analysis using aggregate and individual-level data from clinical trials and routine healthcare data

Hanlon, P. , Butterly, E., Shah, A. S. V., Hannigan, L. J. , Wild, S. H., Guthrie, B., Mair, F. S. , Dias, S., Welton, N. J. and McAllister, D. A. (2022) Assessing trial representativeness using Serious Adverse Events: An observational analysis using aggregate and individual-level data from clinical trials and routine healthcare data. BMC Medicine, 20, 410. (doi: 10.1186/s12916-022-02594-9) (PMID:36303169) (PMCID:PMC9615407)

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Abstract

Background: The applicability of randomised controlled trials of pharmacological agents to older people with frailty/multimorbidity is often uncertain, due to concerns that trials are not representative. However, assessing trial representativeness is challenging and complex. We explore an approach assessing trial representativeness by comparing rates of trial serious adverse events (SAE) to rates of hospitalisation/death in routine care. Methods: This was an observational analysis of individual (125 trials, n=122,069) and aggregate-level drug trial data (483 trials, n=636,267) for 21 index conditions compared to population-based routine healthcare data (routine care). Trials were identified from ClinicalTrials.gov. Routine care comparison from linked primary care and hospital data from Wales, UK (n=2.3M). Our outcome of interest was SAEs (routinely reported in trials). In routine care, SAEs were based on hospitalisations and deaths (which are SAEs by definition). We compared trial SAEs in trials to expected SAEs based on age/sex standardised routine care populations with the same index condition. Using IPD, we assessed the relationship between multimorbidity count and SAEs in both trials and routine care and assessed the impact on the observed/expected SAE ratio additionally accounting for multimorbidity. Results: For 12/21 index conditions, the pooled observed/expected SAE ratio was <1, indicating fewer SAEs in trial participants than in routine care. A further 6/21 had point estimates <1 but the 95% CI included the null. The median pooled estimate of observed/expected SAE ratio was 0.60 (95% CI 0.55–0.64; COPD) and the interquartile range was 0.44 (0.34–0.55; Parkinson’s disease) to 0.87 (0.58–1.29; inflammatory bowel disease). Higher multimorbidity count was associated with SAEs across all index conditions in both routine care and trials. For most trials, the observed/expected SAE ratio moved closer to 1 after additionally accounting for multimorbidity count, but it nonetheless remained below 1 for most. Conclusions: Trial participants experience fewer SAEs than expected based on age/sex/condition hospitalisation and death rates in routine care, confirming the predicted lack of representativeness. This difference is only partially explained by differences in multimorbidity. Assessing observed/expected SAE may help assess the applicability of trial findings to older populations in whom multimorbidity and frailty are common.

Item Type:Articles
Additional Information:Funding: David McAllister is funded via an Intermediate Clinical Fellowship and Beit Fellowship from the Wellcome Trust, who also supported other costs related to this project such as data access costs and database licences (“Treatment effectiveness in multimorbidity: Combining efficacy estimates from clinical trials with the natural history obtained from large routine healthcare databases to determine net overall treatment Benefits.” - 201492/Z/16/Z). Peter Hanlon is funded through a Clinical Research Training Fellowship from the Medical Research Council (Grant reference: MR/S021949/1). None of the funders had any influence over the study design, analysis or decision to submit for publication.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McAllister, Professor David and Butterly, Dr Elaine and Hanlon, Dr Peter and Hannigan, Dr Laurie and Mair, Professor Frances
Authors: Hanlon, P., Butterly, E., Shah, A. S. V., Hannigan, L. J., Wild, S. H., Guthrie, B., Mair, F. S., Dias, S., Welton, N. J., and McAllister, D. A.
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > General Practice and Primary Care
College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
Journal Name:BMC Medicine
Publisher:BioMed Central
ISSN:1741-7015
ISSN (Online):1741-7015
Copyright Holders:Copyright © The Author(s) 2022
First Published:First published in BMC Medicine 20: 410
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173492Combining efficacy estimates from clinical trials with the natural history obtained from large routine healthcare databases to determine net overall treatment benefitsDavid McAllisterWellcome Trust (WELLCOTR)201492/Z/16/ZInstitute of Health & Wellbeing
305232Understanding prevalence and impact of frailty in chronic illness and implications for clinical managementFrances MairMedical Research Council (MRC)MR/S021949/1HW - General Practice and Primary Care