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. 2019 Aug 12;14(8):e0219894.
doi: 10.1371/journal.pone.0219894. eCollection 2019.

Assessing heterogeneity of treatment effect analyses in health-related cluster randomized trials: A systematic review

Monique Anderson Starks  1   2 , Gillian D Sanders  1   2 , Remy Rene Coeytaux  3 , Isaretta L Riley  4 , Larry R Jackson 2nd  1   2 , Amanda McBroom Brooks  1 , Kevin L Thomas  1   2 , Kingshuk Roy Choudhury  5 , Robert M Califf  1   2 , Adrian F Hernandez  1   2
Affiliations

Assessing heterogeneity of treatment effect analyses in health-related cluster randomized trials: A systematic review

Monique Anderson Starks et al. PLoS One. .

Abstract

Background: Cluster-randomized trials (CRTs) are being increasingly used to test a range of interventions, including medical interventions commonly used in clinical practice. Policies created by the NIH and the Food and Drug Administration (FDA) require the reporting of demographics and the examination of demographic heterogeneity of treatment effect (HTE) for individually randomized trials. Little is known about how frequent demographics are reported and HTE analyses are conducted in CRTs.

Objectives: We sought to understand the prevalence of HTE analyses and the statistical methods used to conduct them in CRTs focused on treating cardiovascular disease, cancer, and chronic lower respiratory diseases. Additionally, we also report on the proportion of CRTs that reported on baseline demographics of its populations and conducted demographic HTE analyses.

Data sources: We searched PubMed and Embase for CRTs published between 1/1/2010 and 3/29/2016 that focused on treating the top 3 Center for Disease Control causes of death (cardiovascular disease, chronic lower respiratory disease, and cancer). Evidence Screening And Review: Of 1,682 unique titles, 117 abstracts were screened. After excluding 53 articles, we included 64 CRT publications and abstracted information on study characteristics and demographic information, statistical analysis, HTE analysis, and study quality.

Results: Age and sex were reported in greater than 95.3% of CRTs, while race and ethnicity were reported in only 20.3% of CRTs. HTE analyses were conducted in 28.1% (n = 18) of included CRTs and 77.8% (n = 12) were prespecified analyses. Four CRTs conducted a demographic subgroup analysis. Only 6/18 CRTs used interaction testing to determine whether HTE existed.

Conclusions: Baseline demographic reporting was high for age and sex in CRTs, but was uncommon for race and ethnicity. HTE analyses were uncommon and was rare for demographic subgroups, which limits the ability to examine the extent of benefits or risks for treatments tested with CRT designs.

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Conflict of interest statement

MA Starks - none; GD Sanders - none; RR Coeytaux - none; IL Riley - none; LR Jackson - education support from Medtronic and Biotronik; honoraria from Biotronik; AM Brooks - none; KL Thomas - Consultant: Pfizer, BMS, Janssen; KR Choudhury - none; RM Califf - sits on the corporate board for Cytokinetics and is board chair for the People-Centered Research Foundation. He receives personal fees for consulting from Merck, Amgen, Biogen, Genentech, Eli Lilly, and Boehringer Ingelheim. He is also employed as an advisor by Verily Life Sciences (Alphabet); AF Hernandez - consulting fees from Sanofi, Johnson & Johnson, AstraZeneca, and Cortera; research support from Amylin and Scios/Johnson & Johnson. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Flow diagram of the study selection process for the sample of 64 cluster-randomized trials included.
See this image and copyright information in PMC

References

    1. Code of Federal Regulations Code of Federal Regulations. 1CFR312.33 FDA. Investigational new drug application. Definitions and interpretations. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr.... Accessed February 12, 2015.
    1. National Institutes of Health NIH Revitalization Act of 1993, PL 103–43. Subtitle B—Clinical Research Equity Regarding Women and Minorities. Sections 131 (1993): 133.
    1. Office of Extramural Research, National Institutes of Health. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research. October 2001. Available at:http://grants1.nih.gov/grants/funding/women_min/guidelines_amended_10_20.... Accessed February 12, 2015.
    1. U.S. Food and Drug Administration Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials. 2005. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc.... Accessed February 12, 2015.
    1. U.S. Food and Drug Administration FDA Report: Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products, August 2013. Available at: http://www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFo.... Accessed February 12, 2015.

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