How Context can Impact Clinical Trials : 31 A Multi-Country Qualitative Case Study Comparison of Diagnostic Biomarker Test 32 Interventions

34 Background: Context matters for the successful implementation of medical interventions, but its role 35 remains surprisingly understudied. Against the backdrop of antimicrobial resistance, a global health 36 priority, we investigated the introduction of a rapid diagnostic biomarker test (C-reactive protein, or 37 CRP) to guide antibiotic prescriptions in outpatient settings and asked, “Which factors account for 38 cross-country variations in the effectiveness of CRP biomarker test interventions?” 39 Methods: We conducted a cross-case comparison of CRP point-of-care test trials across Yangon 40 (Myanmar), Chiang Rai (Thailand), and Hanoi (Vietnam). Cross-sectional qualitative data were 41 originally collected as part of each clinical trial to broaden their evidence base and help explain their 42 respective results. We synthesised these data and developed a large qualitative data set comprising 130 43 interview and focus group participants (healthcare workers and patients) and nearly one million words 44 worth of transcripts and interview notes. Inductive thematic analysis was used to identify contextual 45 factors and compare them across the three case studies. As clinical trial outcomes, we considered 46 patients’ and healthcare workers’ adherence to the biomarker test results, and patient exclusion to 47 gauge the potential “impact” of CRP point-of-care testing on the population level. 48 Results: We identified three principal domains of contextual influences on intervention effectiveness. 49 First, perceived risks from infectious diseases influenced the adherence of the clinical users (nurses, 50 doctors). Second, the health system context related to all three intervention outcomes (via the health 51 policy and antibiotic policy environment, and via health system structures and the ensuing utilisation 52 patterns). Third, the demand-side context influenced the patient adherence to CRP point-of-care tests 53 AUTHOR ACCEPTED MANUSCRIPT Page 3 and exclusion from the intervention through variations in local healthcare-seeking behaviours, popular 54 conceptions of illness and medicine, and the resulting utilisation of the health system. 55 Conclusions: Our study underscored the importance of contextual variation for the interpretation of 56 clinical trial findings. Further research should investigate the range and magnitude of contextual effects 57 on trial outcomes through meta-analyses of large sets of clinical trials. For this to be possible, clinical 58 trials should collect qualitative and quantitative contextual information for instance on their disease, 59 health system, and demand-side environment. 60 Trial registration: ClinicalTrials.gov Identifiers NCT02758821 and NCT01918579. 61