title: Stakeholders' views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs.
abstract: We explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders' attitudes towards the implementation of pragmatic trials in the drug development process.
  
  
  
  We conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients' organizations) through telephone or face-to-face sessions. Interviews were structured around the question "what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials." Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets.
  
  
  
  We interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with "real-world" practice reducing the knowledge value of trial results.
  
  
  
  We identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization.
authors.affiliation: Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500, 3508, GA, Utrecht, The Netherlands. s.kalkman@umcutrecht.nl.
authors.forename: Shona
authors.initials: S
authors.lastname: Kalkman
authors.affiliation: Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500, 3508, GA, Utrecht, The Netherlands.
authors.forename: Ghislaine J M W
authors.initials: GJ
authors.lastname: van Thiel
authors.affiliation: Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Diederick E
authors.initials: DE
authors.lastname: Grobbee
authors.affiliation: GMACS GHEOR, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Anna-Katharina
authors.initials: AK
authors.lastname: Meinecke
authors.affiliation: Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mira G P
authors.initials: MG
authors.lastname: Zuidgeest
authors.affiliation: Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500, 3508, GA, Utrecht, The Netherlands.
authors.forename: Johannes J M
authors.initials: JJ
authors.lastname: van Delden
mesh_terms: D001291:Attitude of Health Personnel; D057186:Comparative Effectiveness Research / Q000941:ethics; D032962:Consent Forms / Q000941:ethics; D015507:Drugs, Investigational / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D007722:Health Knowledge, Attitudes, Practice; D006801:Humans; D007258:Informed Consent / Q000941:ethics; D007407:Interviews as Topic; D008297:Male; D061214:Patient Safety; D010819:Physician's Role; D064792:Pragmatic Clinical Trials as Topic / Q000941:ethics* / Q000379:methods; D036301:Qualitative Research; D012107:Research Design; D012108:Research Personnel / Q000523:psychology*; D012307:Risk Factors; D000073597:Stakeholder Participation; D057212:Therapeutic Equipoise; D016896:Treatment Outcome
chemical_list: D015507:Drugs, Investigational
keywords: Comparative effectiveness; Drug research; Pragmatic clinical trial; Qualitative study; Research ethics