title: Ethical complexities in standard of care randomized trials: A case study of morning versus nighttime dosing of blood pressure drugs.
abstract: BACKGROUND
  Pragmatic trials comparing "standard of care" treatments provide comparative effectiveness data to make practice of medicine more evidence-based. With electronic health records, recruiting and conducting such trials can be relatively inexpensive. But some worry that the traditional research ethics framework poses unnecessary obstacles and is not appropriate for evaluating such clinical trials. This concern is based on the view (which we call the "Standard of Care Principle") that such research is similar to usual clinical practice and therefore does not raise significant ethical issues since everyone in the research study will receive an accepted standard of care treatment.
  
  
  METHODS
  A case study of a pragmatic randomized clinical trial (Blood Pressure Medication Timing study) comparing morning versus nighttime dosing of antihypertensive medications. The Blood Pressure Medication Timing study has been proposed as a paradigm example of why the Standard of Care Principle obviates the need for traditional levels of ethical scrutiny and how the current regulatory framework poses unnecessary obstacles to research. We provide an ethical analysis of the Blood Pressure Medication Timing study, drawing on the empirical literature as well as on normative analysis.
  
  
  RESULTS
  The Standard of Care Principle is the main ethical rationale given by commentators for asserting that the Blood Pressure Medication Timing study does not require "significant ethical debate" and by investigators for the assertion that the Blood Pressure Medication Timing study is minimal risk and thus eligible for lessened regulatory requirements. However, the Blood Pressure Medication Timing study raises important ethical issues, including whether it is even necessary, given the considerable randomized clinical trial evidence in support of nighttime dosing, a much larger (N≈17,000) confirmatory randomized clinical trial already in progress, evidence for safety of nighttime dosing, and the cost-free availability of the intervention. Furthermore, the Standard of Care Principle provides a misleading basis for analyzing the informed consent requirements, especially regarding the requirement to disclose alternative courses of treatment that "might be advantageous to the subject."
  
  
  CONCLUSIONS
  The Standard of Care Principle is ethically inadequate and misleading even when it is applied to the pragmatic randomized clinical trial proposed as a paradigm case for its application.
authors.affiliation: Department of Bioethics, National Institutes of Health Clinical Center, Bethesda, MD, USA scott.kim@nih.gov.
authors.forename: Scott Y H
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Bioethics, National Institutes of Health Clinical Center, Bethesda, MD, USA Weill Cornell Medical College, New York, USA.
authors.forename: Franklin G
authors.initials: FG
authors.lastname: Miller
mesh_terms: D000959:Antihypertensive Agents / Q000008:administration & dosage*; D057186:Comparative Effectiveness Research; D004334:Drug Administration Schedule; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007258:Informed Consent; D064792:Pragmatic Clinical Trials as Topic / Q000941:ethics; D016032:Randomized Controlled Trials as Topic / Q000941:ethics*; D059039:Standard of Care / Q000941:ethics*
chemical_list: D000959:Antihypertensive Agents
keywords: Standard of care; comparative effectiveness research; informed consent; pragmatic trials; research ethics