Oxford University Harris-Manchester College 2008 Summer Research Fellowship

1. Oxford UniversityHarris-Manchester College2008 Summer Research Fellowship Cindy Munro, PhD, RN, ANP, FAAN Professor, School of Nursing, IRB Panel A Member, Virginia Commonwealth University

2. Fellowship objective • examine legislation of other countries (particularly European and Asian countries, which have strong critical care research programs) regarding consent in the critical care setting, and compare those to the diversity of state legislation in the United States.

3. Decisional impairment issues in consent of critically ill • Difficulty receiving and comprehending research study information • Difficulty communicating wishes • Difficulty differentiating research procedures from clinical care • Cognitive impairment

4. Cognitive impairment in critically ill subjects • Cognitive impairment can arise from • therapeutic interventions (such as sedation and pain medications) • pathophysiology and disease processes • Delirium is common • Level of cognition can fluctuate widely over a short period of time

5. Which consent? • Consent for care is distinct from consent to participate in research • There is a “heterogeneity of consenting practices” for invasive non-research procedures in critical care in the United States (Manthous, et al., 2003) which affects perceptions of risk and appropriate consent practices for research

6. Decisional impairment • Existing literature regarding focuses on those who will likely not regain competence • Critically ill persons are often decisionally impaired during the acute event, but may regain competence

7. Recall of trial information, Chenaud, 2006, consented in ICU • 44 adults in intensive care unit participating in clinical trial about inflammation • Glasgow Coma Scale score of 15, be fully oriented and free of mechanical ventilation, and be judged competent by both the investigator and the attending physician. • Questioned 10 days after consent

8. Recall of trial information, Chenaud, 2006, consented in ICU

9. Approaches to deal with decisional impairment in consent of critically ill • Waiver of some or all elements of informed consent • Prospective consent • Retrospective consent • Proxy consent

10. Recall of trial information, Chenaud, 2006, consented before ICU • 38 adults in surgical intensive care unit post cardiac surgery participating in coagulation study • Consented day before elective surgery • Questioned 10 days after consent

11. Recall of trial information, Chenaud, 2006, consented before ICU

12. EU Directive 2001/20/EC Comparison of US and EU law • “the written consent of the patient's legal representative, given in cooperation with the treating doctor, is necessary before participation in any such clinical trial.” (covers clinical trials of medicinal products only) • defer to EU member nation laws to define who is authorized to act (these laws vary widely) US Federal Code “legally effective informed consent of the subject or the subject's legally authorized representative” (45 CFR 46.116). (covers all human subjects research) defer to US state laws to define who is authorized to act (these laws vary widely)

13. EU definition of clinical trial • ‘clinical trial’: any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy;

14. State laws in US • ONLY Virginia (since 1999) and California (since 2003) have specific legislation identifying who may give proxy consent • Several states specify legal representative for medical care decisions without specifically addressing research consent • Other states lack legislation addressing proxy consent for either medical care or research

15. Member nation laws in EU • Austria • Legally authorized representative appointed by a judge for proxy consent for research (all research) • Germany • Legally authorized representative appointed by a judge for proxy consent for research (research involving pharmaceuticals) • France • Family members who can consent to care can consent to research

16. Member nation laws in EU • UK, Medical Health Act • 2004, strict interpretation of directive, with no proxy permitted • 2005, legal representative proxy • personal representative not connected with the conduct of the trial and who is suitable to act in this capacity by virtue of their relationship with the patient, and is available and willing to do so • If no personal representative is available, then a professional legal representative not connected with the conduct of the trial, who is either the doctor responsible for the patient’s treatment or someone nominated by the relevant health care provider, can be approached

17. Member nation laws in EU • Netherlands, Dutch Directive on Medical Research Involving Human Subjects • 1998, only spouse or life companion may give proxy consent for research • 2006, broadened to parents, children, siblings

18. Conclusion • In both cases (US and EU), implementation and interpretation of the overarching documents are delegated to the member entities. • In both cases (US and EU), the implementation and interpretations vary widely. • “The legal and ethical acceptability of third party permission for nonbeneficial research is jurisdiction specific, which is a source of ongoing debate and is often subject to inconsistent directives.” (Shaul, 2005)