1. Ethics and Network Research in the Emergency Setting: Experience from the ROC Jeremy Sugarman, MD, MPH, MA ROC Ethics Officer Department of Medicine Berman Institute of Bioethics Johns Hopkins University Baltimore, Maryland

2. What is the Resuscitation Outcomes Consortium (ROC)? Infrastructure Clinical Resuscitation Centers (10) Coordinating Center Project support Collaborative pre-hospital and early hospital clinical trials Cardiopulmonary arrest and life- threatening trauma

3. Purpose of the ROC To conduct clinical research in out-of-hospital cardiopulmonary arrest & life-threatening trauma  Epidemiologic Data Bank-"Epistry" Establish a resuscitation knowledge base that will improve therapeutic decision-making  Clinical trials Test promising therapies and approaches to management of cardiac arrest and trauma  Hospital follow-up Evaluate and correlate functional outcome in resuscitation survivors with therapeutic interventions

4. Organization  10 Regional Clinical Centers (RCCs)  Infrastructure to conduct multiple collaborative pre-hospital and early hospital trials University of Alabama, Birmingham University of Texas Southwestern, Dallas University of Iowa, Iowa City Medical College of Wisconsin, Milwaukee University of Pittsburgh, Pittsburgh Oregon Health & Sciences University, Portland Ottawa Health Research Institute, Ottawa, Vancouver, and the OPALS group University of California San Diego University of Washington, Seattle University of Toronto, St. Michaels Hospital  Data Coordinating Center (DCC)  Coordination, administration & support of activities University of Washington, Seattle

5. Responsibilities of the ROC Ethics Officer  Consultation to the ROC with regard to the ethical issues associated with ROC research.  To attend meetings of the ROC to help identify ethical issues associated with ROC research.  To review documents upon request for matters related to ethics.  To provide education on ethics to ROC or others involved in this research when requested.  Consult with IRBs and the DSMB upon their request to clarify the ethical issues associated with ROC research.

6. Research in the Emergency Setting  Desperate need for data to drive medical decision-making in difficult circumstances  The need for urgent interventions and diminished capability to provide informed consent pose ethical challenges to this research  Substitute procedures implemented to help ensure the protection of the rights and interests of participants

7. Reservoir of Trust  Individual physicians and investigators  Specific institutions  The research enterprise as a whole

8. Trust and Trustworthiness “Not all things that thrive when there is trust between people…are things that should be encouraged to thrive…There are immoral as well as moral trust relationships.” Baier A, 1986

9. Selected Experiences from ROC  Implementing the Final Rule  Clarifying community consultation  Ethics of research design  Research in the spotlight  Conceptual frameworks for research in the emergency setting

10. Provisions of the Final Rule 21 CFR 50.24  Criteria for approval  Procedures for informing subject or LAR  Recordkeeping for approved research  IND/IDE requirement  Responsibilities for unapproved research

11. Criteria for IRB Approval (IRB with concurrence of a licensed physician not-participating in the research)  Human subjects  Obtaining consent is not feasible  Prospect of direct benefit  Not practicable without the waiver  Document attempts to contact LAR  Approved IC procedures  Additional protections of rights and welfare Community consultation Public disclosure Data monitoring committee Contact of family members

12. Experience with Implementation  Requires substantial effort and resources  Popular response has not always been positive  Limited reporting of approaches to meeting the regulatory requirements  Confusion about activities and goals Confounding consultation and consent Confounding consultation and disclosure

13. Strategies  Network-wide teleconference with responsible IRBs Describe experiences using the Final Rule Answer questions about it  Information sheets about ROC  Meet with selected groups upon request  Discuss interpretations with FDA ethics personnel

14. Methods of Community Consultation  Public forums  Community Advisory Boards  Meetings with religious or civic organizations  Radio and television call-in shows  Surveys  Formative research

15. Community Consultation Unanswered Questions  What are the appropriate methods?  How is the information used?  How should the information be shared?

16. Ethical Goals of Community Consultation Neal Dickert and Jeremy Sugarman  Enhanced Protection  Enhanced Benefits  Legitimacy  Shared Responsibility

17. Ethics of Research Design  Uncontrolled observations may not be valid The humbling history of medicine The existence of marked clinical variation  Controlled observations may threaten validity

18. Why Use Randomization?  Minimize observer bias  Minimize patient selection bias

19. Justifying Randomization  Theoretical/Individual equipoise  Clinical equipoise

20. Theoretical Equipoise  “Theoretical equipoise exists when, overall, the evidence on behalf of two alternative treatment regimens is exactly balanced.”  Evidence derives from literature, experience, theory, and instinct  Held by an individual

21. Problems with Theoretical Equipoise  Not suited for a complicated world  Sensitive to the investigator’s perception  Personal and idiosyncratic

22. Clinical Equipoise  “There is no consensus within the expert clinical community about the alternatives to be tested.”  Consistent with decided treatment preferences of an investigator  Medicine is social rather than individual  Clinical equipoise does not require concealing information from subjects

23. Research in the Spotlight  RES can, and will, attract public attention  Be prepared Ensure research is trustworthy so that transparency is not problematic Pick the correct analogies  Lessons from PAD to PolyHeme Rely on knowledgeable spokespersons

24. Central Conceptual Questions  Why is there so much confusion?  What are the ethical rationales for the additional provisions?  What ethical framework(s) might be employed to enhance understanding and optimize the chances of doing good science that protects the rights and interests of those enrolled?

25. Emergency Medicine Clinical Care Research Public Health

26. Ethical Principles for Research  Respect for persons Individual subjects  Beneficence Maximize benefits of research (knowledge to be gained) while minimizing risks to subjects  Justice Libertarian

27. Ethical Principles for Clinical Care  Respect for autonomy Individual decision-making  Beneficence Promote the health of patients  Non-maleficence Not harming individuals  Justice Egalitarian

28. Ethical Principles in Public Health  Respect for autonomy Least restrictive alternative  Beneficence Enhance the health of communities  Social justice Utilitarian (risks/benefits; precautionary)

29. Ethics in Emergency Medicine Clinical Care Research Public Health

30. Preventive Ethics  Sensitivity to the normative aspects of particular practices  Policies and systems  Community engagement

31. Concluding Comments  While there is an ethical obligation to develop improved therapies for persons in life- threatening situations who are unable to provide informed consent, research in this setting has an inherent set of ethical challenges  Nevertheless, paying close attention to these ethical challenges can make this work possible while protecting the rights and interests of participants