1. Basics of Research Ethics Prepared by: R. Bortolussi MD FRCPC Professor Pediatrics Dalhousie University Workshop 2012 1 Google images

2. Basics of Research Ethics Potential Competing Interests: Name Organization Role Name Organization Role Robert Bortolussi Robert Bortolussi MicroResearch Founder Pfeizer Pharm. Consultant Dalhousie U. Employer Workshop 2012 2

3. The objectives of this session Appreciate the historical context of research ethics Understand the basics for international standards for research ethics Identify concerns regarding risk Describe the differences that exist when vulnerable populations are participants. Define “Conflict of Interest” and describe some guiding principles Workshop 2012 3

4. What can we learn from the past ? The history of politics, medicine, and business are rich and detailed. The history of Ethics is brief and short! MEDICINE Workshop 2012 4

5. A Brief History of Human Research Ethics: Nuremberg Code (1947) As part of the verdict in the Nuremberg War Crimes Trials of 23 German doctors, the Court enumerated some rules for “Permissible Medical Experiments”, now know as the “Nuremberg Code”: voluntary consent benefits outweigh risks ability of the subject to terminate participation Workshop 2012

6. A Brief History of Human Research Ethics: Declaration of Helsinki 1964… 2000 Recommendation guiding doctors in Biomedical Research involving human subjects. “Concern for the interests of the subject must always prevail over the interests of science and society” Workshop 2012 6

7. What have we learned ? The Nuremberg Code prohibited most research involving children and many vulnerable populations. The Declaration of Helsinki formally disallowed non-therapeutic research on non- consenting subjects. The codes present difficulties for those who want to advance the health of vulnerable people, including children, and some adults who do not have the capacity for consent. Workshop 2012 7

8. A Brief History of Human Research Ethics: Tuskegee incident In 1972 it was revealed that for 40 years the US Public Health Service had been performing studies on poor black men from Tuskegee, Alabama who had been denied treatment for syphilis without ever consenting. Awareness of these studies created a scandal and demand for more stringent regulations regarding informed and voluntary participation in human research. Workshop 2012 8

9. A Brief History of Human Research Ethics: Belmont Report Belmont Report (1979). Special consideration needed for our primary duty to protect from harm. Regulatory frameworks have been developed to identify acceptable and unacceptable risks in research. Requires research ethics committees to determine the balance of harms and benefits. Workshop 2012 9

10. The unexpected outcome ! Policy that strictly prohibits children and other vulnerable populations from participation in research may harm both individuals and the populations en masse by making them research “orphans.” Overprotection can harm the ones you are trying to protect! Workshop 2012 10

11. Overcoming the dilemma Ethics committees must examine studies for acceptable balance of risk and benefit. Principle of justice for a vulnerable and other populations means risk is distributed equally and benfits are accessible to everyone. An ever-present tension for clinicians Workshop 2012 11

12. Three Principles of Research Ethics Principles: respect for persons, beneficence and justice. The concept of non-malificence is complementary to beneficence: to do good and no harm, to maximize potential benefits, while minimizing risk. Workshop 2012 12

13. Concept of Minimal Risk The US Federal Common Rule describes minimal risk as meaning that “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life.” Workshop 2012 13

14. Equipoise, Risk and Therapeutic Procedures Equipoise “a state of uncertainty as to the relative superiority of two treatments”. Exposure to therapeutic risk may sometimes be acceptable if clinical equipoise exists. Children may be exposed to risk if there is equipoise: treatment A vs B. ◦This is the case in children with cancer in which death, secondary to toxicity of treatment, is a potential event with either. Workshop 2012 14

15. Placebo Interventions A placebo should only be allowed if there are valid reasons to use it rather than an active drug. A placebo must satisfy these conditions: minimal risk, more than minimal risk but a direct benefit from the placebo a minor increase over minimal risk but the study is likely to produce knowledge of vital importance to the subject’s own disease. Workshop 2012 15

16. Conflict of Interest and Integrity in Research One of the best definitions of conflict of interest was proposed by Denis Thompson. "a conflict of interest is a set of conditions in which professional judgment concerning a primary interest (such as a patient's welfare or the validity of research) tends to be unduly influenced by a secondary interest (such as financial gain)" NEJM, 1993. Workshop 2012 16

17. Conflicts of Interest COI for a clinician may occur if financial or personal interests may affect decision: Q: What might a person who has financial interests tied to outcome be tempted to do? Clinicians must always give unbiased results Workshop 2012 17 Google images

18. Specific Conflicts of Interest (COI) Role Confusion: Caregiver vs. Researcher Clinicians doing research, have two goals, ◦to provide best care for the patient, ◦to acquire generalizable knowledge. The two goals can present a conflict. To be ethical, clinicians can’t disadvantage research subjects, particularly when they are patients who come to them for care. Workshop 2012 18

19. Remuneration for Enrolling Patients in Research Trials Finder’s fees Finder’s fees, ie payment for recruiting or enrolling patients in research, is a COI for a clinician. The AMA’s Council on Ethical Affairs has stated that payment by or to a clinician solely for the referral of a patient is unethical. Workshop 2012 19

20. Authorship Conflicts Each author must participate sufficiently to take responsibility for all or part of the work. Requires: a meaningful contribution to the conception and design, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and approval of the final version of the manuscript. Workshop 2012 20

21. Have the objectives been met? Appreciate the historical context of research ethics Understand the basis for international standards for research ethics Identify concerns regarding risk Describe the differences that exist when vulnerable populations are participants. Understand the principles of Conflict of Interest Workshop 2012 21

22. Ethics and Regulation of Research with Children http://www.ehcca.com/presentations/ressummit3/2_04.pdf http://www.ehcca.com/presentations/ressummit3/2_04.pdf Integrity Advisory Panel on Research Ethics (Canada) http://www.pre.ethics.gc.ca/english/index.cfm http://www.pre.ethics.gc.ca/english/index.cfm Canadian Tri-Council Policy Statement on Research Ethics. Section on Minimal Risk, Section 1, C1 http://www.pre.ethics.gc.ca/english/policystatement/policystatement.cfm http://www.pre.ethics.gc.ca/english/policystatement/policystatement.cfm Interactive Research Training Curriculum, http://www.fhi.org/en/topics/ethics/curriculum/default.ht m http://www.fhi.org/en/topics/ethics/curriculum/default.ht m Belmont Report. Ethical Principles and Guidelines http://ohsr.od.nih.gov/guidelines/belmont.html http://ohsr.od.nih.gov/guidelines/belmont.html References on Research Ethics Workshop 2012 22

23. Ethics and Regulation of Research with Children http://www.ehcca.com/presentations/ressummit3/2_04.pdf http://www.ehcca.com/presentations/ressummit3/2_04.pdf Ethical and Scientific Implications of the Globalization of Clinical research. http://content.nejm.org/cgi/content/full/360/8/816 http://content.nejm.org/cgi/content/full/360/8/816 Canadian Tri-Council Policy Statement on Research Ethics. Section on Minimal Risk, Section 1, C1 http://www.pre.ethics.gc.ca/english/policystatement/policystatement.cfm http://www.pre.ethics.gc.ca/english/policystatement/policystatement.cfm Regulation of biomedical research in Africa. http://www.bmj.com/cgi/content/full/332/7545/848?rss http://www.bmj.com/cgi/content/full/332/7545/848?rss The Declaration of Helsinki (Editorial) www.bmj.com/cgi/content/full/335/7621/624?view=long&pmid=17901471 References on Research Ethics Workshop 2012 23

24. References on COI European Guideline on clinical research: http://www.emea.europa.eu/ http://www.emea.europa.eu/ ICH Guidance: Good Clinical Practice: Consolidated guideline: http://www.hc- sc.gc.ca/dhp-mps/prodpharma/applic- demande/guide-ld/ich/efficac/e6_e.html http://www.hc- sc.gc.ca/dhp-mps/prodpharma/applic- demande/guide-ld/ich/efficac/e6_e.html Information on Conflict of Interest issues: http://www.ccjm.org/toc/COI.htm http://www.ccjm.org/toc/COI.htm Dean H and MacDonald N. Who is an “Author”? http://www.diabetes.ca/publications/cjd/2007/03/ Workshop 2012 24