1. MEDICAL RESEARCH AND CLINICAL TRIALS Rels 300 / Nurs 330 30 October 2014

2. What is a clinical trial?  a research study designed to evaluate a new drug or medical therapy; e.g.,  compare a new drug or treatment with a commonly used (older) drug or treatment;  compare [a combination of a new drug + an older drug] with [the older drug alone]  compare different doses of a common drug, or different doses of a newly developed drug 300/330 - appleby 2

3. What else do I need to know? Interventional study – participants receive specific interventions Observational study – assess health outcomes in groups of participants Adverse event – An unfavorable change in the health of a participant Serious adverse event – An adverse event that results in death, is life-threatening, or incapacitating, or causes a congenital anomaly or birth defect Placebo – A substance (or intervention) that does not contain active ingredients Arm (or cohort) – A group or subgroup of participants Masking (or blinding) – Whether none, or one, or both parties involved with the trial (such as the investigator or participant) know to which arm a person has been assigned. 300/330 - appleby 3

4. 4 Phases of clinical trials: Phase 1 clinical trials Is this drug safe? Studies designed to assess safety and tolerability– Is this drug safe?  a small group of healthy volunteers are given the drug to see if there are safety issues or common side effects of a drug;  the healthy volunteers may be given various doses of the drug to see what dosages seem most tolerable;  different drug delivery methods may be tested;  sometimes, phase 1 trials are conducted on people for whom no standard treatment would be effective (can you think of an example of this?) 300/330 - appleby 4

5. Phase II clinical trials Does this drug work? Studies designed to test the clinical efficacy of the drug – Does this drug work?  people who have the relevant condition or disease take the new drug;  some healthy volunteers also participate in this phase;  larger groups are tested;  continued testing for safety at different doses;  initial assessments of efficacy are made. 300/330 - appleby 5

6. Phase III clinical trials Is the new drug more effective than existing treatments? Studies designed to test the effectiveness of the new drug Is the new drug more effective than existing treatments?  much larger numbers of patients and healthy volunteers are involved in studies;  tests efficacy of the new drug to:  prolong life or improve quality of life;  reduce the risk of disease recurrence;  be effective with fewer or milder side effects.  test safety of the new drug 300/330 - appleby 6

7. Phase IV clinical trials Studies conducted after both safety and efficacy have been established Can this drug be used more effectively? Can this drug be used more effectively?  Very large group of study participants;  long-term adverse effects are studied;  dosage adjustments may be done to increase effectiveness or reduce side effects;  Can you think of a fairly recent phase IV study that resulted in the removal of a drug from the market? 300/330 - appleby 7

8. Let’s design a study The research question for this study will be: Do students who drink caffeinated beverages perform better on final exams? 1. Design a phase I study for this research; what will a phase I study be able to establish? 2. Design a phase II study; what will a phase II study be designed to test? 3. Design a phase III study; what do you want to accomplish with a phase III study? 4. If caffeine has passed in phase III studies, how would you design a phase IV study of caffeine? 300/330 - appleby 8

9. Refine your research on caffeinated beverages Is this drug safe? Phase I: Is this drug safe? Does this drug work? Phase II: Does this drug work? Is the new drug more effective than existing treatments? Phase III: Is the new drug more effective than existing treatments? Can this drug be used more effectively? Is it useful for other conditions or purposes? Phase IV: Can this drug be used more effectively? Is it useful for other conditions or purposes? 300/330 - appleby 9

10. EXAMPLE OF PLACEBO- CONTROLLED STUDY Phase 2, Interventional Study with Placebo Title: Improvement of Subjective Well-Being by Ranolazine Among Chronic Stable Coronary Artery Disease Patients 300/330 - appleby 10

11. Phase 2, Interventional Study with Placebo Summary: double-blind, placebo-controlled, randomized, single- center study; 50 study participants, 18 or older, stable, have not had bypass surgery Objective: to determine if ranolazine improves angina symptoms at 4 months compared with placebo among stable coronary artery disease patients Week 1: one tablet (500 mg ranolazine or placebo) twice a day Weeks 2 – 16: one tablet (1000 mg ranolazine or placebo) twice a day Every week: phone call to assess well-being, adverse events End of 4 th month: assess frequency of symptoms and well-being using the Seattle Angina Questionnaire

12. Ethical analysis of placebo controlled studies Why do researchers use placebo controlled studies? What benefit do they provide for the clinical trial results? What concerns do ethicists have about placebo controlled studies? Are there potential patient risks in placebo studies? 300/330 - appleby 12

13. Canadian guidelines on Placebos Therapeutic Products Directorate: “new psychiatric drugs must be tested against placebo, and shown to be better” Medical Research Council of Canada: “[p]articular care must be taken … to ensure that the subject’s best interest is never sacrificed to that of the randomized study” Tri-Council Policy Statement: “the use of placebo controls in clinical trials is generally unacceptable when standard therapies or interventions are available” 300/330 - appleby 13

14. TRI-COUNCIL POLICY STATEMENT: TCPS TRI-COUNCIL POLICY STATEMENT: ETHICAL CONDUCT FOR RESEARCH INVOLVING HUMANS 2 ND EDITION, 2010 http://pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/default/ http://pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/default/

15. Canadian Institutes Of Health Research (CIHR)CIHR The Natural Sciences And Engineering Research Council (NSERC)NSERC The Social Sciences And Humanities Research Council (SSHRC)SSHRC Interagency Advisory Panel on Research Ethics (PRE) 300/330 - appleby 15

16. Respect for Human Dignity Respect for human dignity requires that research involving humans be conducted in a manner that is sensitive to the inherent worth of all human beings and the respect and consideration that they are due. In this Policy, respect for human dignity is expressed through three core principles: 1. Respect for Persons 2. Concern for Welfare 3. Justice 300/330 - appleby 16

17. Core Principles of the TCPS 1. Respect for persons Respect for free and informed consent Respect for vulnerable persons 2. Concern for welfare Respect for privacy and confidentiality The principle of Concern for welfare is applied by Balancing harms and benefits Minimizing harm, and Maximizing benefit 3. Justice Respect for vulnerable persons 300/330 - appleby 17

18. 1. 1. Respect for Persons Recognize the intrinsic value of human persons Recognize the intrinsic value of human persons Demonstrate respect for the person’s autonomy Demonstrate respect for the person’s autonomy consent Seek free, informed and ongoing consent Remove constraints of manipulation, coercion, lack of knowledge capacity Assess a person’s capacity to make his or her own decision If lacking capacity Seek consent from someone authorized to make decisions on his or her behalf verbal assentSeek verbal assent from person 300/330 - appleby 18

19. 2. 2. Concern for Welfare A person’s welfare includes: Physical, mental and spiritual health Physical, economic and social circumstances (determinants of health) privacy and confidentiality Welfare is enhanced by respect for privacy and confidentiality balance of harms and benefits Concern for welfare is demonstrated by maximizing benefits, minimizing risks and harms, and ensuring a favourable balance of harms and benefits 300/330 - appleby 19

20. 3. 3. Justice fairly and equitably Ethical obligation to treat people fairly and equitably equal respect and concern Demonstrate equal respect and concern access to the potential benefits Distribute the benefits and burdens of participating in research – no one bears the burdens without access to the potential benefits vulnerability Respect for vulnerability: Recognition of vulnerability or vulnerable circumstances – children, elderly, women, mentally incompetent, racial minorities, institutionalized people Equitable Equitable inclusion & exclusion criteria power imbalances Be mindful of power imbalances – minimize potential harms 300/330 - appleby 20

21. Tri-Council Policy Statement http://www.pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/Default/ http://www.pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/Default/ Placebo-Controlled Trials Article 11.2 (a) A new therapy or intervention should generally be tested against an established effective therapy. 300/330 - appleby 21

22. a placebo control (b) As with all alternative choices of a control, a placebo control is ethically acceptable in a randomized controlled clinical trial only if:  its use is scientifically and methodologically sound in establishing the efficacy or safety of the test therapy or intervention; and  it does not compromise the safety or health of participants; and placebo control  the researcher articulates to the REB a compelling scientific justification for the use of the placebo control. 300/330 - appleby 22

23. placebo control (c) For clinical trials involving a placebo control, the researcher and the REB shall ensure the general principles of consent are respected and that participants or their authorized third parties are specifically informed  about any therapy that will be withdrawn or withheld for purposes of the research; and  of the anticipated consequences of withdrawing or withholding the therapy. 300/330 - appleby 23

24. “Clinical Equipoise” Benjamin Freedman “at the start of an RCT there must exist honest, professional disagreement in the community of expert practitioners as to the preferred treatment” “Clinical equipoise means a genuine uncertainty exists on the part of the relevant expert community about what therapy or therapies are most effective for a given condition. This uncertainty necessitates the conduct of research to determine the comparative therapeutic merits of existing interventions.” TCPS (text p.108-9) 300/330 - appleby 24

25. TCPS: 5 conditions for ethical use of a placebo in a study 1.there are no established effective therapies; 2.there is substantial doubt within the relevant expert community regarding the benefit of available therapies; 3.patients may be resistant to the available therapies; 4.the trial involves adding a new investigational therapy to established effective therapies: established effective therapy plus new therapy plus placeboestablished effective therapy plus placebo; 5.patients have provided an informed refusal of established effective therapy, and withholding such therapy will not cause serious or irreversible harm. 300/330 - appleby 25

26. Phase 2, Interventional Study with Placebo Title: Improvement of Subjective Well-Being by Ranolazine Among Chronic Stable Coronary Artery Disease Patients Summary: double-blind, placebo-controlled, randomized, single-center study; 50 study participants, 18 or older, stable, have not had bypass surgery Objective: to determine if ranolazine improves angina symptoms at 4 months compared with placebo among stable coronary artery disease patients Week 1: one tablet (500 mg ranolazine or placebo) twice a day Weeks 2 – 16: one tablet (1000 mg ranolazine or placebo) twice a day Every week: phone call to assess well-being, adverse events, etc. End of 4 th month: assess frequency of symptoms and well-being using the Seattle Angina Questionnaire Would this study pass the TCPS 5 conditions for a placebo study?

27. Any Questions? 300/330 - appleby 27

28. Ebola Vaccine Research 2 vaccines currently being tested: 1. VSV-ZEBOV – Public Health Agency of Canada Phase 1; 39 healthy adults, 18 to 65 3 groups; 10 in each will receive different doses of the trial vaccine, 3 will receive a placebo; staggered entry with escalating doses for safety Compare the immune responses at different dosages 2. ChAd3 – US National Institute of Allergy and Infectious Diseases Phase 1; healthy adults, 18 to 65; 10 will receive trial vaccine, 3 will receive placebo 2 doses, 28 days apart; compare immune responses Researchers hope to start Phase 2 studies in January 2015 300/330 - appleby 28

29. CENTRAL ETHICAL QUESTION RAISED: Is it unethical to give volunteers a placebo if they’re at risk for contact with a disease that has a very high fatality rate? Phase 1 studies will move forward quickly with healthy volunteers (now underway). It is likely that Phase 2 studies will involve larger numbers of people, and perhaps health care providers. Health care workers will definitely be the first to receive a vaccine if results are positive. 300/330 - appleby 29