Medical Research and Clinical Trials

1. Medical Research andClinical Trials Rels 300 / Nurs 330 31October 2013

2. 300/330 - appleby 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

3. 300/330 - appleby 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.

4. 300/330 - appleby 4 Phases of clinical trials:Phase 1 clinical trials 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?)

5. 300/330 - appleby Phase II clinical trials 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.

6. 300/330 - appleby Phase III clinical trials 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

7. 300/330 - appleby Phase IV clinical trials Studies conducted after both safety and efficacy have been established – 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?

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

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

10. 300/330 - appleby 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?

11. 300/330 - appleby 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”

12. TCPSTri-Council Policy Statement:Ethical Conduct for Research Involving Humans2nd Edition, 2010http://pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/default/

13. 300/330 - appleby • Canadian Institutes Of Health Research (CIHR) • The Natural Sciences And Engineering Research Council (NSERC) • The Social Sciences And Humanities Research Council (SSHRC) Interagency Advisory Panel on Research Ethics (PRE)

14. 300/330 - appleby 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: • Respect for Persons • Concern for Welfare • Justice

15. 300/330 - appleby Core Principles of the TCPS • Respect for persons • Respect for free and informed consent • Respect for vulnerable persons • 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 • Justice • Respect for vulnerable persons

16. 300/330 - appleby 1. Respect for Persons • Recognize the intrinsic value of human persons • Demonstrate respect for the person’s autonomy • Seek free, informed and ongoing consent • Remove constraints of manipulation, coercion, lack of knowledge • 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 • Seek verbal assent from person

17. 300/330 - appleby 2. Concern for Welfare • A person’s welfare includes: • Physical, mental and spiritual health • Physical, economic and social circumstances (determinants of health) • Welfare is enhanced by respect for privacy and confidentiality • Concern for welfare is demonstrated by maximizing benefits, minimizing risks and harms, and ensuring a favourablebalance of harms and benefits

18. 300/330 - appleby 3. Justice • Ethical obligation to treat people fairly and equitably • Demonstrate equal respect and concern • Distribute the benefits and burdens of participating in research – no one bears the burdens without access to the potential benefits • Respect for vulnerability: • Recognition of vulnerability or vulnerable circumstances – children, elderly, women, mentally incompetent, racial minorities, institutionalized people • Equitable inclusion & exclusion criteria • Be mindful of power imbalances – minimize potential harms

19. 300/330 - appleby Tri-Council Policy Statementhttp://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.

20. 300/330 - appleby (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 • the researcher articulates to the REB a compelling scientific justification for the use of the placebo control.

21. 300/330 - appleby (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.

22. 300/330 - appleby “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 uncertaintyexists 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)

23. 300/330 - appleby TCPS: 5 conditions for ethical use of a placebo in a study • there are no established effective therapies; • there is substantial doubt within the relevant expert community regarding the benefit of available therapies; • patients may be resistant to the available therapies; • the trial involves adding a new investigational therapy to established effective therapies: • established effective therapy plus new therapy • established effective therapy plus placebo; • patients have provided an informed refusal of established effective therapy, and withholding such therapy will not cause serious or irreversible harm.

24. 300/330 - appleby Any Questions?