MEDICAL RESEARCH ANDCLINICAL TRIALS

Rels 300 / Nurs 330

30 October 2014

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

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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.

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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?)

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Phase II clinical trialsStudies 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.

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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

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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?

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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?

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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?

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EXAMPLE OF PLACEBO-CONTROLLED STUDYPhase 2, Interventional Study with Placebo

Title: Improvement of Subjective Well-Being by Ranolazine Among Chronic Stable

Coronary Artery Disease Patients

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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 4th month: assess frequency of symptoms and well-being using the Seattle Angina Questionnaire

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?

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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”

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TCPS

TRI-COUNCIL POLICY STATEMENT:ETHICAL CONDUCT FOR RESEARCH INVOLVING HUMANS2ND EDITION, 2010http://pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/default/

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• 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)

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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

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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

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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

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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 favourable balance of harms and benefits

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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

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.

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(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.

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(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.

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“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)

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TCPS: 5 conditions for ethical use of a placebo in a study1. 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• established 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.

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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 4th 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?

Any Questions?

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Ebola Vaccine Research2 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

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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.

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