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Research and placebo controls

The problem regarding the use of placebo controls in a study is one of the most contentious ones handled by the committee. Often, conflict exists between the REC and the sponsoring agency. Indeed experiments may give "cleaner and faster" answers when placebos are used but this may not be in the best interest of the patient. Since it would be impossible to completely review this important matter here, we have included below the Tri-Council Guidelines section on placebo controls. Hopefully this may clarify some issues.

There are confounding issues however:

1. What is "standard of care"? This is not always clear to the investigator who has a more extensive experience in the given field. He or she may have good reason to believe that the "standard" is really of no value, while this opinion may be at variance with the broader medical community. Whose opinion prevails?
2. It has been stated by many that a placebo control is acceptable if the patient signs a consent form knowing "fully" what they are enrolling in. Others feel that those doing the research must adopt a more "paternalistic" attitude towards the participant and not allow the study to take place even if the consent form is understood and signed. Each protocol must be addressed separately and the REC will review and discuss the issue with the investigator when and if such a problem arises. .

Tri-council guidelines on placebo controls

"The use of placebo controls in clinical trials is generally unacceptable when standard therapies or interventions are available for a particular patient population. - A.7.4 TCG (19

Participants in the test arm of a trial of a new therapy are not receiving proven effective therapy. Risks to the safety of participants can come from lack of efficacy or from undesirable side effects. These risks should be assessed for each treatment arm, including the experimental and control arm(s). The use of an active treatment comparator in a clinical trial of a new therapy is generally the appropriate trial design when an established effective therapy exists for the population and clinical indication under study. Great care should be taken to avoid abuse of placebo comparators. However, they are acceptable in any of the following situations:

1. there are no established effective therapies for the population or for the indication under study;

2. existing evidence raises substantial doubt within the relevant expert community
regarding the net therapeutic benefit of available therapies;

3. patients are resistant to the available therapies by virtue of their past treatment history or known medical history;

4. the trial involves adding a new investigational therapy to established effective therapies: established effective therapy plus new therapy vs. 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.

The determination of response satisfaction and refusal of treatment must take place outside the context of recruitment for the clinical trial and prior to offering trial participation to the prospective participant, and both must be documented.

The use of a placebo comparator in situation (5) is permitted because prospective
trial participants are not using established therapies and therefore are not benefiting from therapy. For that reason, such participants would not be further disadvantaged if enrolled in a placebo-controlled trial than participants in a trial for whom there are no established effective therapies for the indication under study. Research proposals submitted to REBs shall include sufficient support and justification of the trial design and use of placebo comparator.

(*)Equipoise, a term introduced by the late Dr. Benjamin Freedman, Ethicist at this hospital until his death in 1997 is offered below:

"....At the start of the trial, there must be a state of clinical equipoise regarding the merits of the regimens to be tested, and the trial must be designed in such a way as to make it reasonable to expect that, if it is successfully conducted, clinical equipoise will be disturbed."

 For any questions please contact us.