International Ethical Guidelines for Health-related Research Involving Humans

Guideline 5: Choice of control in clinical trials
Although conventional randomized controlled clinical trials are often considered the gold standard,
other study designs such as response-adaptive trial designs, observational studies, or historical
comparisons can also yield valid research results. Researchers and sponsors must carefully
consider whether the research question can be answered with an alternative design, and whether
the risk-benefit profile of alternative designs is more favourable when compared to a conventional
randomized controlled trial.
Established effective intervention. An established effective intervention for the condition under
study exists when it is part of the medical professional standard. The professional standard includes,
but is not limited to, the best proven intervention for treating, diagnosing or preventing the given
condition. In addition, the professional standard includes interventions that may not be the very
best when compared to available alternatives, but are nonetheless professionally recognized as a
reasonable option (for example, as evidenced in treatment guidelines).
Yet established effective interventions may need further testing, especially when their merits
are subject to reasonable disagreement among medical professionals and other knowledgeable
persons. Clinical trials may be warranted in this case, in particular if the efficacy of an intervention
or procedure has not been determined in rigorous clinical trials. Trials may also be useful when
the risk-benefit profile of a treatment is not clearly favourable, such that patients might reasonably
forgo the usual intervention for the condition (for example, antibiotic treatment for otitis media in
children, or arthroscopic knee surgery). When there are several treatment options but it remains
unknown which treatment works best for whom, comparative effectiveness research may help to
further determine the effectiveness of an intervention or procedure for specific groups. This may
include testing an established effective intervention against a placebo, provided the conditions of
this Guideline are met.
Some people contend that it is never acceptable for researchers to withhold or withdraw established
effective interventions. Others argue that it may be acceptable, provided that the risks of withholding
an established intervention are acceptable, and withholding the established effective intervention
is necessary to ensure that the results are interpretable and valid. In such cases, an intervention
known to be inferior, a placebo (see below) or no intervention may be substituted for the established
intervention. This Guideline takes a middle stance on this issue. The preferred option is to test
potential new interventions against an established effective intervention. When researchers propose
to deviate from this option, they must provide a compelling methodological justification and evidence
that the risks from withholding or delaying the established intervention are no greater than a minor
increase above minimal risk.
These principles on the use of placebo also apply to the use of control groups who receive no treatment
or who receive a treatment that is known to be inferior to an established treatment. Sponsors,
researchers, and research ethics committees should evaluate the risks of providing no treatment
(and no placebo) or an inferior treatment, compared to the risks and potential individual benefits of
providing an established treatment, and apply the criteria for placebo use in this Guideline. In sum,
when an established effective intervention exists, it may be withheld or substituted with an inferior
intervention only if there are compelling scientific reasons for doing so; the risks of withholding the
established intervention or substituting it with an inferior one will result in no more than a minor
increase above minimal risk to participants; and the risks to participants are minimized.
Placebo. An inert substance or sham procedure is provided to research participants with the aim
of making it impossible for them, and usually the researchers themselves, to know who is receiving
an active or inactive intervention. Placebo interventions are methodological tools used with the goal
of isolating the clinical effects of the investigational drug or intervention. This enables researchers
to treat participants in the study arm and the control arm in exactly the same way, except that the
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INTERNATIONAL ETHICAL GUIDELINES FOR HEALTH-RELATED RESEARCH INVOLVING HUMANS