International Ethical Guidelines for Health-related Research Involving Humans

Guideline 5: Choice of control in clinical trials
When a researcher invokes compelling scientific reasons to justify the use of placebo, the research
ethics committee should seek expert advice, if such expertise is not already present among members
of the committee, as to whether use of an established effective intervention in the control arm would
invalidate the results of the research.
Minimizing risks to participants. Even when placebo is justified by one of the conditions in this
Guideline, the possibly harmful effects of receiving this comparator must be minimized consistent
with the general requirements to minimize the risks of research interventions (Guideline 4 – Potential
individual benefits and risks of research). The following conditions apply to placebo-controlled trials.
First, researchers must decrease the period of placebo use to the shortest possible time consistent
with achieving the scientific aims of the study. Risks in the placebo arm may be further reduced
by permitting a change to active treatment (“escape treatment”). The protocol should establish a
threshold beyond which the participant should be offered the active treatment.
Second, as discussed in Guideline 4 – Commentary, the researcher must minimize harmful effects
of placebo-controlled studies by providing safety monitoring of research data during the trial.
Minimal risks of receiving placebo. Risks of receiving placebo count as minimal when the risk
of serious harm is very unlikely and the potential harms associated with more common adverse
events are small, as described in Guideline 4 – Potential individual benefits and risks of research.
For example, when the investigational intervention is aimed at a relatively trivial condition, such as the
common cold in an otherwise healthy person, or hair loss, and using a placebo for the duration of a
trial would deprive control groups of only minor benefits, the risks of using a placebo-control design
are minimal. The risks of receiving placebo in the presence of an established effective intervention
must be compared with the risks that an average, normal, healthy individual experiences in daily
life or during routine examinations.
Minor increase above minimal risk. Consistent with Guideline 4 – Potential individual benefits
and risks of research, the minor increase above minimal risk standard also applies to placebocontrolled
trials.
Placebo control in a low-resource setting when an established effective intervention
cannot be made available for economic or logistic reasons. In some cases, an established
effective intervention for the condition under study exists, but for economic or logistic reasons this
intervention may not be possible to implement or made available in the country where the study is
conducted. In this situation, a trial may seek to develop an intervention that could be made available,
given the finances and infrastructure of the country (for example, a shorter or less complex course
of treatment for a disease). This can involve testing an intervention that is expected or even known
to be inferior to the established effective intervention, but may nonetheless be the only feasible or
cost-effective and beneficial option in the circumstances. Considerable controversy exists in this
situation regarding which trial design is both ethically acceptable and necessary to address the
research question. Some argue that such studies should be conducted with a non-inferiority design
that compares the study intervention with an established effective method. Others argue that a
superiority design using a placebo can be acceptable.
The use of placebo controls in these situations is ethically controversial for several reasons:
1. Researchers and sponsors knowingly withhold an established effective intervention from participants
in the control arm. However, when researchers and sponsors are in a position to provide an
intervention that would prevent or treat a serious disease, it is difficult to see why they are under
no obligation to provide it. They could design the trial as an equivalency trial to determine whether
the experimental intervention is as good or almost as good as the established effective intervention.
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INTERNATIONAL ETHICAL GUIDELINES FOR HEALTH-RELATED RESEARCH INVOLVING HUMANS