CIOMS Guidelines - Global Health Trials

event, the researcher must satisfy the ethical review committee that the safety and human rights ofthe subjects will be fully protected, that prospective subjects will be fully informed about alternativetreatments, and that the purpose and design of the study are scientifically sound. The ethicalacceptability of such placebo-controlled studies increases as the period of placebo use is decreased,and when the study design permits change to active treatment ("escape treatment") if intolerablesymptoms occur.Exceptional use of a comparator other than an established effective intervention. An exception to thegeneral rule is applicable in some studies designed to develop a therapeutic, preventive ordiagnostic intervention for use in a country or community in which an established effectiveintervention is not available and unlikely in the foreseeable future to become available, usually foreconomic or logistic reasons. The purpose of such a study is to make available to the population ofthe country or community an effective alternative to an established effective intervention that islocally unavailable. Accordingly, the proposed investigational intervention must be responsive to thehealth needs of the population from which the research subjects are recruited and there must beassurance that, if it proves to be safe and effective, it will be made reasonably available to thatpopulation. Also, the scientific and ethical review committees must be satisfied that the establishedeffective intervention cannot be used as comparator because its use would not yield scientificallyreliable results that would be relevant to the health needs of the study population. In thesecircumstances an ethical review committee can approve a clinical trial in which the comparator isother than an established effective intervention, such as placebo or no treatment or a local remedy.However, some people strongly object to the exceptional use of a comparator other than anestablished effective intervention because it could result in exploitation of poor and disadvantagedpopulations. The objection rests on three arguments:• Placebo control could expose research subjects to risk of serious or irreversible harm whenthe use of an established effective intervention as comparator could avoid the risk.• Not all scientific experts agree about conditions under which an established effectiveintervention used as a comparator would not yield scientifically reliable results.• An economic reason for the unavailability of an established effective intervention cannotjustify a placebo-controlled study in a country of limited resources when it would beunethical to conduct a study with the same design in a population with general access to theeffective intervention outside the study.Placebo control when an established effective intervention is not available in the host country. Thequestion addressed here is: when should an exception be allowed to the general rule that subjects inthe control arm of a clinical trial should receive an established effective intervention?The usual reason for proposing the exception is that, for economic or logistic reasons, an establishedeffective intervention is not in general use or available in the country in which the study will beconducted, whereas the investigational intervention could be made available, given the finances andinfrastructure of the country.Another reason that may be advanced for proposing a placebo-controlled trial is that using anestablished effective intervention as the control would not produce scientifically reliable datarelevant to the country in which the trial is to be conducted. Existing data about the effectivenessand safety of the established effective intervention may have been accumulated undercircumstances unlike those of the population in which it is proposed to conduct the trial; this, it maybe argued, could make their use in the trial unreliable. One reason could be that the disease or