The use of a placebo in clinical research continues to be a topic of debate in the medical community. Some argue that use of placebos is often unethical because alternative study designs would produce similar results with less risk to individual research participants. Others argue that the use of placebos is essential to the protect society from the harm that could result from the widespread use of ineffective medical treatments.
Per the OHRP guidebook, "Placebos may be used in clinical trials where there is no known or available (i.e., FDA-approved) alternative therapy that can be tolerated by subjects." The use of placebos in controlled clinical trials must be justified by a positive risk-benefit analysis, and subjects must be fully informed of the risks involved in assignment to the placebo group. Continued assignment of subjects to placebo is unethical once there is good evidence to support the efficacy of the trial therapy. Some drug trials involve a period during which all participants receive only a placebo prior to the initiation of the study. This period is called a "placebo washout."
The purposes of a washout period include:
- terminating the effects of any drug the subject may have been taking before entering the clinical trial, so that the effects of the trial drug - and only the trial drug - may be observed;
- learning whether subjects cooperate with instructions to take drugs; and
- learning which subjects are "placebo responders," in that they experience a high degree of placebo effect.
In some protocols, the investigators plan to exclude those subjects they find either poorly compliant or highly responsive to the placebo. The risks entailed in withdrawing subjects from therapy during a placebo washout period will be carefully evaluated by the IRB; great care must be taken to exclude subjects who are vulnerable to harm or injury if they are withdrawn from effective therapy. In studies involving a placebo washout, subjects must be told that at some point during the study all subjects will receive placebo treatment (OHRP Guidebook).
Protocol and Consent Requirements for Use of Placebo
Researchers that conduct clinical investigations that involve the use of placebo must address additional questions in the IRB Application via Kuali Research (KR) Protocols. Researchers must:
- justify the use of the placebo,
- compare the use of placebo to standard therapy, and
- outline the methodology that will be used to minimize risks to subjects.
- If vulnerable populations are included in the study, the investigator must discuss and justify their participation and detail how subjects will be adequately protected.
The following are methods that can be used to minimize risks associated with the use of placebo:
- Exclude subjects with an increased risk of harm from non-response.
- Include in the protocol increased monitoring for subject deterioration and the use of rescue medications.
- "Early escape" mechanisms and explicit withdrawal criteria may be built in so subjects will not undergo prolonged placebo treatment if they are not doing well.
- The size of the population placed on placebo may be smaller than the number in active treatment arms.
- Placebo and active treatment may be compared in an "add-on" method, keeping the subjects on identical maintenance treatments and then adding on the active treatment to one arm and placebo to the other. This design is especially applicable when the available treatment is known to decrease mortality or morbidity.
- Shortened treatment periods reduce the risks associated with delayed treatment. In situations in which long-term placebo treatment would not be acceptable, the use of a placebo group for a short period at the beginning of a trial could establish short-term effects. The trial would then continue without the placebo group.
- Unblinded data review by a Data Safety Monitoring Board with interim analysis of study results and safety issues. This is especially important for multi-center site studies.
If a placebo is used in a study, the informed consent form must include all of the following information:
- Subjects must be informed that they may be given a placebo.
- A clear lay definition of the term "placebo."
- The rationale for using a placebo must be explained to the subjects.
- If applicable, subjects must be informed of any viable medical alternatives to being placed on placebo.
- The duration of time that a subject will be on a placebo, degree of discomfort, and potential effects of not receiving medication must all be explained.
- Any consequences of delayed active treatment must be explained to the subjects.
- A statement in the Risk section of the consent that the subject's condition may worsen while on placebo.
- A discussion in the Benefits section that subjects who receive placebo will not receive the same benefit as those who receive active treatment if that treatment is effective.
Protocol and Consent Form Requirements for Placebo Washout Periods
Studies that involve washout periods (with or without the use of a placebo) present similar concerns about risk to subjects as studies using placebos because both involve withholding available therapy from subjects. Therefore, similar attention should be paid to justification of the use of a washout period including methods to minimize risks to subjects. In the IRB application researchers must provide:
- the reason why active therapy is being withheld,
- the duration of the washout period,
- the risks specific to this phase of the study,
- increased subject monitoring during the washout period, and
- instructions to the subjects about what to do if they experience problems while off active treatment.
Use of a washout period, possible risks to the subject, and methodology to address problems that may occur during the washout period must be included in the consent form.