"Inactive interventions" include placebos, treatment interruptions (“washout periods”), treatment withdrawals and sham procedures. It is unacceptable to use an inactive control in place of potentially effective treatment if harm will come to subjects as a result. As such, the use of inactive interventions can pose a serious ethical concern for the protection of human subjects.
When an inactive intervention is proposed to be used in place of an effective therapy — or any time a research protocol calls for the absence, withdrawal or interruption of active treatment — the rationale for the study design must be carefully explained in the IRB Application. In addition, the risks and the steps taken to minimize those risks must be articulated carefully. Serious delays in the IRB review process result when these issues are inadequately explained or unexplained.
Unfortunately, these issues often are not addressed in the multicenter protocols and sample consent forms provided by study sponsors, even when the protocol and sample consent form have been reviewed by the FDA. Local investigators must then have to provide the additional information. (The FDA conducts its scientific review of research with the understanding that there will be local review focused on the protection of human subjects.)
Note: This guidance is not intended as a comprehensive overview of controlled clinical trials. The IRB has no policy for or against particular study designs and raises concerns about study design when the risks to subjects do not appear to be reasonable in relation to anticipated benefits.
Investigators propose a short-term placebo-controlled trial in patients with a chronic condition. Subjects in the control arm will forego standard therapy for a short and clinically insignificant period of time. Subjects in the control arm may experience discomfort from their condition but are very unlikely to be harmed. They will be closely monitored to ensure they are withdrawn from the study and placed on active therapy if their condition deteriorates.
Investigators propose a long-term placebo-controlled trial in patients with a chronic condition. Subjects in the control arm would forego standard therapy for a relatively long and clinically significant period of time. There is a high likelihood that subjects in the control will be harmed if they do not receive active therapy regardless of how closely investigators monitor subjects.
The use of washout periods raises many of the same issues discussed above, whether the washout period involves tapering off of previous treatment, withholding treatment, switching treatment or providing a placebo. The IRB Application Form and consent form should address the issues raised below, taking into account the following differences:
Although washout periods may be of shorter duration than the risks of being assigned to an inactive control group ...
- For some conditions, withholding treatment for even a brief period of time may cause serious risks or discomforts.
- For other conditions, a brief period off treatment may involve negligible risk.
- Some medications may be less effective following a period of withdrawal and re-administration.
Some study designs require withholding treatment from all subjects for a period of time at the beginning of the study. Subjects need to be told that they must go without effective treatment for the specified period.
If it is necessary that subjects be blinded to the initial washout period, the Procedures section of the consent form should explain that at some period in the study, all subjects will receive inactive “treatment” for the specified duration, but that they will not be told when the inactive “treatment” is happening. The risks of going without active treatment for that period of time must be described in the consent form.
When an inactive intervention is used in place of potentially effective treatment (e.g., giving a placebo), the IRB Application Form should address the following questions:
- How is the disease or condition likely to progress over the course of the study or doing the period without active treatment?
- How long will subjects continue to receive the inactive intervention without receiving active treatment?
- What are the consequences of delaying treatment?
In answering this question, the IRB Application should include information on treatments which may be commonly used at UCSF even if not accepted as “standard.”
- Are there significant side effects associated with available treatments?
- Is there a significant placebo effect associated with the available treatments?
- What criteria are used to exclude patients who may be harmed if not given treatment immediately?
- How are subjects monitored during the study to ensure their safety?
- What are the specific withdrawal criteria, stopping rules and unblinding rules?
- What is the plan for the use of rescue medication (if applicable)?
If the IRB finds that the use of an inactive intervention in place of potentially effective treatment is safe and ethical, the procedures and risks related to the control group must be fully described in the consent form. Specifically, the consent form must describe the following issues:
|Section||Info to include||Sample Wording|
|Purpose and Background||
Half the subjects in this study will receive a placebo (an inactive pill).
You will be randomly assigned to one of two groups. This means that you have a 50/50 chance (like flipping a coin) of being in either group and that neither the researchers nor you will make the choice of which group you are in. The two groups are Group A (Drug XXX) or Group B (placebo, an inactive substance).
You will not be told whether you are given the study drug or placebo unless you experience a serious side effect and the study doctors need to find out this information to recommend treatment.
Note: Review the sample Biomedical and Cancer consent form for additional suggested wording.
||If you are assigned to Group B, you will be receiving a placebo in place of active treatment for your condition for 4 weeks. Your symptoms may get worse or become more frequent during this time. You will be closely monitored during the study and if you appear to be getting worse, or even if you think you are getting worse, you will be withdrawn from the study immediately and be given active treatment.|
|Benefits||State that subjects assigned to the inactive intervention will not benefit from being in the study.||If you are assigned to Group B (placebo), you will not benefit from being in the study.|