In a new guidance document, the U.S. Food and Drug Administration (FDA) takes direct aim at some of the ethical and practical issues complicating use of placebos and blinding practices in trials focusing on treatment of hematologic malignancy and oncologic diseases.
FDA calls for sponsors to use a placebo-controlled design only in selected circumstances (e.g., where surveillance is standard of care, or with certain trial design features—such as when the trial uses an add-on design or when the endpoint intended to support a labeling claim has a high degree of subjectivity, for example when patient-reported outcomes are used).
When considering a placebo control, FDA encourages sponsors to consider several factors, including:
- Sponsors should provide a rationale for the trial design. “Justification is particularly important in the setting of a sham surgical procedure or when invasive methods are required for administration of the placebo.”
- FDA does not require patient-level maintenance of blinding at the time of disease recurrence or progression. Unless there are no available appropriate treatment alternatives, the agency recommends unblinding a patient at the time of documented disease recurrence or progression to ensure optimal patient management.
- FDA recommends unblinding the patient and investigator when the patient has an adverse event suspected to be related to the investigational drug product and for which management of the adverse event with one or more drug products with substantial toxicity or invasive procedures is being considered. The patient should be removed from the trial in such cases.
- The sponsor should provide a detailed description in the protocol and statistical analysis plan of the proposal for blinding (including whether the physiological effects or adverse events associated with the investigational drug product will prevent effective blinding) and unblinding (including information regard situations in which unblinding should occur).
- If a sponsor intends to maintain the treatment blinding when disease recurs or progresses, or a suspected adverse event occurs, the informed consent document should specify the risks and potential disadvantages of this approach, and the protocol should include justification for the potential added risk, the FDA says in the guidance.
Author: Michael Causey