With the clear understanding that using a placebo in randomized controlled clinical trials of therapies to treat hematologic malignancy and oncologic disease for which there is known effective therapy is ethically unacceptable, sponsors should consider using a placebo-controlled design only in specific, narrow circumstances, the U.S. Food and Drug Administration (FDA) says in a new guidance issued last week (August 29).
When considering a placebo control, the agency encourages sponsors to take the following into account:
- Sponsors should provide the rationale for the trial design. Justification is particularly important in the setting of a sham surgical procedure, when invasive methods are required to administer a placebo, when primary adverse event prophylaxis is required, when there is an available therapy, or when a placebo is given as monotherapy and not combined with an active drug or drugs.
- 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, FDA recommends unblinding only the patient and the investigator at the time of documented disease recurrence or progression by an objective measurement or measurements to ensure optimal patient management. If sponsors intend to maintain patient-level blinding when disease recurs or progresses and there are existing available treatments, the informed consent document should acknowledge the risks of this approach, and the protocol should include justification for the potential added risk.
- As stated in the guidance for industry and investigators on “Safety Reporting Requirements for INDs and BA/BE Studies” (December 2012), FDA recommends unblinding the patient and the 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. In such cases of unblinding, the patient can be removed from treatment based on benefit-risk analysis, but the patient data should not be removed from the trial. If sponsors intend to maintain patient-level blinding when a suspected drug-related serious adverse event occurs, the informed consent document should acknowledge the risks of this approach, and the protocol should include justification for the potential added risk.
- Sponsors should provide a detailed description in the protocol and in the statistical analysis plan of the proposal for blinding (including whether the physiological effects or adverse events associated with the investigational drug product would lead to some degree of unblinding) and planned unblinding (unblinding driven by potential need for medicines with substantial toxicity or invasive procedures for managing adverse events).
Editor: Michael Causey
