By Jeffrey H. Brochin, J.D.
Guidance provides recommendations to industry about using placebos and blinding in randomized controlled clinical trials in development programs for drug or biological products to treat hematologic malignancies and oncologic diseases.
The FDA has announced the availability of a final guidance for industry titled ‘‘Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug and Biological Products’’ which provides recommendations when using placebos and blinding in randomized controlled clinical trials in development programs for drug or biological products to treat hematologic malignancies and oncologic diseases regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) (Notice, 84 FR 45496, August 29, 2019).
Use of placebos in double-blind clinical trials.Placebos are defined as inert substances with no pharmacologic activity, and are commonly used in double-blind, randomized controlled clinical trials. By blinding investigators and patients participating in those trials as to the treatment patients are receiving, the likelihood of biased observations of the effectiveness outcomes decreases, the differential patient drop out may decrease, and that method of clinical trials allows for unbiased observation of outcome measures. This is particularly important when the assessment includes subjective endpoints. For example, a placebo-controlled study design may be useful or preferred in maintenance therapy, in add-on trial designs, in trials of adjuvant therapies (for which standard of care is surveillance), and for indications where no treatment is available.
Ethical consideration. Obviously, the use of placebos by cancer patients participating in development programs for malignant hematologic and oncologic disease, and the use of a placebo in double-blind, randomized controlled clinical trials presents practical and ethical concerns. In many cases, because of the toxicity profile of the active treatment, patients and investigators may infer which treatment patients are receiving, and therefore using a placebo control may not blind the treatment. For patients with hematologic malignancies and oncologic diseases that have standard effective therapy available, using a placebo—not an active treatment-- generally would not be considered ethical, so an active control trial should be conducted.
Open label trial. One such active control superiority trial design option is to conduct an open-label trial with a physician’s choice of one of a few standard therapies as the comparator. In open-label comparative trials for which investigator bias may be of concern, a blinded central independent review of scans may mitigate bias regarding endpoint assessment. Another option has been to compare the investigational drug product with the placebo, with each added to the standard of care (an add-on trial).
Disease progression and adverse reactions. Continued blinding of patients and investigators at the time of disease progression or occurrence of serious adverse events is usually not acceptable. In a blinded immunotherapy trial, for example, a patient who develops suspected drug-related serious adverse events on the control arm may receive unnecessary treatments (e.g., immunosuppressive drug products including a high dose of glucocorticoids, cyclophosphamide, interleukin-6 antagonist, or infliximab) for management of adverse events incorrectly attributed to the investigational drug product.
Circumstances warranting placebo clinical trials. Given 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, drug sponsors should consider using a placebo-controlled design only in selected circumstances (such as when surveillance is the standard of care) or with certain trial design features. When considering a placebo control, sponsors should 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.
- The 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 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.
- The 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).
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