Given the ethical challenges of using a placebo in randomized controlled clinical trials for therapies to treat hematologic malignancy and oncologic disease, the FDA recommends that a sponsor use a placebo-controlled design only in select circumstances, according to new draft guidance released Thursday.
Such circumstances include “where surveillance is standard of care,” or with specific trial “design features (e.g. if the trial uses an add-on design, when the endpoint intended to support a labeling claim has a high degree of subjectivity, such as patient reported outcomes).”
And when considering the use of a placebo control, the FDA says sponsors should provide a rationale for the trial design and a detailed description in the protocol and statistical analysis plan of the proposal for blinding and unblinding.
“If a sponsor intends to maintain the treatment blind 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 three-page draft says.
The FDA also recommends that sponsors unblind a patient “at the time of documented disease recurrence or progression to ensure optimal patient management.”
Continued blinding at the time of disease progression or occurrence of serious adverse events presents additional challenges, the FDA says.
For example, in a blinded immunotherapy trial, a patient who develops 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.
Maintaining the blind after disease progression could also affect a patient’s subsequent therapy.
The FDA also 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. In such cases of unblinding, the patient should not be removed from the trial.”
In terms of the practical and ethical concerns related to using placebos in some oncology trials, the FDA notes that in many cases, because of the toxicity of the active treatment, patients and investigators may know if they are receiving a placebo treatment.
First published here. Regulatory Focus is the flagship online publication of the Regulatory Affairs Professionals Society (RAPS), the largest global organization of and for those involved with the regulation of healthcare and related products, including medical devices, pharmaceuticals, biologics and nutritional products. Email email@example.com for more information.
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