Limit Placebo Use in Cancer Clinical Trials, Says FDA

The US Food and Drug Administration (FDA) now recommends limiting the use of placebos in cancer clinical trials.

In a new draft guidance, the FDA notes that the use of placebo in double-blind, randomized trials that are conducted in a drug development programs sometimes presents "both practical and ethical concerns."

However, the placebo design may be useful or preferred in trials looking at maintenance therapy, add-on trial designs, or adjuvant therapies where the standard of care is surveillance.

Use of Placebos

In the section providing background in the new document, the agency explains that placebos are very commonly used in double-blind, randomized controlled clinical trials because they can limit the likelihood of biased observations since both the investigators and patients are "blinded" as to which treatment patients are receiving. This is turn can also reduce the number of patients who drop out of the trial and allow for unbiased assessment of outcome measures, especially those that are more subjective, such as quality of life.

However, toxicities associated with an active treatment can in fact "unblind" the trial, as patients and investigators may be able to infer which patients are getting placebo and which are not.

In addition, ethical concerns arise if a standard effective therapy is available but instead eligible patients are receiving a placebo in a clinical trial.

If patients experience disease progression or serious toxicities, even more issues arise if the trial remains blinded, the agency notes. For example, a patient participating in an immunotherapy trial who is in the control group may be treated unnecessarily for events that are attributed to the experimental drug. This could include immunosuppressive drug products such as a high dose of glucocorticoids, cyclophosphamide, interleukin-6 antagonist, or infliximab to manage these symptoms, when in fact the symptoms are unrelated to the drug.

Maintaining the blinded status can also affect adversely affect a patient who is experiencing disease progression. For example, a patient in the placebo group may be prevented or delayed from receiving an approved therapy or prevented from entering another clinical trial.

Recommendations for Placebo Use

In the new guidance, the FDA recommends that placebo-controlled trial designs should be used only in certain circumstances, such as where surveillance is standard of care, in a trial using an add-on design, or when the endpoint that is intended to support a labeling claim has a high degree of subjectivity.

In addition, the agency offers guidance for when a placebo-controlled trial is being considered:

Trial sponsors should provide the rationale for the trial design. This justification is particularly important in the setting of a sham surgical procedure or when invasive methods are required for the administration of the placebo.
The FDA does not require patient-level maintenance of blinding at the time of disease recurrence or progression, so unless no appropriate treatment options are available for the patient, the agency recommends unblinding a patient when disease recurs or progresses.
When the patient experiences an adverse event that appears to be drug related, the FDA recommends unblinding the patient and investigator if treating the event would involve one or more drugs or an invasive procedure; the patient should not be removed from the trial after being unblinded.
A detailed description in the protocol and statistical analysis plan of the proposal should be provided for both blinding (including whether the physiologic effects or adverse events associated with the investigational drug product will prevent effective blinding) and unblinding (including information regarding situations in which unblinding should occur).
If blinding is going to be continued, even if 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 also include justification for the potential added risk

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