FDA’s Guidance on Placebos

Guidance Information

FDA’s Guidance on Placebos:

A placebo is an inactive substance or procedure used in clinical trials to determine whether participant responses result from the actual treatment or occur by chance. Placebos contain no therapeutic ingredients but are used to create a control group for comparison. Participants are often randomly assigned to receive either the placebo or the experimental treatment. In many studies, both participants and investigators are blinded to group assignments.

The U.S. Food and Drug Administration (FDA) provides recommendations on the use of placebos and blinding specifically in randomized controlled clinical trials for drug and biological products intended to treat hematologic malignancies and oncologic diseases. Within that context, the FDA states that placebo-controlled designs may be appropriate in specific situations, such as maintenance therapy, add-on trials, adjuvant therapy studies where surveillance is standard care, or when no effective treatment exists.

FDA Finalized Guidance Highlights:

The FDA finalized a guidance for industry in August 2019, titled “Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug and Biological Products,” finalizing a draft that had been published in August 2018.  The guidance identifies a narrow set of circumstances where placebo-controlled designs are appropriate, including where surveillance is the standard of care, but this is one of several acceptable conditions, not the only one. Although not legally binding, the guidance represents the FDA’s current thinking and does not establish any rights for any person, nor is it binding on FDA or the public, sponsors may use an alternative approach if it satisfies the applicable statutes and regulations.

Placebo use is recommended in:

• Randomized trials for oncologic or hematologic conditions.
• Cases where no alternative therapy exists.
• Add-on or adjuvant studies.
• Trials where surveillance is the current standard of care.

Participants should receive a placebo only in addition to standard treatment. The guidance now states that both the investigator and the participant should be unblinded if an adverse event possibly related to the investigational treatment occurs. Importantly, if a patient is unblinded and removed from treatment following an adverse event, their data should not be removed from the trial. This distinction matters for maintaining the statistical integrity of the study.

Sponsors must justify the use of placebos, especially in cases involving invasive administration, absence of effective treatment, or use of placebo alone. Study protocols should clearly describe blinding and unblinding procedures. If blinding is maintained following an adverse event, the informed consent should explain the risks and provide reasoning. Where a known effective therapy exists for the oncologic or hematologic condition being studied, an active-control trial design must be used. There is no ethical rationale for depriving a control group of available effective treatment, and placebo controls in such settings are considered inappropriate regardless of trial design preferences. The final guidance updates a 2018 draft. Originally, the draft proposed only unblinding the participant after an adverse event. The finalized guidance clarifies that both the participant and investigator should be unblinded.

Ethical Concerns:

This guidance underscores the FDA’s ethical position that patients with life-threatening diseases should not receive placebos when proven effective therapies are already available. At the time of publication, Acting FDA Commissioner Norman “Ned” Sharpless, M.D., himself a former oncologist and director of the National Cancer Institute, presided over an agency that was increasingly focused on ensuring that clinical trial design did not deprive cancer patients of known effective treatments. By definition, blinded placebo-controlled trials are only justified where there is genuine clinical equipoise, legitimate uncertainty within the medical and research communities about the relative benefits of treatments. For many cancer trials, this criterion is not met, making other trial designs ethically necessary.

Developments Since the 2019 Guidance

The 2019 guidance remains current and has not been superseded or revised. However, several related FDA developments since 2019 are relevant for sponsors designing oncology trials with placebo controls.

Accelerated Approval and Confirmatory Trials. In March 2023, the FDA issued guidance on clinical trial considerations to support accelerated approval of oncology therapeutics, emphasizing that randomized controlled trials are the preferred approach both for initial accelerated approval and for post-approval confirmatory studies, a shift from the prior reliance on single-arm trials. In December 2024, the FDA issued updated draft guidance on accelerated approval, reflecting legislative changes that require the FDA to specify conditions for confirmatory studies at the time of approval, and updated procedures for expedited withdrawal where confirmatory trials fail.

Decentralized Clinical Trials. In September 2024, the FDA finalized guidance on conducting clinical trials with decentralized elements, providing recommendations on integrating remote participation, telehealth visits, and digital health technologies into trial design. Sponsors using placebo controls in oncology trials should consider how decentralized elements may affect blinding integrity and unblinding procedures, and ensure these are addressed explicitly in their protocols.

Multiregional Oncology Trials. In September 2024, the FDA also issued a new draft guidance on considerations for generating clinical evidence from oncology multiregional clinical development programs, expanding on existing principles and providing additional recommendations for the planning, design, conduct, and analysis of such trials. Sponsors operating across multiple regions should review this guidance alongside the 2019 placebo and blinding requirements.

Summary Note for Readers

The 2019 guidance on placebos and blinding in cancer clinical trials remains the primary FDA reference document on this topic and has not been amended. Sponsors planning placebo-controlled oncology studies should continue to apply its principles while also reviewing the related guidance issued since 2019 on accelerated approval, decentralized trials, and multiregional development programs, all of which affect broader trial design decisions in which placebo controls may be a component.