Managing Placebo Use When Standard-of-Care Exists in Phase 2 Trials

Ethical and Strategic Approaches to Placebo Use in Phase 2 Trials with Existing Standard-of-Care

Table of Contents

Introduction

Phase 2 trials are designed to evaluate the efficacy and safety of investigational treatments before proceeding to large-scale confirmatory trials. While placebo-controlled designs are the gold standard for assessing efficacy, their use becomes ethically complex when an effective standard-of-care (SoC) treatment already exists. This tutorial explores how to ethically and scientifically manage placebo use in Phase 2 studies while preserving both patient safety and trial integrity.

Why Is Placebo Use Problematic When SoC Exists?

Ethical concerns: Withholding known effective therapy may put participants at risk
Regulatory scrutiny: Authorities may require justification for placebo use when SoC is available
Participant recruitment issues: Patients may decline participation if assigned to placebo

Acceptable Placebo Strategies in the Context of Standard-of-Care

1. Add-On Design

All participants receive SoC; investigational drug or placebo is added
Ethically acceptable and common in oncology, autoimmune, and infectious disease trials

2. Active-Controlled Design

Investigational drug is compared directly against SoC rather than placebo
Provides direct comparative data but may require larger sample size

3. Delayed Start or Early Escape Designs

Patients receive placebo for a short, predefined period before switching to active treatment
Useful when long-term placebo

withholding is ethically unacceptable

4. Enrichment and Randomized Withdrawal

Only responders to SoC or investigational treatment are randomized to withdrawal or continuation
Common in CNS and autoimmune trials

Ethical Guidelines for Placebo Use

Declaration of Helsinki

Placebo-controlled trials are only acceptable when no proven intervention exists
Exception: scientifically sound methodology requires placebo, and withholding SoC does not risk serious harm

ICH E10 Guidance

Recommends active-control when SoC is established
Allows placebo if scientifically justified and ethical safeguards are in place

Informed Consent Considerations

Clearly communicate possibility of receiving placebo
Explain what SoC participants will still receive (if applicable)
Disclose rescue or early exit options for non-responders

Case Example: RA Trial with Placebo and SoC

A Phase 2 trial evaluating a novel IL-6 inhibitor in rheumatoid arthritis randomized patients to:

Placebo + methotrexate (SoC)
Low-dose IL-6i + methotrexate
High-dose IL-6i + methotrexate

All participants continued background SoC, satisfying ethical standards. Primary endpoint was ACR20 at Week 12. Trial successfully demonstrated efficacy while maintaining patient safety.

Statistical and Design Considerations

Power calculations: Must account for SoC effect on both placebo and active arms
Blinding challenges: Side effects of active drugs may unblind participants—use matched placebos
Adaptive design: Can reduce exposure to placebo based on interim analysis

Regulatory Expectations

FDA (U.S.)

Accepts placebo + SoC add-on designs
Placebo alone not acceptable where SoC omission poses risk

EMA (Europe)

Favors active-controlled trials but accepts placebo with proper justification
Delayed start designs supported for neurodegenerative diseases

CDSCO (India)

Requires ethics committee approval and full justification for placebo when SoC exists
Insists on immediate withdrawal from placebo in case of patient deterioration

Best Practices for Sponsors and Investigators

Engage ethics committees early to review trial rationale and control strategy
Use add-on designs whenever possible to ensure SoC continuity
Implement rescue protocols and safety monitoring plans
Train investigators on informed consent discussions related to placebo use
Document all placebo-related decisions in the protocol and IRB submissions

Conclusion

While placebo controls remain essential for scientific rigor, their use in Phase 2 trials must be carefully adapted when effective standard-of-care treatments exist. Ethical designs like add-on, early escape, and randomized withdrawal help maintain patient safety without compromising data quality. By aligning with international guidelines and maintaining transparency, researchers can ethically navigate the complexities of placebo use in modern clinical research.