Observational studies to emulate randomized trials: Some real-world barriers

Area of Science:

• Clinical Trials
• Real-World Evidence
• Regulatory Science

Background:

• Randomized controlled trials (RCTs) are the gold standard for drug approval.
• Real-world evidence (RWE) from observational studies is increasingly used in regulatory decision-making.
• Initiatives exist to assess RWE by emulating published RCTs.

Purpose of the Study:

• To identify and describe challenging aspects of RCT designs that hinder emulation by observational studies.
• To inform the design of future RCTs to facilitate valid RWE generation.

Main Methods:

• The study analyzes specific design features of RCTs that present difficulties for emulation.
• Focuses on three key challenging aspects: pre-randomization treatment discontinuation, run-in phases, and treatment weaning evaluations.

Main Results:

• Pre-randomization treatment discontinuation can distort comparisons in observational studies.
• Run-in phases, particularly for excluding non-compliant subjects, pose emulation challenges.
• Evaluating treatment weaning effects in RCTs is difficult to replicate with observational data.

Conclusions:

• Certain RCT designs present significant challenges for emulation using real-world evidence.
• Future RCTs should consider designs that facilitate emulation to provide valid and complementary RWE.
• Optimizing RCT designs can enhance the utility of RWE in regulatory processes.