Review: Target Trial Emulation in Observational Studies

Introduction:
Randomized controlled trials (RCTs) are the gold standard for evaluating medical interventions but are often resource-intensive. Observational studies using real-world data (RWD) from electronic health records (EHRs) or claims data offer advantages like larger sample sizes and timely availability. However, they are prone to biases. “Target trial emulation” aligns observational studies with hypothetical RCTs to improve validity and causal inference.

Key Recommendations:

1. Design Alignment with RCTs: Observational studies should replicate key trial design elements like eligibility, treatment strategies, follow-up, and outcome measures. This reduces biases and clarifies treatment-effect definitions.
2. Specification of “Time Zero”: Clearly define the start of eligibility, treatment assignment, and follow-up to prevent immortal time and selection bias. Proper alignment ensures comparable treatment groups.
3. Addressing Bias and Confounding: Observational studies remain vulnerable to confounding from unmeasured variables. Researchers must use matching, sensitivity analyses, and robust methods to assess findings’ reliability.
4. Data Quality Challenges: Using RWD requires careful validation of completeness, consistency, and accuracy. Missing or inconsistent data can affect results. Clear descriptions of data sources and quality metrics are essential.
5. Best Practices:
   • Protocols and SAPs: Pre-specify protocols and statistical plans (SAPs) to enhance transparency and mitigate bias.
   • Clear Reporting: State the observational nature of the study to avoid confusion with RCTs. Use tables to outline target trial elements.
   • Sensitivity Analyses: Explore unmeasured confounding and perform negative control outcomes to ensure robustness.

Limitations:
Despite emulating RCTs, observational studies cannot fully eliminate biases inherent in nonrandomized designs. Confounding, selection bias, and data quality issues remain risks. Careful design, pre-specification, and transparency are essential for credible results.

Conclusion:
Target trial emulation enhances observational study design by aligning it with RCT principles, mitigating biases, and improving the reliability of findings. However, it is not a substitute for randomization. Rigorous implementation and interpretation are critical for improving patient care and outcomes.

Reference:
Hubbard RA, Gatsonis CA, Hogan JW, et al. “Target Trial Emulation” for Observational Studies — Potential and Pitfalls. New England Journal of Medicine. 2024 Nov 23. DOI: http://doi.org/10.1056/NEJMp2407586