The potential of real-world data to inform clinical trial design and supplement control arms has gained much interest in recent years. The most common approach relies on matching real-world patient cohorts to clinical trial baseline covariates using propensity score techniques. However, recent studies pointed out that there is a lack of replicability, generalisability, and consensus. Further, few studies consider differences in operational processes. Systematically accounting for confounders, including hidden effects related to the clinical treatment process and clinical trial study protocol, would potentially allow for improved translation between clinical trial and real-world data and enable learning across translational activities. In this paper, we propose an approach that aims to explore and examine these confounders by investigating the impact of selection criteria and operations on the measurements of outcome. We tested the approach on small cell lung cancer patients receiving platinum-based chemotherapy regimens (n=1,224). The results showed that the discrepancy between real-world and clinical trial data potentially depends on differences in covariate characteristics and operations (e.g., censoring mechanism, the process of pre-trial patient selection related to ECOG-performance status 2 patients). This work builds on current approaches and suggests areas of improvement for systematically accounting for differences in outcomes between study cohorts. Continued development of the method presented here could pave the way for transferring learning across studies and developing mutual translation between the real-world and clinical trials to inform future studies design.

The authors have declared no competing interest.

The Swedish Cancer Society (grant no. CAN 2018/597 and CAN2021/1469 Pj01) to R. Lewensohn and from the Stockholm Cancer Society (grant no. #201202 to R. Lewensohn and #174063, #201103 and #231123 to L. De Petris).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the institutional review boards at Karolinska Institutet and at Stockholm County Council (2016/8-31).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors