What is Transportability in RWE?
Transportability in Real-World Evidence (RWE) research refers to the ability to extend findings from one study population to a different, but related, population. This concept is critical when evaluating whether treatment effects observed in one geographical region, healthcare system, or patient cohort could be generalized to another population with different demographic, clinical, or healthcare characteristics.
In essence, transportability allows researchers to leverage existing data from one setting to generate evidence applicable in another, making it a key factor in the external validity of RWE studies.
Why is Transportability Important in RWE?
Transportability is particularly valuable when studying rare diseases, specific subpopulations, or conditions where it is challenging to collect sufficient data in a single region. Several key reasons highlight its importance:
1. Limited Patient Populations - Rare diseases, pediatric conditions, or specific genetic disorders often have a small number of patients in any given country or region. Transportability allows researchers to extend findings from a well-studied population to regions where fewer patients exist.
2. Regulatory Decision-Making - Health authorities in different countries often require evidence specific to their population before approving new treatments. Transportability research helps bridge this gap by adjusting findings from other countries and ensuring they are relevant to local healthcare settings.
3. Cost and Time Efficiency - Conducting large-scale studies across multiple geographies is expensive and time-consuming. Transportability methods allow researchers to optimize resources by applying existing data while maintaining scientific rigor.
4. Generalizability and Equity - Medical research is often conducted in high-income countries with well-established healthcare infrastructures. Transportability ensures that findings can be adapted for use in lower-income regions, promoting global health equity.
Key Regulatory Challenges in Transportability
1. Regulatory Acceptance of Transported Evidence
Regulatory agencies such as the FDA and EMA require rigorous methodological justifications for using RWE from external populations.
The main concerns include:
· Generalizability vs. Specificity: Whether the external population sufficiently represents the target setting.
· Confounding and Bias: Differences in healthcare systems, treatment pathways, and data collection practices.
· Data Quality and Standardization: Variability in how RWD is captured across different regions.
2. Population Comparability and Selection Bias
A key issue in transportability is determining how similar or different populations are. Population-level differences can arise due to:
· Demographics: Age, sex, race, and socioeconomic factors.
· Disease Prevalence and Severity: Variations in disease burden across populations.
· Healthcare Utilization: Differences in access, standard of care, and prescription patterns.
3. Exposure Variability and Treatment Effects
Exposure to a medical intervention (e.g., a drug or medical device) may differ based on:
· Dose and Administration Protocols: Variability in prescribing behaviors.
· Adherence and Persistence: Differences in patient compliance.
· Companion Diagnostics: Requirements for biomarker testing.
Methods for Assessing and Enhancing Transportability
To ensure findings are applicable across populations, researchers use several methodological approaches:
1. External Validation with Local Data - A subset of local patient data can be used to validate the transported results and refine adjustments.
3. Use of Multi-Regional RWD Sources - Combining data from multiple countries or registries can improve the ability to transport findings across settings.
4. Machine Learning and Predictive Modeling - Advanced analytics can identify key factors that influence transportability and refine models accordingly.
Regulatory Perspective on Transportability in RWE Research
Why Do Regulators Care About Transportability?
Regulatory agencies require strong evidence that a treatment is effective and safe in the specific populations they oversee. While randomized controlled trials (RCTs) provide gold-standard evidence, real-world data (RWD) and RWE play an increasing role in regulatory decision-making, particularly in situations where traditional trials are impractical or infeasible.
Transportability becomes a critical issue when:
· A treatment has been studied in one country but needs approval in another with limited local data.
· A rare disease or small patient population makes it difficult to generate region-specific RWE.
· There are significant healthcare system or demographic differences that might impact treatment effects.
Regulatory Challenges and Considerations for Transporting RWE
1. Data Relevance and Applicability - Regulatory bodies such as the European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA), and the UK's Medicines and Healthcare products Regulatory Agency (MHRA) require that RWD used for decision-making is representative of their respective populations. Therefore, transporting RWE from one country to another requires demonstrating that the patient characteristics, treatment patterns, and healthcare system factors are sufficiently similar or have been adjusted for appropriately.
2. Methodological Rigor - Agencies emphasize causal inference methods to ensure that transported RWE is not biased due to differences in data collection, patient characteristics, or healthcare access. Techniques such as external validation, statistical reweighting, and emulated target trials are often required to strengthen the credibility of transported findings.
3. Regulatory Precedents and Acceptance of Transported RWE
- FDA: The FDA has issued guidance on the use of RWE for regulatory purposes, requiring sponsors to demonstrate that the transported evidence maintains high data quality, robustness, and relevance to U.S. patient populations.
- EMA: The EMA has been at the forefront of RWE use in regulatory decision-making, particularly for rare diseases and orphan drugs. Transportability is often addressed through multi-country registry studies and external control arms (ECA).
- Health Technology Assessment (HTA) Bodies: Transporting RWE is also crucial for HTA assessments and reimbursement decisions. Agencies such as NICE (UK) and HAS (France) require strong justifications when evidence from foreign datasets is used to estimate cost-effectiveness.
Regulatory Strategies to Support Transportability of RWE
1. Engaging Regulators Early - Companies seeking approval in multiple markets should engage agencies like the FDA, EMA, and national HTA bodies early in the process to discuss transportability concerns. Parallel scientific advice sessions, such as those offered by EMA & EUnetHTA can help address regulatory differences.
2. Using Multi-Regional Data Sources - Combining data from multiple countries in international disease registries or harmonized electronic health record (EHR) networks increases the generalizability of findings.
3. Leveraging Advanced Analytical Methods - Techniques such as inverse probability weighting, meta-analysis across datasets, and transportability-adjusted external controls can help address population differences.
4. Transparency in Data and Assumptions - Regulators require a clear audit trail of data transformations, inclusion/exclusion criteria, and statistical adjustments when RWE is transported between regions.
In conclusion, transportability in RWE research is essential for overcoming challenges related to small patient populations, regulatory differences, and global healthcare disparities. By applying robust methodological approaches, researchers can ensure that real-world findings are appropriately adapted to new populations, ultimately improving access to evidence-based treatments worldwide. From a regulatory perspective, transportability in RWE research is essential for accelerating approvals, supporting HTA submissions, and improving patient access to therapies in regions where local data is scarce. However, ensuring that transported evidence meets regulatory rigor, methodological robustness, and population relevance is critical for enhancing the acceptance of transported evidence in decision-making.
REFERENCES:
Dahabreh IJ, Matthews A, Steingrimsson JA, Scharfstein DO, Stuart EA. Using Trial and Observational Data to Assess Effectiveness: Trial Emulation, Transportability, Benchmarking, and Joint Analysis. Epidemiol Rev. 2024 Dec 16;46(1):1-16. doi: 10.1093/epirev/mxac011. PMID: 36752592.
Jaksa Ashley , Arena Patrick J. , Chan Kelvin K. W. , Ben-Joseph Rami H. , Jónsson Páll , Campbell Ulka B. Transferability of real-world data across borders for regulatory and health technology assessment decision-making. Frontiers in Medicine. 2022;9. doi:10.3389/fmed.2022.1073678
Levy NS, Arena PJ, Jemielita T, Mt-Isa S, McElwee S, Lenis D, Campbell UB, Jaksa A, Hair GM. Use of transportability methods for real-world evidence generation: a review of current applications. J Comp Eff Res. 2024 Nov;13(11):e240064. doi: 10.57264/cer-2024-0064. Epub 2024 Oct 4. PMID: 39364567; PMCID: PMC11542082.
