A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX

Ralf J. Ludwig; Matthew Anson; Henner Zirpel; Diamant Thaci; Henning Olbrich; Katja Bieber; Khalaf Kridin; Astrid Dempfle; Philip Curman; Sizheng S. Zhao; Uazman Alam

doi:10.3389/fphar.2025.1516126

A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX

Ralf J. Ludwig^*, Matthew Anson, Henner Zirpel, Diamant Thaci, Henning Olbrich, Katja Bieber, Khalaf Kridin, Astrid Dempfle, Philip Curman, Sizheng S. Zhao, Uazman Alam^*

^*Corresponding author for this work

132 Citations (Scopus)

Abstract

Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of both pharmacological and non-pharmacological interventions. However, while they are designed to control confounders and ensure internal validity, their usually stringent inclusion and exclusion criteria often limit the generalizability of findings to broader patient populations. Moreover, RCTs are resource-intensive, frequently underpowered to detect rare adverse events, and sometimes narrowly focused due to their highly controlled environments. In contrast, real-world data (RWD), typically derived from electronic health records (EHRs) and claims databases, offers a valuable counterpart for answering research questions that may be impractical to address through RCTs. Recognizing this, the US Food and Drug Administration (FDA) has increasingly relied on real-world evidence (RWE) from RWD to support regulatory decisions and post-market surveillance. Platforms like TriNetX, that leverage large-scale RWD, facilitate collaborations between academia, industry, and healthcare organizations, and constitute an in-depth tool for retrieval and analysis of RWD. TriNetX’s federated network architecture allows real-time, privacy-compliant data access, significantly enhancing the ability to conduct retrospective studies and refine clinical trial designs. With access to currently over 150 million EHRs, TriNetX has proven particularly effective in filling gaps left by RCTs, especially in the context of rare diseases, rare endpoints, and diverse patient populations. As the role of RWD in healthcare continues to expand, TriNetX stands out as a critical tool that complements traditional clinical trials, bridging the gap between controlled research environments and real-world practice. This review provides a comprehensive analysis of the methodologies and applications of the TriNetX platform, highlighting its potential contribution to advance patient care and outcomes.

Original language	English
Article number	1516126
Journal	Frontiers in Pharmacology
Volume	16
DOIs	https://doi.org/10.3389/fphar.2025.1516126
Publication status	Published - 2025

Funding

Funders	Funder number
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)
Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

2.21-05 Immunology
2.22-19 Dermatology

Access to Document

10.3389/fphar.2025.1516126

Cite this

@article{ebcbcf38aa8840d498278b42b065a781,

title = "A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX",

abstract = "Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of both pharmacological and non-pharmacological interventions. However, while they are designed to control confounders and ensure internal validity, their usually stringent inclusion and exclusion criteria often limit the generalizability of findings to broader patient populations. Moreover, RCTs are resource-intensive, frequently underpowered to detect rare adverse events, and sometimes narrowly focused due to their highly controlled environments. In contrast, real-world data (RWD), typically derived from electronic health records (EHRs) and claims databases, offers a valuable counterpart for answering research questions that may be impractical to address through RCTs. Recognizing this, the US Food and Drug Administration (FDA) has increasingly relied on real-world evidence (RWE) from RWD to support regulatory decisions and post-market surveillance. Platforms like TriNetX, that leverage large-scale RWD, facilitate collaborations between academia, industry, and healthcare organizations, and constitute an in-depth tool for retrieval and analysis of RWD. TriNetX{\textquoteright}s federated network architecture allows real-time, privacy-compliant data access, significantly enhancing the ability to conduct retrospective studies and refine clinical trial designs. With access to currently over 150 million EHRs, TriNetX has proven particularly effective in filling gaps left by RCTs, especially in the context of rare diseases, rare endpoints, and diverse patient populations. As the role of RWD in healthcare continues to expand, TriNetX stands out as a critical tool that complements traditional clinical trials, bridging the gap between controlled research environments and real-world practice. This review provides a comprehensive analysis of the methodologies and applications of the TriNetX platform, highlighting its potential contribution to advance patient care and outcomes.",

author = "Ludwig, \{Ralf J.\} and Matthew Anson and Henner Zirpel and Diamant Thaci and Henning Olbrich and Katja Bieber and Khalaf Kridin and Astrid Dempfle and Philip Curman and Zhao, \{Sizheng S.\} and Uazman Alam",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 Ludwig, Anson, Zirpel, Thaci, Olbrich, Bieber, Kridin, Dempfle, Curman, Zhao and Alam.",

year = "2025",

doi = "10.3389/fphar.2025.1516126",

language = "English",

volume = "16",

journal = "Frontiers in Pharmacology",

issn = "1663-9812",

publisher = "Frontiers Media SA",

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TY - JOUR

T1 - A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX

AU - Ludwig, Ralf J.

AU - Anson, Matthew

AU - Zirpel, Henner

AU - Thaci, Diamant

AU - Olbrich, Henning

AU - Bieber, Katja

AU - Kridin, Khalaf

AU - Dempfle, Astrid

AU - Curman, Philip

AU - Zhao, Sizheng S.

AU - Alam, Uazman

PY - 2025

Y1 - 2025

N2 - Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of both pharmacological and non-pharmacological interventions. However, while they are designed to control confounders and ensure internal validity, their usually stringent inclusion and exclusion criteria often limit the generalizability of findings to broader patient populations. Moreover, RCTs are resource-intensive, frequently underpowered to detect rare adverse events, and sometimes narrowly focused due to their highly controlled environments. In contrast, real-world data (RWD), typically derived from electronic health records (EHRs) and claims databases, offers a valuable counterpart for answering research questions that may be impractical to address through RCTs. Recognizing this, the US Food and Drug Administration (FDA) has increasingly relied on real-world evidence (RWE) from RWD to support regulatory decisions and post-market surveillance. Platforms like TriNetX, that leverage large-scale RWD, facilitate collaborations between academia, industry, and healthcare organizations, and constitute an in-depth tool for retrieval and analysis of RWD. TriNetX’s federated network architecture allows real-time, privacy-compliant data access, significantly enhancing the ability to conduct retrospective studies and refine clinical trial designs. With access to currently over 150 million EHRs, TriNetX has proven particularly effective in filling gaps left by RCTs, especially in the context of rare diseases, rare endpoints, and diverse patient populations. As the role of RWD in healthcare continues to expand, TriNetX stands out as a critical tool that complements traditional clinical trials, bridging the gap between controlled research environments and real-world practice. This review provides a comprehensive analysis of the methodologies and applications of the TriNetX platform, highlighting its potential contribution to advance patient care and outcomes.

AB - Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of both pharmacological and non-pharmacological interventions. However, while they are designed to control confounders and ensure internal validity, their usually stringent inclusion and exclusion criteria often limit the generalizability of findings to broader patient populations. Moreover, RCTs are resource-intensive, frequently underpowered to detect rare adverse events, and sometimes narrowly focused due to their highly controlled environments. In contrast, real-world data (RWD), typically derived from electronic health records (EHRs) and claims databases, offers a valuable counterpart for answering research questions that may be impractical to address through RCTs. Recognizing this, the US Food and Drug Administration (FDA) has increasingly relied on real-world evidence (RWE) from RWD to support regulatory decisions and post-market surveillance. Platforms like TriNetX, that leverage large-scale RWD, facilitate collaborations between academia, industry, and healthcare organizations, and constitute an in-depth tool for retrieval and analysis of RWD. TriNetX’s federated network architecture allows real-time, privacy-compliant data access, significantly enhancing the ability to conduct retrospective studies and refine clinical trial designs. With access to currently over 150 million EHRs, TriNetX has proven particularly effective in filling gaps left by RCTs, especially in the context of rare diseases, rare endpoints, and diverse patient populations. As the role of RWD in healthcare continues to expand, TriNetX stands out as a critical tool that complements traditional clinical trials, bridging the gap between controlled research environments and real-world practice. This review provides a comprehensive analysis of the methodologies and applications of the TriNetX platform, highlighting its potential contribution to advance patient care and outcomes.

UR - https://www.scopus.com/pages/publications/105000734325

U2 - 10.3389/fphar.2025.1516126

DO - 10.3389/fphar.2025.1516126

M3 - Scientific review articles

AN - SCOPUS:105000734325

SN - 1663-9812

VL - 16

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

M1 - 1516126

ER -

A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

CRC 1526, PANTAU: Pathomechanisms of Antibody-mediated Autoimmunity

Cite this

A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

Projects

CRC 1526, PANTAU: Pathomechanisms of Antibody-mediated Autoimmunity

Cite this