GRADE Guidance 44: strategies to enhance the utilization of randomized and non-randomized studies in evidence syntheses of health interventions

TY - JOUR

T1 - GRADE Guidance 44

T2 - strategies to enhance the utilization of randomized and non-randomized studies in evidence syntheses of health interventions

AU - Cuello-Garcia, Carlos A.

AU - Morgan, Rebecca L.

AU - Santesso, Nancy

AU - Alonso-Coello, Pablo

AU - Brignardello-Petersen, Romina

AU - Schwingshackl, Lukas

AU - Brozek, Jan L.

AU - Katikireddi, Srinivasa Vittal

AU - Munn, Zachary

AU - Waddington, Hugh Sharma

AU - Wilson, Kevin C.

AU - Meerpohl, Joerg

AU - Morales, Daniel

AU - Neumann, Ignacio

AU - Tugwell, Peter

AU - Guyatt, Gordon

AU - Schünemann, Holger J.

N1 - Copyright: © 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

PY - 2026/2

Y1 - 2026/2

N2 - Background and Objectives: Ideally, guideline developers and health technology assessment authors base intervention decisions on randomized controlled trials (RCTs). However, relying solely on RCTs is uncommon, especially for public health interventions and harms assessment. In these situations, nonrandomized studies of interventions (NRSIs) can provide valuable information. This article presents Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidance for integrating bodies of evidence RCT and NRSI in evidence syntheses of health interventions.Methods: Following standard GRADE methods, we developed this guidance through iterative discussions and examples with experts from the GRADE NRSI project group in multiple dedicated meetings. We presented findings of the group discussions for feedback at GRADE Working Group meetings in September 2023 and May 2024.Results: The resulting GRADE guidance outlines a structured approach: (1) assessing the certainty of evidence (CoE) after defining the number of decision thresholds and the target of the certainty rating; (2) evaluating congruency of effect estimates between RCTs and NRSIs; (3) identifying which GRADE domains are affected by certainty ratings to inform complementariness between RCTs and NRSIs and the overall CoE; and (4) deciding whether and how to use one or both types of studies.Conclusion: This GRADE guidance offers a structured and practical approach for integrating or not integrating RCTs and NRSIs in evidence syntheses. By addressing the interplay between affected GRADE domains and assessing the congruency of effects, it helps GRADE users determine when and how NRSIs can meaningfully complement or replace RCT evidence to inform certainty ratings and decision-making.

AB - Background and Objectives: Ideally, guideline developers and health technology assessment authors base intervention decisions on randomized controlled trials (RCTs). However, relying solely on RCTs is uncommon, especially for public health interventions and harms assessment. In these situations, nonrandomized studies of interventions (NRSIs) can provide valuable information. This article presents Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidance for integrating bodies of evidence RCT and NRSI in evidence syntheses of health interventions.Methods: Following standard GRADE methods, we developed this guidance through iterative discussions and examples with experts from the GRADE NRSI project group in multiple dedicated meetings. We presented findings of the group discussions for feedback at GRADE Working Group meetings in September 2023 and May 2024.Results: The resulting GRADE guidance outlines a structured approach: (1) assessing the certainty of evidence (CoE) after defining the number of decision thresholds and the target of the certainty rating; (2) evaluating congruency of effect estimates between RCTs and NRSIs; (3) identifying which GRADE domains are affected by certainty ratings to inform complementariness between RCTs and NRSIs and the overall CoE; and (4) deciding whether and how to use one or both types of studies.Conclusion: This GRADE guidance offers a structured and practical approach for integrating or not integrating RCTs and NRSIs in evidence syntheses. By addressing the interplay between affected GRADE domains and assessing the congruency of effects, it helps GRADE users determine when and how NRSIs can meaningfully complement or replace RCT evidence to inform certainty ratings and decision-making.

KW - Certainty of evidence

KW - Evidence synthesis

KW - GRADE

KW - Nonrandomized studies

KW - Randomized controlled trials

KW - Risk of bias

UR - https://www.scopus.com/pages/publications/105024920862

U2 - 10.1016/j.jclinepi.2025.112086

DO - 10.1016/j.jclinepi.2025.112086

M3 - Article

C2 - 41285282

AN - SCOPUS:105024920862

SN - 0895-4356

VL - 190

JO - Journal of Clinical Epidemiology

JF - Journal of Clinical Epidemiology

M1 - 112086

ER -