EU COMBINE Programme Publishes Sponsors’ Guide on Safety Reporting in Combined Studies
The COMBINE programme has published Project 2: Safety Reporting in Combined Studies – Sponsors’ Guide, dated September 2026.
The document has been endorsed by the Clinical Trial Coordination and Advisory Group (CTAG) and the Medical Device Coordination Group (MDCG) and is aimed primarily at sponsors managing studies that fall under more than one EU regulatory framework.
What Are Combined Studies?
For the purpose of the guide, combined studies are studies covered by more than one of the following legal frameworks:
Regulation (EU) No 536/2014 on clinical trials, CTR;
Regulation (EU) 2017/745 on medical devices, MDR;
Regulation (EU) 2017/746 on in vitro diagnostic medical devices, IVDR.
The guidance addresses one of the major operational challenges in such studies: the different definitions, timelines, documentation requirements and reporting processes that apply across these three regulatory systems.
Purpose of Project 2
COMBINE Project 2 aims to clarify how CTR, MDR and IVDR safety reporting requirements should be applied in combined studies.
The guide focuses on serious adverse events, device deficiencies, causality assessment, seriousness criteria and communication between investigators, sponsors and national competent authorities. It also provides best-practice recommendations and diagrams illustrating information flows between stakeholders.
Scope of the Guidance
The document provides practical guidance on managing safety events under the current legislative framework.
It covers the study lifecycle from planning and anticipated adverse event identification through event detection, causality and seriousness assessment, and communication to National Competent Authorities (NCAs).
The guide does not replace existing guidance such as MDCG 2020-10/1 rev.1, MDCG 2024-4 or CTR adverse-event reporting guidance. However, it introduces some harmonised reporting timelines for combined studies where existing timelines are defined only through guidance rather than primary legislation.
Single Protocol Approach Recommended
For combined studies, the guide recommends using a single protocol approach, integrating the clinical trial protocol with the Clinical Investigation Plan (CIP) or Clinical Performance Study Plan (CPSP).
The intended benefits include clearer sponsor responsibilities, clearer reporting requirements for investigators and, for studies following the COMBINE single-application approach, the ability to upload one document into CTIS.
The protocol should clearly define which serious adverse events and device deficiencies are reported to which sponsor, communication flows between sponsors and obligations related to medicinal products, devices, study procedures and combined issues.
Communication Responsibilities
The guidance stresses that sponsors must translate the requirements into study protocols and other applicable documents so investigators can perform safety-related tasks consistently.
Protocols should establish bidirectional communication between investigators and sponsors and, where more than one sponsor is involved, communication between clinical trial, clinical investigation and performance study sponsors.
This communication system should ensure that no reportable SAE or device deficiency is missed in either clinical or laboratory settings.
Harmonised Seriousness Assessment
Although CTR, MDR and IVDR use different terminology and criteria, the guide identifies a common basis for determining whether an adverse event is serious.
In a combined study, an event should be considered serious where it leads, or could have led, to outcomes including:
death;
life-threatening illness or injury;
hospitalisation or prolonged hospitalisation;
persistent or significant disability or incapacity;
congenital anomaly or birth defect.
Additional MDR or IVDR criteria can include temporary but serious deterioration in health, fetal distress or death, chronic disease, necessary medical or surgical intervention and certain patient-management decisions resulting in serious outcomes.
Investigator Responsibilities
Investigators are expected to record and document adverse events and device deficiencies unless otherwise specified in the protocol.
They must assess seriousness and causality with respect to the:
investigational medicinal product;
investigational medical device;
investigational IVD;
comparator;
investigational or study procedure.
The guidance also states that safety recording, documentation and reporting begin with the signing of the Informed Consent Form, including before specimen collection.
24-Hour SAE Reporting by Investigators
A key practical requirement is that investigators should report Serious Adverse Events to the appropriate sponsor or sponsors without undue delay and no later than 24 hours after becoming aware of the event, unless the protocol provides an exemption for specific SAE types.
The investigator’s causality assessment must accompany the initial SAE report and should consider each relevant investigational product or device separately in multi-product studies.
Device Deficiencies
The guide also addresses Device Deficiencies (DDs).
A DD is reportable where it might have led to an SAE if appropriate action had not been taken, intervention had not occurred or circumstances had been less fortunate. This applies to investigational medical devices, investigational IVDs and CE-marked devices used in the study.
Investigators should report relevant DDs to sponsors and, for CE-marked devices, potentially to manufacturers under applicable national vigilance procedures.
Communication in Multiple-Sponsor Studies
For combined studies involving multiple sponsors, communication between sponsors is essential.
The guide provides specific examples involving specimen collection or treatment sites and specimen testing or analysis sites. Sponsors must exchange information to ensure reportable events are not missed and that confirmed issues requiring risk mitigation are communicated promptly to all relevant investigators.
The diagrams on pages 21, 23, 28 and 29 illustrate information flows between investigators, clinical trial sponsors and performance study or clinical investigation sponsors, including feedback loops where additional causality or device information is required.
Double Reporting Remains a Challenge
The guide recognises that the same SAE may need to be reported through more than one regulatory framework.
It states that double reporting remains an unresolved issue while separate CTR, MDR and IVDR frameworks continue to apply and ultimately requires legislative harmonisation.
Sponsors may delegate operational reporting activities to another sponsor or third party, but each sponsor remains responsible for its applicable safety reporting obligations.
Sponsor Responsibilities
Sponsors must review investigator causality assessments but should not overwrite the investigator’s own assessment.
Where sponsor and investigator assessments differ, the sponsor can document its alternative opinion in the relevant safety report or narrative.
For MDR and IVDR purposes, reportable events include SAEs with an actual or reasonably possible causal relationship to the investigational device, comparator or study procedure, as well as relevant device deficiencies and follow-up findings.
Harmonised Reporting Timelines
The guide introduces practical timelines intended to simplify combined-study safety reporting.
For investigators, SAEs and relevant device deficiencies should generally be reported to sponsors without undue delay and no later than 24 hours, unless the protocol states otherwise.
For sponsors, SAEs reasonably possibly related to a medical device, IVD, comparator or investigation procedure, as well as reportable DDs, should generally be reported to relevant NCAs within 7 calendar days after sponsor awareness.
The guidance explains that this seven-day timeline aligns combined-study reporting more closely with fatal or life-threatening SUSAR timelines under the CTR.
CTR Safety Notifications
The guide also summarises CTR timelines.
Fatal or life-threatening SUSARs must generally be reported within 7 days, while non-fatal or non-life-threatening SUSARs must be reported within 15 days after sponsor awareness.
Unexpected events affecting the benefit-risk balance should be notified through CTIS without undue delay and no later than 15 days, while urgent safety measures should be notified within 7 days after the measures are taken.
National Reporting Requirements
The guide includes extensive annexes covering national reporting routes and requirements for medical device clinical investigations and IVD performance studies.
Because the EUDAMED module for clinical investigation safety reporting is not yet available, reporting currently needs to be made directly to the competent authorities in the countries where the investigation is conducted.
The annexes provide country-specific information for EU/EEA/EFTA Member States and Türkiye, including reporting email addresses, submission portals, periodic reporting requirements and additional national obligations.
Impact on Sponsors of Combined Studies
For sponsors, CROs, medical device manufacturers, IVD manufacturers, pharmaceutical companies and clinical research teams, the guide is particularly relevant where one study combines medicinal products with medical devices or IVDs.
Stakeholders should pay particular attention to:
integration of CTR, MDR and IVDR requirements;
use of a single protocol where appropriate;
SAE and device deficiency definitions;
24-hour investigator reporting;
sponsor causality assessment;
seven-day NCA reporting for certain device-related events;
SUSAR reporting timelines;
communication between multiple sponsors;
laboratory and clinical-site information flows;
double reporting risks;
CTIS and EudraVigilance reporting;
national competent authority requirements;
country-specific submission routes.
For organisations conducting combined studies in Europe, the key message is that safety reporting must be designed as an integrated process from the outset. Clear protocol responsibilities, harmonised communication and careful coordination across CTR, MDR and IVDR obligations are essential to prevent missed or delayed safety reports.
