A practical, source-checked analysis of the September 2026 COMBINE Project 2 Sponsors’ Guide and what it changes for safety reporting when a medicinal-product clinical trial and an IVD performance study run together.
The practical headline
For combined studies, COMBINE Project 2 introduces a clearer operating architecture around three timelines: 24 hours from investigator to sponsor for SAEs and device deficiencies in the combined-study workflow, 7 calendar days for specified MDR/IVDR sponsor-to-NCA reporting, and 15 calendar days for unexpected events that may affect the combined clinical trial benefit-risk balance. These timelines must still be read within the binding requirements of the applicable Regulations.
24 hours. 7 days. 15 days.
These are three safety-reporting timelines that sponsors of combined studies now need to understand, and they are not interchangeable.
On 11 September 2026, the European Commission published the COMBINE Programme Project 2 Sponsors’ Guide on Safety Reporting in Combined Studies. The document was jointly endorsed by the Clinical Trials Coordination and Advisory Group (CTAG) and the Medical Device Coordination Group (MDCG), but it expressly states that it is not a European Commission document and is not legally binding. [1]
For pharmaceutical companies developing therapies alongside companion diagnostics, this is an important operational development. Combined studies can sit across the Clinical Trials Regulation (CTR), the In Vitro Diagnostic Medical Devices Regulation (IVDR) and, in some programmes, the Medical Devices Regulation (MDR). Each framework has its own terminology, reporting logic, routes and timelines. COMBINE Project 2 does not create a new law. It provides a detailed operating model for managing safety information when more than one of those frameworks applies to the same study.
COMBINE does not replace IVDR Article 76 or MDCG 2024-4
The regulatory hierarchy remains critical. IVDR Article 76 is the binding legal baseline for recording and reporting adverse events that occur during applicable performance studies. It requires the sponsor to report, without delay, serious adverse events with a causal relationship to the device, comparator or study procedure, or where such a causal relationship is reasonably possible. It also covers specified device deficiencies and new findings. The period for reporting must take account of the severity of the event. [2]
MDCG 2024-4 then provides the practical safety-reporting framework for IVD performance studies. It sets a maximum of 2 calendar days for reportable events that indicate an imminent risk requiring prompt remedial action, 7 calendar days for other reportable events, and a maximum of 3 calendar days for investigator-to-sponsor reporting of reportable events. [3]
COMBINE Project 2 explicitly says that it does not replace MDCG 2024-4 or the corresponding clinical-trial and medical-device guidance. It also states that the only active deviation from those documents is the change of reporting timelines where those timelines are defined in guidance rather than primary legislation. The stated rationale is simplification for combined studies. [1]
Why this distinction matters
A combined-study sponsor should not rewrite the IVDR around COMBINE. The safer approach is to use IVDR as the legal baseline, MDCG 2024-4 as the underlying IVD reporting framework, and COMBINE Project 2 as the cross-framework operating model for the combined study.
The new operating architecture: 24 hours, 7 days and 15 days
The clearest way to understand the change is to separate the information flows rather than treating “safety reporting” as one clock.
| Safety flow | IVDR / MDCG baseline | COMBINE Project 2 approach |
| Investigator to sponsor(s) | MDCG 2024-4: reportable IVD events immediately, maximum 3 calendar days. | SAEs stemming from the CT, CI or PS, plus device deficiencies regardless of causality: without undue delay and within 24 hours, unless the protocol provides differently. |
| Sponsor to MDR / IVDR NCAs | MDCG 2024-4: maximum 2 days for imminent-risk reportable events; 7 days for other reportable events. | Specified device/IVD related SAEs and reportable device deficiencies: within 7 calendar days after sponsor awareness. |
| Potential impact on CT benefit-risk | CTR obligations apply independently. | SAEs or device deficiencies that potentially affect the benefit-risk of the combined study should be notified via CTIS as an unexpected event within 15 calendar days after sponsor awareness. |
1. Investigator reporting becomes a 24-hour combined-study process
Under MDCG 2024-4, the sponsor must maintain a system so that reportable IVD events are provided by the investigator immediately and no later than 3 calendar days after awareness. COMBINE takes a broader combined-study approach. Its reporting table states that SAEs stemming from the clinical trial, clinical investigation or performance study, together with device deficiencies regardless of causality, should be recorded and reported to the sponsor or sponsors without undue delay and no later than within 24 hours, unless the protocol provides differently. [1] [3]
This changes the operational emphasis. The investigator should not have to solve the full CTR-versus-IVDR classification before raising a potentially significant event. The practical model becomes: rapid capture, sponsor assessment, then cross-framework routing. Site training, laboratory instructions, safety forms and the protocol or CPSP therefore need to tell investigators clearly what to report, to whom and how quickly.
2. The 7-day NCA timeline is the most important departure from MDCG 2024-4
MDCG 2024-4 says that reportable events indicating an imminent risk of death, serious injury or serious illness that requires prompt remedial action should be reported immediately and no later than 2 calendar days. Other reportable events have a maximum 7-calendar-day timeline. [3]
COMBINE Project 2 deliberately harmonises this differently for combined studies. It states that SAEs reasonably possibly related to an investigational medical device, investigational IVD, comparator or study procedure, together with reportable device deficiencies, should be reported to all relevant MDR/IVDR NCAs within 7 calendar days after sponsor awareness. The guide expressly acknowledges the 2-day MDCG timeline and explains that the combined-study timeline is harmonised with the CTR timeline for fatal or life-threatening SUSARs. [1]
There is an important legal boundary. COMBINE cannot amend Article 76. The IVDR still requires reporting without delay and says the reporting period must take account of event severity. A 7-day outer timeline should therefore not be interpreted as permission to hold an imminent-risk case until Day 7. [2]
MDx implementation recommendation
Keep immediate internal escalation, and retain a rapid operational target for events suggesting imminent risk, while configuring the formal combined-study reporting architecture around COMBINE Project 2. This is a risk-managed implementation recommendation, not a new legal requirement.
3. An IVD safety issue can also become a clinical-trial safety issue
A device deficiency is not necessarily confined to the IVDR workstream. COMBINE states that SAEs or device deficiencies, regardless of causality, which potentially affect the benefit-risk balance of the combined study should be notified through CTIS as an unexpected event within 15 calendar days after sponsor awareness. [1]
This is a major governance point for drug and companion-diagnostic programmes. The operating model cannot simply be “drug safety belongs to pharma; device safety belongs to diagnostics”. A single event may need to be assessed for IVDR performance-study reporting, CTR benefit-risk reporting, pharmacovigilance reporting and, where applicable, device vigilance. The safety system must connect those functions rather than run them as independent silos.
4. COMBINE recommends one integrated protocol approach
For combined studies, COMBINE recommends a single protocol approach in which the clinical-trial protocol and the CIP or CPSP are integrated into one document. Separate documents remain possible. The guide identifies improved clarity around sponsor responsibilities and investigator reporting requirements as advantages of the integrated approach. [1]
Whether the programme uses one document or several, the safety logic should function as one system. The protocol documentation should describe which SAEs and device deficiencies go to which sponsor, the communication flow between the CT sponsor and CI/PS sponsor, and the reporting obligations for medicinal-product issues, device issues and combined issues. The guide also calls for bidirectional communication between investigators and sponsors, and exchange between the CT sponsor and CI/PS sponsor, so that no reportable SAE or device deficiency is missed in either the clinical or laboratory setting. [1]
5. The investigator’s causality assessment cannot simply be overwritten
MDCG 2024-4 uses four causality categories for IVD performance-study SAEs: not related, possible, probable and causal relationship. COMBINE reinforces the governance behind that process. If the sponsor receives an SAE report, it must take the investigator’s preliminary causality assessment into account. The guide states that the investigator’s causality assessment should never be changed by the sponsor. Where the sponsor disagrees, the diverging opinion can be documented separately. [1] [3]
For systems and databases, the implication is straightforward: preserve both assessments. Do not convert a site assessment into a sponsor assessment by overwriting the original field.
6. COMBINE does not eliminate double reporting
One of the attractions of regulatory harmonisation is the hope that the same event will only need to be reported once. COMBINE Project 2 makes clear that Europe is not there yet. It describes double reporting as an unresolved issue that requires legislative harmonisation. [1]
Sponsors can centralise the operational work. In multiple-sponsor arrangements, reporting duties can be transferred or delegated if the arrangement is properly described in the protocol or safety data handling agreement. However, each sponsor remains responsible for its respective safety data handling and reporting duties. COMBINE also allows sponsors to provide investigators with a single safety-recording and reporting form, leaving the sponsors responsible for routing the information to the correct recipients. [1]
A useful design principle
One front door for the investigator. Multiple compliant regulatory pathways behind it.
7. CDx studies using only left-over samples remain a special case
Under IVDR Article 58(2), performance studies involving companion diagnostics are subject to the Article 58(1) requirements, except that performance studies using only left-over samples are subject to notification to the competent authority. COMBINE Project 2 then makes the safety consequence explicit: for these left-over-sample CDx studies, safety reporting requirements are a matter of national competence. [1] [2]
The guide states that testing genuine left-over specimens with the new device cannot create a patient adverse event from the testing activity itself. Operator-related adverse events can still occur, and device deficiencies may need to be reported according to national requirements. This is why the COMBINE annexes are operationally important: the absence of the standard Article 76 performance-study reporting pathway does not mean that every Member State has the same national requirements. [1]
The qualification of the specimen as genuinely left over remains critical. Sponsors should not assume that any retrospective or archived specimen automatically falls into this category. The exact study design and applicable IVDR route still need to be established before relying on the notification-only pathway.
What COMBINE Project 2 still does not solve
The guide is a major practical step, but it is not full legal harmonisation. Double reporting remains. National requirements remain relevant. Ethics committee reporting is outside the guide’s scope and can differ significantly by Member State. COMBINE also recognises that the MDR and IVDR do not currently provide an equivalent standalone mechanism for implementing an urgent safety measure outside a substantial modification. The guide says that closing that gap would require legislative change. [1]
The right response is therefore not to replace two safety systems with one simplified SOP. It is to build one operating architecture capable of satisfying multiple regulatory pathways at the same time.
What sponsors of combined CTR/IVDR studies should review now
For an ongoing or planned companion-diagnostic programme, the key question is not simply whether the Safety Management Plan mentions MDCG 2024-4. The complete study architecture should be tested against the actual information flows that COMBINE now describes.
• A 24-hour investigator and laboratory escalation pathway for SAEs and device deficiencies, unless a protocol-specific exception is justified.
• Separate and preserved investigator and sponsor causality assessments.
• A defined communication pathway between treatment or specimen-collection sites, testing laboratories, the clinical-trial sponsor and the performance-study sponsor.
• Clear Article 76 decision logic and sponsor-to-NCA reporting responsibilities.
• A cross-framework benefit-risk trigger for identifying device information that may require CTIS notification.
• Country-specific checks where national rules apply, particularly for left-over-sample CDx studies and local ethics reporting.
• Consistency across the clinical-trial protocol, CPSP, Safety Management Plan, safety-data exchange arrangements, site training, laboratory instructions and sponsor SOPs.
A technically correct procedure that cannot move information between the different sponsors quickly enough is not an effective combined-study safety system.
MDx CRO perspective: the interface is where combined studies succeed or fail
Combined CTR/IVDR studies are a core part of MDx CRO’s precision-medicine work. MDx CRO has publicly reported experience from more than 40 combined programmes across more than 20 EU countries. That experience sits precisely at the interface covered by COMBINE Project 2: pharmaceutical clinical trials, IVD performance studies, central laboratories and country-level regulatory execution. [5]
The difficult part of combined-study safety reporting is rarely understanding one regulation in isolation. It is building a system in which the CTR, IVDR, protocol, CPSP, laboratory workflow, sponsor responsibilities and country-specific reporting routes stay synchronised when an actual event occurs.
Following publication of COMBINE Project 2, MDx CRO recommends reviewing combined-study safety architecture end to end: protocol and CPSP safety sections, sponsor communication and safety-data exchange, investigator and laboratory pathways, Article 76 decision logic, CTIS benefit-risk escalation, Member State requirements and site training.
The objective is not more documentation
The objective is to ensure that when an SAE or device deficiency occurs, everyone knows what happens in the next 24 hours, and the information reaches every regulatory pathway it needs to reach.
Frequently asked questions
No. COMBINE explicitly says that it does not replace MDCG 2024-4. The guide says its only active deviation concerns reporting timelines where those timelines are established in guidance rather than primary legislation. The IVDR remains the binding legal baseline.
COMBINE states that SAEs stemming from the clinical trial, clinical investigation or performance study, as well as device deficiencies regardless of causality, should be reported to the sponsor or sponsors without undue delay and within 24 hours, unless the protocol provides differently.
For the combined-study workflow, COMBINE sets a 7-calendar-day sponsor-to-NCA timeline for specified device or IVD related SAEs and reportable device deficiencies, and it expressly notes the difference from the 2-day imminent-risk timeline in MDCG guidance. IVDR Article 76 nevertheless still requires reporting without delay and says timing must take account of severity.
Reporting activities can be allocated or delegated operationally if this is properly defined. COMBINE nevertheless states that each sponsor remains responsible for its respective safety data handling and reporting duties.
COMBINE identifies safety reporting for these studies as a matter of national competence. Operator-related adverse events and device deficiencies can still be relevant, so Member State requirements should be checked individually.
Planning a combined study involving a companion diagnostic
If your clinical programme combines a medicinal-product trial with an investigational IVD or companion diagnostic, the publication of COMBINE Project 2 is a strong reason to review the safety architecture before the next submission, protocol amendment or site activation.
MDx CRO supports precision medicine and companion diagnostic programmes across regulatory strategy, CPSP development, multi-country submissions, safety reporting, ISO 20916 study oversight and sponsor coordination. Designing the CTR and IVDR safety pathways together makes them easier to operate when a safety event occurs.
Talk to MDx about your combined study or CDx programme.
Primary regulatory sources
- COMBINE programme Project 2 Safety Reporting in Combined Studies Sponsors’ Guide, September 2026. Endorsed by CTAG and MDCG; non-binding guidance.
- Regulation (EU) 2017/746 on in vitro diagnostic medical devices, current consolidated text. See Articles 58 and 76.
- MDCG 2024-4 Safety Reporting in Performance Studies of In Vitro Diagnostic Medical Devices, April 2024.
- Regulation (EU) No 536/2014 on clinical trials, current consolidated text. See Article 53.
- MDx CRO Making IVDR Work in Combined Studies Scientific and Operational Lessons from 40+ Programs, April 2026. Source for the dated MDx CRO experience statement.
