（一）Harmonised Seriousness Assessment Criteria for SAEs in Combined StudiesOriginal SAE definitions under CTR, MDR and IVDR are inconsistent. MDR/IVDR include extra criteria such as newly developed chronic disease, surgical intervention to prevent permanent harm, foetal injury, and harm caused by incorrect diagnostic decisions stemming from IVD results.This guidance establishes a common baseline seriousness assessment standard for combined studies: death, life‑threatening illness or injury, hospitalisation or prolonged hospitalisation, persistent or significant disability/incapacity, and congenital anomaly or birth defect. It retains the additional criteria unique to MDR/IVDR and adopts the ICH E2A medical judgement principle — medically significant events may be deemed serious even if they do not fully meet the literal criteria.Business Value：This unified standard can be directly referenced in protocols, investigator brochures and SOPs, avoiding regulatory questioning arising when the same adverse event is classified as an SAE by the drug team but not by the device team.（二）Aligned Reporting Timelines to Simplify Implementation (The only deliberate deviation from prior MDCG guidance)Earlier MDCG guidance required 2‑day expedited reporting to NCAs for high‑risk device events, while SUSAR timelines under CTR were 7/15 calendar days.
COMBINE P2 achieves alignment: in combined studies, sponsor reporting of device/IVD‑related reportable SAEs and DDs to Member State NCAs shall be completed within 7 calendar days after sponsor awareness, matching the timeline for fatal/life‑threatening SUSARs. The former 2‑day expedited requirement no longer applies. Non‑fatal, non‑life‑threatening events follow the 15‑day window.
Investigator obligations remain unchanged: SAEs/DDs must be reported to the sponsor within 24 hours upon investigator awareness.
（三）Clarified Roles for Multiple Sponsors: Liability Cannot Be Contractually DelegatedMany Chinese medical device / IVD manufacturers act as secondary sponsors in combined studies, partnering with overseas pharmaceutical CTR sponsors.The guidance sets clear ground rules:- Event collection workflows may be delegated to the counterparty or a third‑party CRO via the protocol or safety data handling agreement.
- However, legal reporting obligations cannot be transferred. Each sponsor retains full accountability for reporting duties under its respective regulatory framework.
- A single integrated protocol is strongly recommended: merging the CT Protocol, device CIP and IVD CPSP into one document to facilitate CTIS submission and clarify roles. Separate documents are still permitted.
Pitfall Warning：Many domestic companies assume that signing a delegation agreement fully transfers all safety reporting obligations to pharmaceutical partners. The guidance clarifies that only operational tasks may be delegated; legal accountability remains unchanged.（四）Bidirectional Information Flow Rules for Specimen Collection Sites and Testing LaboratoriesThis clause is critical for domestic IVD enterprises developing companion diagnostics (CDx). An SAE occurs at clinical specimen collection/treatment sites, but assessment of causality with IVD reagents requires laboratory retesting and evaluation.The guidance defines a standardised information workflow：- Investigators at specimen collection sites report the SAE to the pharmaceutical sponsor.
- The pharmaceutical sponsor notifies the IVD performance study sponsor.
- The IVD sponsor initiates laboratory review: retest original specimens and assess causality related to the IVD assay.
- Review results are fed back to the pharmaceutical sponsor. For SUSAR cases, laboratory findings must be incorporated into SUSAR follow‑up reports.
- Where risks affect all trial subjects, risk information must be shared with all study sites, rather than only the individual investigator who submitted the report.
（五）Dual Reporting Remains Unavoidable; No Legislative Solution AvailableA single serious adverse event occurring in a combined study triggers reporting requirements under both CTR (submission to EudraVigilance) and MDR/IVDR (submission to multiple NCAs).Note: There is currently no way to eliminate dual reporting. Sponsors may collect information via a single intake form and internally route submissions to different regulatory portals, but both mandatory filings must still be completed.（六）Country‑Specific Divergences for Special Study Types (Key Risk Area)- CDx performance studies using only residual specimens: No harmonised EU‑wide mandatory safety reporting rules under IVDR. Requirements are defined by national legislation of individual Member States, varying greatly between countries; some impose no reporting obligation while others mandate formal submissions.
- MDR Article 82 clinical investigations: For investigations outside the scope of MDR Article 62(1), there are no EU‑level safety reporting requirements; national rules prevail.
Practical Tip for Export Companies: For these two categories of studies, do not rely solely on EU‑level guidance. Verify local NCA requirements country by country for target Member States. Annex 1 and Annex 2 of the source document compile NCA contact emails, submission portals and country variations for periodic safety reports, which can serve as direct tools for pre‑project due diligence.（七）New Requirements for Annual Safety Reports (ASR / DSUR)The drug annual safety report for combined studies must incorporate SAE data originating from medical devices/IVDs. Four acceptable presentation formats are provided:- IMDRF coded line listing as an appendix (A/E/F codes)
- Inclusion within cumulative summary tables of the ASR with explanatory footnotes
- Dedicated tables listing all IMD/IIVD‑related SAE narratives
- Attaching standalone MDR/IVDR periodic safety reports as annexes to the ASR
Note for domestic device teams: It is no longer sufficient to submit standalone device PSRs. Close collaboration with pharmaceutical partners is required to integrate device safety data into the drug ASR. Two coding systems will run in parallel: MedDRA (for pharmaceuticals) and IMDRF (for medical devices), raising higher requirements for safety databases and CRO capabilities.（八）Key Limitation: No Statutory USM Procedure under MDR/IVDRUnder the CTR framework, sponsors may implement Urgent Safety Measures (USM) and notify via CTIS. However, MDR and IVDR do not establish equivalent USM procedures for clinical investigations / performance studies. For devices, corrective actions can only be enforced by Member State NCAs under MDR Article 76 / IVDR Article 72. Enterprises cannot initiate equivalent statutory procedures on their own; this represents an inherent legislative gap.三、Practical Action Checklist for Enterprises（一）Project Initiation PhaseIf you plan to conduct drug‑device / drug‑IVD combined studies in the EU:- Reference the COMBINE P2 guidance for drafting protocols and investigator brochures.
- Evaluate country‑specific reporting requirements of target Member States (refer to Annex 1 & Annex 2 of the guideline).
- Clearly define within sponsor agreements and safety data handling agreements: allocation of event reporting duties, resolution of causality disagreements, site‑laboratory information flow, and data exchange for annual reports. Explicitly document that operational tasks may be delegated, while legal liability remains unchanged.
Prioritise assessment of adopting a single integrated protocol. The protocol shall specify:- SAE/DD seriousness assessment criteria integrating the three regulatory frameworks plus this guidance
- Which category of events investigators report to which sponsor
- Complete information flow paths between collection sites and testing laboratories
- Communication mechanisms among multiple sponsors
- Processing rules for MedDRA and IMDRF coding
（三）Vigilance System Establishment- SOPs shall cover investigators’ 24‑hour reporting obligation to sponsors and the sponsor’s 7‑day NCA submission deadline; separate timelines must be maintained for combined studies and standalone device studies.
- Safety databases or CRO partners need capability to support both MedDRA and IMDRF coding.
- Establish workflows for unavoidable dual reporting; never expect contractual clauses to waive statutory reporting obligations.
This guidance is not binding legislation, but MDCG consensus best practice. Member State NCAs retain authority to raise differing opinions under national law. For major projects, regulatory science consultation with target Member States before submission is recommended.
