EU COMBINE Guide Clarifies Safety Reporting for Combined Studies

The COMBINE Project 2 sponsors' guide, published on 11 September 2026, explains safety reporting for studies covered by more than one of the EU clinical trials, medical devices and IVD frameworks. Its practical change is a departure from existing guidance-level reporting timelines, including a 7-calendar-day device reporting timeline for combined studies.

The September 2026 document is endorsed by the Clinical Trials Coordination and Advisory Group (CTAG) and Medical Device Coordination Group (MDCG). It is non-binding guidance. It does not amend legislation, replace the existing safety guidance, or set a separate implementation date.

Establish the study's legal scope first

Section 1 defines combined studies as studies covered by more than one of Regulation (EU) No 536/2014 (CTR), Regulation (EU) 2017/745 (MDR), and Regulation (EU) 2017/746 (IVDR). A medicines trial alongside an IVD performance study is one example; the definition does not make a medicines trial compulsory in every case.

This scope matters when selecting a reporting route. CTIS, the Clinical Trials Information System, serves the CTR part of a study. Device and IVD reports go to the relevant national competent authorities (NCAs). The existence of a combined study does not make those routes interchangeable.

For a study governed by only one framework, the guide should not be used to replace its existing reporting timelines. Ethics-committee reporting is outside the guide's scope, and national requirements still need to be checked.

Three reporting paths to keep separate

Section 7.3, pages 30–34, distinguishes the following paths:

A reportable DD is not every technical problem. Section 7.2 includes a deficiency that might have led to an SAE if action or intervention had not occurred or circumstances had been less fortunate. New findings and follow-up information on reportable events also need assessment.

The device-side recommendation expressly departs from the existing guidance's 2-day tier for events indicating imminent serious risk. Section 2 limits the departure to timelines set by guidance, rather than primary legislation. It does not abolish the 2-day tier for device investigations generally.

The guide does not permit waiting to address urgent risk

CTR Article 53 already requires notification of unexpected events affecting the trial's benefit-risk, other than suspected unexpected serious adverse reactions, without undue delay and no later than 15 days after awareness. Article 54 separately requires appropriate urgent safety measures and notification without undue delay, no later than 7 days after the measures are taken.

Those are different triggers from the device-reporting clock. The guide does not extend statutory obligations or make a CTIS notification a substitute for a device report. Section 6.5 also explains that duplicate reporting can still be necessary; delegation does not remove each sponsor's responsibility.

Turn the guidance into an agreed reporting plan

Pure Global analysis: build an event-to-recipient matrix before revising the study documents. For each event, identify the applicable legal framework, initial awareness time, recipient, reporting route and responsible sponsor. Include an escalation path for urgent risk and a handoff between specimen-testing and treatment sites where relevant. This makes the distinction between an investigator report, a device report and a CTR notification operational.

Section 4 recommends an integrated protocol but also permits separate documents. Its terminology is clinical investigation plan (CIP) and clinical performance study plan (CPSP). Whichever structure is used, align the reporting sections and co-sponsor communication plan. Also check the national requirements for the particular study type: section 9 highlights leftover-sample companion-diagnostic studies and MDR Article 82 investigations as cases needing separate attention.

For related IVD study context, see MDCG 2025-5 on performance studies.