The HPRA has invited clinical trial sponsors to apply for Phase 2 of the EU COMBINE pilot, which assesses a medicine trial and its linked device or diagnostic study in one coordinated review. Phase 2 adds medical device investigations, advanced therapy trials and studies run by two separate sponsors, and Ireland can lead assessments.
The Health Products Regulatory Authority notice, dated 23 October 2026, says "COMBINE Phase 2 is now open for submissions". The European Commission launched the second phase on 26 June 2026, and its COMBINE pilot page says it will stay open for expressions of interest for at least one year, with monthly application slots.
- What it is: a single, coordinated assessment of a clinical trial of a medicine combined with a medical device clinical investigation or an in vitro diagnostic (IVD) performance study, run through the EU Clinical Trials Information System (CTIS).
- Phase 1: eight applications from six sponsors were accepted; the first was authorised in March 2026, and Ireland took part as a concerned Member State.
- New in Phase 2: medical device studies, trials of advanced therapy medicinal products (ATMPs), and the option of separate sponsors for the trial and the device or diagnostic study.
- Ireland's role: Ireland is one of 18 participating countries and can act as reporting Member State, the authority that leads the assessment.
- How to apply: an expression of interest and protocol synopsis go to EUcombinepilot@ccmo.nl by the 23rd of the month before the planned submission; the next cut-off is 23 November 2026 for December.
What the COMBINE programme is trying to fix
Many new medicines are tested alongside a device or a diagnostic test, for example a companion diagnostic that selects which patients receive a cancer drug. In the EU, the medicine side falls under the Clinical Trials Regulation (EU) No 536/2014 (CTR), while the device or test falls under the Medical Device Regulation (EU) 2017/745 (MDR) or the In Vitro Diagnostic Regulation (EU) 2017/746 (IVDR). Each framework has its own application, assessment and ethics review, so a single study can need parallel paperwork in every country involved.
The European Commission says these combined studies currently face duplication and delays. COMBINE began in June 2023 as a programme of seven cross-sector projects involving the Commission, national competent authorities and ethics committees. Project 1, the "all-in-one" pilot, synchronises submission, validation and assessment so that the authorisations and ethics opinions for the trial and the device or diagnostic study arrive at the same time. One country, the reporting Member State (RMS), coordinates requests for information on both parts, and the sponsor answers them in a single response.
What Phase 1 showed
Phase 1 opened in June 2025 and was limited to multinational trials of an investigational medicine combined with an IVD performance study run by the same sponsor. The HPRA's June 2025 notice said "HPRA colleagues have co-led the development of the pilot" with other national competent authorities, supported by the European Medicines Agency (EMA) and the Commission. The expression of interest period closed in September 2025 with eight applications accepted.
A stakeholder presentation from May 2026 adds detail. The eight applications came from six sponsors, with Germany acting as RMS for five and the Netherlands for three. France, Spain, Belgium, Norway and Ireland took part as participating Member States. The first application was authorised in March 2026, and seven of the eight were in progress or concluded. The presentation says feedback was built into Phase 2 as it arrived, and that a formal analysis of Phase 1 will follow once all applications have concluded and surveys are returned. No outcome data for individual studies has been published.
What changes in Phase 2
The Phase 2 sponsor guide (version 02.01, 3 September 2026) sets the eligibility rules. A study must be a multinational clinical trial of an investigational medicine in at least three concerned Member States, combined with either a medical device clinical investigation or an IVD or companion diagnostic performance study that requires authorisation. The full trial application (Part I and Part II) must be submitted, the device or diagnostic must be investigated with defined endpoints, and the sponsor must be ready to submit within one month of selection.
ATMP trials are now allowed, but without the 50-day assessment extension the CTR normally permits for them. Where two companies are involved, the trial sponsor acts as "coordinating sponsor" and manages the CTIS application. If the two cannot agree confidentiality terms, the device or diagnostic sponsor can file its confidential product documents in a parallel "IMPD-Q" application in CTIS, submitted within 24 hours of the main application. Single protocols and joint documents are encouraged where national rules allow, but are not mandatory.
Some things stay the same. Standard CTR, MDR and IVDR fees apply in each country, CTR timelines are followed with no extensions for answering questions, and substantial modifications after approval still follow the normal procedures. Safety reporting is not harmonised in this pilot; that work sits in COMBINE Project 2.
Phase 1 and Phase 2 compared
| Feature | Phase 1 to Phase 2 |
|---|---|
| Study types | Medicine trial plus IVD performance study only, extended to medical device clinical investigations and companion diagnostics |
| Sponsors | Same sponsor only, now one sponsor or two separate sponsors |
| Advanced therapies | Not included, now permitted without the 50-day extension |
| Application window | Single call closing in 2025, now rolling monthly slots for at least one year |
| Minimum countries | Multinational, now at least three concerned Member States |
| Participating countries | 18 in Phase 2, with Ireland able to act as reporting Member State |
| Fees | Standard national CTR, MDR and IVDR fees in each country |
How sponsors in Ireland can apply
The HPRA directs sponsors to its EU clinical trial initiatives page. Sponsors send an expression of interest form and a draft protocol synopsis for both the trial and the device or diagnostic study to EUcombinepilot@ccmo.nl, a mailbox hosted by the Dutch Central Committee on Research Involving Human Subjects (CCMO). The Commission says an EMA account and Eudralink access are needed, and that the mailbox is only for expressions of interest.
The expression of interest must name the proposed RMS for both parts, list all proposed concerned Member States (including any not in the pilot), give the planned submission date, and confirm that the study meets the eligibility rules. Selection depends on RMS capacity, so studies with several countries and more than one possible RMS are more likely to be chosen. Sponsors should expect a decision by the end of the month in which they apply, and must then be ready to submit in the following month. The RMS is also the contact point for pre-submission meetings.
Ireland is listed as able to act as RMS. For the ethics part in Ireland, the sponsor guide lists extra documents: an ethics committee application form, the address and accreditation status of the testing laboratory, an itemised study budget, and documents in an accessible, searchable format for review by the National Research Ethics Committees (NREC). Irish sites can be checked against our clinical trials in Ireland tracker.
Key dates and timelines
The first Phase 2 procedures began in September 2026. Expressions of interest close on the 23rd of the month before the planned submission, with exceptions: the January 2027 slot closes on 16 December 2026 and the April 2027 slot on 22 March 2027. The November 2026 slot closed on 23 October, the day of the HPRA notice, so the next cut-off is 23 November 2026 for December. The Commission's published list of cut-offs runs to 23 November 2027, and the May 2026 presentation schedules a Phase 2 review for September 2027.
Inside the procedure, CTIS serves as the document store and assessment tool. Because the MDR and IVDR still require a national device or diagnostic application, sponsors file one with each participating country's authority around day 69 of the Part I assessment, or day 38 if no request for information is raised. The sponsor guide says this is an administrative step, timed so that the device or diagnostic decision lines up with the trial decision. If the device or diagnostic track fails at any point, the clinical trial can continue under the normal CTR route and the device or diagnostic study reverts to national processes.
Why it matters for Irish medtech and pharma
Ireland hosts a large medtech and diagnostics sector alongside its pharmaceutical base, and Irish Medtech has backed the European Commission's proposal to reform the MDR and IVDR, as covered in our report on the Galway Global Access 2026 event. The HPRA notice says the pilot aims to reduce administrative burden, streamline authorisation and speed patient access to new treatments. COMBINE runs alongside FAST-EU, a separate pilot that began on 30 January 2026 and gives multinational medicine trials a maximum 70-day timeline from submission to decision, according to the HPRA. For the regulator's own costs, see our article on the HPRA's 2027 fees consultation, and our medical devices tracker follows Irish medtech clearances.
Frequently Asked Questions (FAQ)
Q: What is a combined study?
A: It is a clinical trial of a medicine run together with a clinical investigation of a medical device or a performance study of an in vitro diagnostic, such as a companion diagnostic, within the same study.
Q: Who can apply to COMBINE Phase 2?
A: Sponsors of a multinational medicine trial in at least three concerned Member States that is combined with a device or diagnostic study needing authorisation. One sponsor or two separate sponsors can take part.
Q: Does the pilot cost extra?
A: No extra pilot fee is described. The standard CTR, MDR and IVDR fees of each participating country apply.
Q: Can a trial run only in Ireland join?
A: No. Single-country combined studies are outside the pilot. The sponsor guide notes that several Member States run their own national combined-study projects.
Q: What happens if the device part is not approved?
A: The clinical trial can still be authorised under the CTR, and the device or diagnostic study must be resubmitted through the normal national route.
Conclusion and Outlook
Phase 1 was small, eight accepted applications, but it produced its first authorisation in March 2026 and shaped a wider Phase 2. Allowing device studies, advanced therapies and two-sponsor set-ups brings the pilot closer to how many combined studies are actually run. The main limits remain: national device applications, standard fees and separate modification procedures still apply. A formal Phase 1 analysis and the September 2027 Phase 2 review will show whether the coordinated route saves time. For Irish sponsors, the practical step is the 23 November 2026 cut-off for a December slot.
Sources
- Health Products Regulatory Authority, COMBINE Pilot Phase 2: coordinated assessment of combined clinical trial and medical device or in vitro diagnostic studies, 23 October 2026
- Health Products Regulatory Authority, EU Clinical Trial Initiatives
- Health Products Regulatory Authority, Clinical trials involving IVD performance studies: coordinated assessment pilot, 27 June 2025
- European Commission, COMBINE Project 1: pilot all-in-one coordinated assessment
- European Commission, COMBINE Project 1 Pilot: Sponsor Guide, V02.01, 3 September 2026
- European Commission, COMBINE Project 1 stakeholder meeting presentation, May 2026
- European Commission, Pilot on combined studies to simplify rules, boost innovation and help patients, 17 June 2025
Cover image: Kevin O'Malley House, Earlsfort Centre, Dublin, home of the Health Products Regulatory Authority (photographed in 2010, when the regulator was the Irish Medicines Board). Photo by Earwig, Wikimedia Commons, free to use with attribution to the author, cropped.
