New Guidance on Clinical Investigation Plans for Medical Devices

By Heather Crawford and Evangeline Loh

Background on the MDR and CIPs

The recitals of the Medical Devices Regulation (MDR) (EU) 2017/745 explain the importance of aligning clinical investigation provisions with ISO 14155. Article 2 introduces several definitions relevant to clinical investigation.

Relevant to our topic is Article 2(47) on the clinical investigation plan (CIP). This is described as a document with the following content related to a clinical investigation: “rationale, objectives, design, methodology, monitoring, statistical considerations, organization and conduct”. Article 72(1) asserts that it is this CIP that is approved and as a documented plan, guides the sponsors and investigators.

Detailed information on this CIP is in Annex XV, Chapter II, Section 3. Interestingly, the acronym CIP is not introduced until the Annex. There is also a slight difference in the definition in Article 2(47) and how CIP is defined in the introductory material in Section 3, regarding “record-keeping” and “method of analysis”.

The information delineated in Section 3 (3.1-3.19) forms the CIP (“shall contain in particular the information”).

Background on ISO 14155

The most recent version of the standard on Clinical investigation of medical devices for human subjects —Good clinical practice is ISO 14155:2020. The standard also includes a definition of CIP (Clause 3, 3.9) which similar to Annex XV, Chapter II, Section 3, specifies “pre-specified analysis” and “record-keeping”. Annex A of the standard provides extensive information about the CIP.

Annex A is organized into 18 sections, A.1 through A.18. Annex XV, Chapter II, Section 3 is fairly aligned with Annex A. The most significant difference is likely the expectation in the MDR, Annex XV, Chapter II, Section 3, 3.4 that the clinical investigation needs to be justified based on the “state of the art of clinical practice>” As has been widely discussed, there is no established EU definition of state-of-the-art.

MDCG 2024-3

The Medical Device Coordination Group (MDCG) published guidance (MDCG 2024-3, March 2024) to describe the content of the CIP. The MDCG working group acknowledges the MDR, ISO 14155, and the experience of the competent authorities. The MDR is the legal text and legal requirements, though both ISO 14155 and the MDCG guidance can be helpful resources. Further, the guidance reminds us that Annex XV, Chapter II, Section 3 “must be addressed” or justified as “not applicable.”

MDCG 2024-3 uses the numbering of Annex XV and is not intended to be a template for a CIP though Appendix A is presented as the CIP synopsis template.

Comparison of ISO 14155 Annex A to MDCG 2024-3

MDCG 2024-3 includes some limited guidance on Annex XV, Chapter II, Section 3, 3.4. It generally notes that pre-clinical test data and analysis and previous clinical investigation data are to be used to support the use of the investigational device in humans. And the manufacturer should use the clinical evaluation documented in the Clinical Evaluation Report (CER).

From our perspective, the most interesting guidance in the MDCG is provided in 3.3.1 on benefits. It is possible that “regional differences in availability of alternatives” may lead to benefits that differ by region.

As we all appreciate, the discussion on state of the art, and benefits has not been a topic in which much guidance has been provided. While MDCG 2020-6 provides some counsel on state-of-the-art, the document still refers to MEDDEV 2.7/1, Rev. 4, Appendix A.7 for guidance on benefits. 

Concluding remarks

The MDR requires clinical investigation to be performed for implantable and class III medical devices. The MDCG is slowly releasing guidance on clinical investigations. As we’ve reported, there is guidance, MDCG 2023-7, which clarifies circumstances in Article 61(4)-(6) by which such devices may be exempted from the requirement for clinical investigation. There are also FAQs for clinical investigations (MDCG 2021-6, Rev.1) and guidance on the format of the summary clinical investigation report (2023/C 163/06).

MDCG 2024-3 adds to this compendium of guidance on clinical investigations and should be checked before a manufacturer or sponsor considers a clinical investigation is performed in the EU.

Lastly, the CIP is fundamental to the start of a clinical investigation and will be part of a clinical investigation compliant with the MDR and ISO 14155. In addition, the CIP will be included in the manufacturer’s CER as well.