EU Update: New Guidance on Clinical Investigation Investigator's Brochures

By Heather Crawford and Evangeline Loh

What is an investigator’s brochure?

The investigator’s brochure (IB) is referenced in the European Medical Devices Regulation (2017/745, MDR). However, those unfamiliar with the term IB will find it defined in Annex XV, Chapter II, Section 2. In the interest of completeness, there is a catch-all expectation in MDR Article 62 on clinical investigations. MDR Article 62(4)(m) states “the requirements of Annex XV are fulfilled.”

The IB is intended to include both non-clinical and clinical data on the investigational device. It is to be updated promptly. In addition, the information delineated in Annex XV, Chapter II, Section 2, 2.1-2.8 is expected to be included in the IB.

Background on ISO 14155

ISO 14155 as the standard on Clinical investigation of medical devices for human subjects - Good clinical practice defines IB (Clause 3, 3.1). The intent, of course,  is almost identical to Annex XV, Chapter II, Section 2. The content of the ISO standard Clause 6, Section 6.5 adds more context as to the purpose. The IB should “provide the principal investigator and the investigation site team with sufficient safety or performance data … to justify human exposure to the investigational device…” There is additional instruction directed to the principal investigator.

Annex B of the standard provides extensive information about the IB.

Background on MDCG 2024-5

The Medical Device Coordination Group (MDCG) published guidance on IBs (April 2024), MDCG 2024-5.  Similar to MDCG 2024-3 on Clinical Investigation Plans, the document recognizes the harmonized standard ISO 14155 and proclaims that the document includes experience from the competent authorities.

One significant difference is that there is a recommendation that the checklist in Appendix A of MDCG 2024-5 should be used to confirm the submission of the IB is complete. In addition, if the checklist is used, it is recommended that the Appendix A checklist be submitted as part of the IB.

Comparison of the MDR, ISO standard, and MDCG guidance

Unlike our comments about the utility of MDCG 2024-3, MDCG 2024-5 adds a tome of guidance. There are more than 21 pages to guide the manufacturer and sponsor.

Section 2.3.2 is titled specific recommendations regarding pre-clinical evaluation. For example, Section 2.3.2.2.2 on reliability tests is not a term that has been commonly used in regulatory submissions. Certainly, the concept is recognized and data is provided, though to our knowledge, the term reliability has never been explicitly advanced beyond horizontal test standards. There are reliability requirements for the four device types listed in the section.

We would venture to state that this guidance is a must-read for any manufacturer compiling a technical documentation file for compliance of the device to Annex II, MDR. And, MDCG 2024-5 is so valuable, that one needs to review it for oneself.

Concluding remarks

The MDR requires clinical investigation for implantable and class III medical devices. As stated before, the MDCG is releasing guidance on clinical investigations.

MDCG 2024-5 contributes to this compendium of guidance on clinical investigations and enhances the guidance on IBs. This guidance should be consulted before a manufacturer or sponsor considers a clinical investigation that will be performed in the EU. There is counsel on pre-clinical evaluation which a manufacturer should review as part of the design and development of the investigational device. The Appendix A checklist should also be referred to and submitted as part of the IB.

The IB is integral to a clinical investigation and will be part of a clinical investigation compliant with the MDR and ISO 14155. In addition, the IB will form parts of the manufacturer’s CER.