Global harmonization, its work items and clinical evaluation

The International Medical Device Regulators Forum (IMDRF) is a voluntary group of worldwide medical device regulators working with the aim of accelerating international medical device regulatory harmonization. IMDRF was formed in 2011, replacing the Global Harmonization Task Force (GHTF), which had its first meeting in 1993, formed to foster the global harmonization of medical device regulation. During its years of operation, GHTF issued numerous guidance documents covering medical device premarket evaluation, post-market surveillance and vigilance, quality systems, auditing and clinical studies. These documents have had an important impact on medical device regulation in national and regional jurisdictions worldwide, including Europe. Some GHTF documents are still considered current by IMDRF; however, they are gradually being reviewed and replaced by IMDRF documents.

Because of the active participation in the work of IMDRF of regulatory authorities who are charged with national or regional medical device regulation, it is important for device manufacturers to keep up-to-date with its work program, which currently includes:

• Medical Device Cybersecurity Guide
• Medical Device Clinical Evaluation
• Unique Device Identification (UDI) Application Guide
• Personalized Medical Devices
• Standards - Improving the quality of international medical device standards for regulatory use
• Adverse Event Terminology
• Good Regulatory Review Practices
• Regulated Product Submission

The purpose of the IMDRF Medical Device Clinical Evaluation work item is stated to be to improve the effectiveness and efficiency of premarket review of clinical evidence by promoting increased global harmonization in the evaluation of available clinical evidence, reducing the number of redundant clinical studies, integrating the principles of post-market clinical follow-up and real world evidence, and accelerating “the introduction of new safe and effective medical devices/technologies” to patients. Thus, the Medical Device Clinical Evaluation Working Group, chaired by Dr. Yinghui Liu, Center for Medical Device Evaluation (CMDE), China, is developing IMDRF guidelines by updating the GHTF documents on clinical evaluation. These GHTF documents include:

• Clinical Evidence – Key Definitions and Concepts, GHTF SG5 N1 (May 2007);
• Clinical Evaluation, SG5 N2 (May 2007); and
• Clinical investigations, SG5 N3 (February 2010).

The proposed superseding IMDRF documents are:

• Clinical Evidence – Key Definitions and Concepts, IMDRF MDCE WG (PD1)/N57;
• Clinical Evaluation, IMDRF MDCE WG (PD1)/N55; and
• Clinical investigation, IMDRF MDCE WG (PD1)/N56.

The current European clinical evaluation guidance document, MEDDEV 2.7/1 Rev. 4, was developed to assist manufacturers in complying with Directive 93/42/EEC and Directive 90/385/EEC. It is not known, however, whether it will be revised in future to be fully consistent with the Medical Device Regulation (MDR; Regulation (EU) 2017/745), or whether the gaps between MEDDEV 2.7/1 Rev. 4 and the MDR will be filled by a series of additional guidance documents addressing specific aspects of the MDR clinical evaluation requirements.

It is notable that the European guidelines on clinical evaluation, MEDDEV 2.7.1 Rev 3, which preceded the current Rev.4 version, states that it was “drafted on the basis of GHTF Guideline SG5/N2R8:2007 Clinical Evaluation of 29 June 2007.” In addition, although MEDDEV 2.7/1 Rev 4 is a complete revision of the previous version, the listed references include the GHTF guidance documents, SG5 N1 and SG5 N2. For these reasons, the proposed IMDRF guidance documents should be of interest to device manufacturers marketing or intending to market their devices in Europe. This is because review of these documents is likely to provide an early understanding of concepts that could be included in future European guidelines.

The IMDRF proposed document presents the same general approach to clinical evaluation as presented in the GHTF document and a significant amount of text that has not been modified; however, some important revisions have been made. In some cases, there is commonality with the approach of the MEDDEV 2.7/1 Rev. 4 and MDR; however, in other cases, there is divergence. For example, the approach to comparability (i.e., equivalence in Europe) is more flexible in the IMDRF proposed document compared with expectations concerning equivalence in the MDR and MEDDEV 2.7/1 Rev 4, and even more flexible than comparability considerations in the GHTF document. Appendix A: Some Considerations for Comparability, has been added, which provides potential aspects for consideration when evaluating comparability related to intended use and technical and biological characteristics.

The IMDRF proposed document on clinical evaluation also includes, among other additions:

• reference to an IMDRF document on clinical evaluation for Software as a Medical Device (SaMD)
• an interesting discussion of the use of registry data
• an expectation that documents related to financial disclosure, financial agreements or conflict of interest will be available for consideration when a clinical investigation has been carried out by or on behalf of a manufacturer
• guidance on considering whether clinical data are applicable to the population for which the marketing authorization is sought and also Appendix D: Considerations for the Application of Clinical Investigation Data Generated from Different Jurisdictions.

Readers are encouraged to visit the IMDRF website for additional information on its harmonization efforts and ways in which stakeholders may be involved.

Author: Maria E. Donawa, M.D., is President of Donawa Lifescience Consulting, Rome, Italy, a full service CRO in Europe and North America, and provider of in-depth assistance to clients in all aspects of US and European regulatory and quality system requirements for medical devices, including IVD medical devices.