As we welcome the new year, it is imperative for manufacturers to review the upcoming changes in European medical device regulation that will be significant so they can prepare to implement them. One of the pivotal changes will be the emphasis on medical device clinical data and clinical evaluations.

Increasing scrutiny now will be placed on a medical device's clinical data and Clinical Evaluation Report, as it soon will be the law. These items will be required for all devices (regardless of classification) that already possess CE marking, as well as for devices that will be CE marked.

Before we discuss the new requirements, it's probably helpful for you to know how they came into play. In June 2002, a report, titled Report on the Functioning of the Medical Devices Directive (NBM/061/02), had concluded that:

• Most manufacturers-especially those producing Class I and Class IIa devices-did not possess adequate clinical evidence for their medical devices
• Notified bodies did not adequately verify medical device clinical evidence provided in terms of the device's characteristics and performance

In general, there was concern that the semantics of the Directive were ambiguous. Jumping on the bandwagon, the Medical Devices Experts Group (MDEG), established by the European Commission, cited medical device clinical evaluation as an area of concern after reading this report. (The MDEG is composed of delegates from member state competent authorities and other EU well-known organizations including EUCOMED, EDMA, CEN, CENELEC, NB-MED and EAAR.)

The medical device Clinical Evaluation Task Force (CETF), a sub-group of the MDEG Committee, composed of representatives from member states, notified bodies and industry, was established and charged with addressing these issues. Some of the CETF's subsequent activities led to the changes you will find included in Directive 2007/47/EC.

MDD 93/42/EEC as Amended and the Clinical Evaluation Implications

One section in Recital 8 emphasizes that clinical evidence data now will be "generally required for all medical devices regardless of classification." Recital 8 also acknowledges that the provisions of clinical evaluation need to be enhanced. Furthermore, a definition of clinical data is promulgated and defined to mean "the safety and/or performance information that is generated from the use of a device." Clinical data may be obtained from the following sources: clinical investigation of the device; published clinical investigations or other studies of similar devices in the scientific literature; clinical experience of the medical device or a similar device; or published, unpublished or "historical data."

To end the ambiguity in the MDD about the requirements for a medical device clinical evaluation, it is stated in Annex I, Essential Requirements (Section 6a) that to demonstrate conformity with the essential requirements, a clinical evaluation must be included, in accordance with Annex X, Clinical Evaluation. Therefore, all manufacturers now must possess clinical evaluation documentation.

Annex X also has been amended to impose more stringent requirements on a clinical evaluation. The clinical evaluation of the medical device must be based on clinical data and follow a "defined and methodologically sound procedure," according to the annex. Furthermore, this clinical evaluation must be documented; the annex recommends that a clinical evaluation report and the accompanying "document shall be included and or fully referenced in the technical document of the device." This document is described as a critical evaluation of the relevant scientific literature, clinical investigations or a combination of the two. Therefore, to comply with the MDD 93/42/EEC, as amended, all manufacturers now must possess a medical device clinical evaluation report as part of their existing technical documentation.

Standards and Guidance

A few resources exist to guide the manufacturer in developing a clinical evaluation report, including how to select a format for writing it.

Annex A, Suggested Procedure for Literature Review of the European Norm Harmonized Standard (EN ISO 14155-1:2003, Clinical Investigation of Medical Devices for Human Subjects, Part 1, General Requirements) was published in the Official Journal of European Communities (OJEC) as a harmonized standard to the MDD. The two-page annex describes a method for conducting the literature review and provides a suggested format for structuring the clinical evaluation report. One comment worth noting is that "a literature survey is a scientific activity that should be done with rigour [sic] and objectivity and should allow for verification by third parties."

Although the standards can be adopted on a voluntary basis, it bears mentioning that if a clinical investigation is performed to meet the clinical data requirements, EN ISO 14155 should be considered as your guide-conformity with harmonized standards published in the OJEC presumes compliance with the relevant essential requirements. (By the way, Annex C also describes a format for the final report from the clinical investigation.)

Along with the Annexes, another valuable reference for guidance on developing a clinical evaluation report is the European Commission's guidance document MEDDEV 2.7.1, Evaluation of Clinical Data: A Guide for Manufacturers and Notified Bodies. Published in April 2003, this guidance is meant to assist manufacturers in reviewing and analyzing clinical data, while also assisting notified bodies in reviewing a medical device manufacturer's clinical data evaluation. MEDDEV 2.7.1 provides valuable information on the following topics: literature route method, critical evaluation of the literature, conclusions from analysis literature reviews, the clinical investigation final report and conclusions from analysis of clinical investigation data. Note that some of the text from this MEDDEV document has been incorporated into Directive 2007/47/EC.

The Global Harmonization Task Force (GHTF) published a guidance on clinical evaluation (SG5/N2R8: 2007). The 28-page guidance is a veritable tour de force. In it, the GHTF notes that for medical devices developed by incremental technology modifications, or devices whose design is based on technologies with well-established safety and performance characteristics, it may be appropriate to leverage the clinical experience and literature reports pertaining to the safety and performance of comparable devices or demonstrate compliance with recognized standards. Appendix A includes a possible format for the literature search report, while Appendix E provides a possible format for a medical device clinical evaluation report.

Medical device manufacturers preparing to deal with the changes to the directive are fortunate to have plenty of guidance with developing a format for a medical device clinical evaluation report. In addition to these resources, it is advisable that manufacturers reference the MDD 93/42/EEC as amended to ensure that all the elements required are adequately addressed. Furthermore, BS EN ISO 14155, MEDDEV 2.7.1 and GHTF SG5/N2R8:2007 may be helpful in developing an appropriate format for the clinical evaluation report. Lastly, the clinical evaluation report should be compiled and written as an independent document. If notified body review were required, or even a competent authority involved, this particular report may be the only document provided to the clinical assessor.

The clinical evaluation report may seem like an onerous requirement for devices that already have been on the market for a long time, and the expectation to possess safety and performance data from use of a device may seem like a daunting challenge for devices that simply are modifications of existing technologies. However, manufacturers should note that there is flexibility in addressing the clinical data requirement.

January/February 2008