The Changing Landscape of European Medical Device Regulations
Patrick D. Mize, Ph.D.
Contact Dr. Mize http://goo.gl/PV31NZ
Advisor: Product Development / Regulatory Services
Part 3 of 3
Pre-clinical and Performance Studies
Pre-clinical and verification performance studies are usually summarized in the Technical File and a summary can be presented in the CER or the studies can be referenced here. Preclinical and performance studies are specific to the type of device and its intended use. A detailed list of the device’s Design Characteristics / Critical Features should be available from design documents and risk analysis.
These essential features for performance and safety make up part of the design input-output matrix and are the features that need to be verified and validated in these studies. These studies are, by definition, pre-clinical, and as such are studies with defined objectives, acceptance criteria, protocol and conclusions. Deviations from protocol should be few, well-documented, and explained. Final device prototypes or manufactured and internally approved devices are needed for these studies.
Many standards exist that delineate how these studies are to be performed and give suggested protocols and rationales for statistical sampling and analysis. Use of specific standards and protocols and having safety testing performed independently by a certified third party vendor helps insure impartial data. One cannot emphasize enough that a thorough review of the standards that are applicable for the evaluation of the device should be done early in the design process of the device.
For example, surgical devices require both biocompatibility and sterility validation studies as well as preclinical animal studies to show both safety of the new surgical devices and the efficacy in use of the instruments. Biocompatibility(13) and Sterility studies(14) are required when the device comes in contact with the intended use population and can be performed by many certified 3rd-party vendors. Safety studies are a key part of this section and are of a major focus of regulatory and notified bodies due to increasing reports of devices that do not meet the long term needs of the user. The literature report and pre-clinical studies can in certain instances be sufficient to show safety, efficacy and clinical utility; therefore, an argument can be made that human trials are not necessary.
The European Commission Guidance MEDDEV 2.7.1 rev. 3 Clinical Evaluation: Guide for Manufacturers and Notified Bodies(15) provides details on the process of conducting clinical evaluations such as, but not limited to, starting with either a Standard Operating Procedure (SOP) or a Clinical Evaluation Plan (CEP) describing the literature search, objectives, methods, and endpoints. The document also provides a list of references that can be useful. Also MEDDEV 2.7.4 contains further guidelines for manufacturers and notified bodies for clinical investigations of medical devices(16).
ISO 14155-1:2011 addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out on human subjects to assess the safety or performance of medical devices for regulatory and other purposes. This International Standard specifies general requirements intended to:
- Protect the rights, safety and well-being of human subjects
- Ensure the scientific conduct of the clinical investigation and the credibility of the clinical investigation results
- Define the responsibilities of the sponsor and principal investigator
- Assist sponsors, investigators, ethics committees, regulatory authorities and other bodies involved in the conformity assessment of medical devices.(17)
Discussion and Analysis of Device Design, Safety and Efficacy (Conformance)
This section of the report pulls together the elements of each of the previous sections of the report: design objectives and input statements; risk analysis and mitigation; regulatory and standards review; literature review; performance and preclinical studies; and clinical studies, if any.
This section should discuss the testing data related to the design inputs and show the objective evidence that the design meets both performance and safety objectives. There is a story to tell here. Your medical device’s story; complete with beginning, middle, and an [initial] end. The immediate end is showing that your device conforms to the MDD and can be marketed in the EU.
Post-Marketing Surveillance and CAPA Reviews
The manufacturer has the responsibly for maintaining a Post Marketing Surveillance [PMS] system and notifying the Competent Authorities [CA] of incidents immediately upon learning of them per MEDDEV 2.12-1.18 The notification may be done through the manufacturer’s EC Representative. Vigilance (reports) must be forwarded in standardized format per MEDDEV 2.12/1/Rev. 6. The CA has the responsible for monitoring vigilance reports19 and taking appropriate action. Post Market Surveillance allows the manufacturer to not miss signals of field failures that could result in unnecessary patient injuries. The failure to act increases the possible liability/punitive damages that the company may face.
A good PMS system facilitates development of improved and safer products and reduces loss and damage to a manufacturer’s brand. The international Medical Device Regulators Forum [IMDRF] lists a series of GHTF documents concerning Post Market Surveillance20 and best practices.
Post-Marketing surveillance data make up one part of the information that is regularly reviewed by the Corrective and Preventative Action [CAPA] Team. Regularly reviewing PMS and internal tracking data on product release, significant manufacturing issues or changes in critical components allow the manufacturer to both document occurrences and outcomes. A summary of these data are included in the regular update to the CER and allows easy review by the NB. These data comprise the second [follow-up] end of the medical devices’ story.
18 Part of ISO 13485
19 Vigilance Contact Points within CAs http://ec.europa.eu/growth/sectors/medical-devices/contacts/index_en.htm#vcp