EU Unveils New Medical Device Clinical Investigation Guidelines
New medical device guidelines, MEDDEV 2.7.4, addressing clinical investigations have been issued in the European Union. Based on the Global Harmonization Task Force’s guidance document SG5/N3:2010, the guidelines align with clinical investigation requirements found in Annex 7 of Directive 2007/47/EC. The MEDDEV 2.7.4 document, “Guidelines on Clinical Investigation: A Guide for Manufacturers and Notified Bodies,” provides guidance as to when manufacturers and notified bodies should launch clinical investigations to show compliance with pertinent Essential Requirements, and establishes general clinical investigation principles regarding medical devices. What the guidelines do not provide are comprehensive recommendations for clinical investigations of specific devices; in vitro diagnostic products are also excluded. The guidelines primarily address pre-market clinical evaluations and conformity assessments. For post-market surveillance guidance, manufacturers should continue referring to MEDDEV 2.12.2. On a high level, the new guidelines stipulate that clinical data must form the basis for any device’s confirmation of conformity with directive requirements including Annex I, Essential Requirements, sections I.1 and I.3 (90/385/EEC) as well as sections I.1 and I.2 (93/42/EEC). The specific type and amount of clinical data required will depend on an individual device’s clinical claims regarding performance, safety, and side-effects. (For devices with multiple clinical claims, different data may be necessary to support each of those claims.) Firms will need to conduct clinical evaluations in order to discern which clinical data is necessary and relevant to a conformity assessment, and which data can be supplemented or replaced by prior clinical studies, literature, or even clinical data from equivalent medical devices. MEDDEV 2.7.4 also reminds manufacturers of the requirement to actively update the clinical evaluations using data derived from post-market surveillance efforts. When clinical investigations are necessary EU directives dictate clinical investigations for active implantable medical devices as well as Class III and implantable devices, unless a manufacturer can justify using existing data for a conformity assessment. For non-implantable Class I, IIa and IIb devices, factors such as clinical claims and risk management outcomes may also require clinical investigations. Further clinical investigations may also be warranted for corroborative purposes. General design principles MEDDEV 2.7.4 provides general parameters to which any clinical investigation must conform: • An investigation must be part of a larger clinical evaluation process • Adequate risk management procedures should be in place • Legal and regulatory compliance must be ensured • Investigation design should be appropriate • Adherence to all relevant ethical principles In terms of investigation design, the guidelines emphasize that supplicants ensure that their studies are able to capture clinical data relevant to issues such as clinical performance, safety and side-effects, and residual risk elements. Essential components of a strong study design, according to the guidelines, include a clear statement of objectives, appropriate subject populations, minimized bias factors via methods such as randomization and blinding, awareness of confounding factors, appropriate control selection, design configuration and comparison types. Associated statistical plans should include clinically relevant and clearly defined endpoints, testable hypotheses, statistical significance levels, sample size justifications and analysis methodologies. Once a clinical investigation has been properly designed and conducted, manufacturers must then document investigation outcomes in a final study report, which ultimately becomes part of the clinical evaluation report used for conformity assessment. Investigators should refer to EN ISO 14155-1:2009 for how to structure final study reports.