Comparison GHTF/SG5/N5:2012 vs. MEDDEV 2.7/3:2010 CIE February 14th, 2013

MEDDEV 2.7/3:2010 GHTF/SGS/N5: 2012 Comments 1.General Provides interpretation of Annex 7 of Directive 90/385/EEC and Annex X of Directive 93/42/EEC as amended by Directive 2007/47/EC Note 4: provides clarification on application date Note 5: SAE reporting continues until completion of investigation even if CE mark is granted before Provides guidance of adverse event reporting during pre-market clinical investigations No application date given Dual reporting (SAE and Vigilance) not called out MEDDEV is more explicit on adverse event reporting when study grant CE marking before the end of the study 2. Scope: Pre market clinical investigations conducted with non CE marked devices or CE marked devices used outside the intended use covered by the CE marking 2. Scope: Pre-market clinical investigations undertaken by the manufacturer to obtain regulatory approval for CE marking or pre-market investigation that require authorization before initiation GHTF definition refers to pre initiation approval, while the MeddeV scope refers to the MDD / AIMD CE marking and related intended use Not specifically mentioned that Post-market studies are excluded. Reference to a separate MEDDEV (2.12/2:2012) document for PMCF studies follow up. When the investigational device used in a clinical study is approved in a particular jurisdiction the NCA of that country shall apply the post market reporting requirements per GHTF/SG2/N54 document GHTF is more explicit Certain countries however apply requirements of MEDDEV also for Post-market studies. 3. Definitions: From ISO/FDIS 14155 but not all are used (blinding/masking not in MEDDEV) 4. Definitions : as per ISO14155:2011 but not all are used (SADE not in GHTF) GHTF better aligned with ISO 14155:2011 but not all relevant ISO definitions are used in both MEDDEV and GHTF No term Serious Health Threat but indicated in Note 11 in section 7.1 “Reporting Timelines” refers to events with potential Public Health Hazard as reportable. However, Public Health Hazard is not defined. Serious Health Threat definition: any event type which results in imminent risk to the study population of death, serious injury or serious illness that requires prompt remedial action. Reportable within 48 hours following the determination that the Serious Health Threat exists. No definition of Serious Health Threat or Public Health Hazard in MEDDEV 2.7/3 or ISO 14155:2011 SAE definition: note 2 on device deficiencies that might have led to SAE (not according to ISO 14155) SAE definition: 1 note (aligned with ISO 14155)  GHTF better aligned with ISO 14155:2011

MEDDEV 2.7/3: 2010 GHTF/SGS/N5: 2012 Comments USADE and Sponsor definition aligned with ISO/FDIS 14155 USADE definition: 2nd note added to include unanticipated procedure-related SAEs Sponsor definition: 2nd note added on who can be the sponsor Some clarification notes added to definitions in GHTF. However, unanticipated procedure-related SAEs are not necessarily device related 4.Reportable events: same as GHTF 5. Reportable events: same as MEDDEV + note added referring to events representing a Serious Health Threat Reporting of new finding/updates in relation to already reported events is included Nothing about updates in relation to already reported events   If the manufacturer has a different opinion from the investigator for device and/or procedure relationship, the manufacturer´s opinion has to be documented (specified in the header of the excel tabular format) In the case where opinions on incidence or classification or relatedness of AE differ between sponsor and investigator both opinions have to be reported. Difficult to find the information in the MEDDEV (only in excel tabular format attached to the document) GHTF is better aligned with ISO 14155:2011: The sponsor is responsible for the classification of AEs and on going safety evaluation of the clinical investigation and shall Review the investigator’s assessment of all AEs and determine and document in writing their seriousness and relationship to the investigational device ; in case of disagreement between the sponsor and the principal investigator(s) the sponsor shall communicate both opinions to the concerned parties, as defined in c), d) and e) below” (meaning EC, CA etc…). Reportable events occurring in third countries have to be reported All reportable events must be reported to all NCA’s responsible for the jurisdiction where the clinical investigation is conducted, according to applicable requirements in each jurisdiction. Not clear in the GHTF whether events from third countries have to be reported to Europe 5. Report by whom : Sponsor of the Clinical Investigation Events must be reported by the Sponsor (in section 5) MEDDEV and GHTF are aligned 6. To whom to report All NCAs where investigation has been authorized to start in Member State, at the same time using summary tabulation All NCAs where investigation is conducted per national regulations MEDDEV is more explicit. “at the same time” not mentioned in the GHTF. Where it has been “authorized” in MEDDEV vs. “conducted” in GHTF

MEDDEV 2.7/3: 2010 GHTF/SGS/N5: 2012 Comments 7. Reporting timelines:   From Sponsor to NCAs - Within 2 calendar days for events indicating imminent risk of death, serious injury or illness and that require prompt remedial action for patients, users or other persons (potential public health hazard in Note 11) - All other reportable events : immediately but not later than 7 calendar days after awareness by sponsor 7. Timing for reporting - Within 48 hours: SAEs creating serious health threat - No later than 10 elapsed calendar days: USADEs, SAEs other than unanticipated resulting in life threatening/permanent impairment/ fetal implications - No later than 30 elapsed calendar days: all other reportable events (in-patient or prolongation of hospitalization/ resulting in intervention to prevent life threatening) and device deficiencies which may have led to serious injury Not the same timelines for different categories of reportable events – GHTF has more differentiation. GHTF not aligned with EU directive (i.e. can 30 days be considered as “immediately” per Annex X 2.3.5?) From Investigators to Sponsor Acceptable timely conditions but not later than within 3 calendar days after the occurrence of the event GHTF document does not include a specific section on time of reports from investigator to Sponsor. MEDDEV refers to the date of occurrence which may be different from the awareness of the event by the investigator 8. Format / content of the report Cumulative tabular format to all NCAs - 3 categories for device and procedure relatedness No format: Not clearly defined if tabular format or individual reporting but very detailed information required (initial and final report) 4 categories for device and procedure relatedness  No alignment between MEDDEV and GHTF No special conditions requirements Special conditions requirements included: Combination devices, unblinded controlled studies , implantable medical devices… More explicit in GHTF regarding special conditions Reporting of events occurring with “comparator” is required for all studies   Reporting of events occurring with “comparator” only required in case of unblinded controlled studies (otherwise reporting per post market requirements) SAEs for all devices including comparator in MEDDEV 2.7/3. Nothing mentioned regarding the reporting SAEs of comparator in ISO 14155:2011 (only collecting)  No diagram  Diagram defining AE reportability and timelines