1. Czech Office for Standards, Metrology and Testing www.unmz.cz Prague/Czech Republic

2. TAIEX Kiev Jaromír JEDLIČKANovember 2011 Requirements for carrying out of clinical and laboratory studies Jaromír JEDLIČKA Expert of Testing Department ÚNMZ – Czech Office for Standards, Metrology and Testing Prague / Czech Republic www.unmz.cz jedlicka@unmz.cz

3. TAIEX Kiev Jaromír JEDLIČKANovember 2011 Most of the Directives of EU are issued for safety of products, for safety of users (patients)*. This is valid mainly for medical devices (and of course for medicinal products). Using of medical devices is connected with risk, and of course with benefits. Reaching of the acceptable balance between benefits and risk is prescribed in point 1. of Annex I of MDD SAFETY, SAFETY, SAFETY * There exist another Directives focused on saving of energy, consumer protection etc.

4. TAIEX Kiev Jaromír JEDLIČKANovember 2011 NEW APPROACH AND GLOBAL APPROACH http://ec.europa.eu/enterprise/policies/single-market-goods/files/blue-guide/guidepublic_en.pdf Decision 93/465/EEC was transformed to Decision 768/2008/EC – The New Legislation Frame – the better interpretation of NA&GA – recast of medical device directives is coming

5. TAIEX Kiev Jaromír JEDLIČKANovember 2011 1. The devices must be designed and manufactured in such a way that, when used under the conditions and for the purposes intended, they will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their intended use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety. BENEFITS AND RISKS MDD (93/42/EEC) Annex I point 1 Any benefit of using of the device is, of course, connected with the performance of the device.

6. TAIEX Kiev Jaromír JEDLIČKANovember 2011 6. Any undesirable side-effect must constitute an acceptable risk when weighed against the performances intended. 6a. Demonstration of conformity with the essential requirements must include a clinical evaluation in accordance with Annex X.* PERFORMANCE INTENDED MDD (93/42/EEC) Annex I Section 6 and 6a What is more important – performance of medical devices or the safety of them? But, if the performance of a device has no medical effect, can be such a device considered as a medical device? *The same in AIMDD (90/385/EEC)

7. TAIEX Kiev Jaromír JEDLIČKANovember 2011 Module D Module F Module H1 with EC design examination certificate Medical device in question EC Declaration of conformity and CE marking Module B Modules used for active implantable medical devices

8. TAIEX Kiev Jaromír JEDLIČKANovember 2011 Module A only for Class In Module D or D1 not for Class In Module F or F1 not for Class In Module E or E1 not for Class In + III Module H or H1 for Class IIa + IIb + III Medical device in question EC Declaration of conformity and CE marking Module B only Class IIb +III Modules used for medical devices

9. TAIEX Kiev Jaromír JEDLIČKANovember 2011 CLINICAL EVALUATION MDD (93/42/EEC) Annex X point 1.1. (similarly in AIMDD) 1.1. As a general rule, confirmation of conformity with the requirements concerning the characteristics and performances referred to in Sections 1 and 3 of Annex I, under the normal conditions of use of the device, and the evaluation of the side-effects and of the acceptability of the benefit/risk ratio referred to in Section 6 of Annex I, must be based on clinical data. The evaluation of this data, hereinafter referred to as ‘clinical evaluation’, where appropriate taking account of any relevant harmonised standards, must follow a defined and methodologically sound procedure based on: - „critical evaluation of clinical data“ – next page

10. TAIEX Kiev Jaromír JEDLIČKANovember 2011 CRITICAL EVALUATION MDD (93/42/EEC) Annex X point 1.1. (similarly in AIMDD) 1.1.1. Either a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, where: — there is demonstration of equivalence of the device to the device to which the data relates, and — the data adequately demonstrate compliance with the relevant essential requirements. 1.1.2. Or a critical evaluation of the results of all clinical investigations made. 1.1.3. Or a critical evaluation of the combined clinical data provided in 1.1.1 and 1.1.2.

11. TAIEX Kiev Jaromír JEDLIČKANovember 2011 PRINCIPLES OF EVALUATION MDD (93/42/EEC) Annex X point 1.1. (similarly in AIMDD) 1.1a In the case of implantable devices and devices in Class III clinical investigations shall be performed unless it is duly justified to rely on existing clinical data. 1.1b The clinical evaluation and its outcome shall be documented. This documentation shall be included and/or fully referenced in the technical documentation of the device. 1.1c The clinical evaluation and its documentation must be actively updated with data obtained from the post-market surveillance. Where post-market clinical follow-up as part of the post-market surveillance plan for the device is not deemed necessary, this must be duly justified and documented. 1.1d Where demonstration of conformity with essential requirements based on clinical data is not deemed appropriate, adequate justification for any such exclusion has to be given based on risk management output and under consideration of the specifics of the device/body interaction, the clinical performances intended and the claims of the manufacturer. Adequacy of demonstration of conformity with the essential requirements by performance evaluation, bench testing and pre-clinical evaluation alone has to be duly substantiated.

12. TAIEX Kiev Jaromír JEDLIČKANovember 2011 2.1. Objectives The objectives of clinical investigation are: — to verify that, under normal conditions of use, the performance of the devices conform to those referred to in Section 3* of Annex I, and — to determine any undesirable side-effects, under normal conditions of use, and assess whether they constitute risks when weighed against the intended performance of the device. CLINICAL INVESTIGATIONS MDD (93/42/EEC) Annex X Section 2 (similarly in AIMDD) * „The devices must achieve the performances intended by the manufacturer and be designed, manufactured and packaged in such a way that they are suitable for one or more of the functions referred to in Article 1 (2) (a), as specified by the manufacturer.“ i.e. definition of medical device

13. TAIEX Kiev Jaromír JEDLIČKANovember 2011 2.2. Ethical considerations Clinical investigations must be carried out in accordance with the Helsinki Declaration adopted by the 18th World Medical Assembly in Helsinki, Finland, in 1964, as last amended by the World Medical Assembly. It is mandatory that all measures relating to the protection of human subjects are carried out in the spirit of the Helsinki Declaration. This includes every step in the clinical investigation from first consideration of the need and justification of the study to publication of the results. CLINICAL INVESTIGATIONS MDD (93/42/EEC) Annex X Section 2 (similarly in AIMDD)

14. TAIEX Kiev Jaromír JEDLIČKANovember 2011 2.3. Methods - plan of investigation reflecting the latest scientific and technical knowledge - procedures used to perform the investigations must be appropriate - in circumstances similar to the normal conditions of use of the device - all the appropriate features, including those involving the safety and performances of the device, and its effect on patients must be examined - all serious adverse events must be fully recorded and immediately notified - investigations must be performed under the responsibility of a medical practitioner or another authorized qualified person which have to have access to the technical and clinical data regarding the device - the written report, signed by the medical practitioner or other authorized person responsible, must contain a critical evaluation of all the data collected during the clinical investigation CLINICAL INVESTIGATIONS MDD (93/42/EEC) Annex X Section 2 (similarly in AIMDD)

15. TAIEX Kiev Jaromír JEDLIČKANovember 2011 -The basic rules are in legislation -Outcome of the clinical evaluation (and eventually for pre-clinical evaluation) is the part of the technical documentation of the device and of the documentation of the quality system under which the devices are produced -Clinical evaluation (the critical evaluation of clinical data) is created by the manufacturer or on his behalf by a specialist. Guidance's and standards can be used but they are issued just for this purpose only rarely. -Clinical investigation is process for gaining clinical data. It is outside of the market. There exists, let us say, strong rules for clinical investigation (e.g. Article 15 MDD, Annexes VIII and X MDD, MEDDEVs, standards) RULES FOR CLINICAL EVALUATION AND CLINICAL INVESTIGATION

16. TAIEX Kiev Jaromír JEDLIČKANovember 2011 Guidance’s MEDDEVs 2.7 Clinical investigation, clinical evaluation MEDDEV 2.7/1 rev.3MEDDEV 2.7/1 rev.3 [378 KB] Clinical evaluation: Guide for manufacturers and notified bodies Appendix 1: Clinical evaluation on coronary stents Appendix 1: Clinical evaluation on coronary stents [101 KB] December 2009 December 2008 MEDDEV 2.7/2MEDDEV 2.7/2 [37 KB] Guide for Competent Authorities in making an assessment of clinical investigation; notification December 2008 MEDDEV 2.7/3 [166 KB] Clinical investigations: serious adverse event reporting MEDDEV 2.7/3 SAE reporting formSAE reporting form [87 KB] December 2010 MEDDEV 2.7/4 [180 KB] Guidelines on Clinical investigations: a guide for manufacturers and notified bodiesMEDDEV 2.7/4 December 2010 Understandings, agreements and conventions can be found at: http://ec.europa.eu/health/medical-devices/documents/guidelines/index_en.htm

17. TAIEX Kiev Jaromír JEDLIČKANovember 2011 STANDARDS FOR CI Harmonized standards can be found at: http://ec.europa.eu/enterprise/policies/european-standards/documents/harmonised- standards-legislation/list-references/medical-devices/index_en.htm CEN EN ISO 14155-1:2009 Clinical investigation of medical devices for human subjects - Part 1: General requirements (ISO 14155-1:2003) 07/07/2010 EN ISO 14155- 1:2003 Note 2.1 Note 2.1 Date expired (21/03/2010) CEN EN ISO 14155-2:2009 Clinical investigation of medical devices for human subjects - Part 2: Clinical investigation plans (ISO 14155-2:2003) 07/07/2010 EN ISO 14155- 2:2003 Note 2.1 Note 2.1 Date expired (21/03/2010) Note 2.1: The new (or amended) standard has the same scope as the superseded standard. On the date stated, the superseded standard ceases to give presumption of conformity with the essential requirements of the directive. In fact the standards EN ISO 14155-1:2009 and EN ISO 14155-2:2009 where coupled to the EN ISO 14155:2011 - Clinical investigation of medical devices for human subjects – Good Clinical Practice

18. TAIEX Kiev Jaromír JEDLIČKANovember 2011 (e) ‘device for performance evaluation’ means any device intended by the manufacturer to be subject to one or more performance evaluation studies in laboratories for medical analyses or in other appropriate environments outside his own premises; (without CE marking without NB) PERFORMANCE EVALUATION IVDD (98/79/EC) Article par. 1 letter e) i.e devices intended not for analyses of human specimen but for other laboratories studies. The specificity and sensitivity of them is known (with some tolerance) so they can be used e.g. for calibration

19. TAIEX Kiev Jaromír JEDLIČKANovember 2011 Module A IVD in question EC Declaration of conformity and CE marking Modules used for IVD Module D Module F Module H or H1 Module B Modul Aa1 NB design examination IVD for PE – manufacturer ensures the relevant provisions of IVDD and issues statement with prescribed information

20. TAIEX Kiev Jaromír JEDLIČKANovember 2011 1. For devices for performance evaluation the manufacturer or his authorised representative shall draw up the statement containing the information stipulated in section 2 and ensure that the relevant provisions of this Directive are met. For devices for performance evaluation „the real conformity assessment“ is not described, involvement of a NB is not prescribed. But the manufacturer should ensure the relevant requirements and draw up the statement. PERFORMANCE EVALUATION IVDD (98/79/EC) Annex VIII

21. TAIEX Kiev Jaromír JEDLIČKANovember 2011 PERFORMANCE EVALUATION IVDD (98/79/EC) Annex VIII 2. The statement shall contain the following information: — data allowing identification of the device in question, — an evaluation plan stating in particular the purpose, scientific, technical or medical grounds, scope of the evaluation and number of devices concerned, — the list of laboratories or other institutions taking part in the evaluation study, — the starting date and scheduled duration for the evaluations and, in the case of devices for self-testing, the location and number of lay persons involved, — a statement that the device in question conforms to the requirements of the Directive, apart from the aspects covered by the evaluation and apart from those specifically itemised in the statement, and that every precaution has been taken to protect the health and safety of the patient, user and other persons.

22. TAIEX Kiev Jaromír JEDLIČKANovember 2011 PERFORMANCE EVALUATION IVDD (98/79/EC) Annex VIII 3. The manufacturer shall also undertake to keep available for the competent national authorities the documentation allowing an understanding of the design, manufacture and performances of the product, including the expected performances, so as to allow assessment of conformity with the requirements of this Directive. This documentation must be kept for a period ending at least five years after the end of the performance evaluation. The manufacturer shall take all the measures necessary for the manufacturing process to ensure that the products manufactured conform to the documentation mentioned in the first paragraph. 4. The provisions of Article 10(1), (3) and (5) shall apply to devices intended for performance evaluation. i.e. Registration of manufacturers and devices

23. TAIEX Kiev Jaromír JEDLIČKANovember 2011 STANDARDS FOR LAB There exist many standards for laboratory practice and also for testing of in-vitro diagnostic medical devices. Both of them can be used for „in vitro diagnostic medical devices for performance evaluation“. We can say that it does not exist specialized standards for such devices but the mentioned standards can be used similarly as general laboratory equipment can be used in „IVD laboratories“ and it cannot be counted in-vitro diagnostic medical devices.

24. TAIEX Kiev Jaromír JEDLIČKANovember 2011 Thank you for your attention