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mHealth Israel_The New Regulatory Challenges in Europe The Clinical Evaluation of Your Devices_Michael imhoff


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Presentation by Michael imhoff about the upcoming Medical Device Regulation (MDR) in the EU. Includeds compliance with the General Safety and Performance Requirements. Demonstration of conformity with the general safety
and performance requirements in clinical
evaluation. Clinical evaluation with evidence for safety
and performance of the medical device. Assessment of side effects and the acceptability of the risk-benefit-ratio, based on clinical data. MDR is not a health technology assessment for payers. Results of the clinical evaluation should be documented
in a clinical evaluation report (CER).

Published in: Law

mHealth Israel_The New Regulatory Challenges in Europe The Clinical Evaluation of Your Devices_Michael imhoff

  1. 1. More Experience ► Better Results 1MDR Challenges – Clinical Evaluation The New Regulatory Challenges in Europe The Clinical Evaluation of Your Devices Michael Imhoff, MD PhD Senior Advisor Boston MedTech Advisors
  2. 2. More Experience ► Better Results 2MDR Challenges – Clinical Evaluation Overview • The Medical Device Regulation (MDR) requests the compliance with the General Safety and Performance Requirements in Annex I. • Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation • The clinical evaluation shall give evidence for safety and performance of the medical device, and an assessment of side effects and the acceptability of the risk-benefit-ratio, based on clinical data. • This is not a health technology assessment for payers. • The results of the clinical evaluation are documented in a clinical evaluation report (CER).
  3. 3. More Experience ► Better Results 3MDR Challenges – Clinical Evaluation MDR and MEDDEV 2.7/1 • MDR: What is a clinical evaluation (5 pages) • MEDDEV 2.7/1 Rev 4: How to do a clinical evaluation (65 pages) • Guidance document (legally not binding, but …) • Compliance with Essential Requirements (MDD), General Safety and Performance Requirements (MDR) • Acceptable risk (benefit-risk analysis) • Safety – freedom from not acceptable side effects • Intended performance
  4. 4. More Experience ► Better Results 4MDR Challenges – Clinical Evaluation Requirements • Clinical evaluation along the total product life cycle as a continuous process • Strong emphasis on clinical benefit from all medical devices • Performance, benefit, safety, risk minimization require clinical evidence • Comprehensive (exhaustive) clinical data required • Very strict requirements for equivalence (MEDDEV < MDR) • CER defines requirements for PMS and PMCF • Excessive requirements for the qualification of authors • Frequent updates required
  5. 5. More Experience ► Better Results 5MDR Challenges – Clinical Evaluation
  6. 6. More Experience ► Better Results 6MDR Challenges – Clinical Evaluation General Principles • Clinical evaluation during development of a medical device • The clinical evaluation process begins with the start of development • Definition of the need for clinical data for safety and performance • Gap analysis  (new) data from clinical studies • CER requested for the initial conformity assessment (CE mark), active updates thereafter • Clinical evaluation for the initial CE mark: • Sufficient evidence for compliance with GSPRs (ERs) • Identification of need for PMS/PMCF
  7. 7. More Experience ► Better Results 7MDR Challenges – Clinical Evaluation Equivalence • All relevant aspects of equivalence must be shown in ONE medical device! • Partial equivalence from different products not acceptable • Only CE-marked devices • Detailed comparison on the level of development and production details • Clinical properties (application, intended use, operation mode, etc.) • Technical properties (incl. production process) • Biological properties (e.g. materials in contact with patient) • For implants and class III de facto only products from own production (vs. competitor devices) • In general, equivalence is only accepted for effectively identical devices • Data from “similar” devices may be used to define the state of the art (and for extended safety assessment)
  8. 8. More Experience ► Better Results 8MDR Challenges – Clinical Evaluation Equivalence • MDR Article 61 (5): • A manufacturer of a device demonstrated to be equivalent to an already marketed device not manufactured by him, may also rely on paragraph 4 in order not to perform a clinical investigation provided that the following conditions are fulfilled in addition to what is required in that paragraph: • the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis, and • the original clinical evaluation has been performed in compliance with the requirements of this Regulation, • and the manufacturer of the second device provides clear evidence thereof to the notified body.
  9. 9. More Experience ► Better Results 9MDR Challenges – Clinical Evaluation Risk-Benefit Analysis • Increasing emphasis on risk-benefit analysis Note: Benefit does not equal performance! • Assessment of patient benefit from device • Quantification of patient benefit • Assessment of clinical risks from device • Assessment of the acceptability of the risk-benefit profile • Changes in medical alternatives have to be considered • Results of the risk-benefit analysis may change over time!
  10. 10. More Experience ► Better Results 10MDR Challenges – Clinical Evaluation Risk-Benefit Analysis • Requirements of MEDDEV/MDR for the clinical evaluation • Assessment of risks • Assessment of risk-benefit ratio • Assessment of (not acceptable) side effects • These are core competences of risk management! • Risk management should be done at only ONE place in the tech file Close coordination between RM and CER
  11. 11. More Experience ► Better Results 11MDR Challenges – Clinical Evaluation Clinical Data • All clinical data from within and outside the EU: • Clinical trials and studies • PMS data • Register data/studies • Field safety corrective actions (FDA, competent authorities) • MAUDE, MHRA, SwissMedic, BfArM, etc. • Data from all countries where the device is marketed • Clinical data from the literature • Systematic analysis of all retrieved information
  12. 12. More Experience ► Better Results 12MDR Challenges – Clinical Evaluation Literature • Systematic literature searches • Both for state of the art as well as for the actual medical device • MEDLINE alone not sufficient (explicit statement) • Additional databases required (e.g., EMBASE) • Unpublished data, as available • Literature searches: • Description of the state of the art, medical alternatives • Description of performance, safety and benefit of the evaluated device and (if claimed) equivalent products • Data from similar devices for state of the art and extended safety assessment • Separate search protocols and results reports
  13. 13. More Experience ► Better Results 13MDR Challenges – Clinical Evaluation Literature • Appraisal of each publication ( appraisal plan) • Relevance for clinical use according to intended use • Methodological quality • Determination of the level of evidence • Systematic assessment for the clinical evaluation • Appraisal plan and results in an appendix to the CER • Literature assessment as in a systematic review • Explicit recommendations for the appraisal scheme
  14. 14. More Experience ► Better Results 14MDR Challenges – Clinical Evaluation Clinical Investigations • If gaps are present that cannot be addressed by other means, clinical investigations should be planned and carried out. • Implants and high-risk devices, those based on technologies where there is little or no experience, and those that extend the intended purpose of an existing technology (i.e. a new clinical use) are most likely to require clinical investigation data. • Clinical investigations may also be required for other devices, including for devices in class I and class IIa, and for class IIb devices that are not implantable. • Gaps become wider due to the increased requirements for equivalence • Further aggravation due to changes in classification rules in MDR
  15. 15. More Experience ► Better Results 15MDR Challenges – Clinical Evaluation Example 1 – Vascular Implant (class III) • Large patient population, established therapeutic principles • State of the Art / medical alternatives: • Numerous recent guidelines • Many meta-analyses with moderate to very high quality • Direct competitor (5 years longer in market) • Large RCT • Long-term follow-up • One RCT with own product • < 2 years follow-up • Unambiguous risk-benefit analysis • Very low complaint rate, no serious adverse events • Equivalence to competitor claimed • Equivalence not accepted by NB • Minor structural differences (clinically not relevant) • No access to technical documentation • Status after two years • Certificate not renewed • New clinical studies requested • Large register study, or • New RCT with long-term follow-up (5+ years)
  16. 16. More Experience ► Better Results 16MDR Challenges – Clinical Evaluation Example 2 – Patient Monitoring (class IIb) • Numerous products in market • Established technology for the last 50+ years • Universal use (no specific patient populations) • State of the art / medical alternatives • Guidelines very general • Systematic studies only in special patient populations • Performance and safety comprehensively defined in industry standards • Clinical benefit • Clinical benefit results only from medical action triggered by monitoring! • Example: Perioperative pulse oximetry  outcome benefit cannot be shown • Risk-benefit analysis unclear (and not really appropriate)
  17. 17. More Experience ► Better Results 17MDR Challenges – Clinical Evaluation Example 3 – Documentation SW (class IIa) • Alternative to paper-based patient records • Established application for 2,000+ years • Universal use (every patient), indispensible • State of the art / medical alternatives: • Documentation legally required, in guidelines requested • Method of technical implementation not required/regulated • Clinical benefit • Without documentation no consistent patient care • No clinical studies into the benefit of documenation • Clinical risks • Decision making influenced by missing/erroneous data (technical risk) • Literature search de facto not feasible • Risk-benefit analysis not feasible and not meaningful
  18. 18. More Experience ► Better Results 18MDR Challenges – Clinical Evaluation Updates of Clinical Evaluations • Whenever new relevant information from PMS • At least annually, if the device carries significant risks or is not yet well established; or • Every 2 to 5 years, if the device is not expected to carry significant risks and is well established, a justification should be provided. • Translation: • Class III: at least annually • Class IIb implants, drug administration: annually • Class IIb: every 2 years (PMS annually) • Class IIa: every 2-5 years (PMS every 2 years) • Class I: every 5 years (PMS when necessary) • If the evidence for the product changes (e.g, by new medical alternatives) it may need to be taken off the market
  19. 19. More Experience ► Better Results 19MDR Challenges – Clinical Evaluation Authors – Requirements • Knowledge of the technology and application of the device • Knowledge of scientific work • Knowledge of the design of clinical investigations • Knowledge in biostatistics • Knowledge of the disease to be treated/diagnosed with respective clinical experience • Experience in use of databases and in medical writing • Regulatory knowledge  A team of authors and contributors required!
  20. 20. More Experience ► Better Results 20MDR Challenges – Clinical Evaluation Authors – Example • Vascular implant class III • Main author • MD, board certified surgeon and intensivist • PhD in medical informatics and statistics • Internal reviewer • MD, board certified vascular surgeon • Literature searches • External specialist team • EMBASE database expert • PMS Data • Internal complaint management team • Close coordination with RM team
  21. 21. More Experience ► Better Results 21MDR Challenges – Clinical Evaluation Clinical Evaluation • Clinical evaluation along the entire product life cycle • Strong emphasis on clinical benefit for all medical devices • Stricter requirements for equivalence • Separate data searches and analyses for state of the art and the actual product • Massively increased requirements for data analysis (esp. literature appraisal) • More clinical data required • More clinical studies needed
  22. 22. More Experience ► Better Results 22MDR Challenges – Clinical Evaluation Clinical Evaluation • More emphasis on PMS and PMCF • More frequent updates required • Strong focus on implants • The lower the risk class the higher the incremental effort • Extreme requirements for author qualifications • MEDDEV and MDR overlap with other guidance documents and standards (e.g., RM, PMS, clinical studies) • The MDR does not define the requirements for clinical evaluations in any detail
  23. 23. More Experience ► Better Results 23MDR Challenges – Clinical Evaluation Thank You! Contact information: Boston MedTech Advisors, Inc. 990 Washington Street Dedham, MA 02026 Ph. +1.781.407.0900 Tannenschlag 32 D-23568 Lübeck Germany Ph. +49.451.707698.0