Eu hot topics alliance presentation 2
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This document summarizes recent EU regulatory developments in data protection, medical devices, and in vitro diagnostics. For medical devices, the proposal introduces stricter rules for clinical evaluations, notified body oversight, and transparency. It may introduce concepts of efficacy from pharmaceutical regulations. The in vitro diagnostics proposal significantly increases regulatory requirements, especially for higher risk devices. It aims to improve transparency through registration in a central EU database and making more clinical data publicly available.
![Clinical performance / efficacy?
• Medicinal products trials: “ascertaining its (their) safety and/or
efficacy”
• Medical devices [currently]: “demonstrate the safety and performance
of their devices”
• MDR proposal: inconsistent language
– Explanatory note 3.6: “performance of the clinical evaluation needed to
demonstrate the safety and performance of their devices”
– (34) „clinical investigation‟ means any systematic investigation in one or
more human subjects, undertaken to assess the safety or performance of
a device;
• But:
– Article 26 requires “summary of safety and clinical performance”](https://image.slidesharecdn.com/euhottopicsalliancepresentation-2-130605030212-phpapp01/85/Eu-hot-topics-alliance-presentation-2-27-320.jpg)
Eu hot topics alliance presentation 2
- 1. EU Hot Topics Update Alex Denoon & Erik Vollebregt www.aelslf.eu4 June 2013
- 2. Overview • General Data Protection Regulation Proposal • Medical Devices Regulation Proposal • IVD Regulation Proposal • Transparency of clinical data
- 24. Politics, politics • Revision already started in 2008 with consultations but dossier became political with several medical devices scandals in EU market (MoM hips, PIP breast implants) • Dalli Action plan running in the background • ENVI rapporteur obviously overshooting to reach compromise
- 25. To PMA or not to PMA • EU Commission decided against US FDA style PMA because of costs and limited added value • Rapporteur ENVI committee EU Parliament wants PMA as political project • Current trend points towards „technical compromise‟ between Commission and Parliament • Member states are the dark horse – most are against PMA
- 26. Introduction of new concepts • ENVI rapporteur: – Efficacy – Randomised controlled trials as default It’s a trap!!!
- 27. Clinical performance / efficacy? • Medicinal products trials: “ascertaining its (their) safety and/or efficacy” • Medical devices [currently]: “demonstrate the safety and performance of their devices” • MDR proposal: inconsistent language – Explanatory note 3.6: “performance of the clinical evaluation needed to demonstrate the safety and performance of their devices” – (34) „clinical investigation‟ means any systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a device; • But: – Article 26 requires “summary of safety and clinical performance”
- 28. Clinical performance / efficacy? Amendment ENVI rapporteur: • “to verify the clinical safety and efficacy of the device, including the intended benefits to the patient, when used for the intended purpose, in the target population and in accordance with the instructions of use;” and • “Performance should notably be understood broadly so as to encompass efficacy and benefit to the patient, which shall be checked in cases where clinical investigations apply.”
- 29. Clinical Evaluation & Clinical Investigation • New: – For pre-market evaluations, a mere literature route for new applications will be highly unlikely to be accepted; • Substantial equivalence will not be considered sufficient justification for not doing a clinical investigations. – Introduction of the “sponsor”; – All clinical investigations (both pre-market and post-market) are to be registered and will be published on the central EU database which will be publically accessible; – Clinical studies conducted in multiple member states, will require only one approval; however, local legislations might still apply; – Post marketing clinical follow-up studies shall be planned, unless duly justified.
- 30. Supply chain controls Manufacturer Importer Distributor End User Post market surveillance and vigilance Regulatory compliance of device Verify compliance Verify compliance Supplier
- 31. Qualified person / parallel trade • Manufacturer's organisation must have access to a 'qualified person‟ responsible for regulatory compliance. – Similar requirements exist in EU legislation on medicinal products and in the national laws transposing the Directive on medical devices in some Member States. • A distributor, importer or other natural or legal person shall assume the obligations incumbent on manufacturers if he does any of the following: a) makes available on the market a device under his name, registered trade name or registered trade mark; b) changes the intended purpose of a device already placed on the market or put into service; c) modifies a device already placed on the market or put into service in such a way that compliance with the applicable requirements may be affected.
- 32. Parallel trade • Modification of a devices already placed on the market does not include: – translation of IFU – repackaging for parallel trade purposes HOWEVER (part implementation of pharma repacking case law ECJ) • Repackaging must not affect the condition of the device • Repacker must indicate the activity carried out together with his name, registered trade name or registered trade mark and the address at which he can be contacted and his location can be established on the device or, where that is not possible, on its packaging or in a document accompanying the device • Quality management system for translation and preservation of original condition of the device and that the packaging of the repackaged device is not defective, of poor quality or untidy – QS must be certified by notified body – QS must include vigilance feedback to manufacturer – prior notice and mockups must be supplied to authorities and manufacturer if requested
- 33. Traceability, registration, summary of safety and performance, Eudamed • Aim Commission: address one of the main shortcomings of the current system: lack of transparency: – a requirement that manufacturers fit their devices with a Unique Device Identification (UDI) which allows traceability. • UDI system will be implemented gradually and proportionate to the risk class of the devices; – a requirement that manufacturers/authorised representatives and importers shall register themselves and the devices they place on the EU market in a central European database; – an obligation for manufacturers of high-risk devices to make publicly available a summary of safety and performance with key elements of the supporting clinical data;
- 34. Reprocessing • Commission proposal: – reprocessing is treated and regulated like manufacturing • ENVI rapporteur: – fiction that all devices can be reprocessed unless proven otherwise • Rest of ENVI and amendments: – strict controls on reprocessing, but disagreement about how and what exactly (e.g. negative list)
- 35. Notified Bodies • Proposal contemplates – a shake-out of about 75% of current notified bodies (20-25 remaining) with recertification under stricter requirements and tighter supervision by notifying member states – Mandatory unannounced audits of manufacturer and critical subcontractors • ENVI amendments: – Less freedom for notified bodies to outsource work
- 36. Notified Bodies Transitioning to notified body accreditation 2.0: • Designations under AIMD, MDD, IVD become void at the date of application of the regulation • EC Certificates issued before MDR enters into force remain valid until expiration date • EC Certificates issued after MDR enters into force become void 2 years after the date of application of the MDR • Certificates against MDR can only be issued by notified bodies designated under MDR before the date of application of MDR Aim: make notified bodies more of an extension of competent authorities‟ market surveillance paid by industry
- 37. Notified Bodies In the mean time • Notified Bodies Code 3.0 • Contains specifics on unannounced audits and many other interesting subjects • Commission recommendation on unannounced audits in pipeline • Currently planned for September 2013 • Will trigger applicability of unannounced audit section of Notified Bodies Code 3.0
- 38. Vigilance and market surveillance • Have their own chapter in the MRD now (chapter VII) • Reflect the strong political desire to remedy the problems behind the PIP and metal-on-metal hips cases • Vigilance incorporates vigilance MEDDEV 2.12/1 • Reporting via EUDAMED of • Serious incident • Corrective action • Member States must take measures to encourage healthcare professionals, users and patients to report to their competent authorities suspected serious incidents
- 39. Conformity assessment routes overview (no big changes)
- 40. Money money money • The Commission, the Member States and the designated EU reference laboratories will charge fees for various activities • implementing acts to set the level and structure of fees Commission • EUDAMED registration fees • Fees for scientific advice provided at the request of a manufacturer or notified body Member States • Fees for the designation and monitoring of notified bodies • May levy fees for the activities based on MDR, provided that the level of the fees is set in a transparent manner and on the basis of cost recovery principles EU Reference Laboratories • Fees for scientific opinions provided to notified bodies and manufacturers
- 43. Quantum leap in regulatory burden Source: BSi
- 44. Conformity assessment • Biggest changes because of implementation of GHTF classes A-D • The existing modules established under the 'New Approach‟ do not change – see annexes VIII to X, however – EC verification module was deleted – The concept of batch testing has been clarified Source: BSi
- 45. Conformity assessment • See GHTF SG1-N46:2008 “Principles of Conformity Assessment for In Vitro Diagnostic (IVD) Medical Devices” for model • Class A devices : sole responsibility of the manufacturer, except if intended for near-patient testing, have a measuring function or are sold sterile • Classes B, C and D : notified body involvement – Class D: explicit prior approval of the design or of the type of the device and of the quality management system before they may be placed on the market – Class B and C devices : the notified body checks the quality management system • Class C: in addition of QMS notified body check the technical documentation of representative samples. • After initial certification, notified bodies shall regularly conduct surveillance assessments in the post-market phase.
- 46. Common Technical Specifications • Where no harmonised standards exist or where relevant harmonised standards are not sufficient, the Commission shall be empowered to adopt common technical specifications (CTS) in respect of – the general safety and performance requirements set out in Annex I, – the technical documentation set out in Annex II or the clinical evidence and – post-market follow-up set out in Annex XII. • Compliance with CTS is presumption of compliance with Annexes • Like with standards, diverge allowed but must be justified
- 47. Clinical • Clinical data requirements depend on risk class of IVD • Annex XIII : rules for the conduct of interventional clinical performance studies and other clinical performance studies where the conduct of the study, including specimen collection, involves invasive procedures or other risks for the subjects of the studies – applies only to clinical performance studies carried out for regulatory purposes • The concept of 'sponsor‟ introduced and aligned with proposal for Clinical Trial Regulation
- 48. Vigilance and market surveillance • Vigilance – Introduction of EU portal for reporting of serious incidents and corrective actions taken by manufacturers. • Information will be automatically made available to the national authorities concerned • Coordinating authority that takes direction in coordinating the analysis of the case in multinational matters • Market surveillance – Emphasis on work-sharing and coordination – Use of pan-EU electronic system on market surveillance – Procedures for compliant and non-compliant devices presenting a risk to health and safety at national level – Procedure for national preventive measures with respect to potential risk related to a device or a specific category or group of devices
- 49. Companion Dx • New regime • New definition “a device specifically intended to select patients with a previously diagnosed condition or predisposition as eligible for a targeted therapy” • Class C risk classification, although this is up for debate in amendments • Design or type examination – whereby the notified body shall consult one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or the European Medicines Agency (EMA) in accordance with the procedures set out in Section 6.2 of Annex VIII and in Section 3.6 of Annex IX. • Also consultation in case of changes affecting the suitability of the device in relation to the medicinal product concerned are made
- 50. Transitional regime • Complex • Sunshine clause – you can comply prospectively • Certificates issued by notified bodies under old IVD directive – prior to the entry into force of this Regulation shall remain valid until the end of the period indicated on the certificate • except for certificates issued in accordance with Annex VI of Directive 98/79/EC which shall become void at the latest two years after the date of application of this Regulation. – after the entry into force of this Regulation shall become void at the latest two years after the date of application of this Regulation. • ALL notified bodies will be decertified and have to be recertified under new requirements during transition period
- 51. Unannounced factory inspections • Minimum once per 3 years, more frequent for high risk devices, timing to be unpredictable • Checks will look at: – Manufacturing in line with documentation? – At least one critical process out of: • Design control, purchasing, incoming materials, assembling, sterilisation, packaging product QC • Design Examination/Type Examination sample several products at end of line or warehouse – Test in house or in external labs – Sampling and test criteria determined in advance – If impossible take samples from market, where needed supported by CA – Compare with existing technical documentation, test protocols and results 51
- 52. Transparency
- 54. Impact • Impact on Pharmaceutical and Biopharmaceutical Sector – Already seeing increased investment in competitive intelligence – Relatively little active engagement from researchers, clinicians or reimbursers • Uncertainty is concerning for sector – Prospect that this will exacerbate the current decline in clinical trials conducted in Europe
- 56. Publicity of data / transparency • Recital 20: In order to increase transparency in the area of clinical trials, clinical trial data submitted in support of a clinical trial application should be based on clinical trials recorded in a publicly accessible database. Clinical trial data based on clinical trials conducted before the date of application of the present Regulation should be registered in a public register which is a primary or partnered registry of the international clinical trials registry platform of the WHO. • Recital 20a: Clinical trial data should not be considered commercially confidential once a marketing authorisation has been obtained. • Article 34 (3): Within one year from the end of a clinical trial, the sponsor shall submit to the EU database the clinical study report, including a lay summary of the clinical trial. – Clinical study report: a report containing the full protocol and any subsequent modifications and dates thereof, a statistical analysis plan, summarised efficacy and safety data on all outcomes, and individual anonymised patient data in the form of tabulations or listings
- 57. Publicity of data / transparency • Publication of clinical study report in public database • full protocol (plus modifications) • statistical analysis plan • summarised efficacy and safety data on all outcomes • individual anonymised patient data in the form of tabulations or listings • Clinical data deemed not commercially confidential after market access • How will that work: automatically deemed in the public domain? • Impact on existing NDAs? • What about Article 39 TRIPS?
- 58. Impact on Medical Devices • Will the new regime for medical devices be influenced by that of medicines? – Simultaneous revision of MDD and of Clinical Trials Directive – Med Dev Regulation borrows inconsistently from ICH 1996 – Call for “pharma-style” PMA has also led to favouring of controlled randomized trials as gold standard • Alignment with well-established Pharma practice at Union level may conflict with international approach to medical devices – Proposed MDD Recital (21) The definitions in … medical devices, for example regarding … clinical investigations and vigilance, should be aligned with well established practice at Union and international level... – (47) The rules on clinical investigations should be in line with major international guidance in this field, such as the international standard ISO 14155:2011 on GCP for clinical investigations of medical devices for human subjects and the most recent (2008) version of the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects • Art. 6: Harmonised standards relating to among others clinical investigation still provide presumption of conformity
- 59. Clinical performance / efficacy? – DRB report amendments says randomized controlled trials to prove clinical efficacy and safety - the use of any other design or study has to be justified – Performance should notably be understood broadly so as to encompass efficacy and benefit to the patient, which shall be checked in cases where clinical investigations apply. This is crucial to ensure that devices are technically achieving the aim for which they were designed and produced, but also bring benefit to the patient and are efficient when used in real-life. – Annex XIV – Part I – paragraph 2 – point 2.1. Clinical investigations shall be performed on the basis of an appropriate plan of investigation reflecting the latest scientific and technical knowledge and defined in such a way as to confirm or refute the technical performance of the device, the clinical safety and efficacy of the device when used for the intended purpose in the target population and in accordance with the instructions of use, and the manufacturer's claims for the device as well as the safety, performance and benefit/risk related aspects referred to in Article 50(1);
- 60. Proposals re Med Dev data • Proposed addition to Article 53(2a) of MDR re clinical trials database for medical devices – Upon a reasoned request, all information on a specific medical device available in the electronic system shall be made accessible to the party requesting it, save where the confidentiality of all or parts of the information is justified on any of the following grounds: (a) protection of personal data …; (b) protection of commercially sensitive information; and (c) effective supervision of the conduct of the clinical investigation by the Member State(s) concerned. – See also proposed Recital (37): Adequate levels of access for the public and healthcare professionals to those parts of Eudamed's electronic systems which provide key information on medical devices that may pose a risk to public health and safety is essential. Where such access is limited, it should be possible, upon a reasoned request, to disclose existing information for medical devices, unless the limitation of access is justified on grounds of confidentiality.
- 62. Thanks for your attention Erik Vollebregt Axon Lawyers Piet Heinkade 183 1019 HC Amsterdam T +31 88 650 6500 F +31 88 650 6555 M +31 6 47 180 683 E erik.vollebregt@axonlawyers.com @meddevlegal B http://medicaldeviceslegal.com READ MY BLOG: http://medicaldeviceslegal.com
- 63. Dedicated to Life Sciences Axon Lawyers Amsterdam Italy Legal Focus Milan Lawford Davies Denoon London LCH Avocats Paris Lützeler Klümper Wachenhausen Düsseldorf Hamburg Lübeck www.aelslf.eu
- 64. Links • Joint Statement from biomedical research community re data protection: http://www.wellcome.ac.uk/stellent/groups/corporatesite/@policy_communicat ions/documents/web_document/wtvm054713.pdf • Advice to EMA from clinical-trial advisory groups: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news /2013/04/news_detail_001778.jsp&mid=WC0b01ac058004d5c1 • AbbVie v EMA: http://curia.europa.eu/juris/document/document.jsf?text=&docid=137241&pag eIndex=0&doclang=en&mode=lst&dir=&occ=first&part=1&cid=3667720 • InterMune v EMA:http://curia.europa.eu/juris/document/document.jsf?text=&docid=137242 &pageIndex=0&doclang=en&mode=lst&dir=&occ=first&part=1&cid=3667717