EMA perspective on increasing focus on review of device components of medicinal products TOPRA Annual Human Medicines Symposium 2 4 October 2017 - Victoria Park Plaza Hotel, London Presented by Armin Ritzhaupt, PhD on 04 October 2017 EMA, Regulatory Affairs Office, Scientific and Regulatory Management Department An agency of the European Union
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Outline Introduction Regulatory framework in the EU Definitions EMA s current role in medicinal productmedical device combinations Review Support Experience EMA guideline on quality requirements for drug device combination products EMA s future role as per new Medical Device Regulations 2
EMA - Who are we? established in 1995 7 Committees 975 positive opinions for human medicines since 1995 ~840 staff from 28 EU Member States 24 official languages 3
The EU legal framework Blood 2002/98/EC Clinical Trials EU Reg. 536/2014 & Dir. 2001/20/EC Tissues / Cells 2004/23/EC Other starting materials Human Medicinal Products Medical Devices 93/42/EC 90/385/EEC 98/79/EC GLP Dir. 2004/10/EC Paediatrics Reg. 1901/2006 Community Code Dir. 2001/83/EC Centralised procedure Reg. 726/2004 GMP 2003/94/EC Animal protection Dir. 2010/63/EU Orphans 141/2000 Annex I 2003/63/EC Advanced Therapy Reg. 1394/2007 New EC Proposals Variations 1084(5)/2003 1234/2008 4
5 Medical device Any instrument, apparatus, appliance, material, software, or other article [ ], alone or in combination, intended by the manufacturer to be used in humans for the purpose of: diagnosis, prevention, monitoring, treatment or alleviation of disease, diagnosis, monitoring, treatment, alleviation of or compensation for an injury/handicap investigation, replacement, modifiction of the anatomy; control of conception and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means. Medicinal product Any substance or combination of substances: having properties for treating or preventing disease in human beings or; may be used in or administered to human beings with view to restore, correct, modify physiological function by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.
Primary intended purpose Medicinal products combined with medical device are either regulated by the medicinal product or the medical device directive 6
EMA s current role in review of medicinal product and medical device combinations Medicinal products and drug delivery medical devices Non-integral (CE-mark required prior to CHMP opinion) Integral (No CE mark required) ATMP combination products One or more medical devices as an integral part of the medicine Existing procedural advice on the consultation of Notified Bodies Medicinal substances incorporated in medical devices (ancillary) Consultation of NB with NCA/EMA Established procedure and guidance for initial and post-consultation (210 days) 7
Medicinal product-medical device combinations - what is within EMA remit? (1/3) If device and medicinal product are placed on the market in such way that they form single integral product The following cumulative conditions need to be met: Single integral product Not reusable Device intended exclusively for use with the medicinal product Prefilled syringe EMA responsible for the overall assessment including compliance with Annex I of the Medical Device Directive for safety and performancerelated device features Notified Bodies are not involved (but may be consulted for ATMPs) 8
Medicinal product-medical device combinations - what is within EMA remit? (2/3) For devices requiring CE marking Request proof of CE marking (EC Certificate / Declaration of Conformity) before authorising a medicinal product Directive 2001/83/EC, Annex I, 3.2. (12): Where applicable and if needed, a CE marking which is required by Community legislation on medical devices shall be provided Assessing whether the device is fit for purpose for a given medicinal product (e.g. performance, compatibility with medicinal product, suitability for intended patient population) 9
Medicinal product-medical device combinations - what is within EMA remit? (3/3) For all devices in combination products Authorising product information to ensure safe and effective use (can include instructions for use in the package leaflet) Requesting risk minimisation measures (e.g. training for complex devices) Post-market surveillance Device failure, dosing errors, decreased efficacy resulting from difficulty to use the device, etc PRAC Good practice guide on risk minimisation and prevention of medication errors www.ema.europa.eu/docs/en_gb/document_library/regulatory_and_procedural_guideline/2015/11/wc500196981.pdf Authorising changes of device component during product lifecycle 10
EMA support for combination products Regulatory and Scientific Advice Available from EMA or National Competent Authorities Can be used at any stage of development earlier the better! EMA Innovation Task Force (ITF) Facilitate understanding of issues and regulatory requirements to bring innovative products and processes to market: ATMPs, stratified medicines, nanomedicines, advanced manufacturing techniques, novel drug/device combinations. Applicable to medicines and devices. ATMP classification procedures for combined ATMP Regulation 1394/2007/EC Incorporates as an integral part of the product one or more (active implantable) medical devices; cellular or tissue part is viable; in case of non-viable cells or tissues, the action must be primary to that of the device(s) CAT may require consultation of a Notified Body on the conformity of the device part with Annex I of Medical Device Directive 11
Experience with medicinal product-medical device combinations at EMA MAAs Since 2010, of 360 MAAs; 48 (13%) combination with medical device Orphan; Hybrid (10.3); Duplicates, Biosimilar Device components: MAA with device component Pre-filled syringes / pre-filled pens (eg diabetes; arthritis, fertility treatment) Inhalers (COPD/Asthma) Implant for subcutaneous administration to treat intolerance to light Sealant matrix with human fibrinogen / human thrombin to stop bleeding during surgery Nasal spray to deliver influenza vaccine Tablet delivery system with controller for pain management ATMPs (e.g. autologous cultured chondrocytes embedded in a biodegradable matrix or scaffold) 12
Examples of identified device concerns during review Container closure system: specification; sterilisation methods Compatibility/suitability of drug product with the proposed dosage device Dosing accuracy and precision Declaration of CE missing / information from NB missing Suitability of the drug delivery system (e.g. risk to the patient from potential contamination of the vial adapter surface, in-use) Comparability study between clinical trial version and commercial product Adequate release specifications to identify possible performance failures Justification why application devices were not explored as a covariate in the population PK analysis Product labelling (readability, use, disposal) Risk Management Plan Risk of medication errors (e.g. due to some similarity of devices) Administration of correct dose 13
EMA review of ancillary substances During the conformity assessment, the notified body (NB), having verified the usefulness of the ancillary substance as part of the medical device, shall seek an opinion from a NCA or EMA on the quality, safety of the substance including the clinical benefit/risk profile of the incorporating of the substance in the device The applicant is the NB together with medical device manufacturer When issuing its opinion, the NCA/EMA shall take into account the manufacturing process and the data related to the usefulness determined by the NB Consultation with EMA when the ancillary medicinal substance is: Mandatory - human blood derivative (MP or constituent derived from human blood/plasma) Medicinal product falling within scope of Annex I Ref 726/2004 (i.e. mandatory scope) The NB will convey its final decision to the Agency Post consultation procedures 14
EMA experience with initial consultation of ancillary substances Since 2005: 13 CHMP positive opinions: prior to transplant - 10 IVF media (Human albumin) - 3 fibrin sealants (Human thrombin) 1 withdrawn procedure 1 procedure in evaluation average active review: 198 days EMA publishes the CPAR after the notified body confirms the granting of a Conformité Européenne (CE) mark. The Agency also publishes information on procedural steps taken after a consultation procedure. For more information on the consultation procedure, see Ancillary medicinal substances. 15
Proposal for EMA guideline on quality requirements for drug device combination products (1) 16
Proposal for EMA guideline on quality requirements for drug device combination products (2) Dossier requirements for integral and non-integral combination products > Lack of clear guidance for industry or assessors for assessment of medical device component along with medicinal product In EU, no definition in regulation for a medicinal product and medical device presented together (except for ATMPs) Product Information > Considerations for specific information to be included in the SPC, labelling and leaflet Usability study requirements > target patient population with relevant clinical conditions Product lifecycle management > Data requirements for variations 17
Concept paper consultation Individual pharmaceutical companies Industry associations (pharma and medical device) Individuals Notified Bodies Primarily EU; but also Canada, USA 18
General comments Proposal to develop guidance is welcome; needed across EU Alignment with new MDR (Art 117) Engagement with device stakeholders positive; appreciate WS/training; address advice for development Consistent wording/terminology (ISO), more clarity on scope (applicability for clinical trials?); global alignment 19
Revision of the EU Medical Devices Legislation Directive 90/385/EEC on active implantable medical devices Directive 93/42/EEC on medical devices New Regulation on medical devices (Regulation (EU) 2017/745) MDD 23 Articles 12 Annexes 60 Pages MDR 123 Articles 17 Annexes 175 Pages Directive 98/79/EC on in vitro diagnostic medical devices New Regulation on in vitro diagnostic medical devices (Regulation (EU) 2017/746) Final adoption April 5, 2017, publication in OJ-EU, 5 May 2017 20
EMA s future role in review of medicinal product and medical device combinations Consultation on borderline products Consultation on devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body Consultation on companion diagnostics Mandatory to consult EMA on ancillary substances exclusively within the scope of the Annex to Regulation 726/2004 (e.g. biotech products) Amendments to Annex I to Directive 2001/83/EC (Art 117) 21 Initial MAA to include results of conformity assessment as per Annex I of MD legislation
Acknowledgements Hilde Boone Christine Bugge Sonia Ribeiro Marisa Papaluca Falk Ehmann Pascal Venneugues Alberto Ganan Aleksandar Rusanov 22
Thank you for your attention Armin.Ritzhaupt@ema.europa.eu European Medicines Agency 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact Follow us on @EMA_News