Drug-device combinations regulated as medicines - Revised regulatory framework with implementation of the new Medical Device Regulation from 26 May 2020 IFF – Jan. 2019

TEASER What should I do? When and what to expect from regulators in terms of regulatory guidance

Agenda Definitions Regulatory pathways Status and industry concerns of implementing MDR for medicines Q&A

Definition of a medicinal product One of the following limbs is to be fulfilled: Any substance or combination of substances presented for treating or preventing disease in human beings Any substance or combination of substances which may be used in, or administered to, human beings, either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis Ref: Directive 2001/83/EC Article 1.2

Definition of a medical device Any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used alone or in combination for human beings for one or more of the following specific medical purposes: diagnosis, prevention, monitoring, treatment or alleviation of disease, diagnosis, monitoring, treatment, alleviation of or compensation for, an injury or disability, investigation, replacement or modification of the anatomy or pathological process or state, providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donation, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means Ref: Medical Devices Regulation (MDR), 2017/745, Article 2(1)

Drug delivery systems in the EU - Two regulatory pathways apply How is my drug delivery system regulated? Single integral drug-device combination product which is not reusable Stand-alone device intended to deliver a medicinal product Demarcation between directive/regulation - only one prevails! Medicinal Products Directive 65/65/EEC (MPD) Medical Devices Regulation (EU) 2017/745/EEC

Exchange on the practical considerations for the future regulation of integrated single-use drug-device combinations EMA 4th Industry stakeholder platform on R&D support November 23, 2018 AT

This is a joint industry presentation

Problem statement Current EU Directive 93/42/EEC, Art. 1.3: AGENCY PHARMA Marketing Authorisation Application (MAA) Current EU Directive 93/42/EEC, Art. 1.3: The relevant essential requirements of Annex I to this Directive shall apply as far as safety and performance-related device features are concerned. Future EU Regulation 2017/745; Art. 117: If the dossier does not include the results of the conformity assessment …and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required…the authority shall require an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I issued by a Notified Body… ERC NB OPINION NOTIFIED BODY PHARMA AGENCY Marketing Authorisation Application (MAA) More drug-device combination products to be expected in the future, and more complex Scope of Notified Body Opinion, sequential vs parallel reviews, CMC Module 3 content, LCM and variations, clinical evidence, labelling and instructions for use, QMS vs GMP, pre-submission e.g. scientific advice Impact on existing MAs for products with a device constituent part particularly for products undergoing significant device change Notified Body availability (and capacity to take on a new category of pharmaceuticals) ERC – essential requirements checklist

Fundamentally different regulatory frameworks Medical Devices Medicinal Products DG GROW DG HEALTH & CONSUMERS MDCG Medical Device Coordination Group MDCG Working Groups HMA Heads of Medicines Agencies EMA European Medicines Agency CAMD Competent Authorities for Medical Devices Harmonised Standards EN: CEN, CENELEC CMDh Committee for Human Medicinal Products - Human BWP Biologics Working Party QWP Quality Working Party EU NBs Notified Body associations Private service providers

Practical implementation steps - Where are we now? Issue recognised at senior level of medicines and devices regulators (EMA and HMA) and work is ongoing to address it EMA is taking the lead and working through the Regulatory Network to align across Member States and aims to share information before year end: Q&A – by Jan. 2019: procedural and process issues, impact on legacy products, life cycle considerations & changes that warrant NB opinion BWP/QWP Quality Guideline – by Q2 2019: CMC Module 3 content; variations, EMA in dialogue with NBs Industry: Welcome these initiatives, but helpful to know what will be covered and what is still to be clarified

Questions/items still looking for a home What is the scope for the conformity assessment and what are the limitations of the NB assessment? we assume labelling, clinical evaluation as per MPD (2001/83/EC) user-testing data and reports per MDR (avoid duplicate reviews) acceptability of a risk-based approach (potentially supported by EU standards)? GMP vs. QMS clarifications assume as per MPD (GMP); quality assurance, GMP inspections (not audits) Borderline considerations for container closure versus device (Implementing Act slow to come, ‘soft guidance’ - MDCG borderline subgroup?) Scope of NBO: Who will provide written guidance to the NBs (no mandate within MDR to issue guidance or implementing texts: COM and Standing Committee for Medicinal Products?)

NB designation and capacity Problem: Industry is very concerned not enough Notified Bodies designated and available to review (drug-delivery) devices come 26th May 2020 EC is monitoring situation and on the HMA agenda But if first NB is only designated Q1 or Q2 2019, pharma has limited time to build the business and get the required opinion – Can delay MAAs Proposed action: Industry and regulators must develop a contingency plan in due time for new MAAs in case the NBs are not ready

Next steps and collaboration across stakeholders for implementation of MDR Article 117 products A clearly defined process and transparent expectations are needed to allow businesses to plan for: Continued validity of existing MAs Avoidance of delays to approval of new MAs Welcome clarity on the accountability EMA taking the lead and working for alignment Identify gaps between the EMA Q&A/Quality guideline and other responsibilites outside EMA’s remit and find a home for it Industry survey on planned submissions of drug-device combinations in 2020 Are other areas helpful to make constructive proposals e.g. labelling, GMP aspects? Need for a collaborative approach to implementation of Art. 117 across industry, regulators (drug and device) and Notified Bodies

List of references Medical Device Regulation (EU) 2017/745: Click here EBE Reflection paper 15 Jan. 2018: Medicinal product incorporating a drug delivery component: An Industry Perspective on the EU marketing application technical requirements, regulatory review process and post-approval device related change assessment. Click here Article 117 of the Medical Device Regulation – An urgent need for further guidance: Part 1. Topra, Regulatory Rapporteur – Vol 15, No 5, May 2018 (for members only) Article 117 of the Medical Device Regulation – An urgent need for further guidance: Part 2. Topra, Regulatory Rapporteur – Vol 15, No 6, June 2018 (for members only)