In the final part of our series reporting from the SME Day at EMA, Larissa Gould focuses on the update from the Committee for Advanced Therapies, new Medical Devices Regulation and a Brexit update.
The Committee for Advanced Therapies (CAT)
The Committee for Advanced Therapies (CAT) secretariat, Patrick Celis, gave an overview of the EMA support available for developers of advanced therapy medicinal products (ATMPs). It was confirmed that ATMPs are medicinal products based on cells or genes and an overview of the different types of ATMP was provided. The legislative framework for MA approval was discussed as well as the roles of CAT. The incentives for development of ATPS are set out in the TMP Regulation and include 3 EMA procedures. The first is Scientific Advice on quality, non-clinical and clinical development. The second is a procedure for advice on classification, to provide regulatory certainty that an ATMP is being developed and advice on which guidelines are applicable. This is important for borderline products, such as those that could be either cell therapies or cell/tissue preparations as well as those that could be potential gene therapy products or vaccines. Thirdly, for SMEs, the EMA offer a procedure for certification of quality and non-clinical data pre-MAA in order to check that product development is on track for a future MA Application.
The EMA provides early support for innovative medicines, which include ATMPs, and the Innovation Task Force provides for early dialogue between Industry and the EMA. In 2015 the EMA and EU national agencies established the EU Innovation Network to further this support to developers and encourage dialogue between all EU regulators. In April 2016 PRIME was introduced to enhance the support to developers while generating appropriate data needed to enable accelerated assessment for products targeting an unmet clinical need. ATMP products comprise 43% of PRIME eligibility requests and the majority were for gene therapy products. As well as making use of these EMA tools, parallel EMA-HTA Scientific Advice was recommended.
Combined Medicines and Devices
A combined medicines and devices development session had presentations from both the EMA and SME perspective. The EMA presenters, Armin Ritzhaupt and Ivana Hayes, discussed the new Medical Devices Regulation (MDR) applicable May 2020 and In vitro Diagnostic Regulation (IVDR) applicable 26 May 2022 in relation to combination products integrating both a medicine and a device. Such products are regulated as either a medicinal product with a device component or a device with an ancillary medicinal substance, depending on the principal intended action. Disputed classification of borderline combination products are decided upon by the European Commission, and, where necessary, the EMA are requested to provide a scientific opinion to aid this process. Other EMA roles include consultations by Notified Bodies (e.g. for substances locally absorbed or dispersed, companion diagnostics and for devices incorporating a medicinal product) and workstreams are being implemented to allow for this.
The EMA also reviews MAAs for medicinal products with integral device components. These device components were included within 23% of MAs approved by the EMA since January 2010. New QWP/BWP guidance, as well as EMA Q&As, covering the requirements for such integral combination medicines will be published later in the year that incorporate the new MDR / IVDR. These guidances will include interpretation of the new MDR Article 117 requirement that the device component (Class Im and above) of an integral combination product regulated as a medicine is assessed by a Notified Body. In addition a statement of conformance to the general safety of performance requirements of Annex I of the MDR is obtained before an MAA is granted. The EMA also participates in working groups resulting from the joint task force comprising the European Commission and Competent Authorities for Medical Devices. This was formed to implement the regulatory system incorporating the MDR / IVDR. The presentation concluded with advice to manufacturers to familiarize themselves with the new regulations, engage early with a Notified Body and make use of EMA services such as Scientific Advice, the Innovation Task Force and ATMP classification procedures for combined ATMPs.
Medical Devices Regulation Development
Lars Hyveled-Nielsen of Zealand Pharma presented on the impact of the MDR on the development of a combined drug-device regulated as a medicine (i.e. integral, for use in the given combination, not reusable) from an SME perspective. The major change introduced with the MDR comprised Article 117, that states from May 2020 the MA dossier must contain either a device manufacturer’s EU declaration of conformity or a certificate issued by a Notified Body. Although no guidance has yet been issued regarding the specific remit of the Notified Body involvement, the presentation suggested that the Notified Body would audit the Quality Management System (ISO 13485 or equivalent), as well as ensure that the technical file includes the relevant parts of the general requirements for safety and performance (MDR Annex 1), before issuing a declaration of conformity. This would have a major impact on the business model of an SME, as the SME would need to liaise with two different sets of people to consider both the drug and the device during development and the necessary regulatory procedures. The SME, and not necessarily the device manufacturer, would have to consider the intended use relating to the proposed indication, the risk analysis for the user and design as well as the usability from the patients’ perspective and ensure that these were considered within the technical file.
The presentation ended with a new and updated guidance to aid the implementation of Article 117, as well as reflections on the transparency of the Competent Authority and Notified Body remit, introduction of systems to ensure no duplicate assessment and the timing of the notified Body assessment in relation to the MAA. It was noted that no Notified Body was currently designated under the MDR, but the first was expected Quarter 1 2019. It was confirmed that existing integral combination products already granted MA would not have to comply with Article 117 as long as there were no changes to the product.
The last presentation concerned Brexit, where Leonor Enes discussed EMA guidance relating to UK leaving the EU including the ‘Notice to MAHs’ published January 2018, a ‘Q&A document’ and a ‘Practical guidance’ both last published June 2018. The following aspects of Brexit were discussed during the presentation and during the panel discussion:
- SME status; for a UK SME to continue to benefit from SME incentives they must either directly establish a legal entity in the EU, or indirectly by listing in the Annex of the SME notification of a EU regulatory consultancy.
- MAs and Orphan Designations held by UK companies; must be transferred to a company established in the EU.
- PIPs; There is no requirement to transfer Paediatric Investigation Plan / Waiver addressees as these do not have to be established in the EU.
- UK reference product cited for abridged MA applications; UK product can be cited for MAs granted before 30 March 2019 and not after this date.
- UK sites within a MA; QPPV, site of PSMF, importer, batch release and control sites, intended Official Medicines Control Laboratory and nominated local representatives need to be changed to sites located in the EU.
- Manufacturing and supply of medicines; finished products manufactured in the UK would need to be imported, retested and released into the EU after 29 March 2019. UK GMP certificates issued by the MHRA would continue to be valid, until the new EU supervising body decides that re-inspection is necessary. Active ingredients would need to be accompanied by written confirmation from the MHRA confirming GMP compliance.
- Medical devices; for medicines co-packaged with a CE marked device based on conformity assessment by UK Notified Body, a new certificate issued by a EU Notified Body is required or an alternative device should be used.
- (Co)-rapporteurs; UK centrally authorised products portfolio have already been redistributed to EU member states but new responsibilities will occur from 30 March 2019.
- Clinical trials; for trials conducted in the UK only, no requirement for reporting within EUDRACT.
- SAWP; The EMA have temporarily enlarged SAWP to account for the loss of the UK members (currently the UK contribute to 11% of Scientific Advice procedures).
Anthony Humphreys, Head of Scientific Committees Regulatory Science Strategy at the EMA, contributed to the panel discussion and stated that transition is a hope and, until a deal is signed by all parties, the rules must be applied and the UK considered as a third country from 29 March 2019. Industry was urged to expedite the necessary Brexit actions outlined above. It was confirmed negotiations were at a high political level and there had been no discussions between the MHRA and the EMA to date. Even though medicines are extremely important, all particular industries consider that they require special considerations. If all consider themselves special, then none become so during the high level negotiations.