EU SME info day: Supporting innovative medicines’ development and early access
This small and medium-sized enterprise info day focused on the future EU funding opportunities and platforms for early regulatory dialogue with the European Medicines Agency and the EU networks. Reported by Jayne Hunt, Associate Director, Boyds and published in Regulatory Rapporteur.
The aim of this small and medium-sized enterprise (SME) info day, held by the European Medicines Agency (EMA) on 17 November 2017 was to provide SMEs with an overview of EU initiatives supporting product development. The event was organised in collaboration with the newly launched EU Innovation Network (created to support pharmaceutical innovation both at national and EU level). There was also a chance for SMEs to meet with the EU Innovation Network regulators during the breaks. Finally, an update on Brexit was also provided.
SME programs supporting R&D
Leonor Enes, Scientific Officer, SME Office, EMA, spoke about EMA initiatives supporting SMEs.
The SME Office was launched in 2005 as a result of the adoption of Regulation (EC) No 2049/2005, with the aim to promote innovation and the development of medicines by micro, small and medium-sized enterprises (SMEs). The SME office is involved with the assignment of SME status; acting as a single point of contact for SMEs and providing administrative, procedural and regulatory support. In 2016, 174 SMEs made use of the direct administrative advice of the office, compared with 20 SMEs in 2006. An SME register has also been set up to support partnering and networking between SMEs as well as increasing the information available to SMEs.
Additional benefits of SME status include fee incentives (fee exemptions / reductions / deferrals) and access to translation assistance for the EU countries in the event of a positive centralised opinion for a marketing authorisation application (MAA). Ms Enes described a number of actions for SMEs to consider to support them with their product development, some of which included:
- Consider informal dialogue through the Innovation Task Force
- Use the SME guidance and European Public Assessment Reports for useful information sources
- As well as building in adequate timelines paediatric investigation plans (PIPs) and associated activities, early scientific advice and early MAA pre-submission dialogue are helpful.
- Consider the SME eligibility to use the PRIME scheme (which enhances support for the development of medicines that target an unmet medical need).
- Consider policy 70 on clinical data publication.
Early interactions to support innovation
Through his presentation on the Innovation Task Force (ITF) Falk Ehmann, Science & Innovation Support at the EMA reminded us on how the Regulators are not just ‘gatekeepers’ but also ‘enablers’, as demonstrated with the acronym ASAP.
- Assist knowledge exchange on innovative strategies involving regulatory network.
- Support drug development via early informal dialogue on scientific, legal and regulatory issues and products, methodologies and technologies
- Address the impact of emerging therapies and technologies on current regulatory system
- Preparing for formal procedures
Since 2016, the ITF has supported informal meetings with research and public-private funded consortia such as Horizon 20/20, Innovative Medicines Initiative and Europe’s seventh framework program for research (FP7), all of which provide support for SMEs.
The new EU Innovation Network
Esa Heinonen, Co-chair of the EU Innovation Network (EU-IN), Finnish Medicines Agency, gave a presentation describing the EU Innovation Network. In 2015, the EMA and the EU National Competent Authorities (NCAs) strengthened their collaboration to support medicine innovation and early development of new medicines in the EU by establishing the EU-IN. The network is composed of NCA members and the EMA ITF. The mandate of the EU-IN, adopted in 2016, will be re‑reviewed in 2019 by EMA and Head of Medicines Agencies (HMA). He described some of the EU-IN goals, which include:
- Sharing experiences and knowledge to identify challenges for innovation and experts
- Sharing best practice to support the establishment of innovation offices in other regulatory agencies
- Promoting HMA collaboration in the IMI projects.
- Supporting training needs with the EU-network training centre (EU-NTC).
- Identifying emerging trends that may require guidance from the EU medicines regulatory network and supporting the consolidation of EU experts’ views on innovative therapies and technologies.
The NCA membership of the EU-IN increased from 15 to 23 in 2017, which provides a comprehensive forum for the discussion of challenges of innovative products such as nanomedicines to 3D cell printing. This will increase capabilities to help innovators, academic groups, SMEs and larger companies bring innovation forward from national to EU level.
The PRIME scheme: one year on
Jordi Llinares Garcia, Head of Scientific and Regulatory Management Department at the EMA, provided an update on the
The Priority Medicines (PRIME) scheme was launched in March 2016 to support the development of medicines with major public health interest and to address significant unmet medical needs.
The goals and scope of PRIME is to:
- Reinforce scientific advice and understanding of the development requirements through early regulatory interactions.
- Optimise development to obtain robust and high quality data.
- Enable accelerated assessment of the submission, supported by knowledge gained throughout the product development.
The timeline to receive the Committee for Medicinal Products for Human Use (CHMP) recommendation on PRIME status is 40 days, but the review process is robust with input from several Committees. SMEs have contributed to more than half of the PRIME request submissions, and these account for 44% of products granted PRIME status.
As of 9 November 2017, 147 requests for PRIME eligibility had been submitted, of which:
- 34 were granted (43% were for oncology and haematology products and 26% were for advanced therapy medicinal products [ATMPs]).
- 107 requests were not granted on the basis of unmet medical need not sufficiently justified; failure of similar products; insufficient effect size; robustness issues or the product being too late in development.
- 6 were out of scope (academic/SME with no first in man data or non-SME with no exploratory/proof of concept data; issue with medical product definition).
Re-submission for PRIME status is possible with the presentation of new data, although no resubmissions have been successful to date.
Once PRIME status is awarded companies have the opportunity for a kick off meeting with the rapporteur, assessors, EMA committee members and representatives from the Paediatric Committee (PDCO), Committee for Orphan Medicinal Products (COMP) and the Pharmacovigilance Risk Assessment Committee (PRAC). The enhanced scientific advice, dedicated EMA contact point and also the fee incentives (for SMEs and academics) for scientific advice are all aimed to enable the progression of these important medicines to marketing authorisation approval and beyond.
Maximising the outcome of scientific advice
Jan Regnstrom, from the Scientific Advice Office at the EMA, explained about Scientific advice and its impact on marketing authorisation application reviews.
The legal basis for the provision of scientific advice is laid down in Article 57-1 of Regulation (EC) No 726/2004 which states the agency is “advising undertakings on the conduct of the various tests and trials necessary to demonstrate the quality, safety and efficacy of medicinal products”. This includes both pre- and post-marketing authorisation advice to companies. In 2001, there were 67 requests for EMA scientific advice and Protocol Assistance (PA). In contrast, in 2017, there were 456 scientific advice and 126 PA requests.
Early EMA scientific advice and pre-scientific advice is recommended for SMEs. In addition, national scientific advice and also combined EMA and US Food and Drug Administration or EMA and HTA advice could be considered. Evidence indicates that approximately 90% of companies that obtain and comply with scientific advice obtain a positive outcome of a marketing authorisation application compared to on 40% of companies who do not follow scientific advice.1,2
Multi-stakeholder parallel regulators
Jane Moseley, Scientific Advice, EMA, and Elisabeth Svanberg, Chief Development Officer, Ixaltis, explained the Parallel Consultation procedure. In July 2017, a new initiative for parallel regulatory and health technology assessment (HTA) advice was introduced to optimise development plans and improve patient access to new medicinal products. The Parallel Consultation (PC) procedure replaces the best practice guidance for parallel regulatory–HTA scientific advice procedure (EMA/502692/2015). A comparative analysis of regulatory-HTA parallel scientific advice indicates a potential for lack of consensus between the regulators and HTAs on clinical study plans.3 There may be an advantage for companies to make more use of the new PC procedure prior to study initiation.
The benefits of the new process include:
- A new streamlined procedure through the cooperation of EMA and European Network for Health Technology Assessment (EUnetHTA). It allows for: single gateway for requests to EMA and EUnetHTA with central recruitment of HTAs by the EUnetHTA; new deadlines for the letter of intent & joint briefing document submission; and facilitation between HTAs by the Early Dialogue Committee (EDC) scientific coordinator.
- Increased opportunities to understand and solve problems through more structured interactions and consolidated advice. As of Nov 2017, there have been 11 PC requests (six started and two finished). The limited experience from the new procedure has been positive and SMEs and companies with orphan medicinal products (including ATMPs) are encouraged to try the procedure.
Perspectives on specific populations
The session “Supporting orphan medicines development and addressing significant benefit requirements through protocol assistance” was presented by Matthias Hofer, Scientific Officer, Orphan Medicines, EMA.
Orphan Regulation (EC) No 141/2000, established the procedure for designating orphan medicinal products (OMPs), defined the incentives for the development of OMPs and also established the COMP. Regulation (EC) 847/2000 set out the definitions essential for the application of the Orphan regulation, and enable sponsors to submit applications to the EMA. Orphan designation can be requested for free at any stage of development.
Benefits as a result of the implemented legislation include:
- Extension of marketing authorisation exclusivity for products after receipt of the MAA.
- Fee reductions for SMEs.
- Access to the centralised MA procedures.
- Access to national and EU incentive programmes (for example through Horizon 20/20).
A significant number of 128 Orphan Marketing Authorisation Approvals obtained since the introduction of the EU orphan legislation up to 2016 are associated with the oncology, haematology and pneumonology therapeutic areas. Additionally, the majority of these were developed by SMEs.
The 10-year report on the Paediatric Regulation to the European Commission concludes that there has been a positive impact on paediatric medicinal product development, with more new medicines in use for children.
Mr Hofer described the criteria for orphan designation in the EU, which include:
- Product intended for diagnosis, prevention or treatment
- Serious condition (life threatening or chronically debilitating)
- Affecting not more than 5 in 10,000 or insufficient return on investment
- No satisfactory treatments or significant benefit over satisfactory methods
This was followed by a discussion of the considerations of commission notice (2016/C424/03) on the application of Articles 3, 5 and 7 of Regulation (EC) No 141/2000 on orphan medicinal products, particularly the aspect of significant benefit over relevant products.
It is important to show significant benefit of an OMP against other appropriate products. This can be demonstrated by improved effects (in combination, efficacy in sub-populations, clinical effect, improved safety), add-on effects, targeting different aspects or populations and major contribution to patient care (ease of use, improved dosing schedule, compliance, quality of life and availability). Companies that have taken advantage of the opportunity for early interactions with the COMP via protocol assistance (PA) (with significant benefit queries ) are more likely to keep their orphan status. SMEs may wish to consider PA, with the inclusion of significant benefit queries as part of their development plans.
Support to paediatric medicines development
A session on paediatric medicines was presented by Rocio Fernandez Fresquet, Paediatric Medicines (EMA).
The EU Paediatric Regulation (EC No 1901/2006) was established to improve the health of children through high quality research, increased availability of medicines and knowledge about the medicines with respect to the paediatric population, without delaying authorisation for adults. The regulation applies to medicinal products authorised by both the centralised and national procedures.
The 10 year report on the Paediatric Regulation to the European Commission concludes that there has been a positive impact on paediatric medicinal product development, with more new medicines in use for children, new paediatric appropriate pharmaceutical forms and improved paediatric product information. A PIP should be submitted after adult phase 1 studies and before trials are started in children. It can usually take between eight and 12 months for a PIP to be agreed. At the time of the MAA, there is a compliance check to ensure that the PIP that was agreed or amended by PDCO has been complied with, such as completion of studies described in the PIP in all population subsets unless a waiver or deferral to conduct studies was agreed by PDCO. A list of class waivers is available on the EMA website. It is important to note that as of 2015, PDCO adopted an amended class waiver list which revoked eight, updated fifteen and confirmed nine class waivers. The updated class waiver list comes into force on the 27 July 2018. Companies will need either a PIP or a product-specific waiver for medicines for all conditions that are no longer class waived.
Update on Brexit regulatory preparedness activities
Speakers Anthony Humphreys and Monica Dias alongside panellists Marie-Helene Pinheiro, Sandra Vanlievendael, Christelle Bouygues, Anabela Marcal and Andrei Catalin Spinei, all from the EMA lead a discussion about Brexit preparedness for the regulatory sector. Mr Humphreys spoke about the subsequent steps taken by EMA following the decision of the UK to leave the EU. A lot of work had been completed with respect to the impact assessment, EMAs business continuity plan, assessment of member states bids for relocating EMA, staff and expertise management and industry guidance development.
Ms Dias discussed the EMA working groups on committees’ operational preparedness. Working groups have been established for human and veterinary medicines to explore the options for the reallocation of the UK work portfolio (eg, legacy products, periodic safety update report single assessments, Coordination Group for Mutual Recognition and Decentralised Procedures involvement) to other member states. This reallocation covers many areas such as MAAs (including reassignment of procedures not yet started but currently assigned to the UK), scientific advice, pharmacovigilance procedures, maximum residue limit (MRLs – veterinary medicines) as well as operational adjustments. The workload redistribution of activities such as inspections will be driven initially by legislative requirements and resource availability.
The regular EMA-industry stakeholder interactions related to the UK’s withdrawal from the EU was described by Ms Pinheiro. The first industry-stakeholder Brexit meeting was held on the 4 October 2017. The priority topics that were identified from the industry stakeholders were: marketing authorisation holders (MAHs) transfers; manufacturing and supply chain; pharmacovigilance and cross projects activities (i.e. telematics etc).
The EMA is aware of the need for regular dialogue and updates such as Q&A’s and procedural guidance. The EMA has surveyed MAHs of centrally authorised medicines who are located in the UK or who have quality control, batch release or import manufacturing sites, or a Qualified Person Responsible For Pharmacovigilance or pharmacovigilance system master file (PSMF) in the UK, on their plans to submit transfers, notifications or variations to their marketing authorisations in preparation for Brexit.
- M Hofer, C Jackobson, N Zafiropoulos et al. ‘Impact of scientific advice from the European Medicines Agency’. Nature reviews Drug Discovery 2015;14(5):302–303.
- J Regnstrom, F Koenig, B Aronsson et al. ‘Factors associated with success of marketing authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency’, Eur J Clin Pharmacol 2010;66(1):39–48.
- G Tafuri, M Pagnini, J Moseley et al. ‘How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory HTA parallel scientific advice’, Br J Clin Pharmacol 2016;82(4):965–973.
The meeting report was published in Regulatory Rapporteur, Volume 15, Issue 6, June 2018.