Conference summary: "Expectations of the Annex 2 proposal of Regulation 2019/6” ©

Views, Visions & Discussions

Klaus Hellmann, the CEO of Klifovet, opened the conference with an introduction to current trends and challenges within the veterinary pharmaceutical industry.
Ivo Claassen, Head of the Veterinary Medicines Division of the European Medicines Agency (EMA) provided an overview on the progress of the scientific advice provided by CVMP on the Annex 2 to the European Commission (EC). He highlighted the differences to the current Directive 2009/9/EC with specifics now for biological non-immunological products, provisions for antigen master files, multi-strain dossiers and platform technologies as well as Novel Therapies. The Scientific Advice of CVMP was transferred with minor changes to the current draft version discussed at the European Council level; a public consultation of the outcome of those discussions are expected for public consultation later this year. At the same time the requirements for limited markets and variation classification is reviewed.
David Murphy, Chair of the Committee for Veterinary Medicinal Products (CVMP) at EMA and representative of HPRA Ireland, highlighted that novel therapies to date have been approved in absence of any guidance (Cytopoint, Arti-Cell Forte and Clynav) within 12 months, considered to be the shortest time period achievable for any VMP. The new regulation mentions quite a few implicit requirements with respect to environmental safety, antimicrobial and antiparasitic resistance and the 3R principles that have to be considered within the respective working parties’ activities. The work plan for CVMP requires 56 activities to be started in relation to Regulation 2019/6 in 2020, which in combination with the move of the EMA within Amsterdam is quite a challenge. This includes drafting new guidance for Novel Therapies and Limited Markets. The latter are subject to renewal where also the eligibility for limited markets will be reviewed, assumed to be different than the current criteria for MUMS. He highlighted also that the conditions for extended data protection would need to be specified further and cannot be considered as default.
Ricardo Carpeto, AEMPS Spain, presented the considerations for environmental risk assessment (ERA). In the future, new active substances will have to be considered to be included in the surface water watch list. Environmental incidents now have to be also reported as adverse events and manufacturing sites need to prevent or minimise the discharge into the environment. For generic products an ERA is no more required provided the MA of the reference product has been granted after 01 October 2005. A marketing authorisation has to be refused if the active substance is to be used in food producing animals and (very) persistent (PBT/vPvB) in the environment unless it can be demonstrated that it is essential for animal welfare, e.g. Moxidectin. For aquaculture a closed list for the prescription cascade will be set up.
Christine Schwarz, BVL Germany, updated on the specific requirements for assessing resistance development. She clarified that antimicrobials per definition include antibiotics, antivirals, antifungals and antiprotozoals. This is done on the basis of a risk evaluation including risk mitigation measures, impact on the environment, human exposure and health and other guidance available (e.g. VICH, WHO, OIE, Codex alimentarius), all available on the EMA webpage. Respective risk mitigation measures can be proposed for the SPC. As these requirements may impact on the availability of antimicrobial VMPs, the data protection has been significantly extended to 14 years for major species. There is a preliminary risk profiling document available (EMA website) that can assist in assessing the respective risks.
Marie-Helene Sabinotto, ANSES/ANMV France, reported on few changes for the quality requirements for pharmaceuticals. The quality part of the dossier and also the active substance master file can be submitted as eCDT or NTA. A summary of the quality part of the dossier is not required any more. New is that a packaging size justification is required in particular for antimicrobials. The name and address of the manufacturer is now deleted from Part 2B. Any excipient new to the EU is considered as novel. The container-closure-system is renamed to “packaging”. A definition of ‘isolated intermediates’ has been added. Re-test periods for all active substances need to be set. Applications on well-established use are replaced by applications based on bibliographic data. For limited markets no omission of data is permitted whereas this is the case for applications under exceptional circumstances. Scientific advice from the CVMP was provided in August 2019 and comments from member states are expected by March 2020 with the legal text available in January 2021.
Paul McNeill, HPRA Ireland, focused on the changes with regards to safety requirements for pharmaceutical products for the user, consumer and target species. The current DACS (Detailed and Critical Summary) is replaced by the CER (Critical Expert Report). Pharmacodynamics data will have to be included in part 4 (Efficacy) of the dossier. The use of historical data is encouraged as much as possible. A repeat-dose (chronic) toxicity study will only be required in one species of experimental animal and may be replaced by a study conducted in the target animal. Reproduction toxicity data are only required for the target species in case the animals are intended for breeding and is moved to the MRL dossier with regards to consumer safety. Development toxicity data are required only for the user safety according to VICH GL 32 in case of significant user exposure and for the target animal if use in breeding animals is foreseen. Only a summary of the target animal safety should be included in part 3 as the full study has to be provided in part 4 of the dossier. Genotoxicity testing is only required for new active substances and carcinogenicity testing should follow VICH GL 28. Residue data have to be provided also for wax. The user safety assessment for generics should focus on the differences to the reference product. For combination products target animal safety data are required using the final formulation. For Limited Market applications and Novel Therapies a full or reduced dossier has to be provided based on a risk based approach providing a risk management plan.
Cristina Muñoz, AEMPS Spain, presented the requirements for efficacy of VMPs other than immunologicals, highlighting the difference between clinical (conducted in the field) and pre-clinical studies (all other studies). Pre-clinical safety studies should be conducted to GLP whereas all other clinical and pre-clinical studies in the target species should rather be conducted to VICH GCP. Animal test certificates have to be issued or refused within 60 days of the application according Directive 2010/63/EC. Any studies performed outside of the EU should also be conducted according to the principles of Regulation 2010/63/EC following the 3R principles. For antimicrobials there is a focus now on antimicrobial resistance development and environmental safety considerations and claims for prophylaxis or metaphylaxis require sound justification. Detailed description of administration is especially required for oral formulations to avoid over- or underdosing. For limited marketing authorizations it is noted that salmon is now considered a minor species. For these the benefit must outweigh the risks due to lack of data. Novel therapies will be categorized according to the intended indication(s) for use in the target species. Post-marketing measures and risk management plans may be used for such products in order to control any unforeseen risks and reduce excessive data burden for novel therapies for which there is an essential need. Future challenges will be the regulation of new antimicrobials, antiparasitics, alternatives to antimicrobials and novel therapies.
Frida Hasslung Wikström, Swedish Medical Products Agency, completed the first day with the requirements on biological VMPs other than immunologicals, such as monoclonal antibodies, recombinant proteins, stem cells etc. These products would be assessed for safety and efficacy similar to pharmaceutical products, however if relevant the respective GMO guidance and MRL guidance would need to be considered. For efficacy a focus will be on the mechanism of action, especially for developing respective product specific potency assay(s) and noted that extrapolation across species may not be possible. The quality part would follow that of immunologicals with the addition of some specifics. She recommended to use respective ICH guidance especially with regards to characteristics and specifications.
Martina von Freyburg, Boehringer Ingelheim Germany, kicked off the sessions of the second day commenting on the requirements for immunological products. Whilst there is not much change foreseen apart from part 5 being included in part 4 (efficacy) now, and the focus on avoiding resistance and environmental safety issues, she proposed several options where improvements could be made. These proposals included adjuvant, solvent and media master files in addition to the vaccine antigen master file and to allow for providing non-consecutive stability batches.
Jacqueline Poot, CBG The Netherlands, presented on the particulars for Veterinary Medicinal products. The Vaccine antigen master file (VAMF) can be used for various species but limited to one Marketing Authorisation Holder (MAH). The multi-strain dossier will be applicable to inactivated vaccines and viruses with a high antigenic variability in the field. Any respective eligibility has to be confirmed with EMA and is likely to be a similar process as for the current MUMS application. Platform technologies may apply to different technologies and apart from non-pathogenic viruses also include nanotechnology as carrier. These will be applicable for the same target species. There is the concern that neutralising antibodies against the platform will be formed, if used repeatedly.
David John, Animal Health Europe, presented the industry perspective and raised some interesting points that need consideration. Whilst the VAMF is optional there is the issue on the process for converting already registered antigens retrospectively. For the multi-strain dossier he raised the point of maintaining the eligibility even if there is no application, e.g. via a similar process as for Maximum Residue Limits (MRLs). He also noted that limiting the antigen master file for platform technologies to one species only may not be relevant for all platforms and could be re-considered. He then focussed on the requirement to conduct field trials for immunologicals, where it has been shown that these usually do not add a real benefit to the assessment. Also the sterility requirement for non-parenteral products, e.g. by allowing very low bioburden instead, may have a beneficial effect on availability of products without reducing the safety. The quality requirements for respective excipients should be adapted to allow food or feed grade to be acceptable for such products by definition.
Esther Werner, PEI Germany, presented on Novel Therapies. She highlighted that risk profile methodology needs to be set up similar as for human medicines. Consideration has to be given to treated animals that may be considered GMO. Bacteriophages must have lytic activity. For nanotechnology products agglomerates, the risk of embolism as well as cytotoxic substances (persistent or cumulative) are of concern. Overall there is new guidance required to allow for consistency in the general approach whereas currently these products are handled on a case by case approach. Specific challenges ahead are the dossier structure, variability (e.g. donors), heterogeneity of cell types, and availability of veterinary reference preparations, risk mitigation measures and post-marketing surveillance.
Anja Holm, Central VetPharma Consultancy Denmark, presented on gene therapies. These would be classified as biologicals containing recombinant nucleic acid(s). There are amply delivery types using virus platforms, but there are also virus-free platforms based on replication incompetent rAAV. She highlighted that for development of gene therapies for human applications 2600 clinical trials were conducted until 2017 with only 6 authorised products as a result. Generally one can assume that veterinary health can charge only a 20 times lower price for such products than those for human health (65.000 to >2 Mill. €/treatment). She suggested to use the practical experience from the human development of gene products to reduce the demands for animal health gene therapies, e.g. use of high grade material in pilot studies and TAS requirements limited to max. 6 months duration, and avoid exorbitant clinical trials. This could be fostered by sharing experience and training between regulators and industry.
Jan Spaas, GST Belgium, presented on stem cell therapies based on the experience of developing and obtaining the registration of the first product for veterinary application. He highlighted the challenges in the development, e.g. suitable markers, production process, selection of suitable donors and set-up of relevant potency tests. He also mentioned that in this areas non-authorised “copycat products” are distributed, that do not provide the same assurances and quality as those that underwent stringent criteria for GMP production and registration.
Anne Wünsch, Klifovet Germany, presented on bacteriophage therapies for animal health. These kind of therapies are well known and used in Eastern European countries, Russia and CIS for human health, for more than 100 years especially as replacement of antimicrobial therapies. However, consistent and reliant trials are lacking for these therapies. More guidance is required especially with regards to the requirements for approaches similar to multi-strain-dossiers, as for bacteriophages often cocktails of a number of different strains are required. Also assuring that the bacteriophages reach the site of infection may pose some challenges for therapies to be efficacious.
Dorothe Pfeifer, Klifovet Germany, presented on the approaches for development for RNA Antisense and RNA Interference therapy products, explaining the scientific background and respective concepts. She highlighted the important points to be considered for development, such as RNA degradation, assuring the correct sequence, establishing an appropriate biological (potency) assay, off-target binding and respective adverse effects. She presented some examples for human health, where any such products have been registered to date under the orphan drug registration scheme. Therefore these may also be eligible for limited markets in animal health depending on the intended indication. Further, the concept of multi-strain dossier may be applicable also to such products to improve target specificity and efficacy. The main challenge for these therapies is however to find the appropriate delivery system. Costs for such treatments for humans were identified to be a multiple of 100.000 € per dose.
Finally, a lot of questions are still open and will require more guidance for applicants, but also understanding of the needs for new technologies and novel therapies by all parties involved. The huge workload of EMA/CMP will hopefully allow to draft further guidance for industry, although the absence of guidance allows more flexibility for applicants. David Murphy, current head of CVMP, as well as Klaus Hellmann, CEO of KLIFOVET, concluded that the previous experience with the evaluation of novel therapies provide assurance that even in the absence of specific guidelines, marketing authorisations for novel therapies have been granted in record time, showing that the current systems in place (science based evaluation, scientific advice, ITF meetings, ADVENT group etc.) have been useful and fit for purpose. Based on this, applicants should be motivated to progress developing new products based on a thorough risk based approach and the likelihood of success appears to be high based on the recent experiences.
Overall this conference organised by KLIFOVET, recent winner of the Animal Pharm Award 2019 in the category as “Best Service Provider”, was again a great success and fostered exchange of views between those drafting the Scientific Advice of CVMP to the commission, regulatory authorities, industry, both large multinationals as well as SMEs and start-ups. Registrations from 3 continents, 14 countries and 43 organisations used the excellent opportunities for discussions and networking during breaks and the evening social held in a typical local restaurant.