Project Platform

Project aim

The aim of this project is to identify opportunities for improving the science behind the regulatory testing of medicines and chemicals through the application of the 3Rs. Among the seven sectors involved primarily in this project are those concerned with the development of human medicines, veterinary medicines, and crop protection products.

• The main goal is to examine how each sector approaches the issue of regulatory toxicology and to identify opportunities for cross-sector alignment on best practice and on the introduction of new methodologies advancing the 3Rs.
• Alignment has 2 aspects: industry alignment on testing methodologies, and regulatory harmonisation across sectors and global regions.
• Thus the project aims not only at identifying possibilities but also how these might be translated into regulatory practice

Sectors involved

• Pharmaceuticals, animal health, crop protection

Development and priorities

The project team initially conducted a survey of regulatory requirements in the various sectors and then sent a questionnaire to the relevant EPAA member associations (EFPIA, IFAH-Europe and ECPA).

Respondents were asked for more detailed information on

• the scope for variation in study design within the existing guidelines
• regional variations in regulatory requirements
• individual company practice
• the development of alternatives that could advance the 3Rs

The questionnaire was distributed to the member companies of the aforementioned organisations and the results were collated and analysed by the project team.

It was clear that there is a considerable divergence in practice within sectors, between sectors and between geographical areas, despite the existence of international harmonisation bodies such as ICH and VICH.

Moreover, differing practice was as likely to be a result of tradition than the application of science.

Milestones

• 28 February 2013: EPAA workshop on carcinogenicity testing: scope for harmonisation and advancing the 3rs Flash report (87 kB)

Next steps

• Ongoing discussions on MTD and human effects database

Project aim and rationale

The risk assessment of chemicals and pharmaceuticals continues to rely on the use of in vivo assessments, although there is an international drive towards the replacement of animal testing with mechanistic, in vitro systems.

This new approach includes the in vitro measurement of concentration-response relationships to identify where prolonged or excessive perturbations of biochemical pathways are likely to cause adverse health effects.

• This approach requires a framework, into which a wide range of in vitro, in silico and in chemico generated data, may be integrated and used to predict the consequences of exposure in humans.
• One of the major drawbacks of most in vitro methods compared to intact organisms is indeed their inability or low competence to metabolise xenobiotics. To address this issue, the EPAA launched the Absorption, Distribution, Excretion & Metabolism (ADME) project with the following goal: to develop a new, innovative bioinformatics tool to predict the ADME or human exposure based on inputs from in vitro data (and vice versa).

The tool will be web based on a Peters’ model and freely available for downloading and independent use on desktops PC to ensure confidentiality of data.

Project status

A prototype was already developed in partnership with the British Health and Safety Laboratory (HSL). This project aims to develop a tool that is more tailored to industry needs. The first tasks to be undertaken included the building of the model and interface. These were completed as planned, within the six-month period allocated.

Stakeholders involved

UK Health and Safety Laboratory; GlaxoSmithKline; European Council of the Chemical Industry - Long-range initiative (CEFIC LRI); European Union Reference Laboratory - European Centre for Validation of Alternative Methods (EURL ECVAM); European Centre for Ecotoxicology and Toxicology of Chemicals (ECETC)

Milestones

• November 2008: EPAA In vitro ADME (Absorption, Distribution, Excretion & Metabolism) in Safety Testing Workshop to evaluate jointly with regulators, what information was concerning metabolism is needed to permit safety assessment of substances.
• October 2011 : EPAA –ECVAM Joint ADME workshop on The potential for further integration of PBTK modelling into the prediction of in vivo dose-response curves without animal experiments
• June 2014: Launch of the latest project workstream on user-friendly, web-based tools for toxicokinetics in exposure assessments

References

• Bessems et al., Reg. Tox. Pharmacol., 68 (2014) 119-139): 'PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment. Recommendations from a joint EPAA – EURL ECVAM ADME workshop'
• Peters, S.A., 'Evaluation of a generic physiologically based pharmacokinetic model for lineshape analysis.' Clin. Pharmacokinet., 2008. 47(4): p. 261-75.

Project aim

The overall goal of this platform is to synchronise initiatives for 3R methods in safety and potency testing of vaccines in Europe.

This project aims to create a technical platform for human and veterinary vaccines. The platform:

• includes general strategies and policies to introduce the Consistency Approach in routine release activities
• prioritises the replacement of compendial in vivo tests with validated alternative in vitro tests
• defines minimal acceptance criteria for alternative in vitro tests
• reviews work plans and reports provided by human and veterinary vaccine task forces or groups working on test development and validation.

Background

Vaccines require batch-specific quality control to ensure their quality, including safety and efficacy. Part of quality control, particularly for the final product, is based on animal tests required by legislation. Out of about 100 million animals that are used each year in laboratories throughout the world, 10 to 15 million animals are still being used for vaccine batch testing.

The vaccines consistency approach (VCA) for batch release is based upon thorough characterisation of the vaccine during manufacture, including formulation, using non-animal testing. The quality of subsequent batches is guaranteed by the strict application of quality systems and of a consistent production of batches that are comparable to reference lots of known potency and safety.

The VCA is already used for recently registered vaccines, whereas many vaccines developed several decades ago, continue to rely on animal tests for confirming the quality of each batch.

Due to the potential of the VCA to significantly reduce the number of animal tests used in vaccines quality control, the EPAA initiated this project with the aim to provide a framework for resolving remaining scientific and technical issues and for fostering the regulatory adoption of VCA as a non-animal approach for quality control of established (conventional) vaccines.

Stakeholders involved

The European Commission, industry (European vaccines manufacturers), European Medicines Agency (EMA), national regulators, OMCLs (Official Medicines Control Laboratory), EDQM (European Directorate for the Quality of Medicines and HealthCare), international regulators (observers from US, Canada and India) and academia.

Project organisation

The project activities were organised by a Project Committee (PC) chaired by the coordinator (Ian Ragan, consultant to EPAA) in consultation with a Technical Committee (TC) composed of experts from vaccine manufacturers, EDQM, EURL ECVAM, OMCLs and regulatory authorities for both human and veterinary vaccines. The TC was chaired by Coenraad Hendriksen, academic member of the PC.

At the Technical Committee meeting on 30 September 2011, 4 priority vaccines were identified and progressed further by expert working groups: DTaP, human rabies, veterinary rabies, and clostridial vaccines.

Milestones

January 2010: Workshop jointly organised by EPAA and EURL ECVAM in Brussels discussed the VCA and its potential to reduce the number of animal tests used in quality control of human and veterinary vaccines (De Mattia et al 2011, The consistency approach for quality control of vaccines: A strategy to improve quality control and implement 3Rs, Biologicals 39, p 59-65). As a follow up, in late 2010 the EPAA agreed to initiate a VCA project.

7 April 2011: Kick-off meeting - Application of the Three Rs and the Consistency Approach for Improved Vaccine Quality Control, flash report (265 KB)

Milestones of the specific working groups:

1. DTaP

• Workshop, 30-31 August 2012, flash report (409 KB)
• No activities started under EPAA umbrella since several activities were ongoing elsewhere (to avoid duplication)
• In 2016: activities supported by IMI 2 funding programme (VAC2VAC – IMI 2 Call 3)

2. Human rabies

This work stream aims at replacing the current in vivo immunisation challenge test for batch release (the NIH test) by in vitro tests based on antigen quantification (ELISA).

• Workshop, 8-9 October 2012, flash report (264 KB)
• Workshop, 9-11 May 2015 Joint Veterinary & Human Rabies Vaccines workshop (report in preparation, to be published soon). Agreed that in vitro ELISA is acceptable to replace current challenge/serology tests
• Collaborative study to identify most suitable ELISA was finalised in 2015
• Global agreement reached regarding the way forward
• In 2016: in cooperation with EDQM (Council of Europe), the preparation of a formal validation study supported by EPAA.

3. Veterinary rabies

• Workshop, 5-6 November 2012, flash report (403 KB)
• Activities ongoing at manufacturer level
• Cross-fertilisation from the learnings of the Human rabies project
• In 2016: supported by the IMI-2 funding programme (VAC2VAC – IMI 2 Call 3)

4. Clostridial vaccines

This work stream aims at replacing in-process controls which use testing on animals, with cell-culture-based assays that have been developed by MSD Animal Health with support by the NC3Rs. The application of the consistency approach is feasible for clostridial vaccines but in vitro tests remain to be developed for some important strains.

• Workshop, 19 March 2013 (co-organised with EDQM, Council of Europe), flash report (138 KB)
• Workshop, 11 September 2013 (co-organised with EDQM, Council of Europe), flash report (426 KB). This workshop helped prepare the Clostridium septicum vaccine collaborative study (BSP130). The EDQM BSP130 study was successfully completed in 2015 and demonstrated concordance of ;in vivo and in vitro methods.
• Workshop, 15-16 September 2015 (co-organised with EDQM, Council of Europe, in Egmond aan Zee, the Netherlands). This workshop discussed the results of the BSP130 study as a proof of concept and start of validation for Clostridium septicum vaccine in process control methods.
• In 2016: a Phase III study (formal in vitro test full validation) will be progressed as part of BSP130 and with the support of EPAA.

The final aim is to introduce the alternative methods into the Ph. Eur. relevant monograph(s).

Project achievements

• One peer-reviewed publication: De Mattia et al 2015, The Vaccines Consistency Approach Project: an EPAA initiative, Pharmeuropa Bio& SN, May 2015, p 30-56.

The Technical Committee, where the Commission provided visibility and all parties committed to alternatives shared scientific know-how, has:

• raised awareness in all stakeholders (industry, regulators, civil society) on the Vaccines Consistency Approach
• facilitated cross-sharing between human and veterinary vaccines helping to promote new testing paradigms
• offered coordination, identified scientific gaps and enabled early collaboration helping to address them
• prepared the ground for the IMI-2 Vaccines consistency project to work towards ultimately replacing animal testing in batch release of vaccines. This project has been accepted and will start in March 2016. With a funding of approximately €8 million, this project will help develop new methods, work towards their validation and ensure regulatory engagement with an ultimate aim to lead to acceptance by regulators, implementation and use by industry.

EPAA contributions

The EPAA has:

• provided funding and organisational support for the regular expert meetings, seven workshops and two peer-reviewed publications (De Mattia et al. 2011 and 2015).
• provided a neutral, scientifically based platform for regular discussions and exchanges between the various stakeholders facilitating the development, validation and acceptance of the approach.
• supported specific collaborative studies (e.g. by funding shipment of testing materials for the Clostridials collaborative study BSP130; the European Commission (via EURL ECVAM) funded data analysis within the human rabies vaccines project).
• promoted the VCA through presentations at EPAA Annual Conferences and other events (e.g. briefings to MEPs / Intergroup for Animal Welfare).

Current status

• December 2015: Activities under the general VCA project are completed.

• 2016: Human rabies and Clostridial vaccines continue as stand-alone EPAA projects (see above).

Acknowledgements

The EPAA partners would like to thank the members of the Technical Committe and Project committee for their valuable contributions on the project.

Project aim

In the production of biological products, manufacturers are required to confirm potency and safety of each batch of product. This may involve the use of laboratory animals.

Directive 2010/63/EU prohibits manufacturers in the EU from using an animal test method, if an alternative, non-animal method is recognised by the European Pharmacopoeia.

However, if alternatives are not internationally harmonised and accepted in other regions then excessive or unnecessary animal testing may be undertaken by manufacturers, in order to gain access to other, non-EU markets.

The Biologicals project run by the EPAA aims to achieve global harmonisation in batch testing requirements for human and veterinary vaccines, as well as other biologicals. It is hoped the project will lead to better incorporation of the 3Rs in potency and safety testing strategies.Project deliverables include:

• mapping of regulatory bodies responsible for establishing potency and safety testing requirements
• identifying key differences in QC testing requirements between pharmacopoeias or equivalents
• assessing test methods with related benefits and risks.

Stakeholders

European Medicines Agency, European Commission, Pharmaceutical Industry, Animal Health Industry, Council of Europe - European Directoate for the Quality of Medicines and Healthcare (EDQM)

Milestones

• 2013: Project launch
• 2013: Mapping of regulatory bodies responsible for potency and safety testing requirements
• 15-16 September 2015: EPAA Workshop on international harmonisation of biologicals, Egmond an Zee, the Netherlands. Proceedings (200 kB). Report (172 kB).

Next steps

• Publication of the September 2015 workshop in a peer-reviewed journal
• Further developments within this project are expected. An assessment is currently ongoing by the Project team.

Project aim

Increasing adoption of non-animal integrated testing strategies.

Background

Skin sensitisation is an important endpoint in safety evaluation that must be assessed for chemicals under the current chemical legislation in Europe (REACH: 1907/2006). Other legislation including the EU Cosmetics Regulation (1223/2009), also require assessments of skin sensitisation potential. Furthermore, since March 2013 animal testing for this purpose for products marketed in Europe is prohibited.

3Rs added value and EPAA actions

Performing tests on humans instead of animal tests for the generation of primary skin sensitisation data without good knowledge of sensitisation potential is considered unethical due to the risk of volunteers becoming sensitized. For reasons of good animal welfare and the animal testing ban imposed by the Cosmetics Regulation, substantial efforts continue to be made in the development of non-animal (alternative) methods. This change to in vitro alternatives has been enabled by a growing knowledge of the mechanisms underlying this human health effect, which led to the development of an Adverse Outcome Pathway (AOP).

Furthermore, the combined use of a number of non-animal methods in integrated testing strategies (ITS) has been identified as much more reliable than a single in vitro method. Key questions now include:

• What are the regulatory requirements for acceptance of non-animal methods?
• What do regulators require to be included in non-animal ITS for skin sensitisation that permit confident regulatory decisions to be made regarding human health?

Stakeholders

The EPAA project on skin sensitisation alternatives is addressing these questions by bringing together stakeholders from European and national regulators, and a wide range of industry stakeholders from various sectors (chemicals, cosmetics, fragrances, etc.). The EPAA has been collaborating with Cefic LRI and Cosmetics Europe to ensure optimal cross-fertilization across sectors.

Milestones

• 19-20 September 2011: Workshop 1, Brussels, Belgium: A cross-sector workshop: Skin sensitisation testing: the Local Lymph Node Assay and Beyond (flash report, 185 kB)
• October 2012: Publication: 'Optimized testing strategies for skin sensitisation - the LLNA and beyond. Report from a EPAA/CEFIC LRI cross sector workshop', Basketter et al., Regulatory Toxicology & Pharmacology
• 4 February 2013: Workshop 2, Helsinki, Finland: Joint EPAA-Cefic LRI joint workshop on skin sensitisation alternatives: Moving forward with non-animal testing strategies (flash report, 164 kB)
• 4 January 2014: Publication: 'Skin sensitisation – Moving forward with non-animal testing strategies for regulatory purposes in the EU', Basketter et al. Regulatory Toxicology and Pharmacology
• 23-24 April 2015: Workshop 3 Helsinki, Finland: 'Joint cross-sector workshop on Alternatives for Skin sensitisation testing and assessment' (flash report, 1,7 MB) (proceedings)
• Planned - end 2015: Publication on Workshop 3

Information on this will be available shortly

Information on this will be available shortly

Project aim

Since late 2008, the EPAA has been exploring the opportunities that stem cells could play in developing novel approaches for the potential hazard characterisation of chemicals and drugs:

• Much research on stem cells is currently ongoing within the EU and beyond, and this is considered valuable in assessing how such work may fit into an overall strategy for evaluating safety without animal testing
• This EPAA project aims to direct the stem cells research towards the industry need for safety assessment
• In the opinion of the EPAA Platform on Science, the current research on the use of stem cells lacks clear guidance to develop novel testing strategies for safety assessment
• The identification of gaps in testing strategies is relevant in order to select the cell types of interest, as well as the most appropriate readout to identify modes of action. This is important for multiple sectors and therefore a good opportunity for the EPAA to coordinate this activity.

Workgroups

• Workgroup 1 on fundamental research on stem cells
• Workgroup 2 on communication: stem cells forum

Project added value on 3Rs and priorities

• establishing a permanent stem cell network, which brings together experts from both sides (those working on alternatives and those working on basic research)
• setting up a central unit monitoring the quality of the stem cells
• focusing on inducible pluripotent stem cells (iPSC)
• focusing on pathways, instead of organs or cell types is preferred
• noting that first steps in analysing the signal cascades of human iPSC should be performed with well-known compounds that address a well-defined pathway

Milestones

• 28-29 April 2008: EPAA New perspectives on safety workshop. Flash report (480 KB)
• October 2009: Expert meeting on the future directions of stem cells research for safety testing
• 4-5 October 2011: Stem cells and their derivatives in toxological research programmes and as a possible regulatory tool – A gap analysis. flash report (710 KB)
• 25 April 2013: EPAA Stem Cells Forum kickoff meeting (WG3), flash report (360 KB)
• 28-29 August 2013: Stem cell-derived organ-like models for analysis mid-term and long-term dosing dynamics, flash report, (135 KB)
• August 2014: Joint EPAA-Liverpool University CDSS Stem Cells Forum international meeting