What Types Of Alternatives For Animal Testing Does The European Union Use

J Am Assoc Lab Anim Sci. 2015 Mar; 54(2): 209–213.

Published online 2015 Mar.

The European Partnership for Culling Approaches to Animal Testing (EPAA): Promoting Culling Methods in Europe and Across

Gwenole Cozigou

ⁱEPAA European Commission Co-Chair, DG Enterprise and Manufacture, Belgium

Jonathan Crozier

²EPAA Industry Secretariat, Belgium

Coenraad Hendriksen

³Institute for Translational Vaccinology (InTraVacc), Bilthoven, The netherlands

Irene Manou

^twoEPAA Industry Secretariat, Belgium

Tzutzuy Ramirez-Hernandez

⁴EPAA Industry Co-Chair, BASF SE, Ludwigshafen, Deutschland; and

Renate Weissenhorn

^fiveEPAA Secretariat, European Commission DG Enterprise and Industry, Belgium

Received 2014 Mar 27; Revised 2014 May 29; Accepted 2015 Jan 5.

Abstract

Here in we introduce the European Partnership for Alternative Approaches to Animal Testing (EPAA) and its activities, which are focused on international cooperation toward alternative methods. The EPAA is ane of the leading organizations in Europe for the promotion of alternative approaches to animate being testing. Its innovative public–individual partnership structure enables a consensus-driven dialogue across 7 industry sectors to facilitate interaction betwixt regulators and regulated stakeholders. Through a brief description of EPAA'south activities and organizational structure, we first articulate the value of this collaboration; we then focus on 2 central projects driven by EPAA. The first projection aims to accost research gaps on stem cells for prophylactic testing, whereas the second project strives for an approach toward demonstration of consistency in vaccine batch release testing. Nosotros highlight the growing need for harmonization of international acceptance and implementation of alternative approaches and for increased international collaboration to foster progress on nonanimal alternatives.

Abbreviations: EC, European Committee; EDQM, European Advisers for the Quality of Medicines and Healthcare; EPAA, European Partnership for Alternative Approaches to Animal Testing; EURL–ECVAM, Eu Reference Laboratory for Validation of Alternatives to Animal Testing; REACH, Registration, Evaluation, Dominance, and Restriction of Chemicals; PPP, public–individual partnership

The Eu is a leading trunk for the promotion of culling approaches to animal testing. In accordance to the 3Rs principle (reduction, refinement and replacement of laboratory creature use) proposed in 1959 by WMS Russell and RL Burch,^¹³ the European constabulary has progressed in regulating animal welfare since 1986, when the European Council adopted Directive 86/609/EEC. Since and so, several directives divers standards for housing and care of animals likewise as for the preparation of personnel handling animals and performing the experiments. It is clear that replacement, reduction and refinement of animal testing (3Rs) has been a priority since then. To continue promoting the 3Rs, the European Committee (EC) created its own center for the validation of alternative methods throughout Europe in 1991. This middle, at present known as the European Marriage Reference Laboratory for Validation of Alternatives to Creature Testing (EURL–ECVAM), is a unit of the Articulation Research Eye Directorate General of the European Commission.

In addition, the EC adult collaboration with industry stakeholders. In Nov 2005, European Commissioners Günther Verheugen and Janez Potocnik launched the formation of a public–individual consortium that comprised 5 Directorate Generals and industry representatives from Europe and beyond (including 7 sectors and their respective trade associations; http://ec.europa.eu/enterprise/epaa/about/index_en.htm). In this context, the European Partnership for Alternative Approaches to Animal Testing (EPAA) was born as a unique and innovative public–individual partnership (PPP). The major goal of the organization is the promotion of 3Rs to meet regulatory requirements based on ameliorate and more than predictive science. Since its creation, EPAA has facilitated the dialogue between industry partners that need to comply with regulatory safety requirements and the branches of the EC that envisage the development and implementation of alternatives.

A Transparent Partnership beyond 7 Industry Sectors

As of January 2014, the EPAA gathers 36 corporate members from vii industry sectors and v Directorates General of the European Commission (Figure 1; the updated list is found at http://ec.europa.eu/enterprise/epaa/partners/index_en.htm). The sectors represented are agrochemicals, animate being health, chemicals, cosmetics, fragrances, pharmaceuticals, and soaps and detergents. With the broad representation of several industrial sectors, EPAA's remit encompasses various domains of European police, such as Directive 2010/63/EU on the protection of animals used for scientific purposes, Reach (one component of which is the promotion of alternative methods for the hazard assessment of substances to reduce the number of tests on animals), and the recent marketing ban on creature-tested cosmetics (http://ec.europa.european union/consumers/sectors/cosmetics/brute-testing/index_en.htm). Directive 2010/63/EU is the horizontal legislation for the protection of animals used for scientific purposes, whereas specific legislation covers sectorial areas (for example, REACH for the chemic sector). There are many incentives to promote the 3Rs in every possible sector. Vest to EPAA, stakeholders have the privilege to collaborate with each other and initiate common cross-sector projects in directly collaboration with regulators, including dedicated agencies like the European Chemicals Agency and the European Medicines Agency. Another essential structure of EPAA is the Mirror Group, gathering adept pale holders from academia, civil animal welfare organizations, who also provide advice toward EPAA's projects. (Effigy 1). The EPAA Mirror Group is a consultation forum with an advisory adequacy to the EPAA Steering Committee. The Mirror Group gathers third-political party (that is, nonEC, nonindustry) representatives to provide perspectives from Civil guild, academia, nongovernmental organizations, and other regulators on the development, credence and validation of alternatives (http://ec.europa.eu/enterprise/epaa/near/mirror-group_en.htm). Since EPAA'due south inception, its existence and success take relied on transparency for controlling, consensus amid its members, and mutual trust for each side of the PPP.

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EPAA partners (Nov 2014)

The broad spectra to which EPAA members belong enables a constructive cross-sector dialogue between decision-makers focused on two aspects: 1) the scientific aspect through the prioritization, promotion, and implementation of research projects dedicated to the awarding of the 3Rs and 2) the regulatory aspect through dialogue with EC partners to ameliorate empathise and facilitate the implementation of 3Rs principles.

As a logical consequence of its PPP structure, EPAA is staffed past a permanent EC–Industry shared secretariat. The EPAA Secretariat is formally hosted past the EC's Directorate General Enterprise Internal Market, Industry, Entrepreneurship and SMEs (DG GROWTH). The secretariat's tasks are to coordinate and facilitate the communication within its platforms to ensure a balanced collaboration amongst its members. Both manufacture and EC partners are committed to support EPAA activities and provide experts on a voluntary ground to run the projects. Each side of the PPP appoints a cochair to steer the actions of EPAA; current cochairs are Gwenole Cozigou for the EC and Dr Tzutzuy Ramirez-Hernandez from the manufacture side. Although project operational costs are covered by industry membership fees (currently €10,000 annually for corporate members; €15,000 annually for federations), the EC hosts the Steering Committee, Mirror Group meetings, and the Almanac Briefing.

Development and Acceptance of Alternatives: 2 Examples of the Importance for Internationalization

Since the get-go of EPAA operations in 2006, its partners have worked on various projects considering EPAA is mindful of the demand to consider innovation and advances in engineering science not only within its membership only also to cultivate international initiatives with other prominent stakeholders. In this regard, EPAA has opened international dialogue with various federal agencies, including the US Food and Drug Administration. In 2012, the EPAA identified the need to reinforce international collaboration on the 3Rs, and to put emphasis on this challenge, EPAA members decided to launch this collaboration every bit the leading focus of 2012–2013. To this cease, EPAA invited members from international agencies, US-based animal welfare nongovernmental organizations, India-based vaccine producers, and academics from many regions outside Europe to participate in EPAA projects that could exist enriched through this internationalization. This dynamic was echoed in the creation of the International Cooperation on Alternative test Methods, comprising EURL–ECVAM, the Interagency Analogous Committee on the Validation of Alternative Methods, and other validation laboratories throughout the globe. This initiative has ii main thrusts: 1) the development of more predictive science and ii) the harmonization worldwide of the implementation and acceptance of alternative methods. In the following section, we provide cursory insights into 2 projects that are practiced examples of EPAA activities that encompass innovative technologies in 3Rs and international collaborations. The outset project is being led by members of the platform on scientific discipline, and information technology strives for the sharing of knowledge in the use of nonembryonic stem cells for potential use in toxicologic research prophylactic and its prospective future application under the regulatory context. The second project, led by members of the platform on regulation, aims to implement the vaccines consistency approach into the regulatory framework in accordance with 3Rs principles.

The use of stem cells and their derivatives in toxicologic enquiry programs and equally potential regulatory tool.

Since the end of 2008 and co-ordinate to the recommendation of the experts participating in the workshop "New Perspectives on Safety"^¹⁰, EPAA has agreed to explore the opportunities that stem cells might offer in the development of novel approaches for the label of the potential hazard of new products. Fundamental research on stem cells is performed intensively worldwide, only nonacademic applications still need to be explored. The pharmaceutical sector is particularly interested in improve understanding how this noesis might be integrated into an overall strategy for safety assessment to potentially reduce the use of animals. In this context, this EPAA stem cells project strives for steering stalk cells research toward industry needs for the implementation of 3Rs principles and practices in safety assessment.

In the opinion of EPAA project leaders, electric current research on the application of stem cells is not oriented toward developing novel testing strategies for rubber cess. For this reason, one of the working group'south objectives is to identify gaps between basic and applied research on stem cells. Only with this information volition information technology exist possible to propose relevant models and the well-nigh appropriate readouts to pattern reliable in vitro stem-prison cell-based methods to contribute to improving the deport of science and the application of 3Rs principles. Although much inquiry and a improve understanding of its potential applications are still needed, EPAA is facilitating the dialogue among experts from academia and industry and by this ways is contributing to advancing this field.

This projection is subdivided in 2 major areas, key research on stem cells and communication between international inquiry consortia on stem cells. Regarding central research, the aim is to address the master challenges of the application of cells derived from induced pluripotent stalk cells for safety testing. Induced pluripotent stem cells tin can be derived from human developed tissue and reprogrammed to their embryonic phase. In this sense, theoretically these cells tin requite ascension to copious numbers of whatever kind of cell of the body, thus they represent an bonny alternative method for generating specific models that can be applied to drug discovery assays, drug development, toxicologic purposes, and then along. Experimental protocols using induced pluripotent stem cells are complex and still under development, consequently it is difficult to bear witness their reliability and the biological relevance of the models derived from them. Therefore, additional work is needed to identify the robustness of this technology for its farther use in culling methods. The EPAA experts on the field have agreed that several important questions regarding reliability, relevance, and robustness need to be carefully kept in heed earlier they could exist implemented into the nonregulatory inquiry. And fifty-fifty more when thinking in the future potential application in the regulatory framework.

Regarding communication on stem cells, EPAA created a forum in 2013, the aim is to facilitate dialogue amid stem cells experts worldwide. This forum could profoundly contribute to build synergies and allow pooling of resources on stem cells research. The forum gathers not just EPAA members, but as well representatives of foreign regulators, academia researchers, representatives of various stem cells research consortia. This forum has noncommercial purposes and is intended to share adept practices and advice on stem cells research. The forum is intended to operate on a permanent basis to help to speed up the amend agreement of their potential application and in the long term the potential future adoption of stem cells in many areas of inquiry, such equally toxicological testing. EPAA member AbbVie has committed support to the work of the Forum and provides the leader for this project. Five key issues accept been identified as priorities for the Forum:

1) relevance of standardization of protocols and test methods,
2) confirmation of the maturity of cell phenotype earlier any potential awarding,
iii) definition of criteria for validation and acceptance of novel models,
4) confirmation of biologic relevance (that is, through a gear up of reference test substances appropriate to the adult model), and
5) investigation of the epigenetic status of the mature cells.

The EPAA intends to support this Forum to continue promoting international collaboration regarding the 3Rs in the expanse of stem cells. For this reason, a 2nd workshop on the topic will take identify during 2014: "Benchmarking of Stem Cell Assays in Prophylactic Assessment beyond International Consortia." This workshop is expected to focus on two relevant cellular models for rubber assessment in the pharmaceutical manufacture, cardiomyocytes and hepatocytes.

Awarding of 3Rs through the Vaccines Consistency Approach in regulatory testing.

Another ambitious projection is the EPAA Vaccines Consistency Approach projection. This project started in 2011, involving stakeholders coming from as far every bit New Zealand, and is showing real hope regarding the incorporation of 3Rs principles in animal testing. Homo and animal vaccines worldwide crave batch-related quality control to ensure their safety and potency. Part of this quality control, particularly of the final product, involves tests requiring laboratory animals; consequently, the legislatively mandated employ of laboratory animals is extensive. Of the approximately 100 one thousand thousand laboratory animals that are used each year in laboratories throughout the earth, 10 to 15 million are used for vaccine batch testing. European Directives 2001/82/EC^{^vi} and 2003/63/EC,^⁵ relating to veterinarian and man medicinal products respectively, crave quality-control tests to be conducted to ensure batch-to-batch consistency.

As described by Hendriksen and colleagues,^¹¹ the consistency arroyo is based upon thorough characterization of the vaccine during evolution and the principle that the quality of subsequent lots is guaranteed by the strict application of a quality organization and of a demonstrated consistent production of batches identical to reference lots of known authorization and safety. The consistency approach is already used for recently registered vaccines, whereas many established vaccines (that is, vaccines produced through inactivation or attenuation of the virulent microorganism or the toxin thereof) go along to rely on tests in laboratory animals for confirming the quality of each batch.

The replacement of beast testing past in vitro methods for in-process and final batch testing of vaccines might be hampered past unresolved scientific and technical questions and a reluctance to accept that in vitro methods can provide acceptable assurance of safety and authority. The consistency approach provides a framework for resolving these issues and implementing the 3Rs but requires radical rethinking regarding the current exercise for established vaccines.

One of the flagship projects of the EPAA, the Vaccines Consistency Approach project has the active support of industry and commission partners of the EPAA, likewise as national authorities and academicians, including Professor Hendriksen, who is one of the project leaders and collaborates with the EPAA. Considerable time and resources are existence invested to promote the implementation of the Vaccines Consistency Arroyo more widely. Several past workshops (2010 to 2013) have provided a solid basis for an improved dialogue with stakeholders from Eu and beyond and addressed with priority four types of vaccines through different workstreams on homo and veterinary rabies, clostridial vaccines, and diptheria–tetanus–acellular pertussis vaccines.^{^fifteen}

These priorities were acknowledged as those with the most pressing animal welfare concerns. Of the 4 areas, the clostridial vaccine project is the near advanced to date. To summarize, EPAA fellow member MSD Animal Health, with the financial support of the United Kingdom'southward National Centre for the 3Rs, has developed cell civilization tests equally alternatives to 2 brute methods used every bit in-procedure controls for the industry of a vaccine confronting Clostridium septicum. These tests measure the toxicity of the toxin, the residuum toxicity of the inactivated toxin (toxoid), and the antigenicity of the toxoid. All of these tests rely on the measurement of toxin neutralization, and whereas this testing conventionally has relied on mice, the new tests aim to replace these conventional testing with cell cultures.

The aim of the project is to bring together an skillful grouping of manufacturers, regulatory entities, and standards bodies to pattern and acquit out a collaborative study, which the European Directorate for the Quality of Medicines and Healthcare (EDQM) will oversee. Successful collaborative studies run nether the Biologic Standardization Program of the EDQM will pb to the validation of new methods and their inclusion in the European Pharmacopoeia equally approved alternatives. The skillful group consists of scientists from laboratories in the Usa, New Zealand, Turkey, Spain, Republic of hungary, Germany, Switzerland, French republic, and the Uk, showing that aggressive improvements on 3Rs should involve an audience as large every bit possible. 11 laboratories from the 9 previously mentioned countries will be involved in the study. To ensure the validity of the study, each contributing lab must adhere strictly to the agreed-on experimental protocols for carrying out and reporting the work. Six toxins and 6 toxoids donated by the participants will be coded to ensure that no one knows their origin and will be distributed to the various labs, together with a reference toxin and antidote, so that results from different labs can be normalized to these standards. Each lab volition undertake to test the toxicity of the toxins and the antigenicity of the toxoids in vivo or in vitro (or both).

The data will so exist collated and analyzed past an EDQM statistician to assess the performance of the tests in dissimilar hands and to compare in vivo and in vitro results. The data, still coded, will be shared with the participants through teleconferences and a terminal workshop targeted for 2015. The workshop volition outline the study report to exist published in the EDQM journal and in a peer-reviewed periodical. The eventual inclusion of these tests in the European Pharmacopoeia may be a milestone for the entire EPAA Vaccines Consistency Approach project. In addition to looking for means to extend the methodology to other clostridial species, the group intends to encourage manufacturers to consider how they could adopt the general methodology to their current manufacturing quality control for clostridial vaccines.

The previous examples of EPAA projects illustrate that long-term and concerted efforts are needed to farther promote the development and international credence of alternative approaches. Thanks to its multisectoral composition, the EPAA fosters international and interdisciplinary collaboration equally the near efficient manner to meet the scientific challenges and progressively reduce the need for animal testing. Ten years subsequently the cosmos of EPAA, its work is now best-selling by industry, European Committee, and third-political party stakeholders every bit essential for the promotion of culling methods in Europe. As a political PPP, EPAA intends to keep promoting the development of novel alternatives for regulatory safe testing. The EPAA partners too call for a reinforced international collaboration with European regulatory agencies and international regulators, such every bit the Organization for Economic Cooperation and Evolution, to accelerate the validation of alternatives. Europe has been i of the start areas where 3Rs were promoted, and the European Union'south legislation has inspired that of several countries (for example, Republic of india, Israel, Brazil) throughout the world through a 'spill-over' result. This last outcome is why EPAA shall go along its efforts toward improve scientific discipline, safer testing, and less animal testing.

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Articles from Journal of the American Clan for Laboratory Animate being Scientific discipline : JAALAS are provided here courtesy of American Association for Laboratory Animal Science

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382626/

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