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4 The Japanese Center for the Validation of Alternative Methods (JaCVAM)

4 The Japanese Center for the Validation of Alternative Methods (JaCVAM)

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Fig. 14.2 Framework for validation, peer review and regulatory acceptance of AMs in Japan



reviewed, accepted by regulatory agencies, and made internationally compatible;

and (3) to establish guidelines for new alternative experimental methods through

international collaboration. To accomplish this, JaCVAM assesses the utility, limitations, and suitability for use in regulatory studies of AMs for determining the safety

of chemicals and other materials and also performs validation studies when necessary. In addition, JaCVAM cooperates and collaborates with similar organizations in

related fields, both in Japan and internationally. The Regulation on the Foundation

of JaCVAM of May 1, 2007 (accessible at: http://www.jacvam.jp/files/regulations120813.pdf) establishes JaCVAM’s Rules of Operation.

The framework for the validation, peer review and regulatory acceptance of AMs

in Japan is summarized in Fig. 14.2. JaCVAM is organized around a JaCVAM

Steering Committee composed of the NIHS Director General, the BSRC Director

(chairperson) and other BSRC division representatives, a representative from the

MHLW, a representative from the Pharmaceuticals and Medical Devices Agency,

and the head of the Section for the Evaluation of Novel Methods in the Division of

Pharmacology of the BSR. The JaCVAM Steering Committee deliberates on the

selection/acceptance of novel and modified methods for study by JaCVAM, based

on documentation submitted by a test method developer/proposer. If required, the

Steering Committee proposes the organization of a validation study and commissions a new Validation Management Team (VMT), appointing its chairperson.



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Other members of the VMT are selected in consultation with ICATM partners. If

necessary, the Steering Committee also finalizes budgetary and manpower allocations necessary to implement evaluation and determine the scientific validity of the

methods selected for study. Validation Management Teams are responsible for planning and implementing validation processes. In addition, Validation Management

Teams deliberate on results obtained from validation processes and prepare validation reports that include recommended protocols for submission to the Steering

Committee. A Peer Review Panel is also commissioned by the Steering Committee

each time a test method is submitted for consideration, and consists of experts on

the safety of chemical substances and statistical analysis, who were not involved in

the development or validation of the test method under consideration. After the

Steering Committee appoints a chairperson, additional panel members are named

by the chairperson in consultation with the secretariat and the ICATM partners. Peer

Review Panels evaluate test methods under consideration from a scientific and independent point of view, and prepare draft evaluation reports. When necessary, a Peer

Review Panel can propose implementation of additional validation work and recommends topics of interest for the validation. After deliberating on the results of a

validation study of an AM, the Peer Review Panel issues a report to the Steering

Committee.

An Editorial Committee is also commissioned by the JaCVAM Steering

Committee each time a test method is submitted for consideration, and consists of

domestic experts on the safety of chemical substances and statistical analysis, who

were not involved in the development or validation of the test method under consideration. After the Steering Committee appoints a chairperson, additional panel

members are named by the chairperson in consultation with the JaCVAM Secretariat

and the ICATM partners. The Editorial Committee is responsible for preparing a

Japanese evaluation report based on the validation reports, peer review report and

other background information, which is submitted to a Regulatory Acceptance

Board for examination. The Regulatory Acceptance Board examines the reports as

mentioned above in order to deliberate on the scientific validity, regulatory utility,

and potential for acceptance by society in general of the test method under consideration, after which it issues a final report that undergoes public commenting. The

Regulatory Acceptance Board consists of representatives of NIHS, experts of AMs,

toxicologists, representatives recommended by industry groups, biostatisticians,

and regulatory officers. Once finalized, the report from the Regulatory Acceptance

Board is submitted to the JaCVAM Steering Committee for final deliberation. The

Steering Committee is responsible for establishing the official policy of JaCVAM

regarding test methods judged to be suitable for regulatory studies, and issues documentation of the results of these activities, which are then submitted to relevant

agencies at the MHLW and/or other ministries as well as made available to the

public.

All of JaCVAM activities are overseen by an Advisory Council composed of the

NIHS Director General (chairperson), the BSRC Director, administrators from relevant governmental agencies, experts on animal welfare, representatives from

related academic societies, and industry representatives, as well as other persons



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Fig. 14.3 Framework for the validation and international regulatory acceptance of AMs



judged necessary by the chairperson. The Advisory Council receives reports from

the Steering Committee once or more each year, on which it deliberates and for

which it provides advice.

Japan is a member of the OECD, and therefore “accepts” the use of OECD Test

Guidelines for regulatory testing purposes. Japan has several NCs represented in the

OECD Working Group of the National Coordinators for the Test Guidelines

Programme (WNT), coming different ministries, namely the MHLW, the Ministry

of Economy, Trade and Industry (METI), the Ministry of Agriculture, Forestry and

Fisheries (MAFF), the Ministry of the Environment (MOE) and the Ministry of

Foreign Affairs (MOFA). They aim at developing harmonized consensus views in

Japan on specific test methods and promoting their adoption at OECD level. New

project proposals (SPSFs—Standard Project Submission Forms) and new draft TGs

on AMs proposed by JaCVAM/MHLW need to be agreed by all NCs before submission to the OECD (Fig. 14.3). ICATM partners are also consulted on every new

Japanese proposal to the OECD for adoption of new AMs.

To promote the 3Rs in Japan, the director of JaCVAM collects information about

the 3Rs from Japan and abroad and broadcasts this information through scientific

societies, web sites, publications, and symposia. Additionally, JaCVAM distributes

publications that summarize JaCVAM’s activities to the relating organizations. To

facilitate the conduct of its activities, JaCVAM also cooperates with several scien-



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Fig. 14.4 International cooperation of JaCVAM



tific organizations such as the Japanese Society for Alternatives to Animal

Experiments (JSAAE) (Fig. 14.4). The JSAAE, founded in 1989, is an academic

research organization with the purpose “to promote research, development, education, and studies related to animal welfare and alternatives to animal experiments,

disseminating the results of these activities.” JaCVAM and the JSAAE have also

provided important leadership in the establishment of AMs in other Asian countries.

They collaborated with Korea in launching of the Korean Center for the Validation

of Alternative Methods (KoCVAM).

The English version of the JaCVAM website, launched in August 2009, provides

stakeholders outside of Japan with easier access to their activities. The site provides

details on the organization of JaCVAM, and describes the committees and groups

that participate in advising JaCVAM and in the review of AMs in Japan. The

“Update on JaCVAM” section of the official JaCVAM website (see: http://www.

jacvam.jp/en_effort/index.html) provides a table that describes the validation/peer

review/regulatory acceptance status of different AMs that are undergoing, or have

undergone, evaluation by JaCVAM. Ongoing validation studies coordinated by

JaCVAM are: the SIRC-CVS assay, the Vitrigel-EIT and a “me too” reconstructed

human cornea-like epithelium (LabCyte CORNEA model) for eye irritation testing;

the IL-8 Luc assay for predicting skin sensitization; and a stably transfected transcriptional activation (STTA) antagonist assay for androgen disruptor screening

(AR-EcoScreen). The latter is being supported by the OECD “Validation

Management Group—Non Animal” and is foreseen to be included into a

Performance-Based Test Guideline (PBTG) together with the AR-CALUX test

method currently being validated by EURL ECVAM.



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The Korean Center for the Validation of Alternative

Methods (KoCVAM)



KoCVAM was founded by the Korea Food and Drug Administration (KFDA) in

November 2009 and is hosted by the Toxicological Screening and Testing Division

within the Toxicological Evaluation and Research Department of the National

Institute of Food and Drug Safety Evaluation (NIFDS). In March 2013, the KFDA

was restructured and elevated to ministry status as the Ministry of Food and Drug

Safety (MFDS). The MFDS oversees the NIFDS and is responsible for protecting

the public health by assuring the safety of foods, drugs, biologics, cosmetics, and

medical devices in the Republic of Korea. The MFDS has several regulations in

these areas that relate to AMs, namely:

• Cosmetics: Regulation on evaluation of functional cosmetics (2013.12.31),

which accepts AMs for cosmetics safety evaluation;

• Drugs: Guidance on Nonclinical Safety Studies for the Conduct of Human

Clinical Trials and Marketing Authorization for Pharmaceuticals (2012.06.29)

and Guideline on Photosafety evaluation of Pharmaceuticals (2014.10.24),

which both reflect the 3R principles (Replacement, Reduction, Refinement);

• Medical devices: Standards for biological safety evaluation of medical devices

(2014.4.24), which accepts the Local Lymph Node Assay and in vitro skin irritation tests using reconstructed human epidermis for safety evaluation of medical

devices.

KoCVAM was established based on the Korean Laboratory Animal Act of March

2008, which states in Article 5 (6) that the “establishment of policies and their

execution on the development and approval of alternative test methods” is the duty

of the minister of MFDS. KoCVAM was therefore established with the following

mission:

• To support policies on development and approval of alternative methods to animal testing;

• To manage the overall process of validating AMs, conducting peer reviews, providing recommendations to regulatory authorities, and proposing test guidelines

on validated AMs;

• To promote cooperation and joint research on AMs with domestic and international organizations;

• To disseminate AMs in Korea by providing educational programs and holding

workshops.

KoCVAM seeks to institutionalize AMs through various activities, to build cooperative relationships with both domestic and foreign organizations and to review

and validate proposed alternatives. KoCVAM also intends to keenly respond to

these global trends by globally promoting AMs developed by Korean organizations.

On this basis, KoCVAM’s main activities focus on the coordination of validation

studies on AMs, the implementation in Korea of internationally validated AMs, the



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development and recommendation of international test guidelines, and the dissemination of AMs in and out of Korea.

The KoCVAM’s validation workflow can be summarized into the following consecutive steps:

1. Test method developer/proposer: Submission to KoCVAM of a candidate

AM and validation study proposal;

2. KoCVAM: Review of the proposed AM, decision whether or not to initiate a

validation study on the proposed method, and establishment of an ad-hoc

Validation Management Team (VMT), including experts in chemistry and

biostatistics;

3. VMT: Drafting of a project plan for the validation study, establishment of test

chemicals and biostatistics teams, selection of test chemicals (proposed by test

chemicals team), approval of participating laboratories and approval of the test

method’s protocol/SOP;

4. Lead laboratory: Transfer of the proposed test method to the participating

laboratories and finalization of the test method’s protocol/SOP (if required);

5. KoCVAM: Distribution of coded test chemicals to the participating

laboratories;

6. Participating laboratories: Proficiency testing of coded test chemicals followed by intra- and inter-laboratory validation (assessment of reproducibility

and predictive capacity) conducted by the lead laboratory and other participating laboratories;

7. KoCVAM: Collection of data and QA audit on data and study documentation;

8. Bio-statistics team: analyses and evaluation of the data and drafting of a statistics report;

9. VMT: Preparation of a validation study report (the VMT can propose an additional study if found necessary);

10. KoCVAM: Establishment of a Peer Review Panel;

11. Peer Review Panel: Peer review of the study on the basis of the validation

study report and preparation of a peer review report (the Peer Review Panel can

propose an additional study if found necessary);

12. KoCVAM: Evaluation of the peer review report, decision whether or not to

propose the method for regulatory use and organization of an ad-hoc Regulatory

Recommendation Team;

13. Regulatory Recommendation Team: Provide recommendations based on the

peer review report;

14. KoCVAM: Recommendation of the test method to regulatory authorities.

Korea also participates in several international validation studies and peerreviews coordinated by ICATM partners (Table 14.1). The process usually starts

with an ICATM organization making a formal request to KoCVAM for Korean

experts and/or laboratories to join an international validation study or peer-review

panel. KoCVAM then notifies relevant national academic institutions, research

institutes, GLP facilities, CRO or other laboratories and requests for applications.



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