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2 Participation (WNT, Nominated Experts, Industry Experts, Animal Welfare Organisations)

2 Participation (WNT, Nominated Experts, Industry Experts, Animal Welfare Organisations)

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12



1.3



A. Gourmelon and N. Delrue



Workflow and Decision-Making Processes



National Coordinators can propose new projects. Such proposals have to be motivated by a regulatory need in more than one country or region (to benefit from

international harmonisation), by a progress in science, by animal welfare considerations (e.g. making it possible to use fewer animals or to reduce duration of a test

for example), or by an improvement in the cost-effectiveness of a test method.

Proposals are reviewed and commented on by all members of the WNT a few

months before the annual WNT meeting. At the meeting itself, the National

Coordinators take a consensus decision on whether or not to include the project on

the work plan following discussions. Project proposals can be submitted at different

stages of test method development. In cases where the test method has already been

validated, information and documents supporting the validation and the development of a Test Guideline are brought to the attention of the WNT upon submission

of the project proposal. The WNT takes its decision to include the proposal in the

work plan based on all available information.

If the project is accepted and the test method has already been validated, the lead

country will take the first steps to make the first draft Test Guideline, while the

Secretariat asks the WNT to nominate experts to a group, unless an existing group is

competent and can take the new project on board. When the draft Test Guideline is

sufficiently ready, it is circulated for a commenting round. The National Coordinators,

industry, environmental organisations and ICAPO usually consult their expert networks when providing comments. In case of diverging views expressed by national

experts, National Coordinators can take a national position. The Secretariat collects

and compiles comments received and works with the lead country to address issues

raised and revise the draft Test Guideline. Typically, following two rounds of WNT

comments, the draft documents are mature enough for submission and eventually

approval by the WNT, but there may be exceptions. The OECD Guidance Document

1 on the Development of Guidelines for the Testing of Chemicals, updated in 2009

(OECD 2009a), describes in more details the process and procedures for the development of OECD Test Guidelines and related documents (see Fig. 2.1). When Test

Guidelines are approved by the WNT, they are subsequently endorsed by higher

policy-level bodies of the Organisation until final adoption by the OECD Council

and publication. Guidance documents approved by the WNT do not go to OECD

Council for adoption (because they are not covered by the OECD Council Decision

on the Mutual Acceptance of Data) and they are published under the responsibility

of the policy body overseeing the work on chemical safety at OECD.

Projects may be included in the work plan at various stages of test method development, and the validity of the test method may not necessarily be fully established.

In such cases, the project starts with experimental validation across laboratories,

organised by the lead country(ies), with the assistance of the expert group or a

Validation Management Group (VMG), with support from the OECD Secretariat as

appropriate. When a project starts with a proposal for a test method that has not yet

been validated, the whole process until approval of a Test Guideline takes more time,

as the experimental validation is the most resource-intensive stage of the project.



2



Validation in Support of Internationally Harmonised OECD Test Guidelines…



MEMBER COUNTRIES,

STAKEHOLDER’S INITIATIVE

(NGO, BIAC, etc)



NATIONAL CO-ORDINATOR,

EUROPEAN COMMISSION,

SECRETARIAT



PRELIMINARY PROPOSAL FOR TEST

GUIDELINE(S)



COMMENTING

ROUNDS

WORKSHOP

EXPERT

CONSULTATION



13



STANDARD PROJECT SUBMISSION FORM (SPSF):

- EXPECTED ENDPRODUCTS

- JUSTIFICATION FOR PROJECT



SUPPORTING DATA (e.g.

VALIDATION STUDY,

PEER-REVIEWED

ARTICLE, RING TEST)



WORKING GROUP OF NATIONAL

COORDINATORS OF THE TEST GUIDELINES

PROGRAMME (WNT):

- SPSF / SUPPORTING DATA REVIEW

- DECISION FOR THE WORK PROGRAMME

- DECISION ON THE APPROACH



DRAFT TEST GUIDELINE



WORKSHOP

EXPERT CONSULTATION



COMMENTING

ROUND



PROPOSAL FOR CHANGES OR

REVISED TEST GUIDELINE



LEGEND:



FINAL VERSION OF THE TEST

GUIDELINE PROPOSAL



Possible ways

Normal process



APPROVAL BY THE WNT BY WRITTEN

PROCEDURE/MEETING



ENDORSEMENT BY THE JOINT MEETING



ENDORSEMENT BY ENVIRONMENT POLICY

COMMITTEE



ADOPTION BY

COUNCIL



PUBLICATION



Fig. 2.1 OECD Test Guidelines development flow diagram (from Guidance Document 1

(OECD 2006))



2



Importance of Validation in the Development Process

of Test Guidelines



Regulatory authorities are charged by law with protecting human health and the

environment. The purpose of validation is to ensure that regulators obtain reliable

and useful information for their decision making, and that data generated can be

exchanged and mutually accepted across countries. In the case of test chemical,



14



A. Gourmelon and N. Delrue



regulators use results from various physical-chemical, environmental fate, and

(eco-)toxicological assays to assess the inherent properties of a chemical substance.

It is essential that these assays and methods provide the regulators with reliable and

correct information so that sound science-based decisions are made to protect

human health and the environment. The aim of experimental validation is to demonstrate the ability of the methods to reproducibly provide accurate and relevant data

on a tested chemical.

Fentem et al. (1995) wrote a review of “lessons learned” from experience with

validating in vitro test methods. At approximately the same time, Balls et al.

(1995) also reviewed the various difficulties that in vitro assays had encountered

during the validation process. These reviews examined in the light of practice

and experience the concepts and ideas on validation that had been presented in

1990 by Balls et al. (1990). These lessons were subsequently discussed at an

OECD workshop on validation principles (OECD 1996), and have since been

incorporated into the OECD Guidance Document on the Validation and

Regulatory Acceptance of New and Updated Test Methods for Hazard Assessment

(OECD 2005). Most concerns regarded the preparatory work prior to embarking

in a validation program, including the status of development of the test and the

availability of standard operating procedures for laboratories participating in the

validation, the selection of test chemicals, the selection of laboratories, the

design of the experimental validation study, and the analysis and interpretation

of results.



2.1



Formalisation of Validation Programmes

with the Emergence of Alternative Methods



About two decades ago, a number of test methods intended as possible alternative or replacements of existing in vivo test methods emerged, initially for hazards for which animal testing became less and less ethically acceptable (e.g.,

topical toxicity). These new test models measured endpoints and/or biomarkers

in vivo, ex vivo or in vitro, intended to predict response to a chemical stressor

on a hazard endpoint. These new assays were often designed and intended as

surrogates of traditional endpoints or models. Relevance, transferability and

reliability, including reproducibility over time, needed to be established through

empirical demonstration or validation by means of inter-laboratory studies. The

validation and the determination of the predictive capacity of these new models

for in vivo effects was a pre-requisite to their acceptance and use in a regulatory

context. For alternative test methods to be up taken by chemical regulations,

consensus was needed around clear principles and criteria, transparent practice

in reporting and review of results that establish the scientific validity of a

method.



2



Validation in Support of Internationally Harmonised OECD Test Guidelines…



2.2



15



Readiness of a Test Method for an Inter-laboratory

Validation Programme



Although the perception of the level of readiness of a test method to enter a validation program may vary among experts/developers, the development and standardisation of the candidate test method and the availability of detailed procedure

descriptions are critical to the success of a validation programme; in the absence of

these, participating laboratories may have insufficient guidance for proper conduct

of the test, may not keep records of important parameters, possibly leading to unexplained variations in the results. While controlled deviations in the conduct of the

test are possible and useful to understand how robust the test is to small variations

from the recommended procedure, monitoring of parameters and recording of

effects are essential to characterize the dynamic range of the test.

Also important is the selection of the chemicals to test in the various phases of

the validation, i.e. intra-laboratory, or multi- laboratories. Data generated in one

laboratory are generally collected, and discussions take place on the set of chemicals to choose when evaluating the transferability of the test method, when assessing the between-laboratories reproducibility. Practical considerations are relevant

for the selection of chemicals: easy access and availability, cost, known composition, analytical method available if needed, especially in the case of aquatic toxicity

testing. The test chemicals should be as representative as possible of the intended

applicability domain: range of physical-chemical properties, mode(s) of action,

potency of chemicals to detect/identify or characterise the expected response from

the test (i.e. not only potent or strong chemicals should be used).

Laboratories participating in the validation programme should be characterised

by their experience in using the test or similar test procedures. It is acceptable and

interesting to include naive laboratories in validation studies in order to know the

level of proficiency that may be required for the successful conduct of the test, but

it is important to know in advance who has experience and who has not, and how

much training and guidance may be needed to transfer the know-how. In addition,

an optimal design of the validation study will ensure an efficient use of resources:

not all participating laboratories have to test all chemicals, it is usually considered

sufficient to have three or four laboratories testing the same chemical in order to be

able to assess inter-laboratory reproducibility.

Finally, the analysis and interpretation of results deserves specific attention at the

stage of test method development; it is important to have predefined, clear and

understandable data interpretation rules and procedures for the statistical analysis of

data, rather than a posteriori adjusting data to an expected outcome of the test.

At the OECD level, guidance on technical aspects in the conduct of validation

studies was formalised in a guidance document developed and agreed by the relevant

players involved in validation (OECD 2005), to set the expected standard on good

practice for validation studies, and to ensure future success and regulatory acceptance across countries of resulting Test Guidelines. This was particularly critical for

in vitro methods intended to replace, partly or fully, existing in vivo test methods.



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