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Session E2: Regulatory Acceptance of Alternative Methods: Recent Progress and New InitiativesChairs: Len Leonard Schechtman (USA) and Julia Fentem (UK) E2: The Regulatory Acceptance of Alternatives in the EU Recently, progress has been made towards the regulatory acceptance of replacements in the EU, particularly with the introduction of in vitro methods for the prediction of skin corrosivity, dermal penetration, phototoxicity and embryotoxicity. In vitro genotoxicity tests are well established, and testing for this endpoint can be completed without animals, provided clear negative outcomes are obtained. Tiered approaches including in vitro tests can also be used to address skin and eye irritation endpoints. Reductions and/or refinements in animal use are being achieved following the replacement of the oral LD50 test with alternative methods and the adoption of reduced test packages for materials, such as closed-system intermediates and certain polymers. Furthermore, the use of a 'read-across' approach has reduced animal testing. Substantial gains in refinement will also be made with the recent acceptance of the local lymph node assay for skin sensitization and the development of an acute inhalation toxicity method that avoids lethality as the endpoint. For the future, under the proposed Registration, Evaluation, and Authorization of Chemicals (REACH) scheme, it is envisaged that, where suitable in vitro methods exist, these should be used to support registration of substances produced at up to ten tons per annum. This proposal can only accelerate the further development, validation, and regulatory acceptance of such alternative methods. E2: FDA's Regulatory Role in the Iccvam Process The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), a permanent body set forth in the ICCVAM Authorization Act of 2000 (Public Law 106-545), is charged with establishing criteria and processes for the validation and regulatory acceptance of toxicological test methods of interest to Federal agencies, including alternative methods that replace, reduce, or refine the use of animals for research and testing purposes. In response to that mandate, 15 Federal regulatory and research agencies and programs that would consider utilizing such methods or the results derived from them participate in cross-agency efforts directed toward the standardization, validation, acceptance, regulatory implementation, and international harmonization and adoption of such test methods. As an integral member of ICCVAM since its inception, FDA has established processes for responding to ICCVAM issues and recommendations. The participating FDA units include ORA (Office of Regulatory Affairs) and all FDA research and product-based centers, i.e. NCTR (National Center for Toxicological Research), CDER (Center for Drug Evaluation and Research), CBER (Center for Biologics Evaluation and Research), CDRH (Center for Devices and Radiological Health), CFSAN (Center for Food Safety and Applied Nutrition), and CVM (Center for Veterinary Medicine). FDA product centers respond to distinct regulatory mandates and regulate different products. Upon completion of a validation effort, ICCVAM forwards its recommendations to member government agencies regarding the validity and technical acceptability of a method. FDA's response consists of the conclusions reached by each of its regulatory components and addresses such factors as the practical applicability of the method to the products it regulates and the feasibility of implementation of an accepted method to supplement or supplant those currently used. Each center independently determines which of the ICCVAM-recommended tests are appropriate for implementation to satisfy its regulatory obligations to ensure product safety and protect human health. Adoption of a method triggers a notification process to announce the availability and utility of a method, encourage its use, and inform, educate, and train end-users and regulatory review staff. The points to be discussed will include (a) details of the FDA's participation in the ICCVAM effort, (b) the methods and processes FDA employs to meet its regulatory obligations and to be responsive to animal welfare issues, and (c) the ICCVAM-recommended methods considered by FDA. E2: Validation and Regulatory Acceptance of Alternative Methods--Regulatory Acceptance in Japan Except for the genotoxicity test, there are two regulatory guidelines in Japan for in vitro toxicity studies. One of them is a cytotoxicity test for the safety evaluation of extract from plastic devices for medical use. The other is in vitro endotoxin test (limulus test). These were included in Japanese Pharmacopoeia. Japan also accepts data obtained from the tests conducted according to OECD guidelines. On the other hand, MHW (now MHLW) indicated in 1996, that they would accept alternatives to the Draize eye irritation test for safety evaluation of cosmetics if the method were appropriate. Therefore, we, the MHW/JCIA validation group, conducted validation of several alternative methods and indicated that the results of several cytotoxicity tests correlate very well with those of Draize scores obtained from rabbit tests (Ohno et al: Toxicol. in vitro, 13, 73-98, 1999). Based on the results, we prepared draft guidelines to evaluate the eye irritation potential of cosmetic ingredients and submitted to MHLW 1999, in which, in vitro methods are incorporated. Validation requires a lot of resources and time. Therefore, we recently constructed an evaluation scheme for alternative methods with the support of MHLW. It was based on the research, on published manuscripts, and on validation reports. We intended to clarify performance of the method with its limitation. Without having the information, we, both regulators and industry persons, will make big mistakes in evaluating the results of alternative methods. As a first trial of the project, we started research on in vitro phototoxicity test. E2: Validation in Practice: Suiting the Action to the Word In 1996, an OECD Workshop in Solna, Sweden, reached agreement on principles and criteria for the validation and regulatory acceptance of new test methods used for regulatory hazard assessment. However, in applying these principles in practice, it appeared that: 1) no two validation studies were the same; they all had unique issues not necessarily addressed by the principles and criteria; 2) the interpretation of the principles varied from time to time and from study to study; and 3) they seemed to fit better into in vitro tests than to animal studies. Since their adoption, a number of validation studies have been performed, but adoption of these validated (alternative) tests as internationally accepted guidelines has been rather limited. Furthermore, the management of the validation by OECD of a number of animal tests for the assessment of endocrine disrupters has triggered substantial discussion of issues surrounding validation, including: 1) economic and technical feasibility of comprehensive validation studies of multi-endpoint test methods; 2) the interpretation and use of the test prediction description or data interpretation procedure (previously referred to as Prediction Model); 3) the transparency of the process; and 4) the need of an independent peer review. In March 2002, an OECD Conference addressed these and other issues in order to develop further guidance and policies to facilitate the application of the Solna principles in all cases of test method development.
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