Regulatory Acceptance of Alternative Methods in the Development and Approval of Pharmaceuticals.

Animal studies may be carried out to support first administration of a new medicinal product to either humans or the target animal species, or before performing clinical trials in even larger populations, or before marketing authorisation, or to control quality during production. Ethical and animal welfare considerations require that animal use is limited as much as possible. Directive 2010/63/EU on the protection of animals used for scientific purposes unambiguously fosters the application of the principle of the 3Rs when considering the choice of methods to be used.As such, today, the 3Rs are embedded in the relevant regulatory guidance both at the European (European Medicines Agency (EMA)) and (Veterinary) International Conference on Harmonization ((V)ICH) levels. With respect to non-clinical testing requirements for human medicinal products, reduction and replacement of animal testing has been achieved by the regulatory acceptance of new in vitro methods, either as pivotal, supportive or exploratory mechanistic studies. Whilst replacement of animal studies remains the ultimate goal, approaches aimed at reducing or refining animal studies have also been routinely implemented in regulatory guidelines, where applicable. The chapter provides an overview of the implementation of 3Rs in the drafting of non-clinical testing guidelines for human medicinal products at the level of the ICH. In addition, the revision of the ICH S2 guideline on genotoxicity testing and data interpretation for pharmaceuticals intended for human use is discussed as a case study.In October 2010, the EMA established a Joint ad hoc Expert Group (JEG 3Rs) with the mandate to improve and foster the application of 3Rs principles to the regulatory testing of medicinal products throughout their lifecycle. As such, a Guideline on regulatory acceptance of 3R testing approaches was drafted that defines regulatory acceptance and provides guidance on the scientific and technical criteria for regulatory acceptance of 3R testing approaches, including a process for collection of real-life data (safe harbour). Pathways for regulatory acceptance of 3R testing approaches are depicted and a new procedure for submission and evaluation of a proposal for regulatory acceptance of 3R testing approaches is described.

An integrative test strategy for cancer hazard identification.

Assessment of genotoxic and carcinogenic potential is considered one of the basic requirements when evaluating possible human health risks associated with exposure to chemicals. Test strategies currently in place focus primarily on identifying genotoxic potential due to the strong association between the accumulation of genetic damage and cancer. Using genotoxicity assays to predict carcinogenic potential has the significant drawback that risks from non-genotoxic carcinogens remain largely undetected unless carcinogenicity studies are performed. Furthermore, test systems already developed to reduce animal use are not easily accepted and implemented by either industries or regulators. This manuscript reviews the test methods for cancer hazard identification that have been adopted by the regulatory authorities, and discusses the most promising alternative methods that have been developed to date. Based on these findings, a generally applicable tiered test strategy is proposed that can be considered capable of detecting both genotoxic as well as non-genotoxic carcinogens and will improve understanding of the underlying mode of action. Finally, strengths and weaknesses of this new integrative test strategy for cancer hazard identification are presented.

The RETHINK project on minipigs in the toxicity testing of new medicines and chemicals: conclusions and recommendations.

The objective of the RETHINK project was to evaluate the potential impact of toxicity testing in the minipig as an alternative approach in regulatory toxicity testing that can contribute to the replacement, refinement and reduction of animal testing (3Rs). Expert study groups (Working Groups) were assembled to review five different areas relating to the use of minipigs in regulatory safety testing: ethical issues, welfare and animal care, development of new medicines and chemicals, safety testing issues and emerging technologies in safety testing. The conclusions and recommendations of the projects are presented in this article. It is concluded that there are no specific areas where restrictions to the use of minipigs in toxicology are required for welfare reasons. The minipig model is generally acceptable to regulatory authorities, provided it is adequately justified. The minipig is an interesting model for safety testing since there are numerous anatomical, physiological, genetic and biochemical similarities to humans. In addition many features of the minipig make it a practical and flexible model for safety testing. The use of the minipig in development of products does not bring any financial penalty in terms of the cost of testing. Benefits in terms of 3Rs can be identified in terms of life-cycle analysis of the use of minipigs compared to dogs and non-human primates. Finally the minipig (unlike the dog) is well positioned to take advantage of genomics and gene manipulation technologies. Specific recommendations for further research are made, which could bring 3Rs benefits. To deploy the minipig to the best advantage, clear information is needed about the predictivity of the minipig for human toxicities, and focussed action to define the potential role of the minipig in testing of biologics.

Alternatives models in carcinogenicity testing--a European perspective.

Transgenic mouse strains offer the prospect of significant benefits in the in vivo assessment of carcinogenic potential. The European Regulatory Authorities have been supportive of their inclusion as one of the second-test options in the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human use (ICH). However, there is a concern regarding premature systematic use of these models. At present, the information from the International Life Sciences Institute (ILSI) project suggests that the transgenic models under study are similarly sensitive to genotoxic pharmaceuticals. There are apparently some false negatives and false positives. For regulatory purposes, it is not yet possible to differentiate the models with respect to hazard identification and risk assessment. The evaluation of the models has reached an interesting but, at certain points, equivocal stage. Based on the weight of evidence gathered thus far, regulatory authorities cannot neglect the outcome of such studies but need to be cautious in their interpretation of data from such models, and the application in risk assessment procedures.

The in vivo rodent test systems for assessment of carcinogenic potential.

A Drug Information Association (DIA) workshop was held in May 2001 to discuss the outcome of the International Life Sciences Institute-Health and Environmental Sciences Institute (ILSI-HESI) project on alternative models for carcinogenicity assessment such as the P53(+/-) and XPA(+/-) knockout mouse models, the RasH2 and Tg.AC transgenic mouse models, and the neonatal mouse model. The "ICH Guideline S1B on Testing for Carcinogenicity of Pharmaceuticals" advocates that carcinogenicity testing of pharmaceuticals, when needed, might be carried out choosing one 2-year rodent carcinogenicity study (rat) plus one other study that supplements the 2-year study and providing additional information that is not readily available from the 2-year study: either (1) a short- or medium-term in vivo rodent test system or (2) a 2-year carcinogenicity study in a second rodent species (mouse). Another topic of discussion was pros and cons of the short- and medium-term models being evaluated by the ILSI-HESI project, in particular the usefulness of the models in relation to results of genotoxicity assays. Further discussions were advised following publication of the ILSI-HESI database, which is expected before the end of 2001. The use of the short- and medium-term rodent test systems were not considered appropriate for the assessment of carcinogenic potential of biotechnology-derived medicinal products.