Chief executives have been educated and trained how to handle business, to take executive decisions, and take care of financial and human resources in favor of the company they are leading. CEOs (chief executive officers) of innovative pharmaceutical businesses, among others, have only seldomly been trained to understand the immense time periods involved between decisions and their moment of impact, and the skills and languages used by their internal and external R&D (research and development) staff. R&D staff and regulators, however, have undergone full training, and are usually capable of understanding each other across their various specialties (among them compound finding, quality, safety, efficacy, efficiency, risk assessment and management). What is lacking is the specialized training of CEOs in sectors of R&D, which would benefit the company and patients alike. We propose that CEOs and upper management should undergo cross-border training in R&D topics-wherever possible across all sectors, but minimally to grasp such topics sufficiently to handle those scenarios demanding immediate decisions (be it the CEO cutting off developments, or R&D experts defending their continuation). Learning the language of regulators and R&D scientists will help CEOs to take better decisions. Training programs for R&D staff have been developed and implemented all over Europe and elsewhere. We propose to work with the PharmaTrain3.0 Syllabus (www.pharmatrain.eu/pharmatrain-syllabus) (for details see Supplementary Material), which would support clear-cut training of relevant topics by competent teaching staff towards certification of CEOs and high management. It is foreseen that understanding the language and comprehending the R&D issues and staff will help CEOs in achieving reasoned decisions. It is expected that such decisions will incorporate not only the reasons seen for discontinuation of R&D programs, but also those reasons, which favor their continuation under the same or different headlines (e.g., changing the initially proposed indication). Taken together, training according to "Good Training Practices" (GTP) will benefit the company and the patient, who will receive better medicines as early as possible.

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). Minipigs are strains of domestic pigs that are markedly smaller than farmyard varieties, and thus better adapted to laboratory housing. The pig closely resembles man in many features of its anatomy, physiology, biochemistry and lifestyle. In particular, the cardio-vascular system, skin and digestive tract are considered to be very good models for man. Because of these similarities the toxic effects of chemicals and drugs in pigs may resemble the effects in man more closely than do some other commonly used laboratory animals. The pig also has some features that make it a very practical model for laboratory studies. Finally, being a food animal, testing in the minipig may be more acceptable to the public than animals such as dogs or monkeys. 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. Their conclusions are presented in the articles of this special issue. The RETHINK project was funded as a Specific Support Action under the European Community 6th Framework Programme.

In this paper, changes in serum levels of the cardiac biomarkers troponin I and the heart-type fatty acid-binding protein (H-FABP) following administration of a long-acting beta(2)-sympathicomimeticum (long-acting beta-agonist, LABA) to dogs were measured. We measured troponin I in dogs in a 4-week repeated-dose study with inhalative administration of formoterol (13microg/kgd) and a glucocorticoid/formoterol combination (143/16microg/kgd). The medians of troponin I increased within 3 days in both groups, far beyond the cut-off level (0.1microg/L), but returned to baseline levels on study day 9. The increase was more pronounced in the formoterol-only group (3.29microg/L) compared to the glucocorticoid/formoterol combination group (1.32microg/L). In a second study, we measured serum troponin I as well as serum H-FABP levels in several samples over 7 days in dogs, receiving a single inhalative dose of a glucocorticoid/formoterol combination (120/12mug/kgd). The median of the troponin I concentration increased above the cut-off level within 2h and that of H-FABP within 4h. The medians of both parameters were temporarily above the cut-off levels even on study day 7. Both studies were conducted according to national animal welfare guidelines. To our knowledge, this is the first report that shows a corresponding increase of troponin I and H-FABP in dogs treated with formoterol. Both parameters are more sensitive in detecting a drug-induced cardiac injury compared to total LDH, total CK as well as CK MB activity. However, it is recommended to take at least three blood samples per day to assess a temporary increase of troponin I.

In this article we review the value and utility of the minipig as an animal model in regulatory toxicity testing. Our review is based on detailed consideration of the comparative biology of the minipig, and of the practical features of toxicity testing in the minipig. The minipig presents a favourable profile as a non-rodent toxicology model, in terms of the similarity to man and also in terms of applicability to different study types. Studies of general toxicology can be performed in the minipig by oral, cutaneous, parenteral and inhalation routes. For reproductive toxicology studies the minipig offers numerous advantages as a non-rodent model although the lack of placental transfer of macromolecules may limit the role of the minipig in reproductive testing of biotechnology products. For safety pharmacology studies the minipig is an advantageous model, particularly as regards the cardiovascular system. The immune system of the pig is better characterized than that of the dog, making the pig an interesting alternative model to the nonhuman primate for therapeutic approaches based on manipulation of the immune system. Overall, this review leads us to believe that the minipig might be a better non-rodent toxicology model than the dog. At the present time, however, insufficient comparative data is available to permit a rigorous evaluation of the predictivity of the minipig for human drug-induced toxicities and research is urgently needed to provide experimental data for evaluation of the hypothesis that minipig studies may better reflect human drug-induced toxicities than studies performed in traditional non-rodent toxicology models. It would be of particular value to gain a better vision of the potential utility of the minipig as a model for the safety testing of new biologics, where the minipig could potentially replace the use of non-human primates in the testing of some new products. (C) 2010 Elsevier Inc. All rights reserved.

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.

Teratogenic effects caused by a new nitroimidazopyridazine were examined in Wistar (WU) rats after repeated oral administration of 0, 2.5, 10, and 40 mg/kg, given on days 6-17 post coitum (p.c.) (Day of mating = Day 0) in a regular study on embryo-fetal development according to ICH S5A. At day 20 p.c., fetuses were removed and carefully examined under a dissecting microscope for external, visceral and skeletal malformations. The exposure to the high dose of the test compound during the organogenesis and early histogenesis periods of prenatal development induced prominent CNS malformations (exencephaly, neural tube defects (NTD)) associated with external malformations (hyperflexion of the forelimbs). To support the data from this study additional histological evaluation of the brains was performed with the following results: disorganization of the cerebral cortex associated with ectopic subcommissural organs. Additionally, an in vitro test (whole embryo culture, WEC) showed alterations of the developing neural tube after the incubation of rat embryos with the test compound on gestation days 9.5-11.5. Our data demonstrated that nitroimidazopyridazine caused NTDs and limb malformations during organogenesis. Based on these data the further development of the test compound was stopped.

This chapter contains sections titled: Introduction Application Options for Toxicogenomics Comparative/Predictive Toxicogenomics Mechanistic Studies (Mode of Action) Risk Assessment Dose-dependent Toxicity Interspecies Extrapolation Human Biomarkers of Exposure Regulatory Acceptance: Current Status ICH Process for Harmonization of Guidelines: Experience from the Past Overview ICH Carcinogenicity Guidelines as a Case Study: Experience with the Implementation of Alternative Models in Cancer Risk Assessment Incorporation of Toxicogenomics into Drug Development, Evaluation, and Regulation: Benefits versus risks General Criteria for Successful Exploitation Evaluation Process: Current Status Summary and Outlook References

The assessment of the immunotoxic potential of human pharmaceuticals has drawn considerable attention worldwide in the past few years. In Europe, the Committee for Proprietary Medicinal Products released its immunotoxicity guidance documents. The Food and Drug Administration’s Center for Drug Evaluation and Research in the United States and the Japanese Ministry of Health, Labor, and Welfare are in the process of finalizing similar guidance documents. This report summarizes the discussions on drug immunotoxicity assessment held at a November 2001 DIA workshop held in Noordwijk, The Netherlands. This workshop revealed that an important issue for company attendees was the timing of the immunotoxicity

The approach to chronic toxicity testing over the past decade is reviewed and assessed in the light of developing ICH guidelines. The 1990's have seen a general acceptance that studies with a maximal duration of 6 months in rodents are all that is required for adequate safety assessment of developmental pharmaceutical agents. However, controversy has arisen concerning the most appropriate duration for chronic toxicity testing in non-rodents. Initial suggestions that 6 months duration was sufficient have been countered by findings noted in 12-month studies that were not seen in shorter-term studies. Retrospective analysis of available data eventually lead to a subsequent ICH recommendation that studies of 9 months duration would be now acceptable. However, until recently the FDA position on this recommendation was unclear and an analysis of industry practices since the ICH recommendation was made in 1997 has shown that the 9-month guideline is not widely applied. Recent clarification by the FDA will probably result in a continued but limited use of this alternative. An industry view on the future of chronic toxicology testing in rodents and non-rodents is presented.

Teratogenic effects caused by a new nitroimi- dazopyridazine were examined in Wistar (WU) rats after repeated oral administration of 0, 2.5, 10, and 40 mg/kg, given on days 6-17 post coitum (p.c.) (Day of mating = Day 0) in a regular study on embryo-fetal development according to ICH S5A. At day 20 p.c., fetuses were re- moved and carefully examined under a dissecting microscope for external, visceral and skeletal malfor- mations. The exposure to the high dose of the test compound during the organogenesis and early histo- genesis periods of prenatal development induced prom- inent CNS malformations (exencephaly, neural tube defects (NTD)) associated with external malformations (hyperflexion of the forelimbs). To support the data from this study additional histological evaluation of the brains was performed with the following results: disor- ganization of the cerebral cortex associated with ectopic subcommissural organs. Additionally, an in vitro test (whole embryo culture, WEC) showed alterations of the developing neural tube after the incubation of rat em- bryos with the test compound on gestation days 9.5- 11.5. Our data demonstrated that nitroimidazopyrid- azine caused NTDs and limb malformations during organogenesis. Based on these data the further devel- opment of the test compound was stopped.