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The international harmonisation of guidelines in the future: a viewpoint from the industry
Toxicology Letters 102]103 Ž1998. 551]555
The international harmonisation of guidelines in the future: a viewpoint from the industry Lars Ekman Astra AB, SE-151 85 Sodertalje, ¨ ¨ Sweden
Abstract In the area of safety, 10 completely new toxicology guidelines have been produced up to 1997 under the umbrella of the ICH. Surveys on the use and impact of the ICH guidelines in the pharmaceutical industry in three regions, Europe, the USA and Japan, showed that approximately 80% of the guidelines were utilised and, as expected, the guidelines which had been in place longest were the ones most often used. The work on the different guidelines has initiated a number of specific investigations such as studies on the duration of dosing of male rats to detect adverse effects on male fertility and the duration of chronic toxicity studies in non-rodents. Evaluation of data from various databases on long-term carcinogenicity studies showed that the mouse studies had had very little influence on the outcome of the regulatory decision about the human carcinogenic risk of a specific compound. An important role for the ICH organisation in the future should be to see that changes and amendments to current guidelines are made as soon as they are warranted by the progress of toxicological science. The decision to accept the Common Technical Document as an official ICH topic is important for the industry and will help the industry to reduce the period between drug discovery and regulatory acceptance. In the area of safety there are still topics which could benefit from harmonisation. Such topics are safety pharmacology, clinical pathology, immunotoxicology, juvenile toxicity studies, statistical methods in certain types of toxicity studies, and recommendations for additional short- to medium-term carcinogenicity studies. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: ICH toxicology guidelines; Future aims of ICH; Topics for harmonisation
1. Introduction During the period 1990]1997 10 new ICH guidelines in the area of safety were produced. In addition to the formal guidelines, agreements were reached as early as at the First International Conference ŽICH 1. in Brussels in 1991 about reducing the duration of general toxicity studies in rodents from 12 to 6 months and about abolishing the requirements for exact LD50 test-
ing in rodents and no longer requiring acute toxicity testing in non-rodents. 2. The use of the ICH guidelines Surveys on the use and impact of the ICH guidelines in the pharmaceutical industry in the three regions Europe, Japan and the USA were carried out in 1995 and 1997. In the 1997 survey ŽWatanabe, 1998. 72 companies were asked about
0378-4274r98r$ - see front matter Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0378-4274Ž98.00264-1
552
L. Ekman r Toxicology Letters 102]103 (1998) 551]555
their implementation of ICH guidelines. The overall utilisation of the guidelines was approximately 80%, although, as expected, the guidelines which had been in place longest were also the ones most often used. For example, almost 90% of the European, Japanese and US companies made use of the reproduction guideline, which was the first safety guideline to be adopted by the ICH process. The surveys showed that there is a steady implementation of the guidelines by the industry across all three regions.
ing technical requirements for new medicinal products. The six founder members of the ICH agreed that a second phase of harmonisation should aim to ensure that Žcit..: v
v
3. Research initiated in connection with the ICH working process v
The work on the various safety topics has in several cases prompted the initiation of specific investigations and surveys of databases to give better foundations for the content of the new guidelines. The duration of general toxicity studies in non-rodents was already a controversial issue at the first ICH conference. Studies of the databases in the three ICH regions were performed; unfortunately, however, different conclusions were drawn from the investigations ŽLumley et al., 1992.. The European and Japanese regulators considered that 6-month studies were sufficient to establish findings relevant for human safety. The US regulators identified a few compounds for which 12-month studies were necessary, in their opinion, in order to identify clinically relevant findings. In an attempt to solve this issue, a group of regulators from the three regions looked at the data for 16 compounds for which relevant toxicity studies and human clinical safety data were available. The conclusion drawn by the regulators was obviously a compromise, with a general request for ‘chronic’ studies in non-rodents ŽChristian, 1997.. ‘Chronic ’ means in this case 9-month general toxicity studies. However, in Europe 6-month studies may still be sufficient.
there is a mechanism to harmonise new technical requirements resulting from scientific progress and developments in innovative drug research; there is a process for updating and supplementing the current ICH guidelines, when necessary, and monitoring their use, so that the benefits of the harmonisation achieved are not lost; and future disharmony is prevented through early collaboration and exchange of information on newly emerging issues originating in one of the regions.
5. Maintenance and updating of existing guidelines An important role of the ICH organisation in the future must be to see that changes and amendments to current ICH guidelines are made as soon as they are warranted by the progress of toxicological science. It should be pointed out that in several safety guidelines requirements and recommendations are the result of compromises among the participants in the Expert Working Groups ŽEWGs.. The members of the EWGs and the Steering Committee have been willing to make compromises since the main objectives of the new guideline have been obtained. The guideline on the timing of toxicity studies in relation to different phases of clinical studies is an example of a guideline where it was not possible to come to an agreement on all points, e.g. the requirements for the inclusion of women in clinical trials and the length of general toxicity studies. We can only hope that an agreement can be reached on these points in the near future.
4. General aim of future ICH activities 6. Common Technical Document At ICH 4 in Brussels it was decided that a second phase of harmonisation would continue with the six-party operational basis for harmonis-
A key part of the new phase of the ICH is the adoption of the Common Technical Document
L. Ekman r Toxicology Letters 102]103 (1998) 551]555
ŽCTD. as an ICH topic. The topic was suggested in 1995 by the Pharmaceutical Research Manufacturers of America ŽPhRMA.. A survey of eight international pharmaceutical companies in the USA and Europe showed that in regard to submissions it took an average of 3]4 months to convert one submission to another. The survey showed similar results in the two regions Europe and the USA. A CTD could thus bring real savings by decreasing the time and resources required for preparing different submissions for different regulatory agencies. Based on this information, the Steering Committee of the ICH accepted the CTD as a special project. After some delay the Steering Committee approved a feasibility study to define resource requirements for the project. The industry was asked to compare the format and content requirements in the three regions to see what had already been harmonised as opposed to what was different. Furthermore, with regard to the items that were different, it should consider which ones would be easy to harmonise and which would be difficult. Not surprisingly, the survey revealed that the safety part of the document would most probably be the easiest to harmonise. The CTD was finally accepted as an official ICH topic by the Steering Committee in 1997, and the EWGs for Quality, Safety and Efficacy have been established. The first meetings with the EWGs were held in February this year and it is anticipated that a CTD could be a fact in the year 2002. For the pharmaceutical industry, such an achievement would be a real advantage and an important part of the ongoing projects at all pharmaceutical companies aimed at minimising the period between drug discovery and drug registration. 7. New areas for harmonisation 7.1. Safety pharmacology As early as the first phase of the ICH process, safety pharmacology was proposed as a topic for harmonisation. In a survey conducted in 1995, several independent scientists and regulators
553
pointed out that safety pharmacology was often the most deficient part of the documentation for a new compound. Moreover, there are marked differences in the regulatory requirements for safety pharmacology. At one end we have the FDA not specifying any particular test to be carried out, though requiring reassurance that the effects of a compound on the major organ system of the body have been assessed. At the opposite extreme is the Japanese Ministry of Health and Welfare, which has published ‘Guidelines for General Pharmacology’ Žs Safety Pharmacology.. Listed and described here are a number of tests that must be carried out on all compounds. Tests in a second list may have to be performed, depending on the results of the tests in the first list. So here we have a situation where an ICH guideline might be useful. 7.2. Clinical pathology Clinical pathology, also referred to as clinical chemistry and haematology, constitutes an important part of general toxicity studies in laboratory animals. Some governmental regulatory agencies provide specific guidelines for clinical pathology in toxicity studies, while others do not. Experts in the area of clinical pathology testing have criticised existing guidelines on the grounds that they contain technically inappropriate and impractical recommendations ŽAACC]DACCrASVCP Joint Task Force, 1992.. It can also be claimed that the extent of clinical chemistry testing in general toxicity animal studies is today more influenced by the capacity of modern analytical apparatus to measure blood constituents than by critical thinking about the relevance of the individual tests. With the objective of improving the guidelines for clinical pathology testing, the American Association for Clinical Chemistry and the American Society for Veterinary Clinical Pathology formed a joint committee, which in 1992 presented technical recommendations on blood collection techniques and haematology, serum chemistry and urinalysis tests, which could form the base for an ICH guideline on the topic.
554
L. Ekman r Toxicology Letters 102]103 (1998) 551]555
7.3. Immunotoxicology Immunotoxicity testing of pharmaceuticals has been discussed as a topic for harmonisation since the start of the ICH. In Japan there have been requirements for certain tests to detect the immunotoxic potential of new compounds, although these requirements have now been limited to pharmaceuticals with expected immunomodulating properties or to compounds which in general toxicity studies are shown to have an effect on the immune system. In other areas of toxicology there is no shortage of tests available to assess the immunotoxic potential of new compounds, although it has been considered that there is a shortage of validated methods. Different organisations in Europe as well as in the USA ŽImmunotoxicology Technical Committee, 1995. are discussing and working on guidelines for immunotoxic testing of xenobiotics in general. For pharmaceuticals, there is still a question about the human clinical relevance of immune function tests in experimental animals, whether the tests are performed as part of general toxicity testing or whether they are performed as special studies. 7.4. Ju¨ enile toxicity studies In the new ICH guideline on the timing of toxicity studies in relation to human clinical studies ŽICH Harmonised Tripartite Guideline, 1997a., it is stated that for the inclusion of paediatric patients in clinical trials, safety data from previous adult human exposure usually give the most relevant information. Besides appropriate repeated-dose general toxicity studies, reproduction toxicity studies and the standard battery of genotoxicity tests, juvenile animal studies should be considered on an individual basis in cases where previous animal data and human safety data are considered to be insufficient. It is the experience of the industry that requests for juvenile animal studies are not uncommon and that the design of such studies is often a controversial issue. There are also different opinions about the relevance of toxicity studies in very young animals for human safety assessment. Juve-
nile toxicity studies could therefore be a topic for discussion under the ICH umbrella. 7.5. Statistical methods in certain studies Statistical methods in mutagenicity, carcinogenicity and toxicokinetic studies have been suggested by several pharmaceutical companies as a topic for harmonisation in surveys performed during the first phase of the ICH. So far, this has not been discussed in any ICH EWG, but could be considered as a future ICH topic. 7.6. Recommendations for additionalr alternati¨ e methods of testing carcinogenicity According to the ICH guideline ‘Testing for Carcinogenicity of Pharmaceuticals’ ŽICH Harmonised Tripartite Guideline, 1997b., the basic scheme for carcinogenicity testing comprises only one long-term bioassay, plus one additional shortto medium-range in vivo test for carcinogenicity. This additional test should supplement the longterm carcinogenicity study and provide additional information not obtained in the conventional long-term study. Several transgenic mouse assays are given in the guideline: the p53" deficient model, the TgHras 2 model and the XPA deficient model. Furthermore, the neonatal rodent tumorigenicity model and initiation]promotion models are mentioned. Certain regulatory agencies and many research-based pharmaceutical companies are now engaged in validation programs for these tests. It is of great importance to the pharmaceutical industry that the validation programs result in definite recommendations regarding additionalralternative methods to be used in the future. 8. Concluding remarks It is a general view of toxicologists in the research-based pharmaceutical industry that the first phase of the ICH, with discussions and analyses in EWGs consisting of toxicologists from regulatory agencies and industry in the three regions, has led to new guidelines and recommendations
L. Ekman r Toxicology Letters 102]103 (1998) 551]555
for the toxicity testing of pharmaceuticals which in most areas reflect the latest advances in the toxicological sciences. ICH activities have now moved into a second phase. In the area of safety, as has already been pointed out, it is important to continue harmonisation activities as new scientific information becomes available. Existing guidelines may need to be updated and supplemented, as has already happened during the first phase of the ICH, e.g. ‘evaluation of male fertility’, ‘limit dose’ and ‘length of non-rodent general toxicity studies’. All the work on the new guidelines has been done by members of the EWGs coming from the regulatory bodies and the research-based pharmaceutical industry in the European Union, Japan and the USA. For the future, consideration should be given to inviting toxicologists outside the present ICH organisation to participate as advisors in EWGs on specific topics. By clearly defining the role of outside experts as advisors, it should be possible to maintain the high efficiency that the groups have shown so far. References AACC]DACCrASVCP Joint Task Force1992. Clinical pathology testing recommendations for non-clinical toxicity and safety studies. Toxicol. Pathol. 20r20, 539]543.
555
Christian, M.S., 1997. Overview of the Fourth International Conference on Harmonization. Int. J. Toxicol. Pathol. 20, 659]668. ICH Harmonised Tripartite Guideline, 1997. Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. In: D’Arcy, P.F., Harron, D.W.G. ŽEds.., Proceeding of the Fourth International Conference on Harmonisation, Brussels 1997. Graystone Books Ltd, Antrim, N. Ireland, pp. 1057]1066. ICH Harmonised Tripartite Guideline, 1997. Testing for carcinogenicity of pharmaceuticals. In: D’Arcy, P.F., Harron, D.W.G. ŽEds.., Proceedings of the Fourth International Conference on Harmonisation, Brusssels 1997. Graystone Books Ltd, Antrim, N. Ireland, pp. 949]958. Immunotoxicology Technical Committee1995. ILSI Health and Environmental Sciences Institute, 1126 Sixteenth Street, N.W, Washington, DC 20036, USA., 1995. Immunotoxicity testing and risk assessment: summary of a 1994 Workshop. Food Chem. Toxicol. 35, 887]894. Lumley, C.E., Parkinson, C., Walker, S.R., 1992. An international appraisal of the minimum duration of chronic animal toxicity studies. In: D’Arcy, P.F., Harron, D.W.G. ŽEds.., Proceedings of the First International Conference on Harmonisation, Brussels 1991. Graystone Books Ltd, Antrim, N. Ireland, pp. 236]248. Watanabe, A.W., 1998. Use and impact of ICH guidelines in the pharmaceutical industry. In: D’Arcy, P.F., Harron, D.W.G. ŽEds.., Proceedings of the Fourth International Conference on Harmonisation, Brussels 1997. Graystone Books Ltd, Antrim, N. Ireland, pp. 34]42.
The international harmonisation of guidelines in the future: a viewpoint from the industry Lars Ekman Astra AB, SE-151 85 Sodertalje, ¨ ¨ Sweden
Abstract In the area of safety, 10 completely new toxicology guidelines have been produced up to 1997 under the umbrella of the ICH. Surveys on the use and impact of the ICH guidelines in the pharmaceutical industry in three regions, Europe, the USA and Japan, showed that approximately 80% of the guidelines were utilised and, as expected, the guidelines which had been in place longest were the ones most often used. The work on the different guidelines has initiated a number of specific investigations such as studies on the duration of dosing of male rats to detect adverse effects on male fertility and the duration of chronic toxicity studies in non-rodents. Evaluation of data from various databases on long-term carcinogenicity studies showed that the mouse studies had had very little influence on the outcome of the regulatory decision about the human carcinogenic risk of a specific compound. An important role for the ICH organisation in the future should be to see that changes and amendments to current guidelines are made as soon as they are warranted by the progress of toxicological science. The decision to accept the Common Technical Document as an official ICH topic is important for the industry and will help the industry to reduce the period between drug discovery and regulatory acceptance. In the area of safety there are still topics which could benefit from harmonisation. Such topics are safety pharmacology, clinical pathology, immunotoxicology, juvenile toxicity studies, statistical methods in certain types of toxicity studies, and recommendations for additional short- to medium-term carcinogenicity studies. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: ICH toxicology guidelines; Future aims of ICH; Topics for harmonisation
1. Introduction During the period 1990]1997 10 new ICH guidelines in the area of safety were produced. In addition to the formal guidelines, agreements were reached as early as at the First International Conference ŽICH 1. in Brussels in 1991 about reducing the duration of general toxicity studies in rodents from 12 to 6 months and about abolishing the requirements for exact LD50 test-
ing in rodents and no longer requiring acute toxicity testing in non-rodents. 2. The use of the ICH guidelines Surveys on the use and impact of the ICH guidelines in the pharmaceutical industry in the three regions Europe, Japan and the USA were carried out in 1995 and 1997. In the 1997 survey ŽWatanabe, 1998. 72 companies were asked about
0378-4274r98r$ - see front matter Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0378-4274Ž98.00264-1
552
L. Ekman r Toxicology Letters 102]103 (1998) 551]555
their implementation of ICH guidelines. The overall utilisation of the guidelines was approximately 80%, although, as expected, the guidelines which had been in place longest were also the ones most often used. For example, almost 90% of the European, Japanese and US companies made use of the reproduction guideline, which was the first safety guideline to be adopted by the ICH process. The surveys showed that there is a steady implementation of the guidelines by the industry across all three regions.
ing technical requirements for new medicinal products. The six founder members of the ICH agreed that a second phase of harmonisation should aim to ensure that Žcit..: v
v
3. Research initiated in connection with the ICH working process v
The work on the various safety topics has in several cases prompted the initiation of specific investigations and surveys of databases to give better foundations for the content of the new guidelines. The duration of general toxicity studies in non-rodents was already a controversial issue at the first ICH conference. Studies of the databases in the three ICH regions were performed; unfortunately, however, different conclusions were drawn from the investigations ŽLumley et al., 1992.. The European and Japanese regulators considered that 6-month studies were sufficient to establish findings relevant for human safety. The US regulators identified a few compounds for which 12-month studies were necessary, in their opinion, in order to identify clinically relevant findings. In an attempt to solve this issue, a group of regulators from the three regions looked at the data for 16 compounds for which relevant toxicity studies and human clinical safety data were available. The conclusion drawn by the regulators was obviously a compromise, with a general request for ‘chronic’ studies in non-rodents ŽChristian, 1997.. ‘Chronic ’ means in this case 9-month general toxicity studies. However, in Europe 6-month studies may still be sufficient.
there is a mechanism to harmonise new technical requirements resulting from scientific progress and developments in innovative drug research; there is a process for updating and supplementing the current ICH guidelines, when necessary, and monitoring their use, so that the benefits of the harmonisation achieved are not lost; and future disharmony is prevented through early collaboration and exchange of information on newly emerging issues originating in one of the regions.
5. Maintenance and updating of existing guidelines An important role of the ICH organisation in the future must be to see that changes and amendments to current ICH guidelines are made as soon as they are warranted by the progress of toxicological science. It should be pointed out that in several safety guidelines requirements and recommendations are the result of compromises among the participants in the Expert Working Groups ŽEWGs.. The members of the EWGs and the Steering Committee have been willing to make compromises since the main objectives of the new guideline have been obtained. The guideline on the timing of toxicity studies in relation to different phases of clinical studies is an example of a guideline where it was not possible to come to an agreement on all points, e.g. the requirements for the inclusion of women in clinical trials and the length of general toxicity studies. We can only hope that an agreement can be reached on these points in the near future.
4. General aim of future ICH activities 6. Common Technical Document At ICH 4 in Brussels it was decided that a second phase of harmonisation would continue with the six-party operational basis for harmonis-
A key part of the new phase of the ICH is the adoption of the Common Technical Document
L. Ekman r Toxicology Letters 102]103 (1998) 551]555
ŽCTD. as an ICH topic. The topic was suggested in 1995 by the Pharmaceutical Research Manufacturers of America ŽPhRMA.. A survey of eight international pharmaceutical companies in the USA and Europe showed that in regard to submissions it took an average of 3]4 months to convert one submission to another. The survey showed similar results in the two regions Europe and the USA. A CTD could thus bring real savings by decreasing the time and resources required for preparing different submissions for different regulatory agencies. Based on this information, the Steering Committee of the ICH accepted the CTD as a special project. After some delay the Steering Committee approved a feasibility study to define resource requirements for the project. The industry was asked to compare the format and content requirements in the three regions to see what had already been harmonised as opposed to what was different. Furthermore, with regard to the items that were different, it should consider which ones would be easy to harmonise and which would be difficult. Not surprisingly, the survey revealed that the safety part of the document would most probably be the easiest to harmonise. The CTD was finally accepted as an official ICH topic by the Steering Committee in 1997, and the EWGs for Quality, Safety and Efficacy have been established. The first meetings with the EWGs were held in February this year and it is anticipated that a CTD could be a fact in the year 2002. For the pharmaceutical industry, such an achievement would be a real advantage and an important part of the ongoing projects at all pharmaceutical companies aimed at minimising the period between drug discovery and drug registration. 7. New areas for harmonisation 7.1. Safety pharmacology As early as the first phase of the ICH process, safety pharmacology was proposed as a topic for harmonisation. In a survey conducted in 1995, several independent scientists and regulators
553
pointed out that safety pharmacology was often the most deficient part of the documentation for a new compound. Moreover, there are marked differences in the regulatory requirements for safety pharmacology. At one end we have the FDA not specifying any particular test to be carried out, though requiring reassurance that the effects of a compound on the major organ system of the body have been assessed. At the opposite extreme is the Japanese Ministry of Health and Welfare, which has published ‘Guidelines for General Pharmacology’ Žs Safety Pharmacology.. Listed and described here are a number of tests that must be carried out on all compounds. Tests in a second list may have to be performed, depending on the results of the tests in the first list. So here we have a situation where an ICH guideline might be useful. 7.2. Clinical pathology Clinical pathology, also referred to as clinical chemistry and haematology, constitutes an important part of general toxicity studies in laboratory animals. Some governmental regulatory agencies provide specific guidelines for clinical pathology in toxicity studies, while others do not. Experts in the area of clinical pathology testing have criticised existing guidelines on the grounds that they contain technically inappropriate and impractical recommendations ŽAACC]DACCrASVCP Joint Task Force, 1992.. It can also be claimed that the extent of clinical chemistry testing in general toxicity animal studies is today more influenced by the capacity of modern analytical apparatus to measure blood constituents than by critical thinking about the relevance of the individual tests. With the objective of improving the guidelines for clinical pathology testing, the American Association for Clinical Chemistry and the American Society for Veterinary Clinical Pathology formed a joint committee, which in 1992 presented technical recommendations on blood collection techniques and haematology, serum chemistry and urinalysis tests, which could form the base for an ICH guideline on the topic.
554
L. Ekman r Toxicology Letters 102]103 (1998) 551]555
7.3. Immunotoxicology Immunotoxicity testing of pharmaceuticals has been discussed as a topic for harmonisation since the start of the ICH. In Japan there have been requirements for certain tests to detect the immunotoxic potential of new compounds, although these requirements have now been limited to pharmaceuticals with expected immunomodulating properties or to compounds which in general toxicity studies are shown to have an effect on the immune system. In other areas of toxicology there is no shortage of tests available to assess the immunotoxic potential of new compounds, although it has been considered that there is a shortage of validated methods. Different organisations in Europe as well as in the USA ŽImmunotoxicology Technical Committee, 1995. are discussing and working on guidelines for immunotoxic testing of xenobiotics in general. For pharmaceuticals, there is still a question about the human clinical relevance of immune function tests in experimental animals, whether the tests are performed as part of general toxicity testing or whether they are performed as special studies. 7.4. Ju¨ enile toxicity studies In the new ICH guideline on the timing of toxicity studies in relation to human clinical studies ŽICH Harmonised Tripartite Guideline, 1997a., it is stated that for the inclusion of paediatric patients in clinical trials, safety data from previous adult human exposure usually give the most relevant information. Besides appropriate repeated-dose general toxicity studies, reproduction toxicity studies and the standard battery of genotoxicity tests, juvenile animal studies should be considered on an individual basis in cases where previous animal data and human safety data are considered to be insufficient. It is the experience of the industry that requests for juvenile animal studies are not uncommon and that the design of such studies is often a controversial issue. There are also different opinions about the relevance of toxicity studies in very young animals for human safety assessment. Juve-
nile toxicity studies could therefore be a topic for discussion under the ICH umbrella. 7.5. Statistical methods in certain studies Statistical methods in mutagenicity, carcinogenicity and toxicokinetic studies have been suggested by several pharmaceutical companies as a topic for harmonisation in surveys performed during the first phase of the ICH. So far, this has not been discussed in any ICH EWG, but could be considered as a future ICH topic. 7.6. Recommendations for additionalr alternati¨ e methods of testing carcinogenicity According to the ICH guideline ‘Testing for Carcinogenicity of Pharmaceuticals’ ŽICH Harmonised Tripartite Guideline, 1997b., the basic scheme for carcinogenicity testing comprises only one long-term bioassay, plus one additional shortto medium-range in vivo test for carcinogenicity. This additional test should supplement the longterm carcinogenicity study and provide additional information not obtained in the conventional long-term study. Several transgenic mouse assays are given in the guideline: the p53" deficient model, the TgHras 2 model and the XPA deficient model. Furthermore, the neonatal rodent tumorigenicity model and initiation]promotion models are mentioned. Certain regulatory agencies and many research-based pharmaceutical companies are now engaged in validation programs for these tests. It is of great importance to the pharmaceutical industry that the validation programs result in definite recommendations regarding additionalralternative methods to be used in the future. 8. Concluding remarks It is a general view of toxicologists in the research-based pharmaceutical industry that the first phase of the ICH, with discussions and analyses in EWGs consisting of toxicologists from regulatory agencies and industry in the three regions, has led to new guidelines and recommendations
L. Ekman r Toxicology Letters 102]103 (1998) 551]555
for the toxicity testing of pharmaceuticals which in most areas reflect the latest advances in the toxicological sciences. ICH activities have now moved into a second phase. In the area of safety, as has already been pointed out, it is important to continue harmonisation activities as new scientific information becomes available. Existing guidelines may need to be updated and supplemented, as has already happened during the first phase of the ICH, e.g. ‘evaluation of male fertility’, ‘limit dose’ and ‘length of non-rodent general toxicity studies’. All the work on the new guidelines has been done by members of the EWGs coming from the regulatory bodies and the research-based pharmaceutical industry in the European Union, Japan and the USA. For the future, consideration should be given to inviting toxicologists outside the present ICH organisation to participate as advisors in EWGs on specific topics. By clearly defining the role of outside experts as advisors, it should be possible to maintain the high efficiency that the groups have shown so far. References AACC]DACCrASVCP Joint Task Force1992. Clinical pathology testing recommendations for non-clinical toxicity and safety studies. Toxicol. Pathol. 20r20, 539]543.
555
Christian, M.S., 1997. Overview of the Fourth International Conference on Harmonization. Int. J. Toxicol. Pathol. 20, 659]668. ICH Harmonised Tripartite Guideline, 1997. Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. In: D’Arcy, P.F., Harron, D.W.G. ŽEds.., Proceeding of the Fourth International Conference on Harmonisation, Brussels 1997. Graystone Books Ltd, Antrim, N. Ireland, pp. 1057]1066. ICH Harmonised Tripartite Guideline, 1997. Testing for carcinogenicity of pharmaceuticals. In: D’Arcy, P.F., Harron, D.W.G. ŽEds.., Proceedings of the Fourth International Conference on Harmonisation, Brusssels 1997. Graystone Books Ltd, Antrim, N. Ireland, pp. 949]958. Immunotoxicology Technical Committee1995. ILSI Health and Environmental Sciences Institute, 1126 Sixteenth Street, N.W, Washington, DC 20036, USA., 1995. Immunotoxicity testing and risk assessment: summary of a 1994 Workshop. Food Chem. Toxicol. 35, 887]894. Lumley, C.E., Parkinson, C., Walker, S.R., 1992. An international appraisal of the minimum duration of chronic animal toxicity studies. In: D’Arcy, P.F., Harron, D.W.G. ŽEds.., Proceedings of the First International Conference on Harmonisation, Brussels 1991. Graystone Books Ltd, Antrim, N. Ireland, pp. 236]248. Watanabe, A.W., 1998. Use and impact of ICH guidelines in the pharmaceutical industry. In: D’Arcy, P.F., Harron, D.W.G. ŽEds.., Proceedings of the Fourth International Conference on Harmonisation, Brussels 1997. Graystone Books Ltd, Antrim, N. Ireland, pp. 34]42.