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The impact of the CVMP antibiotic guidelines on research and development of antibiotics
ARTICLE IN PRESS
International Journal of Medical Microbiology 296 (2006) S2, 29–31 www.elsevier.de/ijmm
The impact of the CVMP antibiotic guidelines on research and development of antibiotics Alexander Bo¨ttner Intervet Innovation GmbH, Schwabenheim, Germany
Keywords: Antimicrobial safety; Efficacy; Antibiotic product development; EU licensing requirements
Introduction The Committee for Veterinary Medicinal Products (CVMP) of the European Medicines Agency issued two new guidelines in 2003 for veterinary medicinal products containing antimicrobial substances (The European Agency for the Evaluation of Medicinal Products, 2002a, b). The guidelines refer to data requirements regarding human safety (EMEA/CVMP/244/01) and target animal efficacy (EMEA/CVMP/627/01) of antimicrobial veterinary medicinal products.
Antimicrobial safety guideline Guideline # 244 primarily focuses on products used in food producing animals and applies to all new applications for marketing authorization for veterinary medicinal products containing antimicrobial substances. It describes the studies necessary to assess the potential resistance development in zoonotic organisms (e.g. Campylobacter spp. or non-typhoid Salmonella spp.). The document lists baseline information which has to be provided for every application including antimicrobial class, mechanism of action, antimicrobial spectrum of activity, resistance mechanisms, co- and crossresistance as well as pharmacokinetic data. In addition, the applicant has to demonstrate to what extent the antimicrobial substance reaches the intestinal tract of Tel.: +49 6130 948 190; fax: +49 6130 948 504.
E-mail address: [email protected]. 1438-4221/$ - see front matter doi:10.1016/j.ijmm.2006.01.058
the animal under the proposed conditions of use and the degree of exposure of zoonotic organisms to the substance. The exposure could be quite different depending on the usage conditions of the product, i.e. parenteral or oral administration and the pharmacokinetic properties of the antimicrobial substance. The level of exposure is classified into high, low and no exposure. Furthermore, it is required to assess the importance of the antimicrobial class to human medicine in view of the indications, resistance situation and alternative therapies. Depending on the level of exposure and the importance of the veterinary antimicrobial to human health, the applicant has to provide additional studies. These are studies on mutation frequency, the induction of tolerance, the transferability of resistance and in vivo studies in the target animal species. However, there is no clear guidance given as to when additional studies have to be provided. The guideline has come into force in January 2003 and will be replaced in December 2004 by VICH topic guideline 27 (Anonymous, 2003) which is practically identical with guideline # 244. The international harmonization of guidelines is very much welcomed by the veterinary pharmaceutical industry as it supports a global product development.
Efficacy guideline Guideline # 627 outlines the data requirements for the demonstration of efficacy for new antimicrobial
ARTICLE IN PRESS 30
A. Bo¨ttner / International Journal of Medical Microbiology 296 (2006) S2, 29–31
veterinary medicinal products (except intramammary products) for use in food-producing and companion animals. The objective of the guideline is to establish a therapeutic dosing regimen that aims to minimize the risk of selecting antimicrobial resistant bacteria. An extensive package of in vitro and in vivo studies covering the field of pharmacology, antimicrobial resistance and clinical efficacy is required. This includes data on the susceptibility of target animal pathogens that have to be representative for the EU, should be epidemiologically unrelated and isolated no longer than 5 years prior to the submission of the application. In addition, to select a dose regimen and to demonstrate clinical efficacy a number of dose-determination, doseconfirmation and field studies have to be performed. The applicant also has to propose breakpoints for the specific veterinary pathogens. Further information with regard to resistance is similar to what is already described in the antimicrobial safety guideline # 244. The scope of both guidelines applies to all new product applications (new chemical entities) and line extensions (i.e. indications, species, formulations) of an antimicrobial substance contained in veterinary products already authorized. Generics do not fall under the scope of the guidelines.
Discussion In principle, the guidelines are welcomed by the veterinary pharmaceutical industry. Such guidance documents are necessary to outline safety and efficacy requirements. Both guidelines contribute with respect to that. Guidelines are an important part of the product development process. The development of new veterinary antimicrobial products is very expensive and takes many years, especially for products intended for food producing animals. The regulatory risks must remain calculable. However, both guidelines are still deficient on that subject. The guideline on antimicrobial resistance describes the requirements for a multitude of studies which could be useful for the antimicrobial risk assessment. However, it is not mentioned at all how the study results will be assessed in view of potential risks. It is not clear how results will be interpreted with regard to a possible resistance development and the potential risk that antibiotic treatment may fail in human medicine due to the use of a given product in veterinary medicine. How are high- and low- risk mutation rates characterized? Are in vivo resistance studies in the target animal at all suitable to make a risk assessment? It is mandatory to first define the hazard when a risk assessment is performed. Based on the definition of the
hazard the risk assessment could be quite different and will result in different conclusions. As an example, the hazard could be defined as human disease caused by an antibiotic-resistant zoonotic organism which is caused by the use of a given antimicrobial veterinary medicinal product. A completely different hazard would be the general increase in resistant bacteria which can be caused by a variety of different factors. Guideline # 244 has to be extended for criteria which enable an assessment of the study results in view of the potential resistance development and should conclude in a qualitative risk assessment. For example, how is the risk assessed if there is a certain potential for resistance transfer, but the zoonotic organisms are exposed only to low amounts of the antimicrobial substance? Based on the risk assessment, the guideline should also provide different risk management measures or options for the use of the veterinary medicinal product. Risk management options could relate to the dose regimen, the indications of the product, or extended requirements like resistance surveillance. Adopting such an approach, the evaluation and assessment of the data becomes transparent because a clear link between type and extent of data, risk assessment, and risk management is established. The new antibiotic efficacy guideline will significantly increase the licensing efforts for veterinary antimicrobials. There is the impression that a maximum of in vitro and in vivo studies are required by the guideline, which can be quite useful on their own, but which is not necessarily required in each case as a whole. For example, there is great advancement in pharmacokinetic/pharmacodynamic analysis to establish dose regimens and efficacious treatment schedules, which by all means can reduce dose-finding and dose-determination studies (Craig, 1998; Toutain et al., 2002). It will be difficult to justify the required data for line extensions of existing antimicrobial substances like improved formulations or additional indications and target species. This might be critical with respect to medicines availability. A clear differentiation in the requirement for new and established antimicrobial substances is absolutely required. A first step in the right direction is noted in the antimicrobial safety guideline as there is a differentiation between basic and additional information. The CVMP explanatory note to this guideline also calls for a flexible approach where an application relates to existing substances. However, this note should become an integral part of both guidelines. Another major deficiency of this guideline is the lack of criteria by which the study results can be assessed in view of the objective of the guideline, namely that the therapeutic regimen is aimed at to minimize the risk of selecting antimicrobial resistant bacteria.
ARTICLE IN PRESS A. Bo¨ttner / International Journal of Medical Microbiology 296 (2006) S2, 29–31
Conclusions In summary, both guidelines are welcomed by the animal health industry. However, requirements defined in the guidelines will significantly increase the licensing efforts for veterinary antimicrobials. In addition, the uncertainties during the regulatory approval process and the regulatory risk during the development are increased in the absence of risk assessment criteria. As a consequence, important product characteristics could be excluded from the product licence. Therefore, a fundamental review of the guidelines is required, especially in view of transparent risk assessment criteria and a flexible application and differentiated interpretation of the requirements. This would be an important pre-requisite and a reliable framework to continue the development of innovative antimicrobial products. The veterinarian requires a range of products for efficacious and differentiated antimicrobial therapy and limitations in antimicrobial therapy must be avoided (e.g. Escherichia coli infections in poultry).
References Anonymous, 2003. Guidance on the pre-approval information for registration of new veterinary medicinal products for
31
food producing animals with respect to antimicrobial resistance. VICH GL 27 (antimicrobial resistance: preapproval), www.fda.gov/cvm/Documents/guide144.doc (last accessed 20.11.2005). Craig, W.A., 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 26, 1–12. The European Agency for the Evaluation of Medicinal Products, 2002a. Committee for Veterinary Medicinal Products. Guideline on pre-authorisation studies to assess the potential for resistance resulting from the use of antimicrobial veterinary medicinal products (EMEA/ CVMP/244/01-Final). www.emea.eu.int/pdfs/vet/swp/ 024401en.pdf (last accessed 20.11.2005). The European Agency for the Evaluation of Medicinal Products, 2002b. Committee for Veterinary Medicinal Products. Guideline for the demonstration of efficacy for veterinary medicinal products containing antimicrobial substances (EMEA/CVMP/627/01-Final). http://www.emea.eu.int/pdfs/vet/ewp/062701en.pdf (last accessed 20.11.2005). Toutain, P.L., Del Castillo, J.R.E., Bousquet-Me`lou, A., 2002. The pharmacokinetic–pharmacodynamic approach to a rational dosage regimen for antibiotics. Res. Vet. Sci. 73, 105–114.
International Journal of Medical Microbiology 296 (2006) S2, 29–31 www.elsevier.de/ijmm
The impact of the CVMP antibiotic guidelines on research and development of antibiotics Alexander Bo¨ttner Intervet Innovation GmbH, Schwabenheim, Germany
Keywords: Antimicrobial safety; Efficacy; Antibiotic product development; EU licensing requirements
Introduction The Committee for Veterinary Medicinal Products (CVMP) of the European Medicines Agency issued two new guidelines in 2003 for veterinary medicinal products containing antimicrobial substances (The European Agency for the Evaluation of Medicinal Products, 2002a, b). The guidelines refer to data requirements regarding human safety (EMEA/CVMP/244/01) and target animal efficacy (EMEA/CVMP/627/01) of antimicrobial veterinary medicinal products.
Antimicrobial safety guideline Guideline # 244 primarily focuses on products used in food producing animals and applies to all new applications for marketing authorization for veterinary medicinal products containing antimicrobial substances. It describes the studies necessary to assess the potential resistance development in zoonotic organisms (e.g. Campylobacter spp. or non-typhoid Salmonella spp.). The document lists baseline information which has to be provided for every application including antimicrobial class, mechanism of action, antimicrobial spectrum of activity, resistance mechanisms, co- and crossresistance as well as pharmacokinetic data. In addition, the applicant has to demonstrate to what extent the antimicrobial substance reaches the intestinal tract of Tel.: +49 6130 948 190; fax: +49 6130 948 504.
E-mail address: [email protected]. 1438-4221/$ - see front matter doi:10.1016/j.ijmm.2006.01.058
the animal under the proposed conditions of use and the degree of exposure of zoonotic organisms to the substance. The exposure could be quite different depending on the usage conditions of the product, i.e. parenteral or oral administration and the pharmacokinetic properties of the antimicrobial substance. The level of exposure is classified into high, low and no exposure. Furthermore, it is required to assess the importance of the antimicrobial class to human medicine in view of the indications, resistance situation and alternative therapies. Depending on the level of exposure and the importance of the veterinary antimicrobial to human health, the applicant has to provide additional studies. These are studies on mutation frequency, the induction of tolerance, the transferability of resistance and in vivo studies in the target animal species. However, there is no clear guidance given as to when additional studies have to be provided. The guideline has come into force in January 2003 and will be replaced in December 2004 by VICH topic guideline 27 (Anonymous, 2003) which is practically identical with guideline # 244. The international harmonization of guidelines is very much welcomed by the veterinary pharmaceutical industry as it supports a global product development.
Efficacy guideline Guideline # 627 outlines the data requirements for the demonstration of efficacy for new antimicrobial
ARTICLE IN PRESS 30
A. Bo¨ttner / International Journal of Medical Microbiology 296 (2006) S2, 29–31
veterinary medicinal products (except intramammary products) for use in food-producing and companion animals. The objective of the guideline is to establish a therapeutic dosing regimen that aims to minimize the risk of selecting antimicrobial resistant bacteria. An extensive package of in vitro and in vivo studies covering the field of pharmacology, antimicrobial resistance and clinical efficacy is required. This includes data on the susceptibility of target animal pathogens that have to be representative for the EU, should be epidemiologically unrelated and isolated no longer than 5 years prior to the submission of the application. In addition, to select a dose regimen and to demonstrate clinical efficacy a number of dose-determination, doseconfirmation and field studies have to be performed. The applicant also has to propose breakpoints for the specific veterinary pathogens. Further information with regard to resistance is similar to what is already described in the antimicrobial safety guideline # 244. The scope of both guidelines applies to all new product applications (new chemical entities) and line extensions (i.e. indications, species, formulations) of an antimicrobial substance contained in veterinary products already authorized. Generics do not fall under the scope of the guidelines.
Discussion In principle, the guidelines are welcomed by the veterinary pharmaceutical industry. Such guidance documents are necessary to outline safety and efficacy requirements. Both guidelines contribute with respect to that. Guidelines are an important part of the product development process. The development of new veterinary antimicrobial products is very expensive and takes many years, especially for products intended for food producing animals. The regulatory risks must remain calculable. However, both guidelines are still deficient on that subject. The guideline on antimicrobial resistance describes the requirements for a multitude of studies which could be useful for the antimicrobial risk assessment. However, it is not mentioned at all how the study results will be assessed in view of potential risks. It is not clear how results will be interpreted with regard to a possible resistance development and the potential risk that antibiotic treatment may fail in human medicine due to the use of a given product in veterinary medicine. How are high- and low- risk mutation rates characterized? Are in vivo resistance studies in the target animal at all suitable to make a risk assessment? It is mandatory to first define the hazard when a risk assessment is performed. Based on the definition of the
hazard the risk assessment could be quite different and will result in different conclusions. As an example, the hazard could be defined as human disease caused by an antibiotic-resistant zoonotic organism which is caused by the use of a given antimicrobial veterinary medicinal product. A completely different hazard would be the general increase in resistant bacteria which can be caused by a variety of different factors. Guideline # 244 has to be extended for criteria which enable an assessment of the study results in view of the potential resistance development and should conclude in a qualitative risk assessment. For example, how is the risk assessed if there is a certain potential for resistance transfer, but the zoonotic organisms are exposed only to low amounts of the antimicrobial substance? Based on the risk assessment, the guideline should also provide different risk management measures or options for the use of the veterinary medicinal product. Risk management options could relate to the dose regimen, the indications of the product, or extended requirements like resistance surveillance. Adopting such an approach, the evaluation and assessment of the data becomes transparent because a clear link between type and extent of data, risk assessment, and risk management is established. The new antibiotic efficacy guideline will significantly increase the licensing efforts for veterinary antimicrobials. There is the impression that a maximum of in vitro and in vivo studies are required by the guideline, which can be quite useful on their own, but which is not necessarily required in each case as a whole. For example, there is great advancement in pharmacokinetic/pharmacodynamic analysis to establish dose regimens and efficacious treatment schedules, which by all means can reduce dose-finding and dose-determination studies (Craig, 1998; Toutain et al., 2002). It will be difficult to justify the required data for line extensions of existing antimicrobial substances like improved formulations or additional indications and target species. This might be critical with respect to medicines availability. A clear differentiation in the requirement for new and established antimicrobial substances is absolutely required. A first step in the right direction is noted in the antimicrobial safety guideline as there is a differentiation between basic and additional information. The CVMP explanatory note to this guideline also calls for a flexible approach where an application relates to existing substances. However, this note should become an integral part of both guidelines. Another major deficiency of this guideline is the lack of criteria by which the study results can be assessed in view of the objective of the guideline, namely that the therapeutic regimen is aimed at to minimize the risk of selecting antimicrobial resistant bacteria.
ARTICLE IN PRESS A. Bo¨ttner / International Journal of Medical Microbiology 296 (2006) S2, 29–31
Conclusions In summary, both guidelines are welcomed by the animal health industry. However, requirements defined in the guidelines will significantly increase the licensing efforts for veterinary antimicrobials. In addition, the uncertainties during the regulatory approval process and the regulatory risk during the development are increased in the absence of risk assessment criteria. As a consequence, important product characteristics could be excluded from the product licence. Therefore, a fundamental review of the guidelines is required, especially in view of transparent risk assessment criteria and a flexible application and differentiated interpretation of the requirements. This would be an important pre-requisite and a reliable framework to continue the development of innovative antimicrobial products. The veterinarian requires a range of products for efficacious and differentiated antimicrobial therapy and limitations in antimicrobial therapy must be avoided (e.g. Escherichia coli infections in poultry).
References Anonymous, 2003. Guidance on the pre-approval information for registration of new veterinary medicinal products for
31
food producing animals with respect to antimicrobial resistance. VICH GL 27 (antimicrobial resistance: preapproval), www.fda.gov/cvm/Documents/guide144.doc (last accessed 20.11.2005). Craig, W.A., 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 26, 1–12. The European Agency for the Evaluation of Medicinal Products, 2002a. Committee for Veterinary Medicinal Products. Guideline on pre-authorisation studies to assess the potential for resistance resulting from the use of antimicrobial veterinary medicinal products (EMEA/ CVMP/244/01-Final). www.emea.eu.int/pdfs/vet/swp/ 024401en.pdf (last accessed 20.11.2005). The European Agency for the Evaluation of Medicinal Products, 2002b. Committee for Veterinary Medicinal Products. Guideline for the demonstration of efficacy for veterinary medicinal products containing antimicrobial substances (EMEA/CVMP/627/01-Final). http://www.emea.eu.int/pdfs/vet/ewp/062701en.pdf (last accessed 20.11.2005). Toutain, P.L., Del Castillo, J.R.E., Bousquet-Me`lou, A., 2002. The pharmacokinetic–pharmacodynamic approach to a rational dosage regimen for antibiotics. Res. Vet. Sci. 73, 105–114.