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Workshop summary: Antiparasitic testing guidelines
veterinary parasitology ELSEVIER
Veterinary Parasitology 54 (1994) 317-319
Workshop summary: Antiparasitic testing guidelines Chairman: V.J. T h e o d o r i d e s SmithKline Beecham Animal Health, West Chester, PA 19380, USA
This workshop on 'Antiparasitic Testing Guidelines' covers a topic of great importance. Guidelines will only be acceptable world-wide under any circumstance when they do not contain ambiguous advice that can be interpreted in a variety of ways. This workshop brought together experts from different parts of the world, academia, industry, and regulatory agencies. They should help to spearhead the development of one guideline, with elements and flexibility of individual country idiosyncrasies which should satisfy the world's regulatory needs. Guidelines prepared with this mixed group of experts should serve a useful function throughout the world, avoiding unnecessary duplication, waste of time and resources. W.A.A.V.P. is the catalytic force for this innovation. It should provide the milieu for continuous discussion until the regulatory agencies are committed to mutual acceptance of data which ensures that well-conducted studies, following a valid protocol will be acceptable by all world-wide regulatory agencies. Dr. G. Blanchard (Bureau of Veterinary Drugs, Canada) said that before any new drug can be sold in Canada, the sponsor must file a New Drug Submission (NDS). The NDS must provide evidence that use of the drug in animals presents no demonstrable risk to human health, in that foods derived from treated animals must be free of potential, harmful residues. In addition, the NDS must provide substantial information on the manufacture, as well as substantial evidence of drug efficacy and safety in the target animal. It was stated that anticoccidial agents must not interfere with growth and feed conversion in poultry. In Canada, efficacy data from controlled battery trials (mixed and single coccidial infections), from controlled floor pen studies, and from field trials for under use conditions, are required. Dr. T. Letonja (Centre for Veterinary Medicine, USA) said that harmonisation of registration requirements for animal drugs would prevent costly and unnecessary duplications in data generation. These advantages would include the elimination of unnecessary testing of animals, facilitation of international trade, and the increased availability of safe and effective animal drugs world-wide. In 0304-4017/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSD10304-4017 (94) 03099-I
318
V.J. Theodorides / Veterinary Parasitology 54 (1994) 317-319
the United States, the administration of regulations pertaining to animal drugs is the responsibility of the Food and Drug Administration's Centre for Veterinary Medicine (CVM). CVM accepts foreign, non-clinical safety studies for New Animal Drug Applications, but they must comply with Good Laboratory Practice rules. Foreign clinical trials are not exclusively accepted as a demonstration of drug effectiveness. These trials may, however, serve as either pivotal or corroborative studies which may be used as at least a portion of the basis at approval. At least one pivotal efficacy study must be conducted in the United States. CVM recommends that sponsors of new animal drugs submit detailed protocols for review and comments, and reach agreement with CVM before starting studies. Three testing phases are recommended for evaluating the effectiveness of new antiparasitic agents. The first phase is dose titration to demonstrate a dose response; the second phase is dose confirmation where large studies under tightly controlled conditions verify the target dose; the third phase is the clinical field trials where the drug in its final formula is tested in a variety of commercial and geographical conditions following the proposed label recommendations. Guidelines for testing anthelmintics and anticoccidial drugs can be obtained from CVM. CVM believes that information sharing, such as through the W.A.A.V.P. Workshop, will enable the agency to work toward harmonisation of data requirements. Dr. R.D. Sykes, registrar for Stock Remedies in South Africa, presented procedures for approval of ectoparasiticides. It was stated that the African situation is unique in the number and variety of parasites and the harsh climate with its extremes of heat and cold, drought and floods. For this reason, special efforts must be made to ensure that the development of the product is thorough and its use will be easy to understand and apply. The agency has prepared a number of procedures and standards (guidelines) for the approval of ecto- and endo-parasiticidal drugs. The agency will accept foreign human safety studies, but efficacy, drug stability, and certain target animal safety studies must be performed in South Africa. Dr. N. Taira (National Institute Animal Health, Japan) stated that antiparasitic drugs for animals are under the jurisdiction of the Ministry of Agriculture, Forestry and Fishery. Initial testing for efficacy is carried out in the laboratory using laboratory or target animals. Follow-up work is performed in the field with animals infected either artificially or naturally. In these trials standardised parasitological procedures must be used. There must be untreated control and several treatment groups. Egg counts, as well as worm counts, must be performed. All adverse reactions of the treated animals must be recorded. The results must be generated in accordance with GLP rules and must be analysed statistically. Dr. G.C. Coles (Central Veterinary Laboratory, UK) discussed ( 1 ) detection of anthelmintic resistant nematodes and (2) the European Community proposed antiparasitic testing guidelines. The only definitive method to determine the presence of anthelmintic resistant nematodes is a dose and slaughter trial. The faecal egg count reduction test (FECRT) and egg hatch test (EHT) are recommended by the W.A.A.V.P., but these tests are not reliable if less than 25% of the worms are resistant. The FECRT has given false negative results with ivermectin
V.J. Theodorides / Veterinary Parasitology 54 (1994) 317-319
319
in Scotland. The EHT is a fast, inexpensive method of detecting benzimidazole resistance. There is a need for more reliable testing methods. The Efficacy Working Group, a subcommittee of the Veterinary Medicinal Product (CVMP) has already published draft antiparasitic testing guidelines for the European Community. The following guidelines are available: General Requirements for the Demonstration of Efficacy of Anthelmintics in swine, bovine, ovine, equine, cats and dogs, anticoccidials in poultry, and parasitosis in honey bees. It was stated that CVMP consults with representatives of the pharmaceutical industry prior to issuing the final guidelines. The general requirement for anthelmintics is 90% efficacy. No claim is allowed under 70% activity. The recommended phases for drug development are: ( 1 ) indication of mode of action; (2) titration of dose trials; (3) dose confirmation; (4) clinical field trials. The guideline indicates that pharmacokinetic and pharmacodynamics claimed in the laboratory must be evaluated in the target animal and parasite species. Dose titration studies at 0, 0.5, 1 and 2 times the anticipated recommended dose must be performed. At least two confirmation trials under different experimental conditions should be performed. Clinical field trials are required from two different geographical locations. If claims are to be made against resistant parasites, trials must be performed to demonstrate that the new drug is effective against resistant populations. While results of dose titration and dose confirmation trials are acceptable, irrespective of where they are carried out, member states may ask for additional clinical field trials performed under their conditions. Dr. D.E. Jacobs (University of London, UK) stated that the W.A.A.V.P. guidelines for evaluating the efficacy of anthelmintics for dogs and cats are in draft stage. These guidelines are prepared in the same format as previously published guidelines. Dose titration, dose confirmation and clinical trials are required. Animal welfare is emphasised throughout. It is hoped that these guidelines will provide a basis for uniform international standards. Dr. I.B. Wood appraised the workshop on the revisions of the ruminant anthelmintic testing guidelines. This guideline contains specific procedures for the determination of efficacy against anthelmintic resistant parasites. Also, new procedures for evaluating prophylactic anthelmintic systems have been included in the guidelines. These guidelines were sent to several regulatory agencies for evaluation and comments before being sent for publication. It became clear that this workshop had demonstrated a paradigm shift by regulatory agencies because all the opposing views were canvassed before, instead of after, the guidelines were drafted and published.
Veterinary Parasitology 54 (1994) 317-319
Workshop summary: Antiparasitic testing guidelines Chairman: V.J. T h e o d o r i d e s SmithKline Beecham Animal Health, West Chester, PA 19380, USA
This workshop on 'Antiparasitic Testing Guidelines' covers a topic of great importance. Guidelines will only be acceptable world-wide under any circumstance when they do not contain ambiguous advice that can be interpreted in a variety of ways. This workshop brought together experts from different parts of the world, academia, industry, and regulatory agencies. They should help to spearhead the development of one guideline, with elements and flexibility of individual country idiosyncrasies which should satisfy the world's regulatory needs. Guidelines prepared with this mixed group of experts should serve a useful function throughout the world, avoiding unnecessary duplication, waste of time and resources. W.A.A.V.P. is the catalytic force for this innovation. It should provide the milieu for continuous discussion until the regulatory agencies are committed to mutual acceptance of data which ensures that well-conducted studies, following a valid protocol will be acceptable by all world-wide regulatory agencies. Dr. G. Blanchard (Bureau of Veterinary Drugs, Canada) said that before any new drug can be sold in Canada, the sponsor must file a New Drug Submission (NDS). The NDS must provide evidence that use of the drug in animals presents no demonstrable risk to human health, in that foods derived from treated animals must be free of potential, harmful residues. In addition, the NDS must provide substantial information on the manufacture, as well as substantial evidence of drug efficacy and safety in the target animal. It was stated that anticoccidial agents must not interfere with growth and feed conversion in poultry. In Canada, efficacy data from controlled battery trials (mixed and single coccidial infections), from controlled floor pen studies, and from field trials for under use conditions, are required. Dr. T. Letonja (Centre for Veterinary Medicine, USA) said that harmonisation of registration requirements for animal drugs would prevent costly and unnecessary duplications in data generation. These advantages would include the elimination of unnecessary testing of animals, facilitation of international trade, and the increased availability of safe and effective animal drugs world-wide. In 0304-4017/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSD10304-4017 (94) 03099-I
318
V.J. Theodorides / Veterinary Parasitology 54 (1994) 317-319
the United States, the administration of regulations pertaining to animal drugs is the responsibility of the Food and Drug Administration's Centre for Veterinary Medicine (CVM). CVM accepts foreign, non-clinical safety studies for New Animal Drug Applications, but they must comply with Good Laboratory Practice rules. Foreign clinical trials are not exclusively accepted as a demonstration of drug effectiveness. These trials may, however, serve as either pivotal or corroborative studies which may be used as at least a portion of the basis at approval. At least one pivotal efficacy study must be conducted in the United States. CVM recommends that sponsors of new animal drugs submit detailed protocols for review and comments, and reach agreement with CVM before starting studies. Three testing phases are recommended for evaluating the effectiveness of new antiparasitic agents. The first phase is dose titration to demonstrate a dose response; the second phase is dose confirmation where large studies under tightly controlled conditions verify the target dose; the third phase is the clinical field trials where the drug in its final formula is tested in a variety of commercial and geographical conditions following the proposed label recommendations. Guidelines for testing anthelmintics and anticoccidial drugs can be obtained from CVM. CVM believes that information sharing, such as through the W.A.A.V.P. Workshop, will enable the agency to work toward harmonisation of data requirements. Dr. R.D. Sykes, registrar for Stock Remedies in South Africa, presented procedures for approval of ectoparasiticides. It was stated that the African situation is unique in the number and variety of parasites and the harsh climate with its extremes of heat and cold, drought and floods. For this reason, special efforts must be made to ensure that the development of the product is thorough and its use will be easy to understand and apply. The agency has prepared a number of procedures and standards (guidelines) for the approval of ecto- and endo-parasiticidal drugs. The agency will accept foreign human safety studies, but efficacy, drug stability, and certain target animal safety studies must be performed in South Africa. Dr. N. Taira (National Institute Animal Health, Japan) stated that antiparasitic drugs for animals are under the jurisdiction of the Ministry of Agriculture, Forestry and Fishery. Initial testing for efficacy is carried out in the laboratory using laboratory or target animals. Follow-up work is performed in the field with animals infected either artificially or naturally. In these trials standardised parasitological procedures must be used. There must be untreated control and several treatment groups. Egg counts, as well as worm counts, must be performed. All adverse reactions of the treated animals must be recorded. The results must be generated in accordance with GLP rules and must be analysed statistically. Dr. G.C. Coles (Central Veterinary Laboratory, UK) discussed ( 1 ) detection of anthelmintic resistant nematodes and (2) the European Community proposed antiparasitic testing guidelines. The only definitive method to determine the presence of anthelmintic resistant nematodes is a dose and slaughter trial. The faecal egg count reduction test (FECRT) and egg hatch test (EHT) are recommended by the W.A.A.V.P., but these tests are not reliable if less than 25% of the worms are resistant. The FECRT has given false negative results with ivermectin
V.J. Theodorides / Veterinary Parasitology 54 (1994) 317-319
319
in Scotland. The EHT is a fast, inexpensive method of detecting benzimidazole resistance. There is a need for more reliable testing methods. The Efficacy Working Group, a subcommittee of the Veterinary Medicinal Product (CVMP) has already published draft antiparasitic testing guidelines for the European Community. The following guidelines are available: General Requirements for the Demonstration of Efficacy of Anthelmintics in swine, bovine, ovine, equine, cats and dogs, anticoccidials in poultry, and parasitosis in honey bees. It was stated that CVMP consults with representatives of the pharmaceutical industry prior to issuing the final guidelines. The general requirement for anthelmintics is 90% efficacy. No claim is allowed under 70% activity. The recommended phases for drug development are: ( 1 ) indication of mode of action; (2) titration of dose trials; (3) dose confirmation; (4) clinical field trials. The guideline indicates that pharmacokinetic and pharmacodynamics claimed in the laboratory must be evaluated in the target animal and parasite species. Dose titration studies at 0, 0.5, 1 and 2 times the anticipated recommended dose must be performed. At least two confirmation trials under different experimental conditions should be performed. Clinical field trials are required from two different geographical locations. If claims are to be made against resistant parasites, trials must be performed to demonstrate that the new drug is effective against resistant populations. While results of dose titration and dose confirmation trials are acceptable, irrespective of where they are carried out, member states may ask for additional clinical field trials performed under their conditions. Dr. D.E. Jacobs (University of London, UK) stated that the W.A.A.V.P. guidelines for evaluating the efficacy of anthelmintics for dogs and cats are in draft stage. These guidelines are prepared in the same format as previously published guidelines. Dose titration, dose confirmation and clinical trials are required. Animal welfare is emphasised throughout. It is hoped that these guidelines will provide a basis for uniform international standards. Dr. I.B. Wood appraised the workshop on the revisions of the ruminant anthelmintic testing guidelines. This guideline contains specific procedures for the determination of efficacy against anthelmintic resistant parasites. Also, new procedures for evaluating prophylactic anthelmintic systems have been included in the guidelines. These guidelines were sent to several regulatory agencies for evaluation and comments before being sent for publication. It became clear that this workshop had demonstrated a paradigm shift by regulatory agencies because all the opposing views were canvassed before, instead of after, the guidelines were drafted and published.