Modern science for better quality control of medicinal products "Towards global harmonization of 3Rs in biologicals": The report of an EPAA workshop.

This article summarizes the outcome of an international workshop organized by the European Partnership for Alternative Approaches to Animal Testing (EPAA) on Modern science for better quality control of medicinal products: Towards global harmonization of 3Rs in biologicals. As regards the safety testing of biologicals, the workshop participants agreed to actively encourage the deletion of abnormal toxicity tests and target animal batch safety tests from all relevant legal requirements and guidance documents (country-specific guidelines, pharmacopoeia monographs, WHO recommendations). To facilitate the global regulatory acceptance of non-animal methods for the potency testing of, e.g., human diphtheria and tetanus vaccines and veterinary swine erysipelas vaccines, international convergence on the scientific principles of the use of appropriately validated in vitro assays for replacing in vivo methods was identified as an overarching goal. The establishment of scientific requirements for new assays was recognized as a further means to unify regulatory approaches in different jurisdictions. It was recommended to include key regulators and manufacturers early in the corresponding discussions. Manufacturers and responsible expert groups, e.g. at the European Directorate for the Quality of Medicines and Health Care of the Council of Europe or the European Medicines Agency, were invited to consider leadership for international collaboration.

Incidence of bovine neonatal pancytopenia in 243 farms in Germany.

BACKGROUND: Several research groups from different European countries have worked on the aetiopathogenesis of bovine neonatal pancytopenia (BNP) and an association between the use of the vaccine PregSure BVD (Pfizer, Germany) and the development of this haemorrhagic disease was confirmed. Because BNP is not a notifiable disease, it is difficult to obtain information on its incidence. Based on pharmacovigilance (PhV) data, which are the only officially available data at the national level, the incidence of BNP is considered low. However, voluntary reporting of the disease can lead to underreporting. To gain more insight into the incidence of BNP among the affected herds, an epidemiological study was performed, which focused on 243 farms in Germany with cases of BNP. Farmers were asked to report the occurrence of BNP, including the number of cases, which allowed calculation of incidence in the affected herds. Matching such data with the registered cases in the National PhV System (NPhVS) gave us an opportunity to assess the extent of BNP underreporting. RESULTS: On 243 farms, a total of 1195 calves younger than 4 weeks with haemorrhagic diathesis were registered. In 58 % of the reports, a diagnosis of BNP was confirmed by blood analysis and or by necropsy. The number of cases observed on individual farms ranged from 1 to 80. Based on these results, the incidence of BNP on affected farms ranged from 0.3 to 15.2 % (median 2.9 %). The maximal incidence in the year with the highest number of BNP calves ranged between 0.4 and 18.6 % (median 3.3 %). Comparing the number of cases registered in the NPhVS to the numbers found in this study revealed considerable underreporting to the national database: only 44 % of the farms and 41 % of the BNP calves included in the study were registered in the NPhVS. CONCLUSIONS: In spite of the opportunity to report BNP calves to the Paul-Ehrlich-Institut (Langen, Germany), the estimated number of undetected BNP cases is remarkably high. However, even if the revealed substantial underreporting is taken into account, the incidence of BNP is low. Nevertheless, the incidence on some affected farms is very high, resulting in considerable financial losses that should not be underestimated. Although the exact pathomechanism of BNP at the molecular level is still not known, its incidence is clearly declining following withdrawal of PregSure BVD from the market.

Assessment of local reaction to vaccines in live piglets with magnetic resonance imaging compared to histopathology.

The safety of veterinary vaccines is assessed in clinical trials in Europe. The assessment of the local tissue reaction to vaccination by magnetic resonance imaging (MRI) could reduce the number of animals needed because repeated examinations can be performed in the same animal over time. The present study compared the evaluation of local tissue reactions to vaccination using MRI in live pigs with histopathology of porcine tissue, the current gold standard in regulatory safety testing. Eight piglets each were administered one of two commercial vaccines into marked injection sites. All animals were sedated and scanned repeatedly by MRI using a contrast agent up to day 29 after vaccination. On day 29, the animals were euthanized and underwent a pathological examination. The MRI results were compared with the pathomorphological findings at the injection site by regression analysis. The MR images and the pathological examinations yielded matching results concerning the sizes of the affected tissue volumes or areas. The use of MRI for regulatory safety testing can reduce the number of animals needed to 8 per examination group. The volume of a local reaction and its progression over time can be evaluated and documented. If persistent lesions develop a final pathomorphological examination is needed to identify the kind and local distribution of the reaction.

ECVAM's contributions to the implementation of the Three Rs in the production and quality control of biologicals.

A summary is presented of the activities initiated, and the progress achieved, between April 1993 and December 2001 in implementing the Three Rs in one of the main priority areas of the European Centre for the Validation of Alternative Methods (ECVAM) - the production and quality control of biologicals. These have included organising eight key workshops, and financial contributions to, and sponsorship of, relevant international workshops, symposia and conferences. Noteworthy activities include financial support and/or participation in a number of prevalidation and validation studies. These involved alternative methods for the batch potency testing of: human tetanus vaccines; human and veterinary tetanus antisera and immunoglobulin; rabies vaccines; Leptospira hardjo vaccines; Clostridium perfringens vaccines; and erysipelas vaccines. They also involved a cell culture test for specific toxicity testing of diphtheria toxoid vaccines. In addition, ECVAM funded a study on the use of humane endpoints for vaccine quality control tests involving severe suffering, such as the potency testing of erysipelas, rabies and pertussis vaccines. ECVAM has also contributed financially to the compilation of manuals and expert reports, and to training in test methods. Following the report of an ECVAM Task Force, ECVAM financially supported the prevalidation of some in vitro methods for the potency testing of a recombinant hormone. A proposal is presented for promotion of regulatory acceptance, and suggestions are made for possible future activities.