Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Evaluation of Genotoxicity and Carcinogenicity Assessments of Veterinary Medicinal Products Licensed via the European Centralised Procedure ***

Dr. Niels Krebsfänger (Abschlußjahr: 2010)

Language: English

Evaluation of the genotoxic and carcinogenic potential is a key component within the safety assessment of an investigational medicinal product for human or veterinary use. This is mirrored by a wealth of respective ICH and VICH guidelines. These guidelines define a standard 3-test battery for genotoxicity assessment as well as lifespan rodent bioassays for assessment of carcinogenicity. However, there is continued discussion in the scientific and regulatory community questioning the predictivity and relevance of the recommended test methods, in particular of the in vitro mammalian cell genotoxicity tests and the need for a second rodent species for carcinogenicity assessment.

From the regulatory perspective, a key question is which information drives the final conclusion regarding genotoxicity and carcinogenicity, i.e. which studies have the potential to lead to regulatory action in terms of refusal of application, restriction of proposed indications or warnings and precautions on the Summary of Product Characteristics (SmPC).

This question has previously been discussed for human medicinal products (HMP). To shed some light on this question also for veterinary medicinal products (VMP), all 102 veterinary public assessment reports resulting from the European centralised procedures (CP) completed until end of 2009 were evaluated in terms of genotoxicity studies conducted, results concluded, and overall conclusion by CVMP. Similarly, the public assessment reports were searched for carcinogenicity studies conducted, results concluded and overall CVMP conclusion.

In total, 102 veterinary CP have been completed until end of 2009. In 98 cases marketing authorizations were granted, in 3 cases the application was withdrawn after day 120 of the procedure and in 1 case marketing authorization was refused, notably because of concerns with regard to target animal safety due to potential genotoxicity. Of the 98 approved VMP, 8are generics (all meloxicams) and therefore were not required to (re)assess genotoxic or carcinogenic potential. Another 44 of the approved VMP are vaccines / immunologicals (IVMP) also not requiring any genotoxicity or carcinogenicity assessment. Accordingly, there are 46 centrally authorized VMP remaining for which a genotoxicity and carcinogenicity assessment was required. Of these, 32 are companion animal products (CAP) while 14 are food animal products (FAP). These 46 VMP and the 4 non-approved products were evaluated with regard to genotoxicity and carcinogenicity assessments. They comprise 53 different active ingredients.

From the evaluation of the respective public assessment reports 4 key conclusions can be drawn with regard to genotoxicity and carcinogenicity testing:

• Genotoxicity and carcinogenicity testing and the respective CVMP assessments do not differ between CAP and FAP. The present evaluation clearly shows that the type and frequency of studies conducted (85% Ames, 70% CA / 32% MLA / 32% HPRT, 19% CA in vivo / 74% MNT and 32% mouse and 40% rat carcinogenicity studies) as well as the "stringency" of the CVMP assessments were basically identical for CAP and FAP.
• Positive findings in the in vitro mammalian cell genotoxicity tests (CA, MLA) rarely resulted in regulatory action because of their known tendency to produce false positive responses and the overall weight-of-evidence conclusion, in particular when supported by negative in vivo genotoxicity studies. Thus, the revisions proposed for HMP in ICHS2(R1) with regard to i) a lower maximum test concentration in in vitro mammalian cell genotoxicity tests and ii) an alternative standard battery without the need for an in vitro mammalian cell genotoxicity test should be considered as well in VICH GL23 for VMP.
• In none of the assessments evaluated the mouse carcinogenicity study changed the overall CVMP conclusion. It would appear appropriate to generally waive the second species (mouse) in carcinogenicity testing of VMP and, in case of findings in the rat, call for mechanistic follow-up studies rather than a second lifetime rodent bioassay. At least, VICHGL28 should be aligned with ICH S1B in terms of offering the alternative use of short or medium term in vivo rodent systems.
• None of the 46 relevant SmPC contains any information with regard to genotoxicity or carcinogenicity testing; notably, also not in case of inconclusive or positive tests or even CVMP conclusions.

It will be interesting to see whether any of these aspects will be picked up in future revisions of the veterinary legislation or guidelines and under which circumstances information on genotoxicity or carcinogenicity will for the first time be contained in a veterinary SmPC.

Pages: 66 (incl. annex of 11 pages)