Masterarbeit

Developing biopharmaceuticals - Regulatory aspects of the safety evaluation of monoclonal antibodies in the United States and in Europe ***

Dr. Alexander Kainz (2001)

Monoclonal antibodies (mAbs) have become an important class of biotechnology-derived pharmaceuticals. MAbs are homogeneous populations of antibodies, all of precisely the same specificity towards an epitope (antigen). Newer methods of making antibodies, the humanisation of mouse mAbs, and new types of antibody fragments have increased their therapeutic potential with cancer and transplantation being areas of intense interest for the mAb approach.

Regulatory guidance on the pharmacological-toxicological evaluation of mAbs is available from the ICH, the FDA and the EMEA. While the ICH guideline provides excellent coverage of the general principles of safety evaluation of biopharmaceuticals, there are several issues that are unique to mAbs that require special consideration. These are: the pivotal role of in vitro tissue binding, the specificity of epitope binding, the pharmacodynamic effects attributed to Fc binding, the unique ability of mAbs to target a subset of cells, the possibility of trans-placental passage, and the potential for long-term clinical adverse events.

Studies which provide useful information for the pre-clinical safety evaluation of mAbs include in vitro cross-reactivity studies in human and animal tissue, single-dose pharmacokinetics, repeat-dose toxicity studies and immunogenicity studies. In selected cases, reproduction toxicology studies may need to be performed.

Genotoxicity and conventional two-year carcinogenicity studies are not usually appropriate, nor are classical tissue distribution, metabolism and excretion studies.

The analysis of European Public Assessment Reports on mAbs confirmed that the pre-clinical testing programme for monoclonal antibodies is designed on a case-by-case basis. A step-by-step approach and a continued dialogue with the regulatory agencies are mandatory. Not all pre-clinical studies are conducted because of scientific rationale. Some studies are conducted because of the perceived regulatory expectations or requests from ethics committees. The possibilities to evaluate the toxicity profile of monoclonal antibodies may be restricted when using the conventional approach. New technologies e.g., genetically modified animals and analogous models need to be implemented in the testing programme.

Companies developing mAbs need to take into account the differences that exist between the US and Europe. The FDA regulatory framework offers unique opportunities for companies to accelerate marketing approval such as the early designation of fast-track candidates and priority review. As a consequence, to date, FDA approval of mAbs is considerably faster compared to antibody approval in Europe. Therefore the key imperative for a European company developing mAbs is to familiarise itself with the US legislative structure and the philosophy of the FDA with respect to drug regulation.

However, in a global development programme the requirements of the FDA must be balanced against those of the EU and other key markets. The modification of the existing European legislation as proposed by the European Commission e.g., the implementation of a 'fast track procedure' is promising and will be a key area to watch in Europe the coming years. To date, applying for marketing applications under 'exceptional circumstances' is a valid registration strategy for European companies developing mAbs in order to achieve the shortest possible development time until marketing of the mAb.

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