Masterstudiengang "Drug Regulatory Affairs"


Replacement of In Vivo ATC Studies by In Vitro Cytotoxicity Methods

Ute Ukelis (Abschlußjahr: 2005)

The trend to in vitro assays for determining acute toxicity is positive. However, in order to achieve higher precision as well as independency from confirming tests, more data from broader studies are needed.
Concerning the results of is thesis based on data from Merck, the following observations are stated:

  • The correlation rate of LD50 values with established cell lines, i.e. HepG2 and FAO, is higher than with primary rat cells
  • ATP and WST are suitable parameters for determining acute toxicity
  • 24 and 48 hour assays are necessary to adequately detect toxic effects
  • appropriate prediction of low toxicity classes, thus for dose finding for further studies
  • poor prediction for high toxicity classes, but not relevant for most of the pharmaceutical products
  • Outliers possible, i.e. single cases of false positive or false negative values compared to LD50
  • conformity with RC is given: trend, prediction, known classes of outliers

If standardized in vitro methods are employed, the four aims of ICH M3, as described in 'Regulatory Status', can be achieved:

  • differences in the preclinical concepts of the ICH regions can be eliminated
  • provision of new medicinal products is ensured, because the industry is able to work more efficiently, i.e. more active substances can be tested and led through the regulatory process in shorter periods
  • reasonable use of animals is given when reducing or replacing animal tests
  • safe and ethical development increases with continuous replacement of in vivo studies

At present, there are different requirements of regulatory authorities in the ICH regions regarding acute toxicity testing, as outlined in 'Regulatory Status'. This still binds companies to conduct additional trials, if marketing authorisations are planned for several regions. Consequently, the perspective of a common approach in the sense of harmonisation would be welcome. Moreover, in light of animal welfare as well as for the benefit of efficient yet safe drug development, in vitro techniques should be validated and implemented in regulatory guidelines.

Pages: 36,
Annexes 14