Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Replace, Reduce, Refine - Recent Developments in Alternative Testing Methods in Pharmaceutical Toxicology and their Regulatory Acceptability in the EU ***

Dr. Sandra Mahr (Abschlußjahr: 2018)

Summary
Language: English
In the past decades, there was significant progress in biological and medical research as well as in pharmaceutical and chemical development, also based on animal testing. To date, millions of animals are used every year in biological and medical research as well as in pharmaceutical development. Medicinal products and chemicals need to undergo toxicological tests before they can seek marketing authorisation, and their potential toxicity is mainly investigated in vivo as requested by the regulatory legislation and guidelines.    
However, a rethinking has begun driven by both ethical and financial aspects. The principle of the 3Rs aiming at the replacement, reduction and refinement of animal tests has been introduced in the late 1950s and has already been incorporated in the European regulatory legislation. Therefore, the industry is requested to implement the principle of the 3Rs into their development programs. During the last 20 years, some exciting advances have been made such as organoids ("organ-in-a-dish"), microphysiological systems ("organs-on-a-chip"), "omics" technologies (e.g. "gene chips"), and in-silico tools. However, most of these technologies have not reached full regulatory acceptance so far, except for in-silico models that have already been used for toxicity estimations in registration dossiers of pharmaceuticals.
To date, although promising technologies have been developed, a broad adoption of alternative testing methods by the pharmaceutical industry is still missing. Pharmaceutical companies mainly prefer to rely on long-established animal models and shy to introduce alternative testing methods, which are not yet fit for regulatory purposes. International programs fostering the principle of the 3Rs such as EU-ToxRisk involving all stakeholders need to be expanded and continued to accelerate the implementation process of alternative testing strategies into drug development. A promising example is the process for revision of the ICH guidance S1A involving both the industry and regulatory authorities. The results of this project may lead to the conclusion that 2-year carcinogenicity studies in rodents could be waived in most cases and that the carcinogenic potential of pharmaceuticals could be predicted based on long-term toxicity data. Projects like this make confident that the implementation process of the 3Rs in regulatory testing is in progress.
However, sharing and publication of scientific data by academia and industry as well as a close cooperation with regulatory authorities are needed to further accelerate the implementation process of the 3Rs in regulatory toxicity testing. If all stakeholders pull together, a broad implementation of alternative testing methods in regulatory toxicity testing is within reach.
Pages: 66, Annexes: 1 Pages: 23