Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Nonclinical assessment of immunotoxicity in the EU, United States, and Japan ***

Dr. Rainer Paffenholz (Abschlußjahr: 2005)

Language: English

The exposition of human body to pharmaceuticals can lead to unintended and in some cases even life-threatening changes in the functionality of the immune system. These effects are summarized as immunotoxicity and can best be divided into four categories, namely immunosuppression, immunostimulation, hypersensitivity, and autoimmunity.

Over the past ten to fifteen years, immunotoxicity has gained increasing attention by the regulatory authorities as a serious issue in drug development. By the beginning of this decade, the EU, US, and Japan were working on guidance documents for the preclinical assessment of immunotoxicity. Although these efforts ran in parallel, the requirements differ between the three regulatory regions. While the EMEA has included recommendations for direct immunotoxicity in the guideline on repeated dose toxicity, the FDA has released the final version of a guideline on the “Immunotoxicology evaluations of Investigational New Drugs” in 2002. Japan is still in the process of finalization of a draft guideline.

Currently, predictive immunotoxicity testing is mainly embedded in the context of general toxicity assessment. All three guidance documents are based on the concept of a tiered approach, also some differences exist in the sequence of the tests and the acceptance of some assays.
Routine testing in all regions consists of haematology, histopathology, and weight determination of lymphoid organs. It is still a matter of discussion whether functional testing should be included into routine testing. Currently, only the European authorities require the inclusion of functional tests in first line immunotoxicity screening in addition to enhanced histopathology examination, while FDA and MHLW advocate case-by-case approaches to decide on the need for functional assays.

A major step to reach a standardisation in regulatory requirement was reached in 2004 when an ICH draft guideline for nonclinical immunotoxicity testing was published. This guideline will be a major step in standardization of regulatory requirements for immunotoxicity and streamline the development of new drugs for global markets. It is focused on recommendations for the assessment of immunosuppression only. Basically, it confirms the tiered approach that is being used in immunotoxicity testing for a long time. Functional assays are not requested for all drugs. Instead, the guideline provides detailed advice for information to be considered for a decision on additional studies or follow-up immunotoxicity testing.

In all three regulatory regions, little or no regulatory advice is given for the proper nonclinical assessment of drug induced hypersensitivity and autoimmunity, most likely the most serious manifestations of immunotoxicity. This reflects a fundamental lack in understanding the biological mechanisms of drug induced Hypersensitivity/Autoimmunity, and hence the lack of reliable test systems. More research is needed to close this gap.

Another field that will receive more regulatory attention is the assessment of developmental immunotoxicity. Embedded in a general tendency to address the special requirements of drug development for children and adolescents, regulatory guidance is now developed for the assessment of adverse drug effects on the developing immune system.

Pages: 39