Masterarbeit

The New ICH Guideline ICH S5(R3) on Reproductive Toxicology on Medicinal Products for Human Use - Opportunities and Challenges for European Non-Clinical Drug Development ***

Dr. Ansgar Stüken (2019)

Summary
Language: English
The inception of life is by far the most complex physiologic procedure the nature invented. The complexity is represented by rapid changing processes of cell proliferation, differentiation and migration, organized and supported by intricate autocrine, paracrine and endocrine communication pathways including multiple positive and negative feedback mechanisms. The plethora of maturing processes is kaleidoscoped by the dynamic tripartite interplay of the maternal, placental and embryo-foetal surfaces and its variant, gestational-stage dependent anabolic and metabolic capacities Illustratively speaking, the embryo-foetal development can be viewed as a rapidly growing and subtly coordinated orchestra, where one sequence of tones constantly induces a more complex succession. Some dissonance may be concealed, but too noisy dissonances may be so sonorous that whole parts of the orchestra will never find back into the rhythm of life.
Clashing discords to the rhythm of life were caused by thalidomide leading to one of the most devastating medication catastrophes. The outstanding and soul-stirring severity of this calamity had engraved into history as the unborn life was predominately and irreversibly harmed. All in all, 10.000 - 12.000 severe birth defects were caused by maternal thalidomide consume between 1957 – 1962. Today, even after more than 50 years have passed, the thalidomide tragedy remains as a persistent shadowy nightmare for pregnancy medication and is still echoing as an epitome for drug risks and congenital malformations.
From the thalidomide disaster, serval epistemes of reproductive toxicity could be derived including compound-specific complexity, interspecies variability, time-dependent susceptibility and placental permeability. The illuminating findings led to new teratology concepts, which were translated in novel study design provisions that, in further progression completely changed the way of reproductive toxicity testing in pharmaceutical research.
The fast-emerging study protocols needed worldwide harmonization to avoid redundant testing also causing unnecessary animal sacrifices. Consequently, the ICH guideline on "Detection of Toxicity to Reproduction for Medicinal Products (S5)" was the first document to be endorsed from the ICH harmonization process in June 1993 representing the first major success of this organization. The core principles of this 26-year-old ICH S5 Guideline are still valid today. As self-evident, this long period of non-revision generates obsolete requirements due the evolution of scientific, technological and regulatory knowledge. Regarding their unique scientific history, characterized by a clear before&after of its thalidomide past, reproductive toxicity study designs seem to be arbitrary and may carry deficiencies because of its non-continuous evolution. Due to the surfaced shortcomings of the actual ICH S5(R2) guideline, a complete revision (R3) was drafted in March 2015. The emerged deficiencies of the timeworn guideline will be compared to the new revision and results will be critically discussed in this thesis.
Pages: 86