Masterstudiengang "Drug Regulatory Affairs"
Master-Thesis
The New ICH-Guideline S11 on Nonclinical Safety Testing - Opportunities and Challenges for Overall Development of Paediatric Medicine ***
Dr. Ramsi Siaj (Abschlußjahr: 2021)
Summary
Language: English
With the introduction of paediatric specific legislation, the paediatric drug development has become a compulsory part of the adult drug marketing application in North America and Europe. Since then, the nonclinical drug development programmes tailored to children have gained in importance. The conduct of additional nonclinical toxicity studies can be justified to get knowledge about potentially different safety profiles from those seen in adults. However, the appropriate EU, US guidance and even ICH M3 do not provide clear guidance to the need and design of such studies. These lack of further guidance and harmonisation facilitated the conduct of similar animal studies between regulatory regions without substantial added value and hampered a preferably quick and wide availability of medicines for children. To overcome these challenges the ICH issued the new safety guideline Nonclinical Safety Testing in Support of Development of Paediatric Pharamceuticals, also called ICH S11.
The aim of the ICH S11 is to set "international standards for, and promote harmonisation of, the nonclinical safety assessments to support the development of pharmaceuticals intended for paediatric use" (ICH S11).
The aim of this master thesis is a critical review of ICH S11’ guidance on nonclinical safety testing and their consequences for the overall development of paediatric medicines.
For this purpose, the scope of the guidance, the new decision-making tool for determining the need of additional nonclinical safety studies (i.e., Weight of Evidence (WoE) review) was considered as well as alternatives to juvenile animal studies (JAS), the approach of dose range finding studies, and the consequences, value and timing of JAS and the recommendations to the paediatric-first/only development.
Taken together, the ICH S11 surpasses by far already existing paediatric nonclinical safety guidelines regarding the extent and depth of provided information. Above all, this includes its appendices, i.e., a high-level overview of age dependent development of organ systems by species and table a to principal advantages and disadvantages of various mammalian species for use in JAS. This information should assist in the identification of potential safety concerns, the choice of species and the timing of JAS to corresponding clinical treatment. Particularly noteworthy is ICH S11’ newly decision-making tool, i.e., the WoE review. The WoE review should be performed to determine whether additional nonclinical safety studies are warranted (or not). Beside clear decision criteria, the ICH S11 provides four single cases to ensure the most standardised approach possible. The study objectives should be aligned with the WoE outcome and the intended paediatric use. Furthermore, unlike to the appropriate US and EU guidance the ICH S11 set standards to medicines initially developed for paediatric use (i.e., paediatric-only/first development).
However, the discussion of the results has led to the following suggestions:
- The extension of the WoE review to all kinds of pharmaceuticals (as scientifically applicable for all pharmaceuticals) and the paediatric-first/only development (as under certain circumstances fewer animal studies than recommended can be warranted).
- The adjustment of two WoE factors to sharpen a single case consideration (away from probable estimation).
- Generally, the implementation of more effective measures which could result in regulatory accepted alternative approaches to JAS (which could, in turn, lead to neglected therapeutic needs in more drug development programmes).
- A new concept to determine an acceptable timing of JAS (how to determine an acceptable timing remains unknown).
- The implementation of a phased DRF approach with preweaned animals (as JAS to corresponding paediatric population is particularly challenging and relatively often requested (2 ≤ years of age)).
Pages: 84
Annexes: 1, Pages: 10