Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

News in nonclinical evaluation of anticancer pharmaceuticals: ICH Guideline S9 and beyond ***

Thomas Hengelage (Abschlußjahr: 2010)

Advanced cancer is defined as a heterogenic cluster of malignant tumor types that are life-threatening for the patients affected, associated with a high death rate, and at the same time leave patients suffering from these malignancies with very limited treatment options. It is necessary to distinguish advanced cancer according to this definition and pharmaceuticals intended to treat this subgroup of cancer from pharmaceuticals intended for treatment of other forms of cancer e.g. adjuvant therapies, prophylactic treatments, or for treatment of side effects of anticancer drugs. Because advanced cancer patients may only have a very limited life-expectancy from less than six months up to three years, the benefit of a drug intended for treatment of advanced cancer can be immediately life-prolonging. Consequently, many long-term effects of drugs which are part of the general nonclinical evaluation may be either dispensable or deferrable either due to the short life-expectancy of this target patient population, i.e. long-term toxicity testing or carcinogenicity studies may not provide relevant information because the use of the anticancer drug in many cases may be of rather limited duration.

In the past, the potential risks potentially associated with a new pharmaceutical have largely determined the requirements for its nonclinical evaluation, probably not putting adequate weight on the potential benefits for certain patient populations with advanced disease and limited treatment options like patients with advanced cancer.

The new guidance ICH S9 should allow certain streamlining of nonclinical evaluations of anticancer pharmaceuticals intended for use in advanced cancer. Compared to past nonclinical development programs, drug developers and applicants for marketing authorization could save a considerable amount of time, money, and last but not least animal resources to support their application dossiers when applying the principles and guidance that is provided in the new ICH S9 guideline. This is due to the following features of this new guideline:

1. 1. Providing an ICH guideline with harmonized requirements for nonclinical development of anticancer pharmaceuticals intended for use in patients with advanced cancer in the three ICH regions
2. 2. Inclusion of both, small molecules and biotechnology-derived drugs into the scope of a single guideline
3. 3. More specifically: by generally abandoning the need for 6 month and 9 month repeat dose general toxicity studies (3 months for rodents and nonrodents are deemed sufficient), carcinogenicity studies, and fertility and peri- and postnatal reproduction toxicity trials and by defining the need for only a single species embryo-fetal development study if the study is positive for teratogenicity or embryo-fetal lethality
4. 4. Further, by allowing to include many endpoints for assessment, e.g. of fertility, immunotoxicity, safety pharmacology within the framework of well-designed general toxicology studies
5. 5. Finally, by more precisely defining the evaluations needed prior to starting clinical development, e.g. for small-molecule, genotoxic drugs targeting rapidly dividing cells a single repeat dose study in rodents only can be sufficient, and accordingly, showing recovery is also needed only for a single species prior to Phase I clinical trials.
6. 6. By including specific guidance on the nonclinical dosing schedules that would support corresponding clinical schedules, thus reducing the need to seek scientific advice.

In addition, due to the clarity and more specific language that is used in many places of the guideline (e.g. schedule table for nonclinical schedules to be used for assessments of certain clinical schedules, clarification on recovery groups to be utilized in the general toxicity studies), the need for frequent discussions with regulators may no longer be as prominent, potentially leading to further savings in development time because less meetings for clarification of requirements for nonclinical evaluation of drugs intended for use in advanced cancer may be necessary to develop a drug for the initial NDA/MAA.

Total pages: 50, including Annex; Annex: pages 37-49