Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Evaluation of Carcinogenicity Studies of Medicinal Products for Human Use authorized via the Centralized Procedure (2010 - 2017) ***

Sandra Wagner (Abschlußjahr: 2018)

Summary
Language: English
European Medicine Agency (EMA) publishes all European public assessments reports (EPAR) and corresponding documents as e.g. SmPC, assessment history of centralized assessed medicinal products regardless their current status (approved/suspended/refused/withdrawn) on their website. EPARs and if applicable corresponding documents of medicinal products, which gained marketing authorization between 2010 and 2018 were reviewed and efforts by the applicant to evaluate the carcinogenic potential of medicinal products were analyzed. The following data were recorded: general data, data concerning repeated dose toxicity studies (hyperplastic / tumorigenic findings), data concerning carcinogenicity bioassays (e.g. study design, findings) including rationale if no carcinogenicity studies have been performed, results of genotoxicity assessments and neoplastic undesirable effects listed in section 4.8 in SmPC.
By August 2018 557/614 (87%) initially authorized medicinal products continued to hold a marketing authorization. No carcinogenicity studies have been performed in compliance with legislation for generic medicinal products (n=156), biosimilar medicinal products (n=28), medicinal products with informed consent applications (n=31) and in compliance with EMA guideline for fixed combination preparations regardless of their legal base (n=52). For hybrid application (n=33) results of bioassays described in the literature are presented in same cases in the EPAR. Even (n=75) standard carcinogenicity bioassays are generally inappropriate for biotechnology-derived medicinal products according to current ICH guideline S6 (R1), an evaluation of their neoplastic potential is needed in case of concern, which was the case in 9.6 % (n=7). Excluding biotechnology-derived medicinal products (based on their eligibility for centralized procedure) in 104 out of 229 cases (45.4 %) carcinogenicity bioassays with the active substance have been conducted by the applicant. For the number of 57 out of 104 cases (54.8 %) a traditional/conventional strategy (long-term carcinogenicity bioassay in rat & mice) was chosen; and for  31 out of 132 (26 %) medicinal products an ICH recommended alternative approach (one  long-term carcinogenicity study in rat and a short-medium-term carcinogenicity study in transgenic mice, mainly rasH2 mice), was performed. Regarding animals species: The rat was in most cases selected for long-term bioassays.  In only 2 examples rat was replaced by hamster as the test animal, due to species-specific obstacles in the rat, like metabolic peculiarities. The final outcome of the experiments (excluding biotechnological derived products) revealed that in 39.4 % of cases a positive carcinogenic assessment in a least one species had to be stated. The extrapolation from animal findings  to humans allowed the following conclusion:  In the majority of cases non-clinical positive carcinogenicity evaluation represented  "no special hazard in humans", a conclusion which justifies the granted marketing authorization.  In a minority of cases carcinogenicity potential could not be excluded or was low. In few cases post-marketing measures were required.7 medicinal products (n=3 full dossier application, n=3 hybrid application, n=1 well established use application), which were indicated for cancer treatment were identified as carcinogenic resp. potential carcinogen, while only 1 refers to results of carcinogenicity bioassays (published in literature).
Pages: 73
Annexes: pages: 369