Safety considerations may be nonclinical evaluator The sponsor’s response ‘The raised by the nonclinical and considered no additional has been noted. clinical evaluators through safety concerns would the consolidated TGA’s warrant changes to the request for further nonclinical safety information and/or the specification of the Risk Nonclinical and Clinical Management Plan. The Evaluation Reports clinical evaluator has raised respectively. It is important some concerns regarding the to ensure that the clinical aspects of the safety information provided in specifications in the EU-RMP response to these includes a and these issues are consideration of the addressed within this relevance for the RMP, and response. Please refer to any information M1.13.1 for the updated needed to address this issue version 2.5.’ in the RMP. For any safety considerations so raised, please provide information that is relevant and necessary to address the issue in the RMP. The sponsor should add outlined and discussed in This is considered ‘As infections’ as an section 2.1.5.12 acceptable in the ‘Severe ‘Infections Ongoing Safety Concern. and Infestations’ of M 2.7.4, context of this an overall increased risk of application. infection in patients has been observed in the Phase 3 trials in CRC (Study 14387) as well as GIST (Study 14874). However, the infections were generally of low severity and affected a variety of organ systems. No difference in the rate of infections with fatal outcomes was observed between treatment groups in the placebo-controlled trials. In addition, the rate of permanent study treatment discontinuations due to infection events was low with 1.6% (regorafenib) vs 0.8% (placebo) in Study 14387 and 0.8% (regorafenib) vs 0% (placebo) in Study 14874 (14387-CSR Table 14.3.2/2, 14874-CSR Table 14.3.9/15). Therefore, in the opinion of the applicant, there is currently no signal detected for an increased risk of clinically severe infection
Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated TGA’s request for further information and/or the Nonclinical and Clinical Evaluation Reports respectively. It is important to ensure that the information provided in response to these includes a consideration of the relevance for the RMP, and any information needed to address this issue in the RMP. For any safety considerations so raised, please provide information that is relevant and necessary to address the issue in the RMP. ‘The nonclinical evaluator considered no additional safety concerns would warrant changes to the nonclinical safety specification of the Risk Management Plan. The clinical evaluator has raised some concerns regarding the clinical aspects of the safety specifications in the EU-RMP and these issues are addressed within this response. Please refer to M1.13.1 for the updated version 2.5.’ The sponsor’s response has been noted. The sponsor should add ‘Severe infections’ as an Ongoing Safety Concern. ‘As outlined and discussed in section 2.1.5.12 ‘Infections and Infestations’ of M 2.7.4, an overall increased risk of infection in patients has been observed in the Phase 3 trials in CRC (Study 14387) as well as GIST (Study 14874). However, the infections were generally of low severity and affected a variety of organ systems. No difference in the rate of infections with fatal outcomes was observed between treatment groups in the placebo-controlled trials. In addition, the rate of permanent study treatment discontinuations due to infection events was low with 1.6% (regorafenib) vs 0.8% (placebo) in Study 14387 and 0.8% (regorafenib) vs 0% (placebo) in Study 14874 (14387-CSR Table 14.3.2/2, 14874-CSR Table 14.3.9/15). Therefore, in the opinion of the applicant, there is currently no signal detected for an increased risk of clinically severe infection This is considered acceptable in the context of this application.
auspar-regorafenib-151119.docx