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.
2.1.5.13.3 of Module 2.7.4 provided with the GIST submission). Severe liver injury reported from data (6/30,000) and the ongoing Study 15967 (CONSIGN) (1/3000) indicate that the frequency of severe liver injury is not higher but rather lower compared to the time of first (CRC) submission (3 cases in around 1200 regorafenib-treated cancer patients; see M2.7.4 provided with the CRC submission). Therefore, the information presented in the Precautions – Hepatotoxicity and Dosage and Administration - Table 9 - Recommended measures and dose modifications in case of drug related liver function test abnormalities section of the PI provides adequate liver monitoring and dosing guidance for both indications, CRC and GIST. Experience with the label-defined LFT monitoring schedule indicates that this approach is acceptable.’ In the ‘Precautions’ section, under a separate heading, the PI should include a statement on the association of tyrosine kinase inhibitors with infections (or a statement to that effect). ‘Bayer considers the current approach in the PI describing infection as a very common ADR together with detailed information on the frequency, severity and most frequently observed sites of infection within section ‘Description of selected adverse reactions’ provides adequate guidance to physicians. No additional respective wording in the Precautions section is required – also taking into account that there is no associated specific monitoring or dose modification recommendation.’ This is considered acceptable in the context of this application subject to approval by the Delegate. In the ‘Precautions’ section, a separate heading, the PI should include a statement on the association of tyrosine kinase inhibitors ‘A wide variety of drugs have been implicated among causes of interstitial lung disease (ILD), including VEGFR-targeting TKIs. At This is considered acceptable in the context of this application subject to
has been superseded by: EU Risk Management Plan Version 2.5 (dated 12 August 2014, DLP 28 February 2013) and Australian Specific Annex Version 2.1 (dated September 2014). Key changes to the EU-RMP and ASA are highlighted in Table 8 below. Table 8: Summary of key changes to the RMP and ASA Key changes between EU-RMP Version 2.0 and EU-RMP Version 2.5 Safety specification ‘Thrombotic microangiopathies’ (TMA) added as Important Potential Risk. ‘Long-term safety in GIST patients’ added as Missing Information. ‘Safety in severe or moderate hepatic impairment’ added as Missing Information (previously ‘Safety in severe hepatic impairment’). ‘Safety in severe or moderate impairment’ added as Missing Information (previously ‘Safety in severe renal impairment’). activities Study 14814 (Category 3) completed; Result summary added to section 3 in Part III; Clinical Study Report added to Annex 9. Study 14874 assigned to ‘Long-term safety in GIST patients’ Updates on due dates for study 15808 and 15967. ASA ASA updated to accommodate EU-RMP changes. Suggested wording for conditions of registration RMP Any changes to which the sponsor agreed become part of the risk management system, whether they are included in the currently available version of the RMP document, or not included, inadvertently or otherwise. The suggested wording is: Implement EU Risk Management Plan Version 2.5 (dated 12 August 2014, DLP 28 February 2013) and Australian Specific Annex Version 2.1 (dated September 2014), and future updates, where approved by the TGA, as a condition of registration VI. Overall conclusion and risk/benefit assessment The submission was summarised in the following Delegate’s overview and recommendations: Quality There was no requirement for a quality evaluation in a submission of this type.