Safety specification The sponsor provided a summary of ongoing safety concerns which are shown at Table 9. Table 9: Summary of ongoing safety concerns Important identified risks Important potential risks Missing information Disseminated herpetic infection in severely immunocompromised individuals (those with any severe congenital or acquired cellular and/or humoral immune deficiency). Disseminated herpetic infection in immunocompromised individuals (such as those with HIV/AIDS, leukemia, lymphoma, common variable immunodeficiency, or those who require steroids or other immunosuppressive drugs. Additional clinical biodistribution and shedding data in melanoma. Accidental exposure of HCP to talimogene laherparepvec. Symptomatic talimogene laherparepvec infection in non-tumour tissue in treated patients. Recombination of talimogene laherparepvec with wild-type HSV-1. Cellulitis at the site of injection. Transmission of talimogene laherparepvec from patient to close contacts or HCP via direct contact with injected lesions or body fluids resulting in symptomatic infection (primary of reactivation). Pregnant and lactating women. Symptomatic herpetic infection due to latency and reactivation of talimogene laherparepvec or HSV-1 in patients. Paediatric patients. Immune-mediated adverse events. Patients with renal or hepatic impairment. Plasmacytoma at the injection site. Long-term safety data. Impaired wound healing at the site of injection.
It is recommended to the Delegate that the draft CMI document be revised to accommodate the changes made to the product information document. An updated draft CMI document has been submitted with the response to questions. This is considered acceptable in the context of this application for RMP purposes subject to Delegate approval. Summary of recommendations It is considered that the sponsor’s response to the TGA has not adequately addressed all of the issues identified in the RMP evaluation report. Additional recommendations have been made. Outstanding RMP issues ‘Migration of malignant cells into systemic circulation or to distal sites’ should be added as an Important Potential Risk. ‘Resistance to aciclovir’ should be added as an Important Potential Risk. Cohort Study 20130193 should be improved by including consideration of: the modes of transmission, not just estimates of incidence rates long term individual reactivation risks CNS infections live viral shredding from injection sites the pathogenesis of the virus in non-patients monitoring of close contacts and healthcare providers for asymptomatic infection treatment outcomes in non-patients who become infected with talimogene laherparepvec. Amendments to the registry 20120139 should be made: All patients in Australia receiving Imlygic should be part of the registry. The registry should include active surveillance of close contacts. The sponsor should conduct the same or equivalent risk minimisation activities in Australia as planned in the EU, including the use of a managed distribution program. The following safety concerns are specifically related to oncolytic HSV virus use and should be included in the PEB: Recombination of talimogene laherparepvec with wild-type HSV-1 virus may occur. Loss of efficacy in patients treated with systemic acyclovir for complications. It may be acceptable for the education program not to be accredited by a Learned College, if TGA is satisfied that the additional risk minimisation activities (including, but not limited to accreditation of centres and quality of the education materials as assessed by TGA) will sufficiently mitigate the risks. Prior to approval, the sponsor should provide the TGA with the following details for agreement: All draft education materials; A distribution plan; and A clear plan to measure the effectiveness of the education programme as an additional risk minimisation activity. trial