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T 42: Talimogene Laherparepvec: Advanced Therapy Medicinal Product (ATMP) – A Distinct Risk Management Plan

Poster Presenter

      Heba A. Abdullah

      • Global Safety Medical Director
      • Amgen Inc.
        United States


To present a distinct risk management plan for a first in class oncolytic immunotherapy that is based on a live attenuated virus and the challenges associated in developing a robust plan to minimize and mitigate the risks associated with the viral nature of this product.


When preparing a risk management plan for an advanced therapy medicinal product (ATMP), EMA and EMA Guidance on Safety and Efficacy Follow-up -Risk Management of Advance Therapy Medicinal products were consulted on possible risks in addition to the review of clinical and pre-clinical data.


The marketing authorization holder (MAH) incorporated additional risk minimization activities such as patient alert cards, physician education booklet, patient safety brochure, managed distribution, and traceability into a risk management plan that met the requirements of the EU RMP guidance for ATMPs. A unique risk to the patient as well as the public health was the potential risk of secondary transmission, based on the viral nature of talimogene laherparepvec. The EU Summary of Product Characteristics (EU SPC) and additional educational material include measures for minimizing risks such as accidental exposure and secondary transmission. In order to monitor the potential risk of talimogene laherparepvec transmission, in HCP, patients, and close contacts reporting suspected herpetic lesions, a special qPCR testing process was developed to test for talimogene laherparepvec DNA with a follow-up questionnaire in addition to a post-marketing observational study to solicit follow-up of patients for herpetic illness and potential for transmission. Additional risk management elements under the ATMP classification included the incorporation of a managed distribution and traceability program. The objective of this program is to ensure that institutions (including HCPs) using talimogene laherparepvec are trained on the proper storage and handling requirements due to the unique nature of this product. Most importantly, institutions/HCPs should report adverse drug reactions including batch (lot) level information. Each vial has a peelable label to be placed in the patient chart to ensure traceability between the patient, treatment received, and treating center. Talimogene laherparepvec has been approved in US, EU and other countries. To date the MAH has not received any reports of secondary transmission.


Talimogene laherparepvec is a novel live attenuated oncolytic immunotherapy based on the wild-type herpes simplex virus 1 (HSV-1) genome. It is derived from the HSV-1 strain JS1 from which 2 genes, infected cell protein (ICP) 34.5 (gene responsible for neurovirulence) and ICP47, were functionally deleted. The functional deletion of ICP34.5 results in tumor-selective replication, and deletion of ICP47 enhances antigen presentation. Deletion of ICP47 also increases the expression of the HSV US11 gene, which enhances virus replication in tumor cells. The viral thymidine kinase gene, responsible for phosphorylating acyclovir to acyclovir-monophosphate, is maintained, rendering talimogene laherparepvec sensitive to anti-viral therapy. Talimogene laherparepvec also contains the gene coding for human granulocyte macrophage colony-stimulating factor (GM-CSF) so that GM-CSF is expressed locally upon viral replication. Talimogene laherparepvec has recently been approved in the EU, US, and AU. In the EU, talimogene laherparepvec is considered an ATMP and one of the unique aspects of this first in class, oncolytic therapy, are the associated identified and potential risks that required the development of a distinct risk management plan (RMP) to meet the ATMP classification guidelines in the European Union. Due to the viral nature of this product, special emphasis on the risk of transmission to unintended individuals, such as close contacts, accidental exposure, disseminated herpetic infections in the severely immunocompromised and potential harm to fetus or neonate during pregnancy is provided in the RMP. These risks required the MAH to include comprehensive risk mitigation and minimization measures through succinct labelling and pharmacovigilance activities. Co-author: Deborah Arrindel (Arrindell, A)

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