Regulatory Experience for a Gene Therapy Product in a Large Phase II European Study. Disclaimer

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1 Regulatory Experience for a Gene Therapy Product in a Large Phase II European Study Catherine Mathis Director of Regulatory Affairs transgene 1 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. ( DIA ), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United Statest of America and other countries. ti Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners

2 Agenda Regulatory framework for gene therapy products Definitions Legal Texts CTA process for GTMPs Experience of phase II studies Conclusions 3 3 Agenda Regulatory framework for gene therapy products Definitions Legal Texts CTA process for GTMPs Experience of phase II studies Conclusions 4 4 2

3 Regulatory Framework: Definitions 2009/120/EC: Gene Therapy Medicinal Product (GTMP) Biological medicinal product with the following characteristics: recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence; therapeutic, prophylactic or diagnostic effect related directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence. GTMPs shall not include vaccines against infectious diseases. 5 5 Regulatory Framework: Definitions GTMPs include: naked nucleic acid complex nucleic acid or non viral vectors viral vectors genetically modified cells In Europe, GTMPs are Medicinal Products and Genetically Modified Organisms (GMOs) 6 6 3

4 Regulatory Framework: Definitions Separate therapeutic applications using GTMPs: Inserting a corrective gene, repairing a mutated gene, regulating a gene Genetic diseases Integrative viral vectors used for the gene transfer: retrovirus, lentivirus 7 7 Regulatory Framework: Definitions Expression of immunotherapeutic genes: «therapeutic vaccines» Oncology and infectious disease fields Tumor antigen (like MUC1, CEA), human virus antigens (HCV, HPV, HIV), cytokines (IL2, IFNg, GM-CSF)» MOA: induce cellular immune responses (CTL) against the tumor or the infectious agents Suicide gene (HSV-TK + ganciclovir)» MOA: transformation of prodrug into cytotoxic drug 8 8 4

5 Regulatory Framework: Definitions Today, no GTMPs on the market in EU and/or USA Two GTMPs approved in China Veterinary field: Several vaccines based on the same technology on the market for many years: e.g. Raboral, Eurifel (Merial) 9 9 Agenda Regulatory framework for gene therapy products Definitions Legal Texts CTA process for GTMPs Experience of phase II studies Conclusions

6 Regulatory Framework: Legal texts All GTMPs are regulated by: the EU pharmaceutical regulation: 2001/83/EC Directive Regulation (EC) No 726/2004 Advanced Therapies Regulation (N 1394/2007) with in addition the environmental component regulated by EU GMO Directives 1990/219/EC (2009/41/EC) and 2001/18/EC Directives Regulatory Framework: Legal texts Directive 2009/41/EC repealing 90/219/EC and 98/81/EC related to the confined use of GMO Classification of operations: Type A for R D and non-commercial purposes Type B for any operation other than a Type A operation GMO classification: Group I for non-pathogenic and Group II for the others Class of risk related to the pathogenicity: Class 1, 2, 3 or 4: risk nul (L1), low (L2), moderate (L3) or high (L4) Description of Confinement Biosafety Level: L1, L2, L3, L4: takes into account the facilities organisation, the equipment and the good practices of work

7 Regulatory Framework: Legal texts Directive 1990/220/EC abrogated by the Directive 2001/18/EC Related to the dissemination of GMO and risk for environment: deliberate release Define the risk assessment, a better access of the information to the public and a better traceability of the products Agenda Regulatory framework for gene therapy products Definitions Legal Texts CTA process for GTMPs Experience of phase II studies Conclusions

8 Regulatory Framework: CTA process For any clinical trial with GTMPs: CTA submitted to the Competent t Authorities (CA): Health Authorities + National Biosafety Authorities follow the same format as for any IMPs: IMPD (2001/20/EC) Technical dossier on the GMO: Annex II and III conform to 2001/18/EC: environmental risk assessment (ERA) Specific questionnaire or other documents specific to each EU country Regulatory Framework: the CTA process Clinical site: Must be authorised for GMO manipulation Specific documentation to be submitted to the local and/or national Biosafety Authorities by the clinical site Descriptive documentation of the GMO, facilities description and responsible people Ethics: Protocol to be authorised by national and possibly local Ethic Committees Protocol +ICF + IB + Insurance to be submitted

9 Regulatory Framework: the CTA process GMO specific documentation: Annex III related to the ERA Information relating to the GMO Information relating to the conditions of release and the receiving environment Information relating to the interactions between the GMOs and the environment Information on monitoring, control and treatment of waste and emergency response plans Regulatory Framework: the CTA process e.g. in France Sponsor: EudraCT number + Dossier > 6 months process Haut Conseil des Biotechnologies (Research and Environment Authorities) - GMO classification - Risk assessment - Confined use or deliberate release AFSSAPS Unité Essai Clinique Evaluation by the Gene Therapy Group of Afssaps Central Ethics Committee (Comité de Protection des Personnes) GMO facilities approval Authorization Opinion Clinical sites Start of the Clinical trial

10 Regulatory Framework: the CTA process e.g. in Germany Clinical sites Sponsor: EudraCT number + Dossier > 6 months process GMO facilities approval Landesamt für Gesundheit und Soziales / Bezirksregierung (Research and Environment Authorities) - GMO and facilities i classification - Risk assessment - Confined use or deliberate release PEI Evaluation by the Dept of Clinical Trials (Dept. Klinische Prüfungen) Authorization Ethic Committee (central + local) Opinion Start of the Clinical trial Agenda Regulatory framework for gene therapy products Definitions Legal Texts CTA process for GTMPs Experience of phase II studies Conclusions

11 Experience of phase II studies Transgene focused on: development of immunotherapeutic ti products based on recombinant viral vectors technology Two recombinant viral vector platforms: Vaccinia virus with the use of the highly attenuated MVA strain (Modified Vaccinia virus Ankara) Adenovirus type Experience of phase II studies The product: TG4010 Recombinant vaccinia virus of the MVA strain expressing MUC1 tumor antigen and human IL2 SC route, dose of 10e8 pfu, one injection every week for 6 wks then every 3 wks up to progression The targeted diseases: Cancer diseases expressing MUC1: NSCLC, prostate, breast cancers, RCC

12 Experience of phase II studies Mechanism of action: Stimulation of the patient s immune system with induction of a Th1 immune response expected to eliminate tumor cells expressing MUC1 TG4010 aims at increasing survival, decreases tumor burden and progression with minimal toxicity, in the treatment of NSCLC and potentially other MUC1 expressing tumors TG4010 TH Dendritic cell CD4 CD8 NK Antibody TH2 B adc IFNγ IL-2 Activated Dendritic Cell Adapted from Nature Reviews Immunology Experience of phase II studies Phase II program with TG Phase II studies from 2002 to 2008 > 300 patients in around 60 sites in 7 countries: France, Germany, Poland, Hungary, Belgium, USA, Switzerland UK+Czech Republic: withdrawn

13 Experience of phase II studies UK withdrawn Belgium Germany Czech R withdrawn Hungary Poland France M0 M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M13 M14 M15 Months First patient in CTA submission and approval by the HA EC submission and approval byec Experience of phase II studies Country TTA Regulatory bodies (CA, EC, Clinical site Biosafety) France 4 Centralized process to the CA Site approved for GMO: for pharmaceutical and. simple and quick process <2mo biosafety Logistical aspects for GMO manipulation: slow down the process Some fear from medical staff due to neg impact of agriculture GMO Poland 11 Contracts signed prior to reg Site approved for GMO: submission. long process, technical dossier, Quick process with CA and EC new field for PI, Long process for biosafety: no existing committee TTA: Time To Approval in months

14 Experience of phase II studies Country TTA Regulatory bodies (CA, EC, Biosafety) Germany 7 Quick process with CA Site approval for GMO needed prior CA approval Longer process with EC: local and leading Belgium 4 Clear regulatory process Easy contact with the Authorities Site approval for GMO needed prior CA approval Clinical site Site approved for GMO by the «Lander» authority:. long process, technical dossier, new field for PI if no previous exp. Site approved for GMO:. long process, technical dossier, new field for PI if no previous exp. TTA: Time To Approval in months Experience of phase II studies Country TTA Regulatory bodies (CA, EC, Clinical site Biosafety) Hungary 4 Simple and rapid regulatory process: centralized to the NIP EC advice given to the NIP No direct contacts between EC and sponsor No specific approvals for GMO 5 mo from regulatory approval and first patient in: for contractual issues with the central Lab TTA: Time To Approval in months

15 Experience of phase II studies Country TTA Regulatory bodies (CA, EC, Biosafety) Czech Republic WD Positive and quick approval from CA Biosafety:. additional viral shedding data requested: not justified, CTA withdrawn UK WD CMC questions from CA Conditional approval from GTAC with some questions Not evaluated by the local REC Clinical site Independent Biosafety expert to certify the conformity of the clinical sites: report to be provided to the Biosafety Authorities Request for approval from local biosafety committee (GMSC). No GMSC on site: long process to put it in place Decision to withdraw the CTA TTA: Time To Approval in months WD: Withdrawn Agenda Regulatory framework for gene therapy products Definitions Legal Texts CTA process for GTMPs Experience of phase II studies Conclusions

16 Conclusions The past (> 10 years ago): Study generally limited to small size/monocenter Requirements not in line with large study e.g. patient confinement requested (up to 17 days confinement until absence of any viral particles in the biological fluids) No clear regulatory framework for GMO: lack of guidances, not the same level of information to be submitted, no timelines, lack of expertise Today: Conclusions More experience and expertise from the industry and the CA Improvement in the regulatory submission process with better harmonization of the documentation to be submitted (EU 2001/20) More guidances in place to better define the regulatory framework of GTMPs

17 BUT Conclusions Still lack of harmonisation for CTA particularly in the case of GTMPs different national dossier requirements discrepant application of Community law. Significant administrative burden specifically for GTMPs for the sponsor and the investigators: compliance with national and local biosafety requirements Conclusions Solutions Administrative i ti simplication still needed d Limited re-discussion of issues at different levels: national CA, EC, local EC Simplification of the approval process of the clinical protocol amendments To include the GMO related assessments (risk and clinical sites) in the CTA for centralized review by the Medicinal Agencies

18 Conclusions Europe must become more attractive and more competitive in the development of innovative IMPs Thank you for your attention