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ICH Considerations on Viral/Vector Shedding; and Overview of Gene Therapy Activity in Canada

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ICH Considerations on Viral/Vector Shedding; and Overview of Gene Therapy Activity in Canada ICH Considerations on Viral/Vector Shedding; and Overview of Gene Therapy Activity in Canada Anthony Ridgway, Ph.D. Senior Regulatory Scientist Biologics & Genetic Therapies Directorate Health Canada Open Workshop on Gene Therapy Yokohama, June 12, 2009 Regulatory Authority for Gene Therapy z meets F&D Act definition of drug z satisfies Schedule D to the Act as: "Drugs obtained by rDNA procedures" "Drugs, other than antibiotics, prepared from micro-organisms" "Immunizing agents" (there are no specific regulations) (there are no gaps in regulation) Regulatory Responsibility Government of Canada Health Canada Health Products and Food Branch Biologics and Genetic Therapies Directorate Biologics and Radiopharmaceuticals Evaluation Centre Biotherapeutics Division & Clinical Evaluation Division Scientific Issues I z Route of administration; intralesional, systemic, intra-vascular (organ-targeted) z Replication competence of virus vectors; pathogenicity z Vector integration into host genome z Vector dose z Expressed product dose Scientific Issues II z Frequent lack of appropriate animal models z Choice of toxicologic investigations; (revealing unanticipated toxicities ?) z Targeting specificity z Regulation of gene expression z Immunogenicity z Contamination of drug product Safety & Ethics Considerations z Informed Consent ¾ full disclosure of risk z Institutional Review is critical ¾ protocols and consent forms z Alteration of host genome ¾ 'contamination' of non-target tissues, especially germ cells z Vector “shedding” and inadvertent generation of RC virus ¾ pathogenicity and exposure of patient and contacts Regulatory Process for Clinical Trials IREB Approval Pre-CTA Clinical Advisory Trial 30 Day Trial Meeting Application Default* Proceeds with (CTA) Sponsor No "clinical hold" Each lot of clinical (optional) in Canada material meets specifications (Fax-Back Form) Review Team Clinical CMC Lab Growth of Gene Therapy in Canada 70 60 Cumulative Number 50 of CTAs Approved 40 30 20 10 0 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 Immune Therapy Rationale z recruit immune system into renewed response z address immune avoidance by cancer ¾reduced antigenicity ¾outgrowth of antigenic variants ¾defective T-cell function ¾other deficiencies (immunosuppressive factors?) Immune Therapy Approaches Ex vivo z tumour antigen into autologous dendritic cells z T-cell co-stimulatory molecules into autologous tumour cells ¾ cytokine gene often included ¾ cells irradiated In vivo z intratumoral delivery of genes ¾ may involve direct cell killing Induction of Apoptosis z Re-introduction and expression of tumour suppressor genes (e.g. p53 gene) ¾intratumoral delivery ¾only transduced cells affected Direct Cell Killing z induced cell suicide using pro-drug e.g. HSV-tk gene & ganciclovir z wt viruses that replicate preferentially in cancer cells ¾reovirus ¾Newcastle disease virus ¾vesicular stomatitis virus z viruses genetically modified to limit lytic infection to cancer cells Chemoprotection z enhance delivery of high-dose chemotherapy by limiting immune toxicity z introduce MDR gene to hematopoietic stem cells prior to BMT/PSCT Gene Marker Studies z allow information gathering upon which a true therapy may be based z expression of the marker gene can be used to: ¾follow migration, expansion and persistence of cells modified ex vivo (after stem cell transfer) ¾assess in vivo gene delivery system for cell targeting and for regulation of the encompassed gene Gene Therapy Trials in Canada I 30 25 20 15 10 5 0 producer cells in vivo ex vivo adenovirus in vivo retrovir us DNA wt viruses RN A AAV HSV vaccinia bact er ia Gene Therapy Trials in Canada I 30 25 20 15 10 5 0 producer cells in vivo ex vivo adenovirus in vivo retrovir us DNA wt viruses RN A AAV HSV vaccinia bact er ia Gene Therapy Trials in Canada II number and type of vectors used 16 3 7 2 2 1 1 1 adenovirus retrovirus DNA wt viruses RNA AAV HSV vaccinia bacteria carcinomas: glioma metastatic metastatic renal cell rheumatoid metastatic malignant ulcerative breast solid solid carcinoma arthritis melanoma melanoma colitis i liver carcinoma tumours tumours n prostate of breast HIV monogenic primary d hepato- ovary metastatic carcinoma infection lipoprotein i lipase cellular c bladder metastatic melanoma of prostate deficiency carcinoma a NSCLC melanoma chronic lymphocytic t SCCHN PVD colorectal solid i leukemia multiple cancer tumours o n metastatic myeloma CAD s melanoma BMT multiple malignant (mdr) sclerosis myeloma pulmonary AML arterial hypertension CAD BMT prophylactic (neo) HIV vaccine Gene Therapy Regulatory Comments I z Canada is consistent with the international community in the regulation of gene therapy z Canada has experienced significant growth in gene therapy clinical trials z Regulatory and ethical challenges have been few due to the serious and often terminal nature of the diseases treated Gene Therapy Regulatory Comments II z Careful attention is paid to minimizing the chance of third party exposure to virus z Germ-line gene transfer is prohibited by law in Canada z We fully endorse international exchange of information and ideas perhaps leading to harmonised understanding or approach Scope Regarding what is shed z Gene therapy vectors z Viral vectors z Plasmid vectors z Bacterial vectors z Excluding gene-modified cells (except when harbouring a virus) z Oncolytic viruses (including non-recombinant wt) z Bacteria Scope Routes of shedding z Focus is on excreta and secreta (e.g., urine, faeces, saliva, and secretions sampled using buccal swabs, nasal swabs, bronchial lavage) z Some consideration of potential for transmission from vector escaping the body via leaking injection site or blood from open wound Scope Outcomes of shedding z Focus is on the potential for human-to-human transmission and associated cocnerns z Does not address release to environment z Not under ICH umbrella z Different Regional laws and approaches Intended value To help understand the potential for transmission to others or to environment z Provide recommendations r.e. design of non- clinical and clinical shedding studies z Analytical assays for detection z Sampling profiles and schedules z Interpretation of non-clinical shedding data (and use in designing clinical studies) z Interpretation of clinical shedding data (and potential need for transmission studies) 2.0 Biological properties of the virus/vector (and other factors) z Biological properties of the virus / vector z Replication competence z Genetic modification to affect cell / tissue tropism z Route of transmission of parental virus z Duration of dosing z Potential for immune response z Attributes of parental virus z Pre-existing immunity z Immune status of the patient population 3.0 Analytical assays considerations Molecular detection vs infectivity z Need suitable qualified analytical assays zSpecific, sensitive & reproducible zQuantitative preferred zqPCR and infectivity assays typically used 4.0 Non-clinical Considerations z 4.1 Animal species z 4.2 Dose and route of administration z 4.3 Duration of the study z 4.4 Samples to be taken z 4.5 Sampling frequency z 4.6 Interpretation of non-clinical data and transmission studies 5.0 Clinical Considerations z 5.1 Samples z 5.2 Sampling frequency and duration z 5.3 Assessment.
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