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Note for Guidance on the Quality, Preclinical and Clinical Aspects of Gene Transfer Medicinal Products

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Note for Guidance on the Quality, Preclinical and Clinical Aspects of Gene Transfer Medicinal Products The European Agency for the Evaluation of Medicinal Products Evaluation of Medicines for Human Use London, 24 April 2001 CPMP/BWP/3088/99 COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS (CPMP) NOTE FOR GUIDANCE ON THE QUALITY, PRECLINICAL AND CLINICAL ASPECTS OF GENE TRANSFER MEDICINAL PRODUCTS DISCUSSION IN THE BIOTECHNOLOGY WORKING June – December 1999 PARTY (BWP) DISCUSSION IN THE SAFETY WORKING PARTY (SWP) June 1999 DISCUSSION IN THE EFFICACY WORKING PARTY July – November 1999 TRANSMISSION TO CPMP December 1999 RELEASE FOR CONSULTATION December 1999 DEADLINE FOR COMMENTS June 2000 DISCUSSION IN THE EFFICACY WORKING PARTY September 2000 (EWP) DISCUSSION IN THE SAFETY WORKING PARTY (SWP) February 2001 DISCUSSION IN THE BIOTECHNOLOGY WORKING March 2001 PARTY (BWP) WRITTEN PROCEDURE WITH SAFETY WORKING April 2001 PARTY (SWP) TRANSMISSION TO CPMP April 2001 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 85 45 E-mail: [email protected] http://www.emea.eu.int/ ãEMEA 2001 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged FINAL ADOPTION BY CPMP April 2001 DATE FOR COMING INTO FORCE October 2001 NOTE FOR GUIDANCE ON QUALITY, PRECLINICAL AND CLINICAL ASPECTS OF GENE TRANSFER MEDICINAL PRODUCTS TABLE OF CONTENTS 1. INTRODUCTION....................................................................................................2 1.1 Gene transfer....................................................................................................2 1.2 Gene transfer medicinal products ......................................................................2 1.3 Scope..............................................................................................................3 2. GENERAL CONSIDERATIONS ............................................................................4 2.1 Development genetics.......................................................................................4 2.2 Production.......................................................................................................5 2.3 Purification.......................................................................................................7 2.4 Product characterisation...................................................................................7 2.5 Consistency and routine batch control of final processed product.......................7 3. SPECIFIC CONSIDERATIONS FOR INDIVIDUAL GENE TRANSFER STRATEGIES .................................................................................................................................9 3.1 Plasmid DNA products (e.g. DNA vaccines)....................................................9 3.2 Non viral vectors for delivery of transgenes (e.g. liposomes, receptor mediated ligands) ......................................................................................................................11 3.3 Viral vectors...................................................................................................12 3.4. Cell-based products.......................................................................................14 4. CONSIDERATIONS ON THE USE OF GENETICALLY MODIFIED ORGANISMS (GMO)....................................................................................................................17 5. PRECLINICAL pharmacological/toxicological EVALUATION OF GENE TRANSFER PRODUCTS...........................................................................................................17 5.1 General considerations....................................................................................17 5.2 Specific considerations ...................................................................................18 5.3 Potential efficacy............................................................................................21 5.4 Pharmacological/toxicological evaluation of gene transfer products...................22 6. CLINICAL EFFICACY AND SAFETY EVALUATION......................................25 8. GLOSSARY OF TERMS.......................................................................................30 CPMP/BWP/3088/99 1/31 ãEMEA 2001 1. INTRODUCTION 1.1 Gene transfer Scientific progress over the past decade has led to the development of novel methods for the transfer of genetic material into somatic cells. For the purpose of this Note for Guidance, gene transfer involves the deliberate introduction of genetic material into somatic cells for therapeutic, prophylactic or diagnostic purposes. 1.2 Gene transfer medicinal products Gene transfer medicinal products are presented for treating or preventing disease in human subjects, or are administered to human subjects with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in these subjects. There are currently two principal types of gene transfer vector that are commonly used: i) bacterial plasmid DNA ii) a virus both of which are genetically engineered usually to express a specific protein. Plasmid DNA may be administered either in a simple salt solution (referred to as “naked” DNA) or complexed with a carrier or an adjuvant. Viral vectors are generally replication deficient although replication competent viral vectors are also being used. By using these vectors in-vivo genetic modification of somatic cells can be achieved. Somatic cells may also be modified ex-vivo (e.g. allogeneic or autologous somatic cells) or in-vitro (e.g. bankable cells) prior to administration to the human subject. Other areas under laboratory development include the use of other types of vectors, such as bacteria, and approaches designed to modify or inhibit the functioning of an endogenous gene or genetic elements in mammalian cells. In this context, gene transfer products constitute a wide range of medicinal products of biological origin which are outlined in Table 1. TABLE 1 TYPES OF GENE TRANSFER EXAMPLES MEDICINAL PRODUCTS (a) naked nucleic acid natural or synthesised nucleic acid, generally ligated into appropriate plasmids or cassettes (see section 1.3; excluding antisense oligonucleotides) with or without adjuvant. (b) complexed nucleic (i) as above, but complexed with polycations (e.g. oligodendomer), acid or non viral proteins (e.g. transferrin) or other polymers (e.g. DEAE- vectors Dextran, polylysine) (ii) as above (i) but encapsulated or associated (for example in liposomes (iii) as above, but coated on colloidal particles CPMP/BWP/3088/99 2/31 ãEMEA 2001 (c) viral vectors Usually replication-deficient viruses, including adenoviruses, retroviruses, adeno-associated virus, herpes simplex virus; in some cases replication-competent viruses e.g. vaccinia virus. (d) genetically modified Allogeneic, xenogeneic, or cells of microbiological origin carrying a cells newly introduced nucleic acid segment. 1.3 Scope Gene transfer medicinal products fall within the scope of Part A of Council Regulation EC 2309/93 and must be authorised through the Centralised Procedure1. The objective of this Note for Guidance is to provide recommendations with respect to the quality, preclinical and clinical aspects of gene transfer medicinal products and assistance in generating data supporting marketing authorisation applications within the European Community. This note covers: · the addition and expression of a gene(s) for therapeutic purposes (e.g. gene transfer products and cancer vaccines); · the inoculation of nucleic acids for the purpose of vaccination against foreign antigens (e.g. DNA vaccination) · the transfer of nucleic acids with the aim of modifying the function or expression of an endogenous gene. This document is not intended to apply to chemically synthesised oligonucleotides e.g. anti-sense oligonucleotides or RNA/DNA chimera, where quality control during manufacture will be different. However, the principles as outlined in this document could be considered, where relevant, in the research and development of such products. As for any new technology, a flexible approach to the control of these products is being adopted so that recommendations can be modified in the light of experience of production and use, and of further developments. Whilst the recommendations set out below should be considered to be generally applicable, individual products may present particular quality control and safety concerns, e.g. as in the case of DNA vaccines intended for prophylactic use in a large number of healthy individuals. The production and control of each product will be considered on a case-by-case or product-specific basis reflecting the intended clinical use of the product. Primary xenogeneic cells derived from donor animals cannot be used until more information on the safety of this approach has been obtained. Specific guidance on this subject will be issued by the CPMP at a future date. Considerations of the quality, preclinical and clinical issues pertaining to gene transfer products are covered in separate sections of this Note for Guidance and cross-reference is made between sections where appropriate. For gene transfer medicinal products, it is important to note that some of the preclinical and clinical issues would require a clear understanding of the product characteristics in order to design appropriate preclinical and clinical studies testing relating to the toxicology and the pharmacology of the product. Therefore, it is inevitable that there will be overlaps between sections (e.g. quality
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