Donation of Starting Material for Cell-Based Advanced Therapies: a Sabto Review

Donation of Starting Material for Cell-Based Advanced Therapies: a SaBTO Review June 2014 Table of Contents 1 Acknowledgements 4 2 Executive summary 6 3 Background and process 10 3.1 Introduction 10 3.2 Categories of cellular therapies 11 3.3 Open issues 13 3.4 The regulatory environment 16 3.5 The scope and remit of the working group 17 3.6 The process and membership of the working group 19 4 Infectious risks associated with cellular therapies 23 4.1 Relevant documents considered 23 4.2 General principles 24 4.3 Supplementary points to consider 27 4.4 Whole Genome Sequencing 29 4.5 Special considerations for human stem cell lines 30 4.6 Additional considerations 30 4.7 Prion and prion infectivity 31 5 Genetic risks associated with cellular therapies 37 5.1 Review of current practice 38 5.2 Genetic variation in different populations 41 5.3 Risk posed by genetic abnormality in the donor 41 5.4 What is the relevance of whole genome sequencing to current or future pathology? 42 5.5 Other points for consideration in the formulation of recommendations 43 5.6 Recommendations 43 6 Informed consent and traceability 45 6.1 Worked examples 46 6.2 Examples plotted onto the consent and traceability matrix 48 6.3 Main themes and principles 49 6.4 Operational and practical consequences 58 7 Summary of recommendations 63 8 Appendices 67 Appendix 1: The regulatory context of development and manufacture of cell-based advanced therapies 67 Appendix 2: The remit and terms of reference of the working group 83 Appendix 3: Tissues under consideration for use in cell therapies 91 Appendix 4: Report of the National Clinical Human Embryonic Stem Cell Forum meeting on transmissible spongiform encephalopathy infection risk, 28 March 2012 94 Appendix 5: Current regulations for genetic screening of donors of blood, cells, tissues and organs 98 Appendix 6: Current regulations for genetic screening of gamete donors 100 Appendix 7: Risks of genetic based variations from existing transplant procedures 103 Appendix 8: The genetic basis of disease and screening healthy individuals 106 Appendix 9: Worked examples - Consent and traceability 110 Appendix 10: The donation journey – potential hotspots: issues of consent and traceability to consider 123 Appendix 11: Consent and traceability, summary of worked examples 131 Appendix 12: Glossary and abbreviations 137 3 Acknowledgements 1 Acknowledgements The Cell-based advanced therapies Working Group is grateful for the contribution made to its work by the following groups and individuals. The Adventitious Agents Working Group at the National Institute for Biological Standards and Control (NIBSC). This Group worked closely with the Sub group considering infectious risks on aspects of the potential hazards and risks that need to be considered, and the risk assessment approach. Their input made a significant contribution to this report. The members of the Group are: Dr Kevin Brown, Public Health England Professor Kate Gould, Newcastle upon Tyne Hospitals NHSFT Dr Lyn Healy, UK Stem Cell Bank, National Institute for Biological Standards and Control , a centre of the MHRA Dr Charles Hunt, UK Stem Cell Bank, National Institute for Biological Standards and Control, a centre of the MHRA Dr Graham Jackson, Medical Research Council Prion Unit Professor Paul Kellam, Wellcome Trust Sanger Institute Professor Richard Knight, UK National CJD Research and Surveillance Unit Dr Simon Mead, Medical Research Council Prion Unit Dr Philip Minor, National Institute for Biological Standards and Control, a centre of the MHRA Dr Glyn Stacey, UK Stem Cell Bank, National Institute for Biological Standards and Control, a centre of the MHRA Professor Richard Tedder, University College London Medical School Professor Marc Turner, Scottish National Blood Transfusion Service Dr Jonathan Wadsworth, Medical Research Council Prion Unit. The Regulators. The Human Tissue Authority and the Human Fertilisation and Embryology Authority had observers on the group, who were able to provide helpful clarification of the regulatory position. Mr Ian Rees and his colleagues from the Medicines and Healthcare products Regulatory Agency provided detailed feedback, and will play an important role in SaBTO’s recommendations being adopted. 4 Acknowledgements Observers. Other organisations which had an observer on the Working Group include the BioIndustry Association (whose observer played an active role as a member of the Consent and traceability Sub group), the Cell Therapy Catapult and the Medical Research Council. Their involvement has been most helpful. The Cell Therapy Catapult. Dr Jacqueline Barry, Head of Regulatory Affairs at the Cell Therapy Catapult Ltd, and her colleagues worked with the MHRA to compile Appendix 1, detailing the relevant regulatory requirements applying to cell-based advanced therapies of which developers and manufacturers will need to be aware. Providers of feedback. The report was shared in draft form with a number of key stakeholders in academia, the commercial field, regulation, and relevant clinical professional and patient groups. The Working Group is grateful to those who considered the draft and provided detailed and helpful feedback, enabling points in the report to be clarified, amended, expanded or corrected. Attendees at the SaBTO Open Meeting on 28th April 2014, on the topic of Cell-based advanced therapies, also raised and discussed a number of points which SaBTO took into account when finalising the report. 5 Executive Summary 2 Executive summary Cell–based advanced therapies span the donor selection and screening, procurement, processing, immunological matching and clinical transplantation seen in blood transfusion, cell, tissue and organ transplantation and the level of manufacturing seen in the pharmaceutical and biotechnological industries. These therapies vary from minimally manipulated autologous products through to potentially large scale allogeneic products derived from pluripotent stem cells of considerable complexity. They are rightly subject to stringent regulatory control which, depending on their classification, may be under one or more of the blood, tissue and cells or medicines pieces of legislation and their approved guidance documents. However there are a number of open issues beyond mandatory requirements, some of which, in the UK, fall into the remit of SaBTO (the Advisory Committee on the Safety of Blood, Tissues and Organs), including the extent of donor screening for infectious agents and genetic abnormalities, the nature and extent of informed consent and the duty of care to the donor should findings arise which are of relevance to his or her health, family or public health. There are also risks associated with the manufacturing process itself, the characterisation of the cellular product and its behaviour in the recipient post-transplant, but these exogenous risks were considered to be out-with the remit of SaBTO. The Working Group was therefore established to review the endogenous risks associated with cellular therapies, particularly with respect to donor selection, consenting and testing, and to make recommendations to SaBTO on how these can be optimised in order to support the development of cellular therapies in the UK whilst maximising donor and patient safety. The possibility of infection from transplanted cell therapies remains one of the greatest risks to potential recipients. Whereas the majority of infectious agents will have a cytopathic effect on the cell line and be detected by mandatory product (Quality Control) testing so that their existence will be recognised and the cells discarded before use, there are some potential, and possibly some as yet unknown pathogens, which may be able to incorporate themselves into cells and establish persistent yet non-evident infection. These infective agents may originate from the donor cells themselves, contamination at the time of harvesting, or during the propagation process. 6 Executive Summary The Working Group recommends that the selection and testing of blood and tissue donors for cellular therapies should follow existing SaBTO guidance on the selection and assessment of donors, and on risk assessment for infection; abide by legal requirements, and follow the best available professional guidance. Consideration should be given to infectious agents that may not be cytopathic and may not be detected by mandatory tests but could replicate in in vitro culture systems or precipitate cellular transformation. Vigilance should be maintained for new and emerging infections, and consideration given to the potential for their transmission through a cell line. Consideration of the short term follow up of the donor is also deemed important, for which baseline legislative requirements exist. When considering the safety of a product, account needs to be taken of the effect of inactivation/decontamination strategies undertaken during processing, and their effect on the infection potential of the final product. For live donors, a risk assessment should be done to mitigate risk at the point of donation, for infections and for agents that could replicate in vitro and cause cell replication or transformation. An assessment of the risk to the potential recipient should be performed, for example whether they are immunosuppressed or not. Existing SaBTO guidance on donor testing should be followed, but also testing of the end product for bacteria and fungi using assays such as the existing 16S and 18S PCRs1 should be considered, and these and other tests required

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