GTAC GENE THERAPY ADVISORY COMMITTEE SEVENTEENTH ANNUAL REPORT Covering the period from January 2010 to December 2010 GTAC ANNUAL REPORT 2010 About the Gene Therapy Advisory Committee (GTAC) The Gene Therapy Advisory Committee (GTAC) is a Non-Departmental Public Body (NDBP), acts independently of Ministers and is recognised as a Research Ethics Committee by the UK Ethics Committee Authority (UKECA). Under the the Medicines for Human Use (Clinical Trials) Regulations 2004, GTAC has UK-wide statutory responsibility for the ethical oversight of clinical trials involving gene therapy. GTAC’s terms of reference also include the ethical oversight of clinical trials involving cell therapies derived from stem cell lines. In July 2010 the Government's Advisory Non-Departmental Public Bodies Review concluded that the Gene Therapy Advisory Committee (GTAC) no longer needed to provide advice directly to Ministers and that responsibility for supporting its Research Ethics Committee (REC) statutory functions should be transferred to the National Research Ethics Service (NRES). The Committee works with other Government agencies with an interest on the development and use of gene and stem cell therapies and this area, such as the Medicines and Healthcare products Regulatory Agency (MHRA), the Health and Safety Executive (HSE) and the Human Tissue Authority (HTA). GTAC’s Secretariat is provided by the Department of Health for England. The GTAC Secretariat may be contacted at: Room 12, 4" Floor West Charing Cross Hospital Fulham Palace Road LONDON W6 8RF Tel: 020 331 10103 Fax: 020 331 17280 Email: [email protected] Website: http://www.dh.gov.uk/ab/GTAC/index.htm Mil WellcomNe LibUra L 7 2250 3580425 GTAC ANNUAL REPORT 2010 GTAC GENE THERAPY ADVISORY COMMITTEE SEVENTEENTH ANNUAL REPORT WELLCOME LIBRE FOREWORD SUMMARY SECTION 1: PROTOCOLS REVIEWED BY GTAC IN 2010 1.1 Cancer 1.1.1 Malignant Melanoma GTAC 172: A Phase I/II trial of SCIB1, a DNA immunotherapy, in the treatment of patients with malignant melanoma 1,1.2 Blood Cancer GTAC 128: WT1 TCR gene therapy of leukaemia: A phase I/II safety and toxicity trial. GTAC 173: WT1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation 1.1.3 Lung Cancer GTAC 174: A Phase II trial to assess the safety, immunological activity of TroVax® plus Pemetrexed/Cisplatin in patients with malignant Pleural mesothelioma GTAC ANNUAL REPORT 2010 1.2 Haematopoietic Stem Cell Transplantation GTAC 116: Phase I/II clinical trial of T cell suicide gene therapy following haploidentical stem cell transplantation 1.3. Cardovascular disease 1,3.1 Heart Failure GTAC 136: Investigation of the safety and feasibility of SERCA gene transfer in the human failing heart using an adeno-associated viral vector 1.4 Neurological Disorders 1.4.1 Parkinson’s Disease GTAC 170 A: A multicentre, open-label study to determine the long term safety, tolerability and efficacy of ProSavin® in patients with bilateral, idiopathic Parkinson’s disease 1.5 Compassionate Use Applications 1.5.1 Compassionate use of Trovax® 1.5.2 Compassionate use of Gene Therapy for GTAC 116 1.5.3 Compassionate use of gene therapy for GTAC 132 1.6 Pre proposal presentations 1.6.1 Pre-proposal presentation on the clinical application of hydrodynamic gene delivery to the liver 1.6.2 Pre-proposal presentation on research in a coronary artery bypass graft GTAC ANNUAL REPORT 2010 1.6.3 Pre-proposal presentation on research into lentiviral vectors in ADA SCID 1.6.4 Pre-proposal presentation on survival motor neuron (SMN) replacement therapy for spinal muscular atrophy 1.7 Amendments to ongoing protocols SECTION 2: REGULATORY AND GUIDANCE ISSUES 2.1 Public consultations considered 2.1.1 Detailed guidelines on good clinical practice specific to advance therapy medicinal products 2.1,2 Concept Paper on the Development of a guideline on the Risk-Based approach according to Annex 1, Part IV of Dir. 2001/83/EC applied to advanced therapy medicinal products 2.1.3 Concept paper on the revision of the note for guidance on the quality, pre-clinical, and clinical aspect of gene transfer medicinal products 2.1.4 Questions and answers on gene therapy paper 2.1.5 The European Medicines Agency Road Map to 2015: the Agency's contribution to science, medicines, health 2.1,6 Consultation on Stem Cell-based Medicinal Products 2.1.7 EMA Consultation paper: guideline on quality, non-clinical and Clinical aspects of medicinal products containing genetically modified cells 2.1.8 CONSULTATION: CHMP/CAT Position staternent on Crutzfeldt-Jacob Disease and advance therapy medicinal products 2.1.9 Consultation from the Academy of Medical Sciences - Call for evidence on the function and scope of a proposed ‘single research regulator’ GTAC ANNUAL REPORT 2010 2.2 Regulatory issues specific to GTAC 2.2.1 Assessment of Mouse Feeder Cells 2.2.2 Guidance on Clinical Trials Involving Cell Therapy SECTION 3: UPDATE OF CLOSED UK CLINICAL TRIALS 3.1 Cancer 3.1.1 GTAC 083: A Phase I/II safety study of MetXia-OB83 in patients with pancreatic cancer 3.1.2 GTAC 105: An exploratory study of the safety and biological activity of OncoVex*™’“ in combination with radiotherapy and cisplatin in the treatment of locally advance epithelial cancer of the head and neck. 3.2 Infectious Disease 3.2.1 GTAC 118: Phase I study evaluating the safety and immunogenicity of a new TB vaccine, MVA85A, in healthy volunteers who are infected with HIV. SECTION 4: ANNEXES A. Membership of GTAC in 2010 B. Members Record of Attendance in 2010 C. Register of Members Interests in 2010 D. External Advisers to GTAC in 2010 E. Summary of UK Gene Therapy Clinical Research 1993 - 2010 GTAC ANNUAL REPORT 2010 FOREWORD This year we considered seven new protocols all of which received favourable opinions. The protocols included treatments for various cancers, haematopoietic stem cell transplantation, cardiovascular disease and Parkinson's disease. In addition, the Committee gave advice on four research projects undertaking preclinical research and also held discussions with three clinicians on using gene therapy investigational products in patients who do not meet the inclusion criteria of a study. We held a discussion with The National Institute of Biological Standards and Controls which also runs the UK Stem Cell Bank, about the preparation of a seed stock of mouse 3173 fibroblasts. These cells act as ‘feeder cells' for human cell cultures used in certain healthcare applications, such as corneal stem cell transplantation and skin grafting. We were presented with the preparative methods and characterisation of a new 313 line. The new 3T3 line has been prepared to replace the various mouse 3T3 feeder cell lines in use around UK transplantation centres. GTAC endorsed the use of these new feeder cells for human stem cell cultures. GTAC and the MHRA have worked together to produce advice for investigators in the UK wishing to conduct clinical trials involving cell therapy A ‘Points to Consider’ document was produced and although it is believed that it is still too early to offer prescriptive regulatory and ethical advice to stem cell researchers, it was felt that it might be helpful to set out some of the issues that need to be thought through before proceeding to a Clinical trial involving stem cells. These include immunological responses of the patients and transplanted cells, the genetic stability of cells, long term monitoring, as well as age and gender issues in patients. This advice was prepared taking into account the EC consultation document ‘Detailed Guidelines on Good Clinical Practice Specific to Advanced Therapy Medicinal Products’. We also took part in a number of EC consultation processes relating to the production of guidelines relating to trials involving Advanced Therapies. These_ included, ‘Guidelines on Good Clinical Practice Specific to Advanced Therapy Medicinal Products’, ‘Concept Paper on the Development of a Guideline on the Risk-Based Approach According to Annex 1, Part IV of DIR.2001/83/EC applied to Advance Therapy Medicinal Products’, ‘Concept Paper on the Revision of the Note for Guidance on the Quality, Pre-clinical and Clinical Aspects of Gene Transfer Medicinal Products’, ‘EMA Consultation paper: guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells’, “CHMP/CAT Position statement on Crutzfeldt-Jacob Disease and advance therapy medicinal products’, ‘Committee for Medicinal Products for Human Use — Questions and Answers on Gene Therapy’ a document which sets out a harmonized position on issues that can be subject to different interpretation or require clarification on gene therapy medicinal products and ‘The European Medicines Agency Road Map to 2015: The Agency's Contribution to Science, Medicines, Health’ which is a draft document setting out EMEA’s longer term strategy on contributing to better promotion and protection of public health, improving the regulatory environment for medicinal products and helping to stimulate innovation, research and development in the EU. This year saw a major change in GTAC’s position and processes following a review by the Chancellor the Exchequer and the Chief Secretary of the Treasury of the number and cost of Arms Length Bodies (ALBs) and Advisory Non-Departmental Public Bodies (ANDPBs) of which GTAC is one. The major change for GTAC is our transfer from Health, Science and Bioethics Division of the Department of Health (DH) to the GTAC ANNUAL REPORT 2010 National Research Ethics Service (NRES) which is accountable to the R&D Directorate, who lead on research ethics policy within DH. DH research ethics policy is set out in the Governance Arrangements for Research Ethics Committees (GAfREC) and applies to all NRES RECs. An updated harmonised UK-wide edition of GAfREC had been issued for consultation in 2009 and was now very close to being finalised for publication by RDD in collaboration with the Health Departments in the other UK countries and NRES. The policy in GAfREC will also apply to GTAC which is a new area for GTAC because up to now, GAfREC did not apply to GTAC. The plan is for us to adopt the NRES Standard Operating Procedures (SOPs) from 01 June 2011. We will remain a specialist committee and potential investigators would still be encouraged to present novel strategies and accompanying preclinical work prior to formal submission of clinical proposals. We still intend to obtain external peer review of protocols and continue our close working relationship with MHRA. This is regarded as a source of strength in current arrangements and MHRA colleagues would continue to be welcome to observe GTAC meetings. Finally | would like to express my personal thanks to past and present colleagues in the Health, Science and Bioethics Division of the Department of Health who have give GTAC such wonderful support over many years . Their knowledge, dedication and hard work have been central to the success and effectiveness of our work. Professor Martin Gore GTAC ANNUAL REPORT 2010 SUMMARY In 2010, GTAC considered seven applications to conduct gene therapy clinical trials under its remit as the National Research Ethics Committee for gene and stem cell therapy clinical research. As in previous years, the majority of applications 58% (4 studies) were for cancer with the other three single applications (14% each) in haematopoietic stem cell transplantation, cardiovascular disease and Parkinson’s disease respectively. More detailed information on all applications is contained in Section 1. In its lifetime to date, the Committee has reviewed 189 applications. Of these, 166 trials have come to fruition, with 109 closed to patient enrolment and 56 currently open or due to open for recruitment. The remaining 24 applications were either declined by the Committee or never recruited patients as they were withdrawn following initial GTAC approval. Short summaries on some of the studies which have closed during 2010 are given in Section 3. Although there was a reduction in number of submissions in 2010 than in previous years which could be attributed to the general downturn in economic activity worldwide, four separate research teams brought their preclinical data to the Committee for further discussion and advice. The Committee has always supported early discussions with researchers who are very close to bringing their study to the clinic and look forward to reviewing formal clinical applications in the not too distant future. More detailed information on these discussions is given in Section 1.6. On three occasions the Committee also informally discussed with clinicians the scientific and clinical implications of using gene therapy investigational medicinal products in patients who would not be eligible to meet the inclusion criteria for entry into a trial. Researchers value the opinion, expertise and advice that Committee members are able to provide in exploring both the benefits and possible risks that this may incur. More information on the three gene therapy products involved in these discussions are given in Section 1.5. In September the Committee contributed to the Academy of Sciences independent review of the regulation and governance of UK medical research. This call for evidence will have a long term implication for medical research in the UK and is connected to the Department of Health’s published ‘Report on the arm’s-length bodies review’ on 26 July. The report set out the steps to abolish and reorganise arm’s-length bodies in an attempt to: ‘create a more streamlined sector’; ensure ‘less bureaucracy’, ‘reduce intervention’; and enable ‘greater efficiency through contestability’. This reorganisation had already impacted on the Committee’s standing as an advisory body to Ministers and it is also planned that overall accountability for the Committee would move to the National Research Ethics Service (NRES) in 2011. In order to enable GTAC to adopt the NRES SOPs in full, some adaptation will be required to reflect the special provisions for trials of medicinal products for gene therapy under the Clinical Trials Regulations. NRES were keen to ensure that the gene and stem cell therapy research community engaged in the discussions on this transition and in November opened a consultation process until 31 December 2010. GTAC ANNUAL REPORT 2010 Over the years GTAC has continued to ensure delivery of high quality gene therapy research to patients. The Committee has seen and encouraged successful trials progress from the first in man stage through to the phase III stage where hundreds of patients may be treated in order to prove the safety and efficacy of the treatment. This commitment will continue into the future. The final section of this report details GTAC’s membership and external expert advisers who have so generously given of their time in providing expert comments on new applications. Between 1993 and 2010, GTAC has recorded the participation of over 2,000 patients in UK gene therapy trials. 10