Present: Professor Norman Nevin (Chair), Professor Terry Hamblin, Dr Peter Harris, Professor Andrew Lever, Professor Alex Markham, Mrs Fiona Sandford, Mr Michael Harrison, Bishop Dr Lee Rayfield (to item 10), Professor David Harrison, Mrs Debbie Beirne, Professor Jim Neil and Professor Martin Gore.

Secretariat: Dr Monika Preuss, Dr Jayne Spink & Mr Daniel Gooch

Observers: Dr Liz Pollitt (MHRA), Dr Paul Raptopoulos (MHRA), Dr Paul Logan (HSE), Mr Jim Connelly (DH) and Dr Carol Penning (MHRA).

Apologies: Dr Adrian Lepper, Professor Nick Lemoine, Dr Caroline Benjamin, Dr Michael Waterhouse and Dr Richard Ashcroft.

1: Welcome

The Chair welcomed the Committee to its 55th meeting.

2: Minutes of the 54th meeting of GTAC

The minutes were agreed as an accurate and true record of the 54th meeting.

3&4: Matters Arising & Chairman's Actions

A number of letters were sent out, and received, concerning correspondence arising from the last meeting, and Chairman's Actions, none of which gave rise to any discussion.

5: Report from the DH/GTAC flagging workshop

Since the last meeting a working group has produced five recommendations on the future of the flagging project.

Recommendation 1: The flagging project should continue with the pilot phase to end with first GP returns in 2005. The intention is to publish the results from the pilot phase in a peer-reviewed journal.
Recommendation 2: Following the completion of the pilot phase, the dataset for collection should be reconsidered. An assessment of the long-term viability of project should be conducted. This may need an exploration of ways of automating and simplifying the reporting process (scanning etc) and the GP questionnaire.
Recommendation 3: The flagging project should be appropriately resourced. DH should look into providing additional funding and/or collaborators and should consider outsourcing the project to an external contractor.
Recommendation 4: Flagging may not be appropriate for all trial participants. A tiered system based on risk & hazard assessment and patient population should be developed.
Recommendation 5: The potential for global/european harmonisation on long-term follow-up for gene therapy patients should be explored.

The Committee was content with the five recommendations, and discussed the requirement for flagging should be dependent on a risk assessment per trial, with possibly a tiered approach to monitoring.

The secretariat will look into this.

6: Future processing of antisense applications

What applications of antisense does GTAC wish to consider in future?

GTAC was asked whether it wished to continue to review all applications of antisense, and whether it would be workable for some applications to be considered by an ordinary MREC.

GTAC discussed the possible options in detail. In particular, there were implications and issues around which forms to use, time tables for dealing with applications (60 days vs 90 days), whether more frequent GTAC meetings would be needed, and what to do about long term monitoring.

The secretariat said that they would write to UKECA to seek recognition as an MREC that would allow for GTAC approval of trials outside the European definition for the purposes of future applications.

7: New Protocol: GTAC 110: A Single Arm Open-Label Phase I study of an injectable replication-incompetent adenoviral vector encoding a factor VII immunoconjugate to induce a cytolytic immune response against the vasculature of carcinoma of the bowel with metastatic lesions to the liver

This was an application for gene therapy in 12 patients with inoperable adenocarcinoma of the colon with metastatic disease to the liver, for a three country trial (US, UK & Holland).

Tumour growth and the ability to metastasise are linked to the ability of the tumour to promote angiogenesis. The hypothesis is that if it were possible to cut off the blood supply, the tumour would die. The study seeks to exploit this by way of a designer molecule called the "Icon" protein.

In discussion, the Committee decided to decline this application as their view was that they were not being presented with a complete protocol at this stage. However, they stated that they would welcome a resubmission at a later stage.

8: Pre-submission presentation: Proposed trial of CFTR gene transfer to CF patients and non-CF patients

The Cystic Fibrosis Consortium is planning to conduct two clinical trials of gene transfer to the lung and wanted GTAC's view on a number of issues to do with trial design.

The first a phase I pilot study (standard rising dose, single application) in CF patient. The second an additional pilot study, involving non-CF subjects who are scheduled for lobectomy or pneumonectomy, predominantly for lung cancer indicators. This would be timed to provide data for expression some weeks later when the lobe or lung is resected.

GTAC discussed the merits of the proposal and decided that because of ethcial issues that the risk that the procedure may make the patient unfit for surgery, the approach would be unethical. It would be better simply to go for a phase II trial in CF patients based on the results from the previous phase I trials and other work since then.

GTAC declined this approach as it stands and asked the secretariat to give feedback on this pre-submission presentation.

9: GTAC 111 A Phase II Double Blind, Cross-Over Study to Compare the Safety and Efficacy of 125, 250 and 500 ug/kg Monarsen (EN101) administered to Patients with Myasthenia Gravis

Myasthenia Gravis (MG) is an autoimmune condition that causes weakness and fatigue in muscles. It has previously been tested in Israel and the UK in a phase I study in 16 patients with few side effects and some promising results.

The Committee was content with this protocol, so the discussion was relatively short before approval was given.

10: New protocol: GTAC 112 and 113 A Phase III Randomized, Open-Label Study of Docetaxel in Combination with CG1940 and CG8711 versus Docetaxel and Prednisone in Taxane-Naïve Patients with Metastatic Hormone-Refractory Prostate Cancer With Pain

A Phase III Randomized, Open-Label Study of CG1940 and CG8711 Versus Docetaxel and Prednisone in Patients with Metastatic Hormone-Refractory Prostate Cancer who are Chemotherapy-Naïve

These are two related protocols for phase III trials in patients with prostate cancer that has metastasised to the bone. his is the first application to GTAC for use of an AAV vector.

• The GTAC 112 study aims to recruit patients with hormone refractory prostate cancer with pain. The idea is to compare chemotherapy+vaccine with chemotherapy alone.
• By contrast, the GTAC 113 study will enrol patients who are chemotherapy-naïve and who are not taking pain relief. It aims to compare the vaccine to chemotherapy treatment.
  

There was some discussion as to whether the two trials could be merged into one, but given that each study has a different patient set and are both up and running in the US this didn't seem a productive way forward. Other comments concerned text in the PIL and consent form, as well as amending the inclusion criteria concerning CD4+ lymphocytes, and including additional immunological measurements. Approval was granted to both protocols.

11: Pre-submission presentation: Gene correction therapy for DMD

Dr Dominic Wells, on behalf of the DMD consortium, joined GTAC for this discussion. In 2004, the Muscular Dystrophy Campaign was awarded by DH £1,600,000 for research, followed by a phase I/II clinical trial, on Duchenne Muscular Dystrophy (DMD) (the Genetics White Paper money).

The consortium wanted to discuss with GTAC the design of this clinical trial. In discussion the Committee considered that it would be better to go for a systemic delivery trial in children. GTAC also discussed pre-clinical toxicology, pain from muscle biopsies and setting the lower age limit for inclusion

12: SUSAR update

The Secretariat had compiled the new SUSARs/SAEs (#178 to #184) received since the last meeting. There were no comments.

13: GTAC/CSM final recommendations

The final GTAC/CSM recommendations were published on the GTAC website in July 2005. The recommendations were expected to be printed in the next issue of Human Gene Therapy (October issue).

14: GTAC's guidance on compassionate use applications

In view of comments received about an application to treat a patient off protocol, the Committee had a brief discussion of "compassionate use" and the circumstances under which GTAC would consider such applications.

15: Any other business

There was only one issue for discussion, the response letter by Dr Evans to GTAC's approval letter of the GTAC 102 trial. At the time, GTAC had asked for additional pre-clinical data which are now provided. The Committee was content with the information provided.

Next meeting: 7 December 2005

GTAC Secretariat
November 2005

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