Minutes of the second meeting of the Scientific Advisory Committee on Genetic Modification (Contained Use), held on 19th May 2004 atRose Court, Southwark Bridge, London
Minutes of the second meeting of the Scientific Advisory Committee on Genetic Modification (Contained Use), held on 19th May 2004 atRose Court, Southwark Bridge, London
Prof. Janet Bainbridge
Dr David Lewis
Dr Brian Robertson
Dr Michael Skinner
Dr Penny Hirsch
Dr Phillip Minor
Prof. Peter Williams
Prof. Martin Gore - Vice Chair
Dr Peter Searle
Mr Bob Osbourne
Dr Gary Burns
Dr Martin Carrier
Prof. Ernie Gould
Dr Peter Coyle
Dr Keith Howard
Dr Paul Logan
Mr Lee Wilson
Dr Claire Pitcher - DEFRA
Dr Androulla Gilliland - DEFRA
Dr Paul Manser - DEFRA
Dr Leslie Wilkie - Scottish Executive
Dr Paul Heeney - HSE
Dr Liz Pollitt - HSE
Ms Liz Sawyer - HSE
Mrs Sarah Senior - HSE
Dr Tony Colgate - Chiron Vaccines
Mr Lee Petts - Remsol
Dr John Wood - NIBSC
Dr Rob Coffin - Biovex Ltd
Dr Colin Love - Biovex Ltd
The meeting opened with the Professor Bainbridge welcoming everyone to the second meeting. There were apologies from Dr Mayer, Prof. Baulcombe and Dr Carr.
The minutes of the first meeting were agreed as a true record of proceedings.
The Chair canvassed members on their thoughts regarding the Q&A approach to the FMDV appendix. Members agreed that this was a clear and effective format.
The Secretariat informed the Chair that they had now received all but one of the members' declarations of interest.
The members' attention was drawn to the draft committee logo projected onto the OHP screen. Members were generally happy with the design, but suggested some minor amendments.
Action: Lee Wilson to amend and circulate to members via email.
Members were informed that the minutes would be used to draft guidelines on the use of FMDV replicons, and these would eventfully be placed onto the web site. There was a query over what had happened with the risk assessment considered at the last meeting. It was explained that it had not been an official application and had therefore progressed no further than the GMSC and that a copy of the minutes would be circulated to Dr Ryan in support of moving forward with work. Dr Ryan had also been informed by Defra that he would need to apply for an animal pathogens order and that Defra were keen to agree, with HSE, guidance on the replicon. Members were informed that the final guidelines on the FMDV replicon would come back to the committee in draft for further consultation, before being placed onto the web site.
Members were asked to consider the booklet on Security Standards for Laboratories, which had been given out on the day. They were informed that the document was restricted to users and not available for wider dissemination.
Action: Secretariat to send draft guidelines on FMDV
replicon via
email to members for further consideration at the next meeting.
The Secretariat suggested to members that it would be useful at future meetings to have a slot on the agenda for SACGM to link into other committees, particularly GTAC and ACRE. It was agreed that this would help forge a clearer understanding of what was happening in the GM world.
Members were informed that the web site, although in an embryonic stage, was up and running and that initial faults were being addressed. Furthermore, the Clinical Trials working group had now been set up and that the first meeting had been very useful. Members were reminded that the group were set up to look at how clinical trials should fit into GM and the perceived need for guidance from investigators to get trials up and running. It was further suggested that it would useful to link into GTAC and SACGM for all round clarity. The draft minutes would be ready for circulation early June and all comments would be welcomed by the secretariat.
Action: Secretariat to circulate draft minutes to members for comment.
The Chair introduced the paper and the Secretariat summarised the key scientific issues. Following the recent outbreaks of the H5N1 strain of avian 'flu, a major research programme has been instigated to develop a vaccine to protect humans from what is considered by the WHO to be a strain with pandemic potential. The main thrust of this work has been to use reverse genetics to produce a candidate vaccine. Following initial safety testing, the vaccine will be produced at pilot production scale for clinical trials. If these are successful, the WHO would like to see the vaccine produced on a large scale as part of a global pandemic preparedness programme. As the vaccine is currently produced in eggs, the containment issues are complex, and require special consideration.
HSE has been asked to clarify the legal status of reverse genetics systems, and this is covered in this paper. A question had arisen regarding the harmonisation of approach between the USA and Europe. It was suggested that authorities in the USA had ruled that the technique did not constitute genetic modification. The Secretariat was seeking confirmation from the FDA.
The Secretariat informed members that the Competent Authority has received several notifications relating to the use of influenza A viruses generated by reverse genetics systems and considered it appropriate to gain the view of SACGM.
The Chair then invited Dr John Wood from National Institute Biological Standards and Control (NIBSC) to give a presentation on the use reverse genetics to produce a H5N1 candidate vaccine.
Dr Wood outlined the background to the development of the vaccine, and the approach that had been taken to develop a safe and effective candidate strain. He explained to members that the human vaccine strain PR8 had been chosen as the recipient, and that the haemagluttanin and neuraminidase genes (H and N) would be replace by the H and N genes from the Hong Kong avian strain H5N1. He further informed members that the H5 gene had been modified to remove the polybasic cleavage site, and that this was expected to significantly reduce pathogenicity.
Following the presentation, members raised a number of questions relating to the work. The main risks appeared to be the potential for reassortment between the vaccine strain (PR8/H5N1) and a wild type influenza leading to a novel human virus with the H5 antigen. Such a scenario could theoretically lead to serious consequences of a 'flu outbreak with a novel antigen with no background community immunity.
Dr Wood agreed that this was the main risk, and was why the WHO had classified the work as requiring BSL 2+. Dr Wood stated that this was a precautionary approach that should be backed up by a vaccination programme.
Following Dr Woods presentation there were two more outside speakers. Dr Tony Colgate who is production manager at Chiron vaccines outlined the key issues involved in large-scale vaccine production from eggs. He reminded members that the notification to HSE covered both the pilot plant production and the large-scale commercial production of vaccine. He showed members a series of pictures of a typical production facility, and highlighted the key issues as protecting the workers from direct exposure, and preventing environmental exposure through airstreams or through waste streams.
Following Dr Colgate's presentation, Mr Lee Petts of Remsol gave members an outline of the key issues relating to the disposal of waste. He reminded members that the scale and nature of the waste presented particular difficulties. When heated the liquid waste solidified, forming a solid "omelette" which could not be pumped or easily removed from "kill tanks". Consequently the traditional approach used in pharmaceutical production was not available. He informed members that a range of options were being considered, however, approaches such as chemical treatment or disinfection were not viable options, due to the proteinaceous nature of the waste and it's physical properties. He informed members that in the short term the solution was to seal all waste in steel drums and take it for incineration.
The difficulties in containing an egg based production process were discussed. Dr Colgate reminded members that the plant had been in operation since the 1960s, and that it was old but successful technology, producing high yields of virus and allowing manufacture of large quantities of vaccine. The process conditions were primarily concerned with product protection, and airflows were designed to keep the working environment clean. In the longer term cell culture methods may be a viable option, but the technology was not sufficiently well developed or established at present to consider replacing the egg based approach.
The pilot work did not pose the same difficulties as the smaller scale allowed a more conventional laboratory approach to containment. Members were informed that staff would be vaccinated against 'flu, and would be provided with full respiratory protective equipment.
In response to members questions Dr Colgate noted that the approach to containing the production side of the work was still being developed, and full details would be provided prior to work commencing.
The Chair then went through a series of questions that had been included in the cover paper, noting that many of the answers had come out during the discussions.
a) Are reverse genetics systems, such as that used by NIBSC to create H5N1/PR8 with deletion of the polybasic cleavage site in HA, genetic modification as defined by the GMO (CU) Regulations?
Members agreed that within the current regulatory framework the reverse genetics process used to generate the H5N1/PR8 vaccine did constitute a GM activity. This was because the process used falls within the definition of a GM activity. This was particularly true, as the H5 gene had been modified to remove the polybasic cleavage site. Members discussed the possibility of an emergency derogation in the event of a pandemic and were made aware that there was a facility within the GM regulations for fast-track derogations. It was suggested that the user could build in a pandemic scenario to their risk assessment.
b) Are reverse genetics systems, which result in generation of viruses such as NS1 H5N1/x31, which could have been created by reassortment, genetic modification as defined by the GMO (CU) Regulations?
Members agreed that the GM regulations applied to the process used to generate the virus and not the end product. Members agreed that any work aiming to create a novel flu virus that was more pathogenic than existing strains would be covered by current GM legislation.
c) Does work with H5N1/PR8 viruses that have been shown to be non-pathogenic in avians and mammals warrant the use of level 3 containment measures and classification at class 3?
It was noted that the containment level was dependant upon the circumstances. If the H5N1 strain already existed in the population, the work could be categorised at containment level 2, but as it was not it should be containment level 3. Members generally agreed that the risk assessment should include epidemiology evidence to justify classification, but that this would change with evidence of human-to-human spread. It was also noted that any potential leak into the environment could have serious economic repercussions with the possibility of a bird slaughter policy. Members discussed the possibility of a phased risk assessment, whilst acknowledging the difficulties in suddenly changing the process of such a big production. It was recognised that waste disposal at containment level 3 on such a large scale was not really feasible unless there was scope for the process to be modified. One member asked whether the process was scaling up to produce vaccine, or to show that vaccine production could be done at this scale? Members were informed that it was to see if it could be achieved in the event of a full pandemic situation. Members were asked to consider applying containment level 3 to the work whilst the virus was not prevalent and with phased risk assessment in the event of a pandemic situation. However, members were reminded that the containment level should be applied to the risk to the operators' exposure and not the waste.
d) Are there any containment measures from class 3 that are not required for work in the laboratory or with infected animals?
Meeting containment level 3 in the pilot production laboratory was not considered to be difficult to achieve. Waste inactivation could be through the use of an autoclave, but larger volumes of egg waste would be placed into "burn bins". Derogation from full level 3 should be fully justified. It was noted that the BSL 2+ recommended by the WHO did not correlate with classification under UK (or European) legislation. Chiron would carry out no animal studies.
e) What classification is appropriate for large-scale production of characterised H5N1/PR8 virus in eggs?
Members noted that the classification was difficult to correlate with the approach outlined in the regulations. The large-scale containment tables did not reflect the unique production conditions required to produce vaccines from eggs. Containment level 3 was considered necessary to ensure that human health and environmental protection was achieved.
f) Which containment measures are required to adequately control the risk to humans (both staff and other) and the environment from large-scale production of H5N1/PR8 in eggs? In particular, please consider the following areas:
Is the use of respiratory protective equipment (RPE) appropriate?
Members considered that in current circumstances where H5N1 is not prevalent in Europe the use of RPE was required, unless the process could be fully enclosed. Dr Colgate replied that it was not possible to enclose the production process and the best way to protect operators was to put them in suits. Members agreed that RPE equipment would be desirable, because the production process could not be contained.
Action: Members agreed that RPE equipment desirable
Members went on to discuss occupational health procedures. Although there was an occupational health nurse on-site and doctor on call, they had never screened for H5N1 in blood samples. One member asked if they had mechanisms in place should there be a sudden surge in flu amongst staff. Dr Colgate replied that this would be difficult due to ethical problems and Union issues, as flu was all too common. One Member asked whether an analogy could be drawn with BCG production, because staff had to be monitored for TB and this did not present an ethical problem. One Member asked what the timescale for the work and furthermore, was it feasible to protect operators with prophylaxis during the trials? Members generally agreed that vaccination was the most sensible prophylaxis, but that it would have to be stated in the risk assessment that vaccination was compulsory.
Waste transportation/Inactivation
Members were informed that waste from production would need to be transported to Southampton once every two weeks for the duration. Members agreed that for the pilot stage they should use 45 gallon sealed drums and incinerate, but acknowledged that this would present a problem for the production stage. Members agreed that the current methodology was not suitable for large-scale work. The secretariat informed Members that HSE and Chiron would be working closely towards resolving this issue. One member asked if there was monitoring after decontamination for the presence of H5N1. Mr Colgate said that because decontamination was a standard procedure there was generally no monitoring for previous virus.
Action: Members agreed that large-scale waste disposal was
inappropriate. HSE and Chiron to work towards resolving.
6. Risk assessment enquiry - classification of selectively replicating herpes vectors for use in clinical trials - SACGM (CU)/05/04/P3
The Secretariat outlined the background to this paper. It related to the classification of a viral construct to be used in gene therapy clinical trials. It highlighted difficulties that researchers had in classifying activities in a clinical setting, where approaches to containment were not stipulated in regulation. Members were informed that in the original notification it had been stated that patients would be kept in a side room that was under negative pressure, and this was the main measure that Biovex wished to change. The Chair then invited Dr Rob Coffin and Dr Love from Biovex Ltd to outline the background to the development of the herpes vector, and why they wished to alter the classification.
Dr Coffin informed members that the vector had been developed for use as an oncolytic vector, and had been used in a number of clinical trials. He stated that the company was not seeking to change the overall classification from level 2 at this stage, but only to seek approval not to use negatively pressurised rooms. Such facilities were not widely available in hospitals and the method of administration combined with the biological properties of the vector made spread through aerosol route highly unlikely.
One Member raised concerns about HSV 1's selective replication in dividing cells and questioned the potential risk to foetal tissue and pregnant women and asked whether HSV 1 had been tested in pregnant mice? Biovex said that they had not tested the virus in pregnant mice and further stated that pregnant women would not be a target group for treatment.
One Member then asked about the risks to pregnant members of staff who may administer the treatment. Biovex responded that this issue had not been addressed.
Members were informed that all patients had been tested and were all immuno-competent. One Member said that although studies carried out with rodents had proven safe, had they considered a primate study to see if the virus could travel through the blood to the brain. Biovex responded that they did not have any plans for a primate study and that there was a good data on the historical safety profile built up in man for the G207 herpes virus. One Member observed that it was safe material and had therefore performed as predicted, adding that it was easy to say if a patient was immunocompromised, but not partially compromised. Furthermore, it was important that the nursing standard operation procedure was adhered to, particularly in the unlikely event of potential aerosol from the dead space of the needle. The secretariat responded saying that there was no indication that the herpes virus could be spread through aerosol and that although there was a potential for splashing, goggles were worn. The Chair asked how many facilities would be involved in the large trial? Dr Coffin said that there would be 20-40 patients spread across 5 specialist carer facilities.
Members agreed that there would be no requirement for patients to be nursed in negatively pressured rooms.
With regards to classification, one Member suggested that there was need to receive more information on the foetal situation because of the potential for a pregnant staff member accidentally injecting herself.
Action: Members agreed that the vector should be kept at containment level 2; however, there was no requirement for treatment rooms to be under negative pressure.
7. Increased virulence associated with Mycobacterium tuberculosis gene deletion mutants - Implication for Risk Assessment - SACGM (CU)/05/04/P4.
Dr Paul Heeney introduced the paper and summarised the key scientific issues. The paper is intended to bring to the attention of the SACGM members, recently published findings of increased Mycobacterial virulence following targeted gene deletion. It might be anticipated that most gene deletions would lead to pathogens that are less virulent. However, strains of Mycobacterium tuberculosis with engineered deletions in two-component regulatory signal transduction systems were shown to be hyper virulent using in vivo challenge experiments issues.
One Member noted that it should be obvious to users that if you delete a regulatory gene it was not an unexpected phenomenon to produce something more dangerous. Furthermore not every deletion meant attenuation; although people do often make the assumption that gene deletion meant less virulence. It was also noted that gene insertion could prove problematic too. It was noted that models used to define hyper virulence were arbitrary and did not necessarily make good models for humans. One Member said that it was unusual to see increased virulence and that many deletions do not have any effect, but occasionally virulence was increased. The Secretariat noted that you would not change the category 3 containment level for the TB work because it would be handled the same way and that the deletion mutation was the only cause of increased virulence. It was suggested that this issue could be brought out in a newsletter, with examples in the updated compendium.
The Chair asked that Dr Sue Mayer be given the opportunity to comment on this issue in the draft minutes.
8. Revision of the ACGM Compendium of Guidance - Update.
The Secretariat said that highlighting the risk assessment enquiry on herpes was to show that the current Compendium was deficient in some key areas, particularly the virology section. He informed Members that he would like to contact them with a view to setting up working groups aimed at updating the Compendium.
9. A.O.B.
The Chair informed Members that we were being encouraged to be more open and whilst acknowledging the inherent difficulties this presented, asked Members to go away and consider workable scenarios.
Action: Members asked to consider practical ideas for an open meeting and email their thoughts back to the Secretariat for further discussion at the next meeting.
10. Date of next meeting
The Secretariat informed Members that they had secured two dates for the next meetings:
11. Close
