Minutes of the 16th meeting of the Scientific Advisory Committee on Genetic Modification (Contained Use)

Held on Wednesday 18th March 2009 in the Globe Room, Rose Court, London

Open Session

Welcome

1. The Chair welcomed everyone to the 16th (and 3rd public) meeting of the Committee and extended a warm welcome to the audience and HSE's Chief Scientist, Mr Patrick McDonald. The Chair commented that the varied nature of the agenda would provide something of interest to everyone. The Chair then invited Patrick McDonald to provide some opening remarks.

2. HSE's Chief Scientist thanked the Chair and Members for the service that they provide to Government, stating that independent scientific advisory committees are very important for many reasons, in that it:

• Provides a robust degree of scrutiny;
• Provides proportionality in a regulatory framework dealing with new technologies; and
• Achieves this through participation and contribution on a 'Pro bono' basis 

3. The Chief Scientist expressed the Government and HSE's gratitude to the Committee and passed on his thanks on behalf of Professor John Beddington.

4. The Members and Assessors introduced themselves and the Chair described how the Committee functioned and its role, which is ultimately to provide independent advice to the Competent Authority through a competency-driven membership. The Committee was soon to embark on an exercise to recruit three new members and the Chair encouraged appropriately qualified members of the audience to consider applying.

Minutes of the previous meeting

5. Other than one amendment to paragraph 7, the minutes were accepted as a true and accurate recording of the proceedings of the 15th meeting.

Matters arising & Secretariat report

6. The Secretariat updated the Committee on a number of matters arising and informed Members of several other activities:

7. SACGM(CU) members comments on the proposed clinical trial involving a live attenuated bovine parainfluenza virus, for vaccination against respiratory viral diseased, were circulated to Defra and raised with the Advisory Committee for Releases into the Environment (ACRE). The notifiers have since responded to the questions raised and Defra has issued consent for the experimental release under the Genetically Modified Organisms (Deliberate Release) Regulations.

8. Members were informed that the revised Section 2.11 of the SACGM(CU) Compendium of Guidance related to retroviruses/lentiviruses and ratified at the last meeting, has replaced the original section in the on-line version of the Compendium. Duty holders have been notified of this change.

9. Classification of non-circulating strains of influenza considered to have pandemic potential is the subject of a working group being led by the Advisory Committee on Dangerous Pathogens (ACDP). The SACGM(CU) has been asked to participate and will be represented by Dr Keith Howard, health permitting.

10. Dr Martin Cannell (Defra) provided feedback from ACRE, in particular that a new member (Professor Kathy Bamford of Imperial College) has been successfully recruited to the committee. Professor Bamford has a background and expertise in clinical microbiology.

11. Professor Martin Gore provided feedback from the Gene Therapy Advisory Committee (GTAC) on three aspects of the Committee's business:

• The committee recently reviewed a protocol for the use of retroviral transduced foetal-derived stem cell for treatment of stroke patients;
• Through GTAC facilitation with other regulators and interested parties, a draft regulatory route map for those proposing to develop stem cells for clinical application has been devised;
• GTAC working with other regulators and scientists have discussed a way to clarify the regulatory requirements for the GMP production of gene therapy vectors. GTAC have indicated that they welcome dialogue with investigators at any stage in the vector development process.

12. John Newbold provided feedback from ACDP. In particular the committee has been involved (in conjunction with SACGM(CU)) in the development of the new containment guidance, covering human, animal and genetically modified pathogens as part of a new single regulatory framework (SRF) for deliberate handling of pathogens, discussion of which is the subject of one of the main agenda items. ACDP has also been involved in revising guidance on the management of viral haemorrhagic fever patients - this is over 10 years old. The first draft of the new guidance is expected in June 2009.

13. The Chair invited Dr Gary Burns to update the Committee on the report of 'Biosafety Europe', a consortium funded through the European Commission, which makes several key recommendations in respect of high containment facilities (containment levels 3 and 4). Of note, are some parallel recommendations within the Biosafety Europe and those of the Callaghan review. The recommendations include the need for containment to be risk based; adoption of a similar approach to risk assessment and containment for both -naturally occurring and genetically modified micro-organisms; and development of competency standards for biosafety professionals.

Action: Secretariat to provide details of where the report can be obtained - the report can be downloaded from the following website: Biosafety Europe - Final Considerations

Single regulatory framework for contained use of human, animal and genetically modified pathogens - SACGM/03/09/P7

14. The paper was introduced by HSE representatives Mrs Lorraine Medcalf and Mr John Newbold. The proposed single regulatory framework (SRF) is intended to encompass the work involving the deliberate handling of human, and animal pathogens and genetically modified micro-organisms, currently regulated by three separate pieces of legislation - the Control of Substances Hazardous to Health Regulations 2002, the Specified Animal Pathogens Order 2008 and the Genetically Modified Organisms (Contained Use) Regulations 2000 (as amended in 2005). Mrs Medcalf provided the Committee with an update on progress with developing the SRF. Of note has been the challenges presented by amalgamating several pieces of legislation based on different European directives, which on the one hand, necessitates implementing minimum standards and on the other, avoiding over-implementation standards.

15. Mrs Medcalf explained that a legislative reform order was necessary to amend section 1 of the Health and Safety at Work etc Act 1974 (HSWA), which would in turn provide the legal mechanism to make new regulations for animal pathogens under HSWA. A formal three month consultation period on the LRO and SRF is planned for July 2009.

16. Mr Newbold went on to describe a workstream, led by ACDP and involving participation by SACGM(CU), to formulate a set of common containment measures for human, animal and genetically modified pathogens. In addition, the working group intends to produce associated guidance to support the proposed common containment measures. One aim of the working group is to devise four appropriate hazard group definitions, from which will be derived an Approved list of human and animal pathogens and that will underpin four common containment levels. The proposed SRF will require activity classification based on risk assessment akin to the current system implemented by the GMO(CU) regulations. The principle of derogations for containment measures deemed not necessary by the risk assessment will form a key tenet of the containment guidance. A final draft of the common containment measures and associated guidance is expected to be delivered by June.

17. SACGM (CU) Members of the containment working group provided insight into their participation in the working group, highlighting the extensive deliberations over the hazard group definitions, tasked with encompassing animal and human pathogens that differ greatly. The definitions are also intended to accommodate emerging pathogens.

18. Members were reminded that the focus of the SRF did not at this time include animal pathogens currently outside of SAPO (e.g. bee pathogens) or indeed plant pathogens. It is anticipated that the proposed hazard group definitions would be able to accommodate the former, should this be deemed necessary in the future. The issue of plant pathogens is currently being considered by Defra and may be taken forward as a parallel workstream. The security requirements imposed by the Anti Terrorism Crime and Security Act is also outside the scope of the SRF and will remain as separate legislation. The Chair thanked all involved, and encouraged the audience to become involved in the consultation process.

Consideration of a notified activity involving Eimeria tenella as an heterologous vaccine vehicle - SACGM/03/09/P4

19. HSE representative Dr Paul Heeney introduced the agenda item and informed the Committee that HSE sought advice on the appropriate classification of this work, which involves the protozoan parasite Eimeria, an organism which although endemic in the UK causes significant economic impact on the poultry industry but is not classified as a SAPO pathogen. The parasite is not a human pathogen. Based on the selection of control measures (e.g. room fumigation) from containment level 3, the CA are of the view that the work should be classified as Class 3, whilst the notifier's view is that the proposed measure is largely based on the need for strain purity rather than environmental protection.

20. Dr Damer Blake (Institute for Animal Health) gave a short presentation outlining the biological properties of the organism (including host range, specificity, prevalence, life cycle), the proposed genetic modifications and the containment measures and philosophy for the work. 

21. Following wide ranging discussion by Members, the Committee concluded that although the proposed modifications of Eimeria were not considered to increase the virulence of the protozoan parasite, the novel nature of the parasite and its known pathogenicity in poultry is considered to pose a significant hazard to the environment. The proposed containment, including the necessity for whole room fumigation, whilst assisting with the need to ensure strain purity, was also recognised as necessary to prevent dissemination of the protozoa into the wider environment. Consequently, the Committee agreed that the proposed containment measures appear to be warranted and appropriate for the work, and therefore necessitate a classification of Class 3.

22. Members pointed out that not all containment measures from containment level (CL) 3 were deemed necessary for the proposed activity hence it should be possible for the IAH to request appropriate derogations from the CA.

Action: HSE to write to IAH based on the scientific advice from the Committee

Emerging genetically modified stem cell therapies - SACGM/03/09/P5

23. The Secretariat introduced the agenda item by outlining the expected benefits of stem cell research and its extension into clinical applications. Given the rapidly expanding topic, and following from the initiative of GTAC in formulating a regulatory route map for those working in this area, the evolving area of stem cells was brought to the attention of the Committee to seek some advice on areas of potential or inherent risks of the technology and guidance on the classification requirements for such work. The Chair reminded the meeting that the remit of SACGM(CU) is to look at the risk to the safety of workers and the wider environment rather than patient welfare or ethical considerations, which were dealt with by others.

24. The Chair welcomed Professor Andrew Baker (University of Glasgow) an expert in the field and member of GTAC, who gave a short presentation on the approaches to genetic modification of stem cells including embryonic and adult derived origin. Initial attempts to induce pluripotency in adult stem cells have focused on the use of integrating viral vectors and involving the use of potential oncogenic sequences. For applications destined for the clinic, it is more likely that modification will involve the application of adult derived stem cells and the use of non-viral delivery systems tailored to individual patients thereby avoiding risks related to allogenicity and tumourogenicity.

25. Members considered that although the pluripotent nature of some stem cells present some inherent risks (e.g. uncontrolled growth) that needed to be adequately considered, the approach to genetic modification of mammalian cells is well established (e.g. the use of viral vectors). Whilst it is anticipated that much of the development work will be aimed at clinical applications, a significant proportion of research will focus on the use of modified stem cells to engineer models of disease. It is envisaged that such work will continue to use replication defective retroviruses to deliver oncogenes (e.g. c-myc) or a raft of genes that might induce pluripotency in cells that are exposed. SACGM(CU) existing guidance on the use of such vectors is pertinent and should be adequate to facilitate appropriate risk assessment. However, there are specific examples where further consideration by the committee may be necessary e.g. where stem cells are developed that are intended to avoid an allogeneic immune response, which may be more hazardous given the greater potential for unchecked self renewal.

Action: Where appropriate, Secretariat to bring relevant notifications related to stem cells to the attention of the committee

Audience Questions

26. The Chair thanked Members and invited speakers for their contribution to the morning session before inviting questions from the audience. The following questions were posed and answers provided:

• Q1) Stem cell research - question raised related to the classification of activities involving the use of lentiviral/retroviral vectors expressing multiple genes that might induce pluripotency in adult stem cells? The Committee were of the view that the risk assessment for the activity would conclude that provided the viral vector was replication defective, then Class 2 is likely to be the maximum classification for the work. Indeed, for some constructs, where the insert is not considered to present a risk to human health and where sharps are not used, then it would be possible to classify the work as class 1 - this is in line with the existing guidance in the SACGM(CU) compendium.
• Q2) Stem cell research - question related to how the HSE would be made aware of such work if it were classified as Class 1 activity? The Secretariat responded by indicating that all sites need to register with HSE their intention to undertake genetic modification activities for the first time. However in this instance if the site had already registered with HSE, there would be no need to notify subsequent Class 1 activities, which are deemed to be of no or negligible risk to human health and the environment. The notification requirements are supplementary to the overarching requirements to undertake risk assessment for the work, for the local genetic modification safety committee to advise on the risk assessment and for the individual undertaking the work to apply appropriate and sufficient containment and control measures. HSE also undertakes inspections of sites undertaking GM activities across the risk classes, which includes discussions in respect of classification of GM activities.
• Q3) Single regulatory framework - question related to what changes in laboratory containment are likely to result from development of a common set of containment measures for human, animal and genetically modified pathogens and will this have implications for the design and new build of laboratories? One Member involved in the containment working group felt that adoption of the GMO(CU) model would have a greater impact on those currently working with human or animal pathogens in compliance with COSHH or SAPO respectively. The GMO(CU) regulations introduce the concept of activity classification and derogation of measures deemed unnecessary. The Secretariat added that the changes to the containment requirements were limited by the requirements of the two European Directives for genetically modified organisms and human pathogens. The two directives have not been changed hence neither have their containment requirements. There is a legal requirement to implement these minimum standards, which is balanced with the need to avoid over implementing or 'gold plating', whereby the national standard is significantly greater than that required by the directive. A great deal of time has been spent by the working group in considering these factors.
• Q4) Single regulatory framework - question related to the process of derogation from applying full containment and control measures required by a particular containment level and whether organisations would criticised for applying too many derogations? The Secretariat responded that the intention of the new single regulatory framework is to develop a legislative framework that is risk based. Sir Bill Callaghan recognised the merits of such an approach and identified the GMO(CU) regulations as a framework on which to deliver such a regulatory system. The principle of derogation is pivotal to the success of these regulations given that they encompass a huge range of pathogens that present different risks to the operator and the environment. Consequently if the risk assessment determines that a particular containment measure is not required then it is not necessary to apply that measure. Clearly where derogation is sought, then the rationale needs to be justified and agreed with the regulator. Based on this system, the GMO(CU) regulations have worked effectively and provide a transparent, risk based and proportionate approach to containment.
• Q5) Single regulatory framework - question related to whether it was possible to avoid the use of certain terminology i.e. 'class', which has a different meaning when used to refer to microbiological safety cabinets and activity classification? The Committee pointed out that the regulations and terminology had yet to be finalised. However it recognised that one of the issues raised by Sir Bill Callaghan was the complexity and variation in terminology used in the existing three pieces of legislation and the wider international biosafety community. Every effort is being made to introduce clarity to the new regulatory framework.
• Q6) Single regulatory framework - question related to what activities were planned to bring those unfamiliar with the GMO(CU) regulations up to speed with their requirements upon which the single regulatory framework will be based? The Secretariat responded that a number of stakeholder events had already taken place, including this SACGM(CU) public meeting and further events were planned prior to the formal consultation process. It was acknowledged that it had proved more difficult to engage certain groups (e.g. clinical diagnostics) than others but efforts were on-going and would continue beyond implementation of the new regulatory framework.

27. The Chair thanked the audience for their contribution and brought the morning session to a close.

Afternoon Session

Synthetic biology - recovery of a synthetic bat SARS-like coronavirus - SACGM/03/09/P6

28. Secretariat introduced the paper, which highlights a scientific article by Becker et al (2008)¹ in which a chimeric bat/human coronavirus was successfully engineered, to address a specific evolutionary question in relation to human severe acute respiratory syndrome coronavirus. The paper was provided for Members information, in respect of developments in the area of creating synthetic microorganisms.

29. Members briefly discussed the paper and were of the view that the techniques being used were not significantly different than those used for other viruses, which utilise a reverse genetics approach. Similarly Members were of the view that the existing procedure for risk assessment would have been appropriate to identify the change in tropism seen with the constructed virus and consequently existing guidance is deemed adequate.

Feedback from European Commission new techniques working group - SACGM/03/09/P8

30. The Secretariat provided brief feedback from two meetings of the European Commission working group (WG) on new techniques involving genetic modification. The main output of the WG will be a report containing scientific advice on a number of new techniques and their applicability to the two GM directives (i.e. contained use (90/219/EEC) and deliberate release (2001/18/EC)), which is expected to be delivered October 2009.

31. The two working group meetings were deemed to have been productive. The initial meeting was used to: clarify and finalise the terms of reference of the working group; identify and prioritise the list of techniques for consideration; and allocate work to the different Members of the working group, involving assessment of a specific technique against a set of defined criteria.

32. The second meeting was spent discussing each of the techniques and their assessments. Whilst conclusions on whether the techniques were encompassed by the GM directives were not reached, the discussions identified some significant differences in the approach to interpreting the directives by different member states. These cross cutting issues are likely to be the focus of the next meeting in April 2009.

33. Members were supportive of the initiative and cognisant of the difficulties in reaching consensus across different member states. However, the Committee were of the view that a consistent approach across Europe to GM activities would greatly facilitate pharmaceutical and medical applications of the technology.

Draft annual report for 2008 - SACGM/03/09/P9

34. The Secretariat introduced the paper, in which the SACGM(CU) draft Annual Report for 2008 was brought to Members attention. The Chair commented that the annual report is an important part of informing the Chief Scientific Advisors as well as the wider community of the work of the committee. Members were asked to provide comments on the report with the aim of publishing the report on the website in the summer.

Action: Members to forward comments on the annual report to the Secretariat for publication of the report in July.

Any other business

35. The Secretariat circulated a report from the European Centre for Disease Prevention, which related to an incident involving the contamination of an experimental live attenuated influenza vaccine with live A(H5N1) virus, which was used in a commercial research setting in Austria. The contaminated vaccine was distributed to contracted laboratories in Slovenia, Germany and Czech Republic. Although representing a serious biosafety failure, there have been no reports of operator or environmental exposure.

Close

36. The Chair thanked everyone for their attendance and contributions and drew the meeting to a close.

Date of next meeting

37. Wednesday 15th July 2009 at HSE offices in Rose Court.

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Footnotes

• Becker, M. et al (2008), 'Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice'; Proceedings of the National Academy of Sciences, 105(50), 19944-19949