Draft minutes of the 15th meeting of the Scientific Advisory Committee on Genetic Modification (contained use)

Held on Thursday 20th November in the Globe Room, Rose Court, London

Welcome

The chair welcomed everyone to the 15th meeting and extended a welcome to new attendees, Dr Sara Hayes from the Welsh Assembly and Dr Susan Grogan from HSE. Members were reminded to submit their expenses claims promptly following the meeting.

Minutes of the previous meeting

The minutes were accepted as a true and accurate recording of the proceedings of the 14th meeting.

Matters arising & Secretariat report

The UK Competent Authority intends to pursue the issue of the exemption of safe organisms and the item has been added to this year’s work plan. The suggested approach is to: a) canvas views from other Member States on their approach to the issue i.e. both Germany and Netherlands are seeking to exempt some organisms; b) undertake a desk-based exercise to review the approach to this issue internationally to ascertain what can be learned from other countries; and c) possibly pulling together an example submission, which could be used to assess the existing system – both b) & c) are dependent on securing resources for the work. Given current priorities (specifically the implementation of the Callaghan recommendations), it is likely that this issue will be addressed next year.

Action: Secretariat to add this topic to the work plan for 2009. Views from other EU member states will be canvassed.

Members’ comments in respect of the Griffin review of high containment facilities were forwarded to the secretary of the Griffin review; some of which were incorporated into the final report. The Chair reiterated the need to invest in the on-going support/maintenance support of Containment Level (CL) 4 facilities.

The committee were informed that the categorisation of non-circulating influenza strains of pandemic potential (e.g. 1918 influenza virus) has been discussed by the Advisory Committee for Dangerous Pathogens (ACDP). It is ACDP’s intention to supplement existing guidance on work with influenza viruses to include specific reference to these influenza strains. Representatives from the Health Protection Agency are to be invited to draft the guidance. It is likely that input will be required from SACGM(CU) if any genetic modification (GM) related issues arise. The time scales for drafting this guidance have not been set but it is likely to commence in 2009.

The Secretariat updated the committees on a recent Biotechnology Biological Sciences Research Council organised event, attended by representatives from SACGM(CU) and ACRE, to discuss the topic of synthetic biology and whether existing legislation i.e. contained use and deliberate release regulations are adequate to encompass the proposed techniques in this field.  The meeting involved representative scientists, research funding agencies and other interested parties including a number of Royal Societies. A number of scenarios were discussed, the outcome of which was a consensus that most of the proposed techniques would be encompassed within the existing GM legislative framework. It was recognised that some of the activities would present significant challenges in respect of risk assessments, however, possibly not any greater than currently presented. One area that may not be covered is the generation of completely artificial organisms. Current legal opinion is that such artificial organisms generated from proto-cells would be outside of the UK legislation, which is dependent on altering existing microorganisms.

Dr Gary Burns provided feedback on synthetic biology from a meeting in Washington hosted by the US National Science Advisory Board for Biosecurity at which a speaker from the National Institutes for Health indicated that it is likely that the National Institutes for Health guidelines for recombinant DNA activities will be revised to encompass synthetic genomes. At the same meeting, a speaker from the gene synthesis industry also expressed support for the creation of a governance framework and associated safety protocols to foster an appropriate regulatory environment for the synthetic biology industry.

Action: Secretariat to provide updates on any relevant developments in the field

The SACGM(CU) annual report for 2007 will be published on the HSE website imminently.

The Code of Practice for SACGM(CU) has been drafted to support the implementation of the Code of Practice for Scientific Advisory Committees (CoPSAC). The draft has been circulated (as an annex to the papers) for Members’ comments and will be ratified at the next meeting.

Action: Members views/comments on the Code of Practice should be sent to the Secretariat. Final version is to be ratified at next meeting.

The Chair thanked the following Members namely Gary Burns, Peter Coyle, Ernie Gould, Penny Hirsch, Phil Minor, Brian Robertson and Peter Searle for agreeing to renew their membership of SACGM(CU) for a further three years and thanked all Members for their efforts and commitment to the work of the committee and noted the benefits in maintaining continuity. Three additional Members need to be recruited to bring the committee to full cadre.

Action: Secretariat to undertake recruitment of new Members

The Secretariat informed the committee of two minor GM incidents, investigated by HSE inspectors:

• The first incident involved the unauthorised consumption of an experimental genetically modified tomato expressing anthocyanins (from Snapdragon flowers), by a visitor at a GM premises. The transgenes potentially confer health protecting properties to the fruit as a result of their antioxidant and anti-inflammatory activity. The duty holder was advised to raise staff awareness of site rules regarding supervision of visitors.
• The second incident involved a needlestick injury with a vaccinia virus (Western Reserve strain) construct. The injured person inadvertently grazed the back of the hand whilst undertaken in vivo procedures. A lesion developed and cleared without medical intervention.

Members were provided with an update on issues, relevant to SACGM (CU), discussed at other scientific advisory committee meetings specifically ACDP, the Advisory Committee for Releases into the Environment (ACRE) and the Gene Therapy Advisory Committee (GTAC):

• ACDP - reclassification of N. meningitidis from hazard group (HG) 2 to HG3 was discussed. The outcome was to recommend retaining a categorisation of HG2, however providing additional guidance on working with Neisseria meningitidis, particularly in the diagnostic environment, that would advocate use of a microbiological safety cabinet for handling suspect specimens;
• ACRE - a European Commission working group on ‘new technologies’ was discussed. The objective of this working group is to ‘evaluate a list of new techniques for which it is unclear whether they result in genetic modification’. This working group was established in response to an increasing number of enquiries about the status of products developed through new techniques. In addition, the next meeting of ACRE will be an open meeting and will include applications submitted under GM food and feed regulations, Part B application for an experimental release as part of a clinical trial for a GM respiratory diseases vaccine;
• GTAC - ethical approval for the GM respiratory disease vaccine (to be discussed in paper SACGM/11/08/P5) was given.

Callaghan update - development of a single regulatory framework for contained use of biological agents (SACGM/11/08/P3)

Members were reminded of the proposed development of new regulations, which will cover deliberate work with wild-type human and animal pathogens (currently regulated under Control of Substances Hazardous to Health (COSHH) and Specified Animal Pathogens Order (SAPO)) and all genetically modified microorganisms currently encompassed by the GMO(CU) regulations. The possibility of extending the regulatory framework to include wild-type plant pathogens and non-SAPO animal pathogens is being explored by Defra. Inadvertent exposure to hazardous microorganisms (e.g. Legionella) will be retained within the COSHH regulations.  

The Secretariat explained to Members that the European Directives set out minimum requirements, which have to be encompassed within the single regulatory framework. This may present some difficulties, where derogations used effectively in GMO(CU) regulations, may not be as amenable to the minimum requirements of the Biological Agents Directive. Conversely, the opportunity exists to address specific areas where the Contained Use Directive may have been over implemented. One objective of the new framework is to reduce the regulatory burden on dutyholders from the various sets of regulations. The workstreams on formulating a set of common containment measures and the activities involving stakeholder engagement were raised as points of relevance to the committee. Members were in agreement that the next SACGM(CU) meeting in March 2009, will be an open meeting and will include an interactive agenda item on progress with the single regulatory framework.

Action: Secretariat to confirm dates for March open meeting and send reminder to Members that a good attendance is important.

Genetic modification of bacterial regulatory systems – alteration of virulence in Burkholderia mallei (SACGM/11/08/P4)

Advice was sought from the committee on whether there are any generic factors that risk assessors can be directed to when tackling activities involving modification of bacterial regulatory systems. A specific example of modification of a global regulator in Burkholderia mallei was discussed, whereby alteration in the regulator resulted in changes to ~50 downstream genes. It was noted that although changes in pathogenicity were feasible and indeed likely, tight regulation of gene expression is a key component of bacterial virulence in different environments hence disrupting this process is often associated with a loss of fitness. Members also raised the difficulty in extrapolating results from pathogenicity studies in animals to humans. The B. mallei work highlighted the need for a cautionary approach to risk assessment.

The committee recognised the complexity and challenge for undertaking risk assessments for work of this nature and were of the view that given the inherent complexity of global regulatory systems, drafting generic advice for risk assessors would be problematic and possibly misleading. The suggested approach was that each case needs to be considered individually.

Attenuated inhalation vaccine for respiratory viral disease (SACGM/11/08/P5)

The sponsors of this proposed clinical trial in infants and children involving a live attenuated bovine parainfluenza virus (bPIV) expressing human PIV and respiratory syncytial virus (RSV) proteins, have elected to consider the trial as a deliberate release rather than contained use GM activity. Consequently, the sponsors have applied for consent, from Defra, for a Part B experimental release under the GMO(DR) regulations. Although SACGM(CU) is concerned with contained use activities, the trial was brought to the attention of the committee for interest and because of their experience in dealing with similar contained use clinical trials. One Member declared an interest, as their employer is part of the same organisation as the trial sponsor, however as they have no direct interest in the work they were invited to contribute to the discussion.

Members discussed a number of issues in relation to the risks to human health and the environment from this clinical trial, including whether the possibility of circulation of virus causing subclinical infection may contribute to emergence of a more hazardous or new virus; and whether more basic studies in primary rather than cell lines would be informative. However, the construct Medi-534 and the bPIV backbone have been used for a number of human clinical trials in both adults and children, with no significant adverse events and little evidence of virus shedding from vaccine recipients. Members felt that more information could be provided in the following areas:

• potential for enhanced respiratory disease in vaccine recipients i.e. the study age group reportedly being at greatest risk of antibody mediated enhanced disease is 0-12 months (i.e. RSV naive individuals) hence the proposed monitoring for RSV enhanced disease is highly appropriate and is of relevance to the expected consequences of exposure of RSV naive children in the wider environment;
• potential for virus shedding from naive volunteers (particularly in paediatric units which might care for immunocompromised or HIV+ children or indeed those receiving immunosuppressive therapies for treatment of cancer) and may involve the same staff in administering the vaccine and treating in-patients;
• relevance of the proposed sampling time points for virus detection i.e. sampling is planned from day 7 onwards, however in previous trials the only detected shedding was at day 3. Given the potential for enhanced shedding in this age group of RSV naive volunteers, an earlier commencement of sampling may be more informative, if practical;
• potential for residual virus infectivity in cattle (bPIV3 backbone) i.e. there appeared to be an absence of data relating to the degree of pathogenicity for Medi-534 in bovine cells or cattle; or a clear rationale for an expected reduction in replicative capacity or pathogenesis in comparison to wild type bPIV. Given that there is no reason to suspect that the virus will not be able to replicate in bovine cells, it may be important to include in the exclusion criteria, steps to minimise contact between the vaccine recipients and susceptible cows, calves (e.g. preclusion from attending open farms during trial period).

Action: Secretariat to formulate discussion into advice for the ACRE Secretariat.

Classification of retroviral / lentiviral vectors - revision of the SACGM(CU) compendium of guidance (SACGM/11/08/P6)

The retrovirology section of the SACGM(CU) Compendium of Guidance has been revised. Members’ comments from the last meeting have been incorporated and the revision circulated to a key group of stakeholders, the feedback from whom, was on balance very positive, particularly in terms of clarifying what was expected for classification of the work. Members’ discussed the revised guidance and the stakeholder comments, one of which raised concerns over the impact of the revised guidance on clinical applications. Members felt that the Compendium adequately provides practical guidance (Section 6) on application of containment and control measures to the clinical environment, such that the revised retrovirus guidance would not place additional burden on clinical applications. Members agreed that the revised version was comprehensive and clear on what was expected and ratified its publication.

The relevant section will be replaced in the Compendium of Guidance and duty holders informed of the changes by email and GM newsletter. The Chair commented that the revision exemplifies the way in which the Compendium of Guidance was intended to work, i.e. as scientific understanding changes; the guidance can be adapted and thus remain up-to-date.

Action: Secretariat to revise on-line version and inform duty holders of change to the Compendium of Guidance.

Seasonal influenza virus vaccine – classification of high growth reassortants derived through reverse genetics (SACGM/11/08/P7)

The use of reverse genetics in the production of high growth A/PR8 based reassortant seasonal influenza vaccine seed strains was discussed. The technique offers a number of advantages over traditional reassortment methods. However, the use of this GM technique possibly raises additional regulatory oversight and requirements. The committee was asked for advice on whether the use of reverse genetics conferred any additional hazards over and above traditional reassortment and provide advice on the most appropriate classification for this activity.

The committee agreed that the use of reverse genetics to construct A/PR8 based seasonal influenza vaccine seed strains was more specific and targeted than traditional methods and did not induce any additional safety concerns above those generated by traditional reassortment. In terms of classification, whilst the PR8 reassortants were considered to present negligible risk to human health, Members felt that further information would be needed on the residual pathogenicity of A/PR8 in mice and infectivity in pigs, for the work to be classified as a Class 1 activity. Members could not envisage the need for any additional control measures above those for current production with traditional reassortants as being required for seasonal influenza A/PR8 based strains generated by reverse genetics.

New Technologies Working Group (SACGM/11/08/P8)

The European Commission joint Competent Authorities for GM activities have established a working group to look at whether new and novel techniques fall within the existing definitions as presented in the Contained Use and Deliberate Release Directives. SACGM(CU) was provided with the terms of reference and a list of the new techniques to be discussed by the working group. The first meeting of the working group will be on 15th December 2008 will be attended by the Secretariat of SACGM(CU) and ACRE as representatives of the UK Competent Authorities for GM contained use and deliberate release activities.

Action: Secretariat will provide feedback to SACGM(CU) on the first meeting of the working group at the next meeting.

Any other business

The next meeting will be an open meeting. It was agreed that the format will follow that of a normal business meeting with an initial overview of the work of the committee and incorporate an agenda item on implementation of the Callaghan review. SACGM(CU) input on this item will focus on the containment guidance and risk assessment rather than legislative matters.

Close

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

Date of next meeting

Wednesday 18th March 2009 at HSE offices in Rose Court.