Correspondence

ASRU operational newsletter, 5 October 2023

Published 12 October 2023

Introduction

Dear all,

I am pleased to present the October 2023 ASRU operational newsletter. This newsletter provides the latest updates on ASRU’s regulatory reform programme, the licensing and compliance functions, and demonstrates our commitment to maintain open and transparent communication regarding ASRU’s regulatory delivery. In this update, I hope to provide assurance and clarity on service and regulatory delivery and provide you with clear expectations on ASRU’s operating model and current priorities.

As you will be aware, ASRU is continuing to update and improve our processes and systems, which strengthens our delivery of ASRU’s purpose: protecting animals in science by maintaining compliance with ASPA. We are committed to ensuring that the regulated community remain updated and engaged in any changes to our processes and systems.

We will continue to keep you informed through our stakeholder engagement activities, including these newsletters.

I hope you find this newsletter helpful and informative. Kate Chandler

Head of Unit, ASRU

ASRU Regulatory Reform Programme

In July 2021 we launched our new interim operating model, Bridging Ways of Working (BWOW), as part of ASRU’s Regulatory Reform programme. At the beginning of 2022, the reform programme was paused to embed these changes and prepare for the next stages of reform.

In May 2023 we restarted the regulatory reform programme. You should not expect any immediate changes to our operations or the service you receive.

Reform will ensure that ASRU is adopting leading practice regulation to maximise quality, efficiency, and timeliness. We also aim to strengthen the clarity of guidance for the regulated sector to support compliance and enhance establishments’ confidence in their own systems and governance for protecting animals. In this way we will best serve the needs of the regulated community and the public.

We intend to provide substantial notice and undertake engagement and user testing where appropriate ahead of implementation. The regulatory community will be kept updated as the Regulatory Reform programme progresses, and notice will be given before any changes are implemented. All public bodies should strive for excellence, and this includes embracing continuous improvement to keep pace with the changing regulatory and scientific landscape. Taking further steps to integrate leading regulatory practice into ASRU forms part of this continued commitment.

This programme of work will put ASRU in the best position to deliver its purpose, while helping facilitate the benefits of science and building the UK’s position as a top scientific innovator.

If you have any questions, please direct them to the ASRU Operational Relationship Management mailbox: ASRUOperationalRelationshipManagement@homeoffice.gov.uk.

Licensing

Cosmetic Testing Licensing

On 17 May the Government announced that no new licences will be granted for animal testing of chemicals that are exclusively intended to be used as ingredients in cosmetics products.

A written Ministerial statement setting this out can be found here: https://questions-statements.parliament.uk/written-statements/detail/2023-05-17/hcws779.

This means that, from that date, ASRU will not grant new project licences that request authority for such testing under the Animals (Scientific Procedures) Act. The Government is also engaging with the relevant companies to urgently determine a way forward on legacy licences. Relevant establishments can expect to be contacted by Home Office colleagues in due course. For extant project licences that authorise testing of chemicals which are exclusively for use in cosmetic products, testing is still permitted under such licences, subject to further review.

For applications already submitted or new applications received that request authority for testing of cosmetic ingredients, assessment by ASRU will be paused. Applicants may wish to withdraw such applications completely or amend to remove the request for such testing before resubmission.

If you have any questions, please contact ASRU at ASRUlicensing@homeoffice.gov.uk.

Animals in Science Committee review of antibody licences

On 17 August 2022, the Home Office commissioned the Animals in Science Committee (ASC) for advice on the use of animals in the development and production of antibodies.

In response to this, the ASC undertook a strategic review of 31 licence applications from the last 5 years. The ASC published a report of its findings on 17 October 2022. The report sets out recommendations of the ASC to the Home Office, focusing on 6 areas in which the licence review process can be strengthened for applications involving antibodies.

Following careful consideration of the report, the Home Office accepts all recommendations provided by the ASC. These actions were described in detail in a letter from Lord Sharpe to the Chair of the ASC of 20 July 2023.

https://www.gov.uk/government/publications/review-of-antibody-licences-report-by-the-animals-in-science-committee

ASRU will implement changes to strengthen the requirement for robust justification for any proposed use of animals to produce antibodies, in order to carry out its duty of assuring compliance with ASPA.

These changes will be implemented through both a short and a long-term approach. The short-term approaches address the need for immediate measures to action the Committees’ recommendations. These actions focus on raising awareness of the recommendations and ensuring licence assessors take account of the recommendations during licence assessment; these build on the steps already taken by the ASRU to respond to the report. The longer-term approach will involve a more holistic strengthening of ASRU through its regulatory reform programme. As part of the programme, ASRU plans to review the processes it has in place to provide assurance of compliance with the principles of replacement, refinement, and reduction.

As a result of these recommendations, ASRU will now be asking applicants to address additional questions in their applications. This list can be found in Annex A.

Compliance Assurance

Audit

2023 Programme

The 2023 Audit programme is well underway. While in some instances we will notify establishments in advance to arrange an audit, ASRU will continue to undertake both announced and unannounced audits.

Following feedback from establishments we have further refined the report you will receive following an audit. I hope Establishment Licence Holders and others continue to find this a useful summary of the findings of the audit and required actions.

ASRU is continuing to contact establishments as part of our annual check to ensure that we hold the latest visit risk assessments, and arrangement and bio-security requirements. If you have not already been contacted, please look out for the email over the next few months. I would be grateful if you could provide the information requested as soon as possible as it will help ensure best preparation for any visits.

Enforcement

Non-compliance Reporting Form

ASRU would like to thank those who provided feedback about the new form to report potential non-compliance, which was piloted in June and July 2023. This has been carefully considered and the form amended accordingly. We are now releasing the new version of this form on GOV.UK.

Please use this form to notify ASRU of any incidents where there has been a potential breach of ASPA or a licence condition (which also includes the Code of Practice). As much information should be provided as possible.

This form has been provided, following feedback from a piloted version, to make it easier for establishments to provide the right information first time when self-reporting non- compliance and to improve efficiency of the process.

Incidents of non-compliance should be reported to ASRU. Self-reporting indicates that an establishment is making efforts to ensure compliance. It demonstrates that role holders are aware of their responsibilities and are committed to building a compliant culture. ASRU expects self-reporting to be embedded within good governance frameworks and that employees are aware of the process for raising concerns within their establishment. This is set out in ASRU’s published Compliance policy (PDF, 280KB) and Guidance on the operation of the ASPA.

Please provide any further feedback about the form to: ASRUOperationalRelationshipManagement@homeoffice.gov.uk

Standard Condition 18

We are currently improving our process for managing SC18 reports and will update you shortly. We thank you for your patience if you are waiting for a response to a previously submitted report, and please continue to submit SC18 reports in the normal way. If you have any questions about specific cases, please contact us through ASRUStandardCondition18@homeoffice.gov.uk.

Relationship Management

Complaints process

ASRU is committed to providing a high-quality service to its regulated community.

We are launching a new process for reviewing and responding to complaints. The new complaints procedure will ensure that complaints are received and responded to in a consistent way. The complaints process will provide a formal route for the regulated community to bring a complaint to the attention of ASRU.

This process will cover any aspect of the regulatory service provided by ASRU such as:

• policies or regulation have been implemented incorrectly
• inconsistencies in the service provided
• work has taken longer than published indicative timelines
• the standard of service provided is not acceptable
• the behaviour of staff is not acceptable

This process will not cover:

• matters that have already been fully investigated through this complaints procedure.
• complaints about access to information under the Freedom of Information Act 2000
• complaints about the content of legislation that we enforce
• ongoing compliance cases

The new complaints process and accompanying form will be published shortly on GOV.UK.

Establishment Licence Holder meetings

New establishment licence holders may be interested in the Establishment Licence Holders’ Induction Training, run by LASA, on 20 November 2023. LASA are also holding the Establishment Licence Holders’ Autumn Forum on 17 October 2023.

More information and details on how to book can be found on the LASA website – https://www.lasa.co.uk/lasameetings/.

Contacting ASRU

Compliance assurance

Audit:

• audit related queries

ASRUAudit@homeoffice.gov.uk

Standard Condition 18:

• requests to keep animals alive

• Standard Condition 18 reports

ASRUStandardCondition18@homeoffice.gov.uk

POLE notification:

• notifying ASRU of upcoming work at a POLE - please ensure the email subject line includes the PPL number, PPL holder’s surname and the name of the establishment

ASRUPOLEnotification@homeoffice.gov.uk

Enforcement:

• reports of potential non-compliance

• reports required by a licence condition or as a result of enforcement action

• advice on whether a non-compliance may have occurred

• contact during a non-compliance investigation ASRUEnforcement@homeoffice.gov.uk

Licensing:

• specific queries relating to an individual licence application

• evidence to support an exemption from mandatory training

• requests to re-home animals where not already authorised

• advice on interpretation of licence authorities

• guidance on becoming an establishment

• advice on whether work needs to be regulated

• advice on applying for licences

• guidance on how we will assess applications

• information to support a PEL application or amendment notification of AWERB dates

• AWERB terms of reference

ASRULicensing@homeoffice.gov.uk

ASPeL Technical Queries:

• technical advice on the use of ASPeL

ASPELTechnicalQueries@homeoffice.gov.uk

Home Office liaison (HOLTIF) and complaints inbox:

• raising concerns about the timeliness or completeness of response from any of our teams or any other concerns about any individual request or interaction • raising concerns about the timeliness or completeness of response from any of our teams or any other concerns about any individual request or interaction from the regulated community

ASRUOperationalRelationshipManagement@Homeoffice.gov.uk

Fees or business enquiries

ASRUBusiness@homeoffice.gov.uk

Annex A

Additional questions based on ASC recommendations relating to antibody licences

Benefits:

• Describe the expected outputs form the proposed project and explain how these will satisfy your scientific aims and objectives

• Describe how you will maximise the outputs of this work

• Describe who or what is likely to benefit and how they will benefit from these outputs in the short, medium and longer term

• Describe your commitment to promulgating the 3Rs including, for example, populating databases and resource sharing

Replacement:

• Which non-animal alternatives did you consider for use in this project?

• What are the scientific limitations of the non-animal alternatives in terms of how they relate to the objectives of this study?

• What steps did you take to confirm that the antibodies (animal derived or non-animal derived) sought are not available and cannot be produced using non-animal approaches? This should be explained for each new antigen and each application of the antibody.

• What measures did you take to resolve technical issues experienced with the use of non-animal alternatives?

• Explain why the non-animal alternative(s) were not suitable or appropriate for your needs.

• How was the library characterised and validated?

Reduction:

• How have you estimated the numbers of animals you will use? What measures, apart from good experimental design, will you use to reduce the number of animals you plan to use in your project?

• What is your protocol for producing each type of antibody, including the number of animals typically required within each stage of the process? What steps are you taking to reduce overall number of animals for each stage of the process?

• What is the scientific justification for the numbers of animals required to produce each specific antibody?

• To reduce overall numbers of animals proposed for use, please explain whether you have considered challenging animals with multiple antigens either sequentially or simultaneously. Why would such an approach be inappropriate towards the achievement of your scientific goals?

• Explain why you cannot use large animals that can undergo multiple harvesting of samples?

• Justify the use of any special species (dogs, cats, non-human primates and Equidae) that have additional protection under ASPA.

Refinement:

Please provide an example of a standard assessment proforma that will be used by your local AWERB both at prospective review of the application or amendment and retrospectively annually. Such reviews will be made available to ASRU on request and on Establishment audits.

Such an ASSESSMENT PROFORMA should include the following:

• A concise account of the current state of knowledge in the scientific area of research to which the antibody relates

• Description of any validated non-animal alternative already existing

• Description of any identically active antibody or alternative binding/affinity reagent already available either commercially or through other means

• Details of why such existing antibodies or reagents are unsuitable and why it is necessary to raise an animal-derived antibody

• Details of the robust, legitimate, scientific justification of each of the antibodies raised in living animals. Examples of such justification are:

  • A non-animal alternative has been tried and this approach has failed for defined scientific reasons supporting the use of animal derived antibodies for the specified purpose at present

  • Extrapolation of existing data gives a strong indication that a non-animal antibody alternative is highly unlikely to be suitable

  • Target epitope does not bind to non-animal alternative

  • Availability and timeliness of non-animal antibody alternative – this may be particularly relevant for therapeutic applications or where there is a scientific urgency (for example, global infectious disease pandemics where there is a need for a new diagnostic)

  • Neither cost nor convenience are legitimate reasons, acceptable to the regulator, to hinder or stop the development or adoption of non-animal alternatives (or the use of a third party to produce them)

• Details of the animal models and numbers, antigen(s) and methods proposed for use during this project

• Details of any specific problems to be addressed and how the antibody be used

• Describe who or what is likely to benefit and how they will benefit from these outputs in the short, medium and longer term

• Details of how the adjuvants, techniques, and administration routes are considered to be the most appropriate and refined

• Details of how the PPL holder will stay informed about advances in the 3Rs, and implement these advances effectively, during the project

• Details of the implementation of any 3Rs learnings from previous projects

• Details of how the procedures will be refined to minimise the potential harms to the animals

Action plan:

The aim of the following question is to provide assurance and evidence that appropriate governance measures are in place.

• Describe how non-animal alternatives will be sought or developed for all or part of the proposed research

• Describe how the quality of the products will be assured

• Describe how the supply of products will be matched with demand

• Describe the process and specific criteria for accepting or rejecting requests for antibody production, include details of other parties that you may consult and the active involvement of the AWERB in the process (including consideration of adjuvants, techniques, and administration routes, refinements to minimise the potential harms to the animals, application of other 3Rs advances during the project).

• The AWERB undertakes to prospectively review and consider the legitimacy of each request for antibody production using living animals and the AWERB will retrospectively review the project addressing all points detailed in the assessment proforma annually for the duration of the project licence to include details of the robust, legitimate, and detailed scientific justification of each of the antibodies raised in living animals and any results achieved.

Protocols

These should follow these principles:

• Applicants should have standalone protocols for antibody production

• The severity category should be mild because adverse effects are expected to be transient and minor, even with the use of FCA if it is used in the most refined way.

• A scientific rationale for the step should be provided alongside the step.

• For the primary immunisation step, it may be necessary to combine the antigen with an adjuvant in order to enhance the antibody response. A range of adjuvants are available; one should be chosen which will stimulate antibodies of the desired affinity, avidity, titre and class, with minimal local tissue damage. Some adjuvants, such as Freund’s Complete Adjuvant (FCA), cause significant local reactions and should be used as set out below. No adjuvants should be used via the intravenous route, although antigen in PBS may be given intravenously, usually as the final booster inoculation. The intradermal route should be avoided when adjuvants are used.

• For the primary immunisation step, when a significant local reaction is expected, such as with FCA, the antigen/adjuvant mixture should be given subcutaneously in areas of loose skin and doses should not exceed 0.1 ml at each of 2 sites in mice, 0.2 ml at each of 2 sites in rats and 0.25 ml at each of 4 sites in guinea-pigs, rabbits, sheep, goats and equids. FCA should never be used on more than one occasion in the same animal. Stable emulsions should be used with no more that 50% FCA mixed with antigen in aqueous solution. FCA should not be used in horses or other equids. The intramuscular route may be used in chickens and should not exceed 0.1 ml in each of four sites.

• For the blood sampling step, superficial blood vessels are usually adequate for blood collection during monitoring of antibody titre in all species. No more than 15% of total blood volume (TBV) should be taken over any four-week period and usually no more than 10% TBV should be removed as a single collection. The TBV of laboratory animal species averages 65 ml/kg. Consideration should be given to the use of local or general anaesthesia as appropriate for the species.

• If single housing is required e.g. for chickens for egg collection then this should be added as a separate step.

• For boosting, in order to raise or maintain the antibody titre it may be necessary to administer the antigen on one or more further occasions. These ‘boosters’ should conform to the principles set out for primary immunisation, but must not include FCA, and should be no more in number than required to achieve and maintain the required titre. Animals that fail to respond within four ‘boosts’ should be withdrawn from the protocol. Please see the Advice Note on Use, keeping alive and re-use, for the conditions that will need to be satisfied if such animals are to be kept alive. The correct fate will need to be selected for in ASPEL NTS for the right questions to come up

• For harvesting it is recommended that when the antibody titre has reached a plateau, rodents and rabbits should be bled out under terminal general anaesthesia. The serum can then be separated, divided into aliquots and deep frozen. Eggs should be collected during a laying season, but moulting must not be induced. Where serial harvesting is appropriate, the volume of blood collected should be limited as set out above, unless special arrangements such as haematological monitoring can be included in the licence authority.