approval of hosted clinical trials using investigational

Approval of hosted clinical trials using Investigational Medicinal Products (MPs) which are considered to be Genetically Modified Organisms

UCLH policy

If reading a printed copy always check that it is the most recent approved version which can be found on the Policies & Procedures page on Insight.

Policy number 048/CLN/T

Issue number 3

Issue date 22/07/16

Approved by Executive Board Policy Approval Sub Group

Responsible Director Medical Director Corporate

Policy Author Head of Risk and Regulation, Joint Research Office

Review Body JRO Advanced Therapy Regulatory Managers

Documents to read in conjunction with this policy

None

Complete review by date

June 2019

http://insight/pandp/Pages/default.aspx


UCLH Approval of hosted clinical trials using IMPs which are considered to be GMOS Policy

UCLH - 2016 ii Issue date: (22/07/16) Review by date : (30/06/19) Policy/procedure only current on date printed, visit the Policies & Procedures page on Insight for latest approved version.

Review amendment log Must be completed each time the policy is amended. Examples

Version No Date amendments made

Description of change

3 31 May 2016 Minor updates only – grammatical changes and changes to job titles. Reference to additional GCP guidance document ‘European Commission Guidance: Detailed guidelines on good clinical practice specific to advanced therapy medicinal Products’.

Updated UCLH pharmacy contact from Rita Gupta to Chi Chung.

Environmental

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List of reviewers & contributors Include here whether Counter Fraud; Infection Control Team or Interserve Facilities Management (IFM) were asked to review the policy and if comments were received

Alison Evans and Kim Champion, Advanced Therapy Regulatory Managers and Sue Kerrison, Head Of Risk and Regulation

Summary of main points from consultation

Review body Author to complete

JRO Advanced Therapy Regulatory Managers

Date of meeting when policy reviewed and endorsed: 31/05/16

Date of meeting when policy approved

21/07/16



UCLH - 2016 iii Issue date: (22/07/16) Review by date : (30/06/19) Policy/procedure only current on date printed, visit the Policies & Procedures page on Insight for latest approved version.

Table of contents Page Numbers

1. Introduction 1

2. Equality Impact Assessment 2

3. Definitions/Acronyms 2

4. Purpose 4

5. Objectives 5

6. Scope 5

7. Duties & responsibilities 5

8. Implementation 7

9. Flow Charts for Assessment and Approval Process 8

10. Contacts 10

11. Monitoring 10

Appendix 1: Terms of Reference for Joint UCL, UCLH and RFH Genetic Modification Safety Committee

11



UCLH - 2016 1 Issue date: (22/07/16) Review by date : (30/06/19) Policy/procedure only current on date printed, visit the Policies & Procedures page on Insight for latest approved version.

1. Introduction This policy sets out the requirements for approval of hosted Clinical Trials which use an investigational medicinal product (IMP) considered to be a genetically modified organism (GMO), such as for example genetically modified viral vaccines or some gene therapy medicinal products including genetically modified cells and viral vectors. These will be referred to as GMO-IMPs throughout this policy. The product and patient safety aspects of these trials are regulated under the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended). The protection of human health and the environment from these products is regulated under the Genetically Modified Organisms (Contained Use) Regulations (2000) as amended by Genetically Modified Organisms (Contained Use) (Amendment) Regulations in 2002, 2005, 2010 and 2014. There are four levels of containment identified in the latter regulations with Level 1 being considered the lowest risk and Level 4 the highest risk. Whichever containment level is deemed appropriate effectively sets the class of the activity that in turn determines the notification requirements. The use of nucleic acids (e.g. plasmid DNA, antisense or siRNA) is excluded from the scope of the Contained Use Regulations, except where it is vectored by a Genetically Modified Microorganism (GMM) or can give rise to an infectious agent (for example, siRNA delivered by retroviral vector or use of a viral cDNA). This policy deals with activities classified as Class 1 and Class 2, involving IMPs. The Health and Safety Executive (HSE) Scientific Advisory Committee on Genetic Modification (SACGM) advises that IMPs classified as Class 1 represent no or negligible risk to human health and the environment and require only routine clinical practices to reduce infectivity 1. IMPs classified as Class 2 represent low potential hazard to personnel and the environment, and although the containment requirements are not significantly greater than those for Class 1, staff handling such products must be appropriately trained to avoid exposing either themselves or others1. IMPs classified as Class 3 represent medium risk and Class 4 high risk to human health and the environment. If you plan to perform a Clinical Trial with a Class 3 GMO please contact the chair of the Genetic Modification Safety Committee at the earliest opportunity to discuss the feasibility of the proposed Trial. The trust will not perform Clinical Trials with a class 4 GMO. UCLH Trust has notified the HSE of its use of Class 1 GMO. No further notification is required under the Contained Use regulations for Class 1 activities. Class 2 activities must be notified to the HSE prior to commencement of the trial. There is

a fee associated with this which must be incorporated into the costing of the trial. Fees

1 Scientific Advisory Committee on Genetic Modification. Part 6. Guidance on the use of genetically modified

micorganisms in a clinical setting. HSE http://www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/




can be found on the HSE website http://www.hse.gov.uk/biosafety/gmo/acgm/acgmwarn.htm

2. Equality Impact Statement [mandatory] The author of this policy has undertaken an Equality Impact Assessment (EIA) and has concluded that there is no negative impact on any of the protected equalities groups. The completed EIA form is available from the Policy Compliance Officer.

3. Definitions/ Acronyms

Gene therapy medicinal product

A gene therapy medicinal product means an Advanced Therapy Medicinal Products that is a biological medicinal products which has the following characteristics: (a) It contains an active substance which contains or consists of a

recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the products of genetic expression of this sequence.

(b) Its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.

A Gene Therapy Medicinal Product includes naked nucleic acids, complex nucleic acid or non-viral vectors and viral vectors. Vaccines for infectious diseases are excluded from the definition.

GCP Good Clinical Practice (GCP) is an international quality standard that is provided by International Conference on Harmonisation (ICH), an international body that defines standards, which governments can transpose into regulations for clinical trials involving human subjects. See also the European Commission Guidance: Detailed guidelines on good clinical practice specific to advanced therapy medicinal Products (ENTR/F/2/SF/dn D(2009) 35810)

GMO Genetically modified organism. An organism (with the exception of humans) in which ‘the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination’ using ‘recombinant nucleic acid techniques involving the formation of new combinations of genetic material by the insertion of nucleic acid molecules, produced by whatever means outside an organism, into any virus, bacterial plasmid or other vector system and their incorporation into a host organism in which they do not naturally occur but in which they are capable of continued propagation.

GMO - IMP Genetically modified organisms which fall under the classification of an Investigational Medicinal Product (IMP) in a clinical trial. These can be genetically modified viral vaccines and some gene therapy medicinal


http://www.hse.gov.uk/biosafety/gmo/acgm/acgmwarn.htm

http://en.wikipedia.org/wiki/International_Conference_on_Harmonisation_of_Technical_Requirements_for_Registration_of_Pharmaceuticals_for_Human_Use

http://en.wikipedia.org/wiki/Clinical_trial



products including viral vectors and cells genetically modified by viral vectors.

GMM Genetically modified microorganisms GMMs are a category of GMOs which includes bacteria, viruses parasites and fungi.

GMSC Joint UCL, UCLH and RFH Genetic Modification Safety Committee. Committee required by HSE to advise the UCLH Trust on the infectivity of the GMO and the management of risks to patients, staff and the public.

GTAC The London – West London and Gene Therapy Advisory Committee (GTAC) is the UK national Research Ethics Committee for clinical trials of gene therapy, other advanced therapy medicinal products and (for example) non-interventional gene therapy research

DIPC

Director of Infection Prevention and Control The DIPC at UCLH undertakes a similar role as a Biological Safety Officer, to advise the GMSC on matters of safety and reviews recommendations and requirements from the GMSC. The DIPC assists the clinical trial teams in undertaking the actions required to comply with statutory obligations.

HSE Health and Safety Executive HSE operates and enforces legislation in Great Britain that aims to control the risks to human health and the environment arising from activities involving GMOs in containment under the Genetically Modified Organisms (Contained Use) Regulations 2014.

IB Investigator’s Brochure The IB is a compilation of the clinical and non-clinical data on the IMP(s) that are relevant to the study of the product(s) in human subjects

IMP Investigational Medicinal Product: a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form

IMPD Investigational Medicinal Product Dossier The IMPD includes information related to the quality, manufacture and control of the Investigational Medicinal Product.

JRO The Joint Research Office (JRO) supports the development of the clinical research portfolio of UCL, UCLH and Royal Free London and provides research management support to a network of local trusts associated with UCL.

MHRA The Medicines and Healthcare products Regulatory Agency (MHRA) is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe. They regulate clinical trials of medicines and ensure compliance with statutory obligations.

PI Principal Investigator The PI is responsible for the conduct of a clinical trial at a trial site. If a trial is conducted by a team of individuals at the trial site, the PI is the




leader responsible for the team.

SOP Standard Operating Procedure Detailed, written instructions to achieve uniformity of the performance of a specific function.

Sponsor The organisation who, under the Medicines for Human Use (Clinical Trial) Regulations 2004 takes responsibility for initiating, management and financing of the Trial. Sponsors may be academic institutions or commercial companies.

The Regulations

Genetically Modified Organisms (Contained Use) Regulations (2000) as amended.

4. Purpose

4. In order to conduct Trials using such GMO-IMPs the University College London

Hospitals NHS Foundation Trust (UCLH) must:

4.1.1 Notify the HSE of its intention to carry out clinical trials using GMO-IMPs for the first time.

− UCLH was notified to the HSE for the first time on 28/01/09

− HSE GM centre number for UCLH is GM3048

− For Class 1 activities, no further permission is required after the first notification

4.1.2 Notify the HSE of its intention to carry-out trial activities within the Trust involving Class 2 GMO-IMPs prior to the commencement of any related work:

− The activity must be notified to the HSE though submission of the CU2 -

Notification of intention to conduct individual contained use activities form

(available on the HSE website), GMO Risk Assessment Form and associated

fees

− Following the first notification of a Class 2 activity, work may commence 45

days after receipt of acknowledgement from the HSE (or sooner if agreed by

the HSE)

− For subsequent notifications of a Class 2 activity work can commence

after the HSE acknowledge receipt of the notification

4.1.3 Receive advice from a Genetic Modification Safety Committee (GMSC) as to the level of risk related to specific GMO-IMPs.

4.1.4 Put in place any specific requirements relating to the risk of infectivity from such GMO-IMPs as advised by GMSC.

This policy documents the arrangements and responsibilities for these requirements.




5. Objectives 5.1. To ensure that UCLH receives expert advice on the risk of infection from particular

GMO-IMPs. 5.2. To ensure that Trials using GMO-IMPs are conducted in compliance with the required

regulations and managed in a way to reduce risks of infectivity to patient, staff, and public and environment.

6. Scope 6.1 The policy applies to all commercial and non-commercial clinical trials involving IMPs

considered to be GMOs (GMO-IMPs), which will be administered to UCLH patients or handled and administered on UCLH premises. All staff members who are involved in the approval and conduct of such Clinical Trials must be aware of this policy, along with the responsibilities and requirements specified throughout.

7. Duties and responsibilities 7.1 UCL/UCLH/RFH Genetic Modification Safety Committee (GMSC)

The committee is a subcommittee of the Research Governance Committee. Its membership, terms of reference and reporting arrangements are shown Appendix 1.

The committee will:

7.1.1 Ensure that the HSE is appropriately notified of UCLH activities relating to clinical trials of GMO-IMPs. The GMSC will liaise with the JRO to ensure appropriate review of the Risk Assessment and CU2 form prior to submission to the HSE and review the acknowledgement on receipt.

7.1.2 Review the protocol, the GMO risk assessment form (associated document) and

other relevant trial documentation including the Protocol, Investigators Brochure (IB) and IMP dossier (IMPD) if available.

7.1.3 Provide the Trust and the Sponsor with a written risk assessment about the Class of

GMO-IMP and its infectivity. 7.1.4 Provide an approval decision on whether the trial can be carried out within the Trust

and communicate this decision to all relevant parties. 7.1.5 Recommend any specific safety measures that need to be put in place to protect

patients, staff and public in the conduct of the trial and the appropriate arrangements for receipt, storage, preparation and handling, transportation, disposal and spillage of the GMO-IMP.




7.2 Joint Research Office (JRO) will:

7.2.1 Ensure that the HSE is appropriately notified of the Trust activities relating to clinical trials of GMO-IMPs. The JRO will coordinate the review by the GMSC and submission to the HSE, of the GMO Risk Assessment form and CU2 form for any class 2 activities proposed to take place in the Trust. The JRO will ensure receipt of acknowledgement from the HSE.

7.2.2 Notify the Principal Investigator and/or trial sponsor of this policy and provide the GMO risk assessment form to be completed.

7.2.3 Provide advice and assistance to PIs and/or Sponsors on the risk assessment and approval process in line with this policy.

7.2.4 Before NHS permission is granted ensure that:

a. the GMSC has reviewed and approved the GMO risk assessment

b. the Director of Infection Prevention and Control (DIPC) has received and reviewed the GMSC’s approval letter (including recommendations/conditions for starting the trial), any other relevant documentation requested, and has no objections to the commencement of the trial within the Trust.

c. pharmacy have been informed about the trial and are satisfied that appropriate arrangements (as applicable for the trial) for receipt, onsite storage, onsite preparation and handling, onsite transportation, and disposal of GMO-IMP, in line with GCP, will be in place prior to the commencement of the trial.

7.3 Director of Infection Prevention and Control (DIPC) will:

7.3.1 Review the protocol, relevant Trial specific SOPs (if applicable), the GMSC’s opinion and confirm one of the following:

a. that adequate measures have been considered and/or arranged (includes handling, use and disposal of the product within the trust) for the Trial to commence

b. that further risk reduction measures need to be put in place before the trial can obtain NHS permissions to commence at UCLH by the JRO

c. that the trial should not take place at UCLH




7.4 Principal Investigator will:

7.4.1 Prepare the risk assessment form in consultation with the Sponsor.

7.4.2 Ensure the risk assessment form, protocol, IB and IMPD (if available) are submitted to the GMSC for review.

7.4.3 Ensure the risk assessment form, GMSC approval letter, protocol and any other required documents are submitted to the DIPC following GMSC approval.

7.4.4 Ensure that Standard Operating Procedures (SOPs) reflecting the requirements of the GMSC and DIPC are in place before the trial is opened (if required).

7.4.5 Notify UCLH pharmacy clinical trial lead about the trial as early as possible, provide associated documentation required by pharmacy and discuss to ensure compliance with Good Clinical Practice (GCP) aspects of medicines management.

7.4.6 Ensure the clinical team and other staff who may come into contact with the GMO-IMP are appropriately trained (as applicable for the trial and individuals) in the receipt, onsite storage, onsite preparation and handling, onsite transportation, administration and disposal of GMO-IMP in line with GCP. This training should be documented in the site file and the individuals named on the trial delegation log.

7.5 Pharmacy Clinical Trial Lead will:

7.5.1 Work with the PI (and others where relevant) to ensure that the on-site arrangements for receiving, handling, storage and destruction of the GMO-IMP will be in compliance with GCP.

7.5.2 Ensure that suitable arrangements for dispensing will be in place, if applicable at site.

7.5.3 Ensure that suitable arrangements will be in place for transportation from on-site storage or on-site preparation to administration area, and that storage in the administration area, if applicable, is compliant with the requirements of GCP.

8. Implementation 8.1 The policy will be disseminated through the JRO website and by email from the JRO to

Principal Investigators requesting NHS permission for trials falling under the contained use GMO regulations. Furthermore the policy will be made available to relevant research departments within UCLH and UCL.

8.2 Review and feedback

The policy will be reviewed every three years.

The JRO welcomes feedback on this policy and is keen to learn from and respond to local experience. All comments should be addressed to [email protected].


mailto:[email protected]



9. Flow Charts for Assessment and Approval Process

9.1 Class 1 Activity

PI/Sponsor Prepares GMO Risk Assessment (RA)

Submits GMO RA, Trial Protocol, IB and IMPD (if available) to GMSC

GMSC reviews GMO RA and advises PI and JRO of their opinion

DIPC reviews GSMC approval and documentation

Notifies PI and JRO of any additional procedures required to undertake trial at UCLH

PI contacts Pharmacy to notify and discuss trial

JRO ensures that GMSC, DIPC approved the measures to be taken and that pharmacy has no objection before

issuing NHS Permissions approval for the trial

Not approved Approve

Approve subject to conditions

Advice

JRO notified of trial with IMP considered to be GMO

Provides GMO Risk Assessment Form and policy to PI/Sponsor

PI provides GMSC approval and all relevant documentation to DIPC for review

Further risk reduction required

Proposed measures approved as adequate

Trial cannot take place at UCLH

Advice

Advice

Advice

PI ensures that all risk management procedures are in place and conditions of approval have been met before trial commences.

PI ensures that all individuals are appropriately trained throughout the study




9.2 Activity Class 2

PI Prepares GM Risk Assessment Submits GM Risk Assessment, Trial Protocol, IB and IMPD (if

available) to GMSC PI contacts Pharmacy to notify and discuss trial

GMSC considers and advises

DIPC considers GSMC approval and advice

Notifies PI and JRO of any additional procedures

required to undertake trial at UCLH

JRO ensures that GMSC, DIPC approved the trial and proposed containment measures and that pharmacy has no objection before issuing NHS Permissions

approval for the trial

Not approved Approve

Approve subject to conditions

Advice

Trial cannot take place at UCLH

Further risk reduction required

Advice

Trust submits CU2 form, Risk Assessment and Fee to notify HSE of its intention

to conduct Class 2 contained use activities

HSE Acknowledgement received *

* Subject to NHS permissions/R&D approval:

- GM activities can commence 45 days from receipt of acknowledgement for the first Class 2 notification.

- GM activities can commence on receipt of acknowledgement following subsequent Class 2 notifications

Proposed measures approved as adequate

PI ensures that all risk management procedures are in place and conditions of approval have been met before trial commences.

PI ensures that all individuals are appropriately trained throughout the study

JRO notified of trial with IMP considered to be GMO

Provides GM Risk Assessment Form and policy to PI/Sponsor

Advice




10. Contacts

Joint Research Office

Should you have any queries about this policy, the process/requirements or require help at any stage of the process you can contact one of the JRO Regulatory Managers (advanced therapies) by emailing [email protected]. Joint UCL/UCLH/RFH Genetic Medication Safety Committee Professor Emma Morris is the Chair of the GMSC. GMO Risk assessment forms, CU2 forms and associated documents should be sent to [email protected] for review. Director of Infection Prevention and Control Annette Jeanes is the DIPC for UCLH Trust. Risk assessment forms, GMSC approval letters and associated documents should be sent to [email protected] to review. UCLH Clinical Trial Pharmacist Chi Chung is the clinical trial pharmacist for UCLH pharmacy. Pharmacy should be notified as early as possible about a forthcoming trial via email to [email protected].

11. Compliance Monitoring

For all trials undertaken at UCLH compliance will be monitored through:

the quality assurance checks which are undertaken as part of UCLH approval processes for the study;

the Joint Research Office research governance audit programme.

All audit reports are reviewed by the Clinical Research Governance Committee.

Monitoring compliance will also be part of UCL arrangements for monitoring the trials it sponsors.








Appendix 1

TERMS of REFERENCE OF JOINT UCL, UCLH and RFH GENETIC MODIFICATION

SAFETY COMMITTEE Remit of Committee:

Risk Assessment of planned clinical trials involving GMO/GMMs involving UCLH and RFH as a trial site.

Risk Assessment of planned clinical trials involving GMO/GMMs where UCL is acting as Sponsor.

Risk Assessment to take into account any conditions of approval from GTAC and the MHRA.

Provision of safety advice and recommendations specific for individual clinical trials to UCL (UCL, UCLH & RFH Research Governance and Research Safety Sub-Committees) and involved Trusts.

To advise the relevant Trusts and UCL of any identified risks, the likely frequency of risk events occurring, an estimate of their impact on patients, staff and the environment, and to provide advice on risk reduction strategies.

Formal Risk Assessment and ensure notification of high risk trials to the HSE where indicated.

Copies of the GM Risk Assessment to be retained by the Chair of the Joint UCL, UCLH &RFH GM Safety Committee (Clinical Trials).

More general provision of advice for clinical trial Investigators and Trusts.

To report to the JRO Research Governance Committee (RGC) and to the UCLH and RFH Trust Boards.

To maintain an up to date knowledge of the risks and benefits of gene therapies. Definition of ‘UCL/Trust involvement’:

Use of UCLH/RFH infrastructure – e.g. clean rooms, vector production/storage facilities, pharmacy, clinical areas.

UCL/Trust staff participating in the clinical trial.

Trust patients to be treated on a clinical trial sponsored by UCL or other Sponsor.

Where in first instance ‘Trust’ refers to UCLH and RFH.




Reporting Structures:

GMSC reports to the Research Governance Committee (ECM, RB and DCL members).

Cross representation from Research Safety Sub-Committee by RB (Chair).

JRO RGC reports to UCL School of Biomedical Sciences and Quality and Standards Committee of UCLH and RFH Trust Boards.

Committee Membership: Chair Professor Emma Morris (Member Joint UCL, UCLH, RFH Research Governance Committee, Senior Lecturer in Immunology and Hon Consultant Haematologist, UCL/RFH/UCLH) Members

Professor Amit Nathwani (Reader and Hon Consultant – Haematology, UCL/UCLH)

Professor David Linch (Professor – Haematology, UCL/UCLH)

Professor Robin Ali (Professor – Human Molecular Genetics, IOO)

Professor Bobby Gaspar (Professor – Paediatric Immunology, ICH/GOSH)

Dr Ross Breckenridge (Chair, Joint UCL, UCLH, RFH Research Safety Committee, Member Research Governance Committee, UCL/UCLH)

Ms Jillian Deans (UCL Biological Safety Advisor, Member UCL GM Safety Committee, UCL)

Mr Kofi Owusu (RFH Biological Safety Officer) Additional representation required on Committee (on an Ad Hoc Basis – application/trial dependent):

Pharmacy Representatives

Infection Control/Virology – Annette Jeanes at UCLH (DIPC) to receive copies of risk assessment for UCLH trials and relevant SOPs.

UCLH Clinical Research Facility

UCL JRO Regulatory Managers, Advanced Therapies

UCL JRO Regulatory Managers, Pharmaceuticals

Nursing representative
