MEDICINES FOR HUMAN USE (CLINICAL TRIALS) REGULATIONS Memorandum of understanding between MHRA, COREC and GTAC

Transcription

1 MEDICINES FOR HUMAN USE (CLINICAL TRIALS) REGULATIONS 2004 Memorandum of understanding between MHRA, COREC and GTAC 1. Purpose and scope 1.1 Regulation 27A of the Medicines for Human Use (Clinical Trials) Regulations 2004 provides that the licensing authority and an ethics committee may disclose to each other any information acquired in carrying out their respective functions under the Regulations where disclosing such information may assist the other party in carrying out its functions under the Regulations. 1.2 The United Kingdom Ethics Committee Authority (UKECA) has appointed the Central Office for Research Ethics Committees (COREC) under Regulation 5(4) to provide advice and assistance to NHS Research Ethics Committees which are recognised by the UKECA under the Regulations and to the Ethics Committee constituted by regulations made by the Scottish Ministers under sections 51(6) of the Adults with Incapacity (Scotland) Act Under Regulation 14(5) the Gene Therapy Advisory Committee (GTAC) is the national ethics committee responsible for reviewing clinical trials of gene therapy. Advice and assistance to GTAC is provided by the GTAC Secretariat. 1.4 This memorandum summarises the arrangements agreed between the licensing authority (acting by the Medicines and Healthcare products Regulatory Agency (MHRA)) and COREC and the GTAC Secretariat for effective collaboration and communication between MHRA and ethics committees in the implementation of Regulations in the United Kingdom. 1.5 In respect of NHS RECs and GTAC, the memorandum fulfils the requirements of Article 6.3 of the European Commission s Directive on Good Clinical Practice (2005/28/EC), relating to communication between ethics committees and the competent authority. (Within the UK, the MHRA exercises the functions of the competent authority.) The memorandum has no application to other ethics committees recognised by UKECA. 2. Terminology Chief Investigator means the investigator who submits the application to the ethics committee and has overall responsibility for the conduct of the trial. Clinical Trials Directive means Directive 2001/20/EC of the European Parliament and of the Council. OREC means the Central Office for Research Ethics Committees, a directorate within the National Patient Safety Agency. CTA means the clinical trial authorisation from the MHRA.

2 CTIMP means a clinical trial of an investigational medicinal product. CTU means the Clinical Trials Unit at the MHRA. EudraCT means the European Clinical Trials Database. GCP means the principles of Good Clinical Practice in clinical trials as set down in Articles 2-5 of the GCP Directive and implemented in the UK by Schedule 1 of the Medicines for Human Use (Clinical Trials) Regulations 2004 (S.I.2004/1031) as amended by S.I. 2006/1928. GCP Directive means the European Commission s Directive on Good Clinical Practice (2005/28/EC). GTAC means the Gene Therapy Advisory Committee, the national ethics committee for clinical trials involving medicinal products for gene therapy under Regulation 14(5). Head of CTU means the senior manager within the Clinical Trials Unit. IAG means the MHRA Clinical Trials Inspection Action Group. IMP means an investigational medicinal product. Main REC means the REC that carries out the ethical review of a new application and gives an ethical opinion under Regulation 15. MHRA means the Medicines and Healthcare products Regulatory Agency. The MHRA acts for the licensing authority in the United Kingdom in relation to the Clinical Trials Directive. NHS REC means a research ethics committee established in accordance with the Governance Arrangements for NHS Research Ethics Committees, issued by the Department of Health in July 2001, or with equivalent arrangements made by the devolved administrations in Scotland, Wales and Northern Ireland. References to NHS RECs should be taken to include HPSS research ethics committees in Northern Ireland and the Ethics Committee constituted by regulations made by the Scottish Ministers under sections 51(6) of the Adults with Incapacity (Scotland) Act Operations Director for COREC means the senior manager responsible for day-today operational management of the NHS REC system within the National Patient Safety Agency (NPSA). The Operations Director is accountable to the Chief Executive of the NPSA. Operations Manager for GCP means the manager of the GCP Inspectorate at the MHRA. REC operational manager means the manager responsible for providing advice and assistance to research ethics committees in a particular area of the UK. Principal Investigator means the investigator who takes responsibility for the conduct of the trial at a local trial site. REC means a research ethics committee. Except where stipulated otherwise, references to RECs should be taken to include the GTAC in relation to trials of gene

3 therapy products and the Ethics Committee constituted by regulations made by the Scottish Ministers under sections 51(6) of the Adults with Incapacity (Scotland) Act RED means the Research Ethics Database, the database used by all NHS RECs to manage applications for ethical review. Recognised ethics committee means an ethics committee that is recognised by the United Kingdom Ethics Committee Authority in relation to clinical trials of investigational medicinal products. The Regulations means the Medicines for Human Use (Clinical Trials) Regulations 2004 (S.I.2004/1031) as amended by S.I.2006/1928. SOPs means the Standard Operating Procedures for NHS RECs issued by COREC. SSA means the site-specific assessment carried out by a local Research Ethics Committee or R&D Department and notified as advice to the main REC on the suitability of the local site and investigator. UKECA means the United Kingdom Ethics Committee Authority, established under Regulation 5 of the Regulations. 3. Roles and responsibilities 3.1 The Clinical Trials Unit s primary role is to protect public health by ensuring that CTIMPs meet the required regulatory standards with respect to quality and safety. Its clinical, toxicological and pharmaceutical assessors review CTA applications to ensure that sufficient, appropriate data are available to support the proposed clinical trial and that planned safety monitoring and reporting procedures are adequate. It is also responsible for monitoring the emerging safety profile of the IMP, risk /benefit assessment and overall safety of the trial. It is responsible for taking appropriate regulatory action, together with the GCP Inspectorate and other MHRA Divisions, where necessary. 3.2 The GCP Inspectorate assesses compliance with the Regulations and GCP by conducting inspections at the sites of pharmaceutical companies, contract research organisations, non-commercial organisations, investigational trial sites, clinical laboratories, GCP archives and other facilities involved in CTIMPs. Inspections are carried out to protect the public (both current and future patients), to meet legal obligations and enforce applicable legislation, to provide assurance of compliance with the Regulations and GCP, to detect and take action relating to serious non-compliance (including fraud and misconduct) and to assist with quality improvements in clinical research. 3.3 The Clinical Trials Inspection Action Group (IAG) is a non-statutory, multidisciplinary group whose role is to advise the MHRA Directors of Inspection and Standards, and Licensing, on any recommendations for regulatory or adverse licensing action, resulting from clinical trials/gcp inspections. Appendix 1 summarises potential outcomes from referrals to IAG. 3.4 The UKECA is responsible for monitoring the extent to which RECs adequately perform their functions under the Regulations, and may provide

4 advice and assistance to RECs. COREC is authorised by the UKECA to provide advice and assistance to recognised RECs within the NHS, including the co-ordination of systems to enable committees to comply with the Regulations. Within the COREC structure, REC operational managers are responsible for providing advice and assistance to NHS RECs within a geographical area of the UK. The operational managers are professionally accountable to the Operations Director for COREC. 3.5 The main REC is responsible for giving an ethical opinion on an application to conduct a CTIMP, and on substantial amendments notified to trials with a favourable opinion. It may generally rely on the MHRA to assess the safety of medicinal trials. It is not required to undertake its own safety assessment but may seek advice from MHRA on safety issues where these are relevant to the ethical review. The main REC has no formal responsibility for proactive monitoring of trials but should be ready to notify any concerns about trials to the MHRA and where appropriate to sponsors and Chief Investigators. 3.6 The REC Co-ordinator is responsible for managing the business of the REC in accordance with SOPs. 3.7 In the case of clinical trials of gene therapy products, the main REC for the trial is the Gene Therapy Advisory Committee. In addition to its statutory responsibilities under the Regulations, the GTAC has a general responsibility for advising UK Health Ministers on developments in gene therapy research and their implications. The GTAC Secretariat is responsible for managing the business of the GTAC in accordance with its SOPs and for providing advice and assistance to the committee. The Secretariat is part of the Department of Health and is accountable to Ministers. 4. New applications 4.1 The MHRA and the main REC should exchange relevant information on new applications for CTA or ethical review. In particular, the main REC may seek information or clarification on safety issues that may be relevant to the ethical review, for example the description of risk in the participant information sheet. Requests for information should be sent to the Head of CTU by and will receive a response within two working days. 4.2 Applications to the MHRA and the main REC may be made in parallel. Where significant changes are made to the terms of applications or to supporting documentation as a result of either the ethical review or authorisation process, it is the responsibility of the sponsor to ensure that both the MHRA and main REC are informed where the changes are relevant to their responsibilities. Substantial amendments should be notified where appropriate (see paragraph 5.1). Standard letters issued by the MHRA and main RECs will remind sponsors and Chief Investigators of their general responsibilities in this regard. 4.3 These arrangements apply to all CTIMPs. They are of particular importance in the case of Phase 1 clinical trials in higher risk categories and subject to special precautions by the MHRA (for example, a requirement for independent scientific review by the Commission of Human Medicine or other referees). The sponsor is responsible for ensuring that the main REC is fully

5 informed of the outcome of the independent review. The main REC may seek assurances about this from the Head of CTU where appropriate. 4.4 The main REC will issue an opinion on the application to the Chief Investigator within 60 days of receiving a valid application, allowing for the clock to stop once to request any further information. (For gene therapy trials, the timeline is extended to 90 days.) Under article 6.5 of the Clinical Trials Directive, the ethics committee is required to notify the MHRA of its opinion so that this can be entered on EudraCT. Notifications should be sent to the MHRA by 1 (see paragraph 12.2). 4.5 The MHRA will issue a written notice to the sponsor within 30 days of receiving a valid request for authorisation, either confirming authorisation or setting out grounds for non-acceptance. It is the responsibility of the sponsor to arrange for the main REC to be provided with a copy of the notice giving authorisation when available. This may be provided either before or after issue of the ethical opinion. 5. Substantial amendments 5.1 The sponsor is required to submit the EudraCT notification of amendment form to both the CTU and the main REC when proposing a substantial amendment to the CTA, including substantial amendments to the terms of the REC application. Substantial amendments will normally be submitted after a trial has started. It may exceptionally be necessary for the sponsor to submit a substantial amendment during the process of initial application where either the MHRA or the main REC has requested significant changes, which need to be formally notified to, and considered by, both agencies before final decisions on applications are made. 5.2 It is the responsibility of the sponsor to determine whether an amendment is substantial. The CTU and main REC may give advice to the sponsor if requested. Where the main REC has grounds for believing that the sponsor has failed to notify a substantial amendment, the procedure for reporting noncompliance to the MHRA applies (see paragraph 8.1). 5.3 Where the sponsor requests an ethical opinion on a substantial amendment, the main REC will issue an opinion within 35 days of receiving a valid notice of amendment or within 14 days in the case of a modified amendment submitted under Regulation 25. Notifications should be sent to the MHRA by 1 (see paragraph 12.2). 5.4 Where the sponsor requests authorisation from the MHRA, the CTU will issue a written notice within 35 days of receiving a valid notice of amendment, accepting the amendment or giving grounds for non-acceptance. It is the responsibility of the sponsor to arrange for the main REC to be provided with a copy of the notice when available. 1 It is planned to give MHRA access to relevant information on RED. This will enable all opinions on new applications and substantial amendments to be automatically notified as soon as they are entered by the REC Co-ordinator. When implemented this will supersede the requirement for main RECs to notify the CTU by .

6 6. Addition of new sites and investigators 6.1 The sponsor is required to submit a notification of amendment when proposing to add a new site, unless it was included in the list of planned trial sites submitted with the original applications to the CTU and the main REC. 6.2 The main REC will issue an opinion on the site within 35 days of submission of both the notification of amendment and an application for site-specific assessment (SSA). The CTU will be notified by (see paragraph 5.3 and footnote). 6.3 Where a site is to be included in the trial, which was listed as a planned site originally but has not yet been given approval by the main REC, there is no requirement to submit a notification of amendment. However, the sponsor should still arrange for the local Principal Investigator to apply for SSA. The main REC will issue an opinion on the site within 35 days of receipt of the application for SSA. The CTU will not be notified. 6.4 The appointment of a new Principal Investigator at an existing site requires notification of amendment and application for SSA. The procedures will be as under paragraph There is no routine requirement for the main REC to provide the CTU with the list of approved sites (form SF1). The CTU or the GCP Inspectorate may request a copy of SF1 at any time to check the position on approval of sites. 7. Safety monitoring 7.1 Responsibilities for safety monitoring are as follows: The CTU is responsible, in collaboration with Competent Authorities in other Member States as necessary, for monitoring the emerging safety profile of the IMP, the risk/benefit analysis and the overall safety of the trial. It is also responsible for any decision to suspend or terminate the CTA. The main REC is not formally responsible for safety monitoring and has no power to suspend or terminate the CTA or legally withdraw the ethical opinion given on the initial application under Regulation 15. However, it should draw the attention of the CTU, sponsor and Chief Investigator to safety concerns that come to its attention from any source, as well as any other new concern about the ethical acceptability of the trial. In particular, the main REC should keep under review the adequacy of the informed consent process and documentation in the light of new information about risks and benefits. The main REC should also notify the CTU, sponsor and Chief Investigator where it no longer has a favourable opinion of the trial (see paragraph 11.2). 7.2 Where the CTU has any concern about the safety of trial subjects or there is a change in the risk/benefit analysis, it will keep the main REC informed of any action it takes. The Head of CTU will ensure that any relevant correspondence with the sponsor is copied to the main REC. The main REC may seek further information or clarification from the Head of CTU by or

7 telephone. It may also recommend that the CTU takes action in relation to the CTA, for example to request amendment of the participant information sheet. 7.3 Expedited reports of SUSARs occurring in the UK will not normally be reviewed by the main REC, as the overall safety of the trial cannot be assessed on the basis of such limited data. 7.4 Periodic safety reports from the sponsor will be reviewed by the main REC in accordance with its SOPs. The review will normally be confined to the sponsor s summary of safety issues. Where substantial concerns arise about the safety of trial subjects, the accuracy of the risk/benefit analysis or the need for new information to be given to subjects, the REC may write to the Head of CTU. The correspondence will be copied to the sponsor and Chief Investigator. 8. Reporting of non-compliance or serious breaches 8.1 Where a NHS REC receives information from any source suggesting that serious non-compliance with the Regulations (including serious breaches of the protocol or the conditions and principles of GCP) may have occurred in relation a trial, it will pass the information promptly and confidentially to the REC operational manager in writing. A copy will be sent to the REC s appointing authority. If the REC concerned is not the main REC for the study, a copy will also be sent to the main REC. The operational manager responsible for the REC making the report will forward the information to the Operations Director for COREC. The Operations Director will collate and evaluate reports and advise on whether information should be shared with the MHRA, taking into account the seriousness of the alleged non-compliance, the evidence provided and any pattern of reporting. A REC or its appointing authority may notify the MHRA directly if it considers it appropriate to do so. Reports to MHRA should be sent by to the Operations Manager for GCP copied to the Head of CTU. 8.2 Relevant information held by GTAC will be reported direct by the GTAC Secretariat to the Operations Manager for GCP and the Head of CTU, copied to the Operations Director for COREC. 8.3 Receipt of information under paragraph 8.1 includes any report from a member of an investigator s team of alleged fraud, misconduct, noncompliance or serious breaches of GCP or the protocol in relation to a trial. 8.4 The Operations Manager for GCP and Head of CTU will always be notified where one of the following is suspected and the matter has not already been reported to the MHRA by the sponsor or CI: Conduct of a trial without CTA. Conduct of a trial without a favourable opinion. Conduct of the trial at a particular site without a favourable opinion for the site or the Principal Investigator. Provision of false or misleading information to the main REC in relation to an application for ethical opinion or notification of substantial amendment.

8 Implementation of a substantial amendment without authorisation and/or a favourable opinion as appropriate. Failure to notify SUSARs occurring in the trial in the UK in an expedited manner or to provide an Annual Safety Report. Failure to notify urgent safety measures. Failure to notify the early termination or conclusion of the trial. A serious breach of GCP or the protocol. Any other fraud or serious misconduct. 8.5 A breach of the conditions or principles of GCP or of the protocol will be regarded as serious if it is likely to affect to a significant degree: The safety or physical or mental integrity of the subjects of the trial, or The scientific value of the trial. 8.6 The Operations Director for COREC and GTAC Secretariat will consider notifying the Operations Manager for GCP where a pattern emerges of repeated minor breaches of GCP or the protocol. 8.7 All reports received by MHRA will be acknowledged. Feedback will be provided to the Operations Director for COREC (and if applicable to the GTAC Secretariat) on the findings of any resulting inspections or investigations. The Operations Director will arrange for relevant RECs and operational managers to be notified. 9. Inspections 9.1 Inspections under the Regulations do not include assessment of the compliance of the main REC with the Regulations or the SOPs. The inspectors may however seek evidence that trials have a favourable opinion from a recognised REC and are being conducted in accordance with the terms of the opinion. This may require verification of the application documentation and correspondence held by the main REC. Any request from the GCP Inspectorate to inspect documentation will be made in writing to the Co-ordinator of the main REC (copied to the REC operational manager) or to the GTAC Secretariat. The main REC will normally facilitate the inspection. Any concern on the part of a NHS REC about the inspection will be referred to the appointing authority for the REC and the REC operational manager. If the matter cannot be resolved locally with the GCP inspection team, the REC operational manager will notify the Operations Director for COREC, who will contact the Operations Manager for GCP. 9.2 Where inspectors receive information which is relevant to the responsibilities of the UKECA for monitoring the performance of RECs, it should be passed to the UKECA Secretariat, copied to the Operations Director for COREC and/or GTAC Secretariat as appropriate. 9.3 Copies of inspection reports will not be routinely provided to the REC system. However: Any report on a Phase 1 trial site will be provided to the REC responsible for undertaking SSA relating to the site.

9 Reports will be disclosed in any case where regulatory action is taken (see paragraph 10.1 below). Relevant information from other inspections (or copies of inspection reports where appropriate) may be disclosed on request to the Inspectorate from the main REC, the REC operational manager, the Operations Director for COREC or the GTAC Secretariat. 10. Regulatory and enforcement action 10.1 Where the MHRA takes regulatory action following critical inspection findings, whether in relation to a particular trial or the conduct of trials generally by a sponsor or Contract Research Organisation, the Chair of IAG will notify the Operations Director for COREC (and if applicable the GTAC Secretariat) and provide a copy of the relevant inspection report. The Operations Director will arrange for relevant RECs and REC operational managers to be notified and to receive a copy of the inspection report Where the MHRA takes enforcement action under Regulation 48, the Operations Director for COREC (and if applicable the GTAC Secretariat) will be informed. The Operations Director will arrange for relevant RECs and REC operational managers to be notified Where the need for regulatory or enforcement action is under active review by IAG pending further inspection or response to critical findings, the Operations Manager for GCP may alert the Operations Director for COREC (and if applicable the GTAC Secretariat). The purpose of the alert is to ensure that an ethics committee can be made aware of information about serious noncompliance, which could be relevant to the ethical review of any new application, substantial amendment or SSA. Any such alert will be authorised by IAG. The alert procedure will be as follows: The Operations Manager for GCP will notify the Operations Director for COREC (and if applicable the GTAC Secretariat) in confidence. Details will be provided of the name of the sponsor, trial site or investigator concerned together with a contact point at MHRA. The Research Ethics Database (RED) will be flagged by COREC to alert the Operations Director (and if applicable the GTAC Secretariat) where any new application for ethical review, substantial amendment or SSA is submitted naming the sponsor, trial site or investigator. The alert will be visible only to the Operations Director, GTAC Secretariat (if applicable) and any members of COREC staff acting under delegated authority from the Operations Director. The Operations Director or GTAC Secretariat will contact the MHRA to seek further information about the reasons for the alert. The Operations Director will decide whether information relating to serious noncompliance should be disclosed in confidence to relevant RECs. The sponsor will be notified of any information disclosed.

10 10.3 All current alerts under paragraph 10.2 will be reviewed at each quarterly review meeting (see paragraph 13.1) and will be removed from RED except where MHRA advises that an alert should remain in place The GCP Inspectorate will brief the Operations Director for COREC, REC operational managers and GTAC Secretariat at least annually on issues arising from GCP inspections. Briefing will include both oral presentation and a written summary for distribution to all RECs. 11. Suspension or termination of the CTA 11.1 Where the CTU suspends or terminates the CTA, either for the trial as a whole or at an individual trial site, it will provide the main REC with a copy of the letter to the sponsor Where following discussion at a quorate meeting of the full committee the main REC decides that it no longer has a favourable opinion of a trial, it will write to the Head of the CTU by , copied to the Operations Manager for GCP, explaining its concerns in full. The correspondence will be copied to the sponsor and Chief Investigator and, in the case of NHS RECs, to the REC operational manager, the Operations Director for COREC and the appointing authority for the REC. Any dissenting views on the committee will be recorded in the letter. The main REC may recommend that consideration is given to suspending or terminating the CTA. Any such recommendation should relate to serious concern about one or more of the following: (a) (b) (c) (d) (e) (f) The scientific value of the trial The safety or physical or mental integrity of participants The competence or conduct of the investigator(s) A delay of at least 2 years in the commencement of the trial leading to doubts about the continuing validity of the ethical opinion given on the original application The adequacy of the site or facilities Any other significant ethical issue On receipt of correspondence under paragraph 11.2, the CTU will consider what action should be taken in relation to the CTA and will notify the main REC accordingly. The action taken could include request to the sponsor for further information, request for amendment of the trial, or suspension or termination of the CTA. Further information or clarification may be sought from the main REC about its concerns. The CTU may seek separate advice from referees. The CTU will notify the Operations Director at COREC, the GTAC Secretariat (if applicable), the main REC and the REC operational manager of the action taken. The Operations Director or GTAC Secretariat will notify the UKECA Secretariat once action by MHRA is completed The main REC will keep the CTU informed of any further action it takes or where it is aware of any action taken by the sponsor, trial investigators or care organisations hosting the trial in the light of the concerns raised by the committee.

11 12. Communications 12.1 Communications referred to in this agreement will normally be sent electronically Copies of final opinion letters on new applications and amendments should be sent to and should be marked REC opinion letter for EudraCT Correspondence with the Head of CTU will be sent by to and should be marked URGENT: REC correspondence for Head of CTU Correspondence with the GCP Inspectorate will be sent by to the Operations Manager for GCP, copied to the senior GCP inspectors responsible for liaison with the REC system (see details at Appendix 2) Correspondence from MHRA to RECs will be sent to the REC Co-ordinator using the address on the COREC website Wherever possible, communications will include the EudraCT number for the trial (for trials authorised after 1 May 2004), the full title, the name of the Chief Investigator, the sponsor s protocol number and the REC reference number issued by the main REC For trials authorised prior to 1 May 2004, a reference for the CTX or DDX exemption letter will be given instead of the EudraCT number Where information on the main REC for the study and REC reference number is not available to the MHRA, a request for the information will be sent to the Business Manager for COREC, citing the full title of the trial and the EudraCT number. COREC will search the Research Ethics Database and provide the information within two working days Contact details for key personnel are listed in Appendix Review of the agreement 13.1 Quarterly meetings will be held between representatives of the CTU, GCP Inspectorate, COREC and the GTAC Secretariat to review the implementation of the agreed arrangements and consider any necessary amendments. The terms of reference for these meetings is set out in Appendix Amendments may be made to the Memorandum of Understanding at any time by agreement of all parties. The UKECA Secretariat will be notified Where the terms of the agreement are not complied with, the matter should be resolved as follows: In the case of non-compliance by an individual NHS REC, the matter should initially be raised with the relevant REC operational manager. The Operations Director for COREC should be kept informed.

12 Any other non-compliance should be raised directly with the Head of CTU, the Operations Manager for GCP, the Operations Director for COREC or the GTAC Secretariat as appropriate. The matter should be discussed and resolved at the following quarterly review meeting held under paragraph Signatures Signature:.. Date:. (Dr. Martyn Ward, Head, Clinical Trials Unit, MHRA) Signature:.. Date:. (Dr. Bernadette Sinclair-Jenkins, Chair, Inspection Action Group, MHRA) Signature:. Date:. (Mr. Ian Oulsnam, Operations Manager for GCP, MHRA) Signature:.. Date:. (Dr. Janet Wisely, Operations Director for COREC) Signature:.. Date:. (Dr. Monika Preuss, GTAC Secretariat)

13 APPENDIX 1 Potential outcomes from Clinical Trials Inspection Action Group (CTIAG) This appendix summarises the role of the Clinical Trials Inspection Action Group at the MHRA and the potential outcomes from referrals considered by the Group. Background The Inspection Action Group (IAG) is a non-statutory, multi-disciplinary group constituted to advise the Director, Inspection and Standards (I&S) Division and the Director, Licensing Division at the MHRA on any recommendation for referral or enforcement action appropriate to the Divisions. Primary objective The primary objective of IAG is to protect public health by ensuring that clinical trials of investigational medicinal products meet the required regulatory standards. Remit The Group considers referrals relating to critical findings arising from GCP inspections of clinical trials. Potential outcomes 1. Early re-inspection within 6 12 month period of initial inspection. 2. Meeting of sponsor/investigator with MHRA representatives at Market Towers to discuss non-compliances and future actions. 3. Warning letter from IAG no legal status. 4. Infringement notice under Regulation 48 of S.I.2004/1031 (as amended) in relation to specific breaches. Breach of an infringement notice is itself an offence for which criminal prosecution may be considered. 5. Regulatory action suspension or termination of Clinical Trial Authorisation (CTA) under Regulation 31. Rejection of marketing authorisation applications may also occur, if clinical trial data included in the application are found to be unreliable. 6. Notification to the Clinical Trials Unit that there are unresolved safety concerns regarding trial activities associated with a particular sponsor and recommend that all future CTAs by that sponsor be refused on the grounds of safety pending resolution of those concerns. 7. Suspension or revocation of the manufacturing authorisation for the IMP under Regulation 45.

14 8. Notification of the competent authorities of other states in the European Economic Area (EEA). 9. Notification of the General Medical Council. 10. Notification of COREC and/or GTAC Secretariat. 11. Notification of European Medicines Agency (EMEA) who may, where relevant, inform other Authorities outside the EEA, for example the US Food and Drug Administration (FDA). 12. Referral to Enforcement for consideration of criminal prosecution (where breach is a criminal offence under Regulation 49). A person convicted of an offence shall be liable (a) on summary conviction, to a fine not exceeding the statutory minimum or to imprisonment for a term not exceeding three months or both, or (b) on conviction on indictment, to a fine or to imprisonment not exceeding two years or both. Note: Definition of GCP critical finding: (a) Where evidence exists that the safety, well being or confidentiality of trial subjects has been jeopardised, and/or (b) Where evidence exists that reported data are unreliable, and/or (c) Where inappropriate, insufficient or untimely corrective action has taken place regarding major non-compliances.

15 APPENDIX 2 Contact details [To be included in signature version. Not included in published version.]

16 APPENDIX 3 MHRA/COREC/GTAC Collaboration Group Terms of reference 1. Definition 2. Remit The MHRA/COREC/GTAC Collaboration Group is constituted under the Memorandum of Understanding (MoU) between the Medicines and Healthcare products Regulatory Agency (MHRA), the Central Office for Research Ethics Committees (COREC) and the GTAC Secretariat relating to the implementation of the Medicines for Human Use (Clinical Trials) Regulations 2004 in the United Kingdom. The remit of the Group is to facilitate collaboration and communication of information between ethics committees and the MHRA (acting on behalf of the licensing authority) as prescribed by the European Commission Directive 2005/28/EC article Objectives 3.1 The primary objective of the collaboration is to protect public health and the rights, safety and dignity of research participants by ensuring that clinical trials of investigational medicinal products meet the required regulatory and ethical standards. 3.2 This primary objective is achieved by ensuring: a) Effective communication and sharing of information between MHRA and the ethics committee system in relation to: i. New applications for CTA or ethical review ii. Approved trial sites iii. Substantial amendments iv. Addition of new sites and investigators v. Safety concerns emerging from SUSARs or periodic safety reporting vi. Risk/benefit analysis conducted by CTU vii. New ethical concerns arising during the trial viii. Non-compliance with the Regulations or GCP (identified by MHRA Inspection or referrals to any of the parties) ix. Fraud or misconduct, including reports by whistleblowers x. Verification of correspondence and application documentation. xi. Suspension or termination of CTA. b) Clear understanding of the roles and responsibilities of MHRA CTU, MHRA GCP Inspectorate, COREC, the GTAC Secretariat and ethics

17 4. Membership committees in the implementation of the Regulations. c) Regular discussion of issues relating to effective collaboration and communication. d) Full compliance with the operational procedures provided for in the MoU. 4.1 Minimum membership of the Group will be: i) A senior representative of COREC (for example the Operations Director or the Policy Lead). ii) A MHRA GCP Inspector. iii) Head of the Clinical Trials Unit (or nominee). iv) The GTAC Secretary or another representative of the Secretariat. 4.2 The Group may seek specific advice from persons other than members either by inviting the appropriate person to attend a meeting or by requesting written advice. 4.3 In the event that one of the parties is unable to attend the meeting or send a deputy, the meeting may take place depending on the number and nature of issues residing with the remaining parties. Appropriate follow-up will be actioned to ensure buy-in from all parties and agreement of any actions in which the third party may have an interest. The meeting minutes will record agreement of the outcomes by all parties. 5. Frequency of meetings Meetings will be held on at least a quarterly basis. Additional meetings may be held where necessary by agreement of the parties. 6. Standing agenda items Review and follow-up of previous meeting Current alerts under paragraph 10.3 of the MoU Other current issues Agreement of next meeting date 6. Chair and minute taking 6.1 Responsibilities of the Chair will be agreed at the beginning of each meeting. 6.2 Responsibility for minute taking will be rotated between the parties. Minutes will be produced in a timely manner, where possible within 20 working days of the meeting. 7. Circulation of the minutes

18 Minutes will be sent to representatives of all the parties for distribution within the MHRA GCP and Pharmacovigilance Inspectorates, MHRA Clinical Trials Unit, relevant MHRA line management, senior management in COREC, GTAC and the UKECA secretariat.