Good Clinical Practice (GCP) for studies involving Investigational Medicinal Products June 2018

1. Good Clinical Practice (GCP) for studies involving Investigational Medicinal ProductsJune 2018

2. What is GCP? “An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects” ICH-GCP E6 (1996)

3. Introduction to GCP • GCP The standards - This section will look at the timeline of different legislations that have formed the regulations researchers have to comply with. • Study Set-up: Responsibilities, Approvals and Essential Documents - This section will include the requirements and approvals needed to set up a trial, researcher responsibilities, site files and the essential documents required • The Process of Informed Consent - This section looks at who is responsible for and eligible to take informed consent and the consent process. • Safety Reporting - This section looks at why safety reporting is required, how to report serious adverse events, and the reporting timelines in place . • Drug Accountability/ Sample - This section looks at why/how we account for medicinal products and remote sample storage. • CRF, Source Data and Data Entry Completion - This section looks at data management, source data verification and completion of case report forms. • Inspection/Audit/Monitoring - This section will focus on who will audit and what they will look at during an audit visit. June 2016 3

4. GCP The Standards • At the end of this section you will: • Understand that there is a set of interwoven laws, guidelines and regulations that govern the set-up and conduct of clinical research • Understand the different types of studies and the requirements that govern their conduct

5. ICH-GCP is a Standard consisting of 14 principles which focus on the need for researchers to protect people who participate in clinical trials and the data their participation generates Ensure the safety of patients participating in a trial is protected Ensure that drugs/interventions developed are safe for patients in the future Ensure that the data about the drug/intervention is valid & reproducible Give public assurance that the data is credible

6. GCP A Brief History • 1947 Nuremberg Code - A set of research ethics principles for human experimentation set as a result of the subsequent Nuremberg Trials at the end of the Second World War. This laid down the need to obtain informed consent • 1964 Declaration of Helsinki – A set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association (WMA). It is widely regarded as the cornerstone document of human research ethics • 1996 ICH-GCP - Implemented in 1996, these are the standards that researchers are expected to work to today • European Directive 2001/20/EC – This provides a framework which sets out how clinical trials investigating the safety or efficacy of a medicinal product in humans must be conducted. It includes medicinal trials with healthy volunteers and small scale or pilot studies.

7. GCP A Brief History cont.. • 2004 Medicines for human use regulations - Statutory Instrument 2004/1031 transposed the 2001 EU directive into UK law, prior to this the standards had only been guidelines. This governs all clinical trials involving Investigational Medicinal Products • 2001 & 2005 Research Governance Framework - The Research Governance Framework for Health and Social Care sets out the broad principles of good research governance. The first edition was issued in March 2001. The second edition was issued in April 2005. This is not law but might as well be as it must be adhered to for all studies conducted within the NHS in England • EU 2005/28/EC (The GCP Directive) - Also known as the GCP Directive, this directive clarified and extended the previous directives and was transposed into UK law by Statutory Instrument 2006/1928

8. GCP A Brief History cont.. 2016/2017 GCP E6 (R2 Addendum) Adopted in November 2016. Implementation in June 2017. 14 Principles of GCP. Since the development of the ICH GCP Guideline, the scale, complexity, and cost of clinical trials have increased. Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus on relevant activities. This guideline has been amended to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and data integrity. 2017 UK Policy Framework for Health & Social Care. The Policy Framework sets out principles of good practice in the management and conduct of health and social care research that takes account of legal requirements and other standards. These principles describe ethical conduct and proportionate assurance-based management of research to support & facilitate high quality research in the UK

9. Main Implications of EU Directive 2001 • All interventional studies must be performed to same GCP standards • Each member state had to have a Competent Authority to oversee trials being undertaken. In the UK this is the Medicines and Healthcare products Regulatory Agency (MHRA) • Introduction of mandatory inspections • The requirement to report a specific type of serious adverse event – Suspected, Unexpected Serious Adverse Reactions(SUSARs) • The requirement to provide notification of the end of a study • The requirement to publish trial results

10. European Directive 2005/28/EC • The “GCP Directive” • Clarified and extended previous directive • Requires archiving of essential documents for 5 years after study completion • Legal requirement for Sponsors to report “serious breaches” of GCP or protocol to MHRA

11. Other laws/guidelines The data protection act lays down rules governing how personal identifiable data can be stored and used. 2018 Data Protection Act/ General Data Protection Regulations The protection of children act applies if you are conducting studies involving minors 1999 Protection of Children Act The human tissue act applies if conducting studies involving human tissue samples 2004Human Tissue Act The mental capacity act applies if you are involving adults who have temporarily or permanently lost their mental capacity 2005 Mental Capacity Act

12. Summary • No single document provides the standards and laws by which you conduct a trial • A set of interwoven laws, guidelines and frameworks govern the set-up and conduct of clinical research

13. Study Set-up: Requirements, Responsibilities and Essential Documents • At the end of this section you will: • Have an understanding of the regulatory requirements for setting up a study • Understand the responsibilities and/or duties of research staff • Understand the importance of the Trial Master/Investigator Site File • Be familiar with a range of essential documents

14. Types of Trials and Regulations Clinical Trials of Investigational Medicinal Products (CTIMP) Trials involving an Investigational Medicinal Product are governed by the Medicines for Human Use (2004) Regulations Medical Devices Trials involving medical devices are governed by the Medical Devices Regulations Clinical Trials NOT involving Investigational Medicinal Products (Non-CTIMP) Trials which do not involve an Investigational Medicinal Product are governed by the UK Policy Framework for Health and Social Care 14

15. Requirements for setting up a Clinical Trial of Investigational Medicinal Product Identify a Sponsor A Sponsor can be an NHS Trust, a University, a Pharmaceutical Company or a Charity Health Research Authority approval & Research Ethics Committee favourable opinion HRA approval & REC favourable opinion must be given before your trial commences The Research Office at the NHS Trust which will be hosting your research must confirm capacity and capability Host Research Office confirmation of capacity and capability Conduct trial to GCP guidelines Your trial must be conducted to GCP guidelines

16. Requirements for setting up a Clinical Trial of Investigational Medicinal Product Are governed by law and come under the jurisdiction of the UK Competent Authority This is the Medicines & Healthcare Regulatory Authority Must receive a Clinical Trial Authorisation (CTA) The authorisation from the MHRA to conduct your study Must register for a EudraCT number (European Clinical Trials Database) A database which holds details of all CTIMP studies conducted in Europe Usually conducted by the MHRA Are subject to mandatory inspections J

17. Requirements for setting up any Clinical Trial Must collect accurate data Must be aware of safety reporting requirements Must create clear audit trail Must demonstrate financial transparency Must maintain study master file Must ensure the trial is adequately funded from start to finish Must receive consent from participant Must have adequate qualified staff and facilities to safely conduct the trial Must have sufficient time to properly conduct and complete trial within agreed time

18. Check your approvals before you commence recruitment: • CTIMP • Research Office confirmation of capacity & capability • HRA & Ethics • Sponsor Greenlight • Competent Authority • EudraCT number • Non-CTIMP • Research Office confirmation of capacity & capability • HRA & Ethics • Sponsor Greenlight

19. Quick Question For each study, state which laws, guidelines or frameworks apply and what approvals are required: Approvals Law or Framework Trial First administration of swine flu vaccine in humans evaluating safety and efficacy Questionnaire about experiences of inpatients with incontinence. Study of the use of a new pacemaker in patients looking at survival and quality of life 19

20. Responsibilities of the Sponsor • Initiation, management (and financing) of trial • All trials • HRA approval & favourable opinion from REC • Protocol amendments correctly processed • Suitable indemnity/insurance in place • Ensure trial conducted to GCP • Notify REC and/or HRA when trial has ended • Ensuring the final study report is completed and submitted to the HRA, REC and Regulatory Authority • CTIMP • EudraCT number • Clinical Trials Authorisation • Pharmacovigilance reporting timelines are adhered to • EudraCT and MHRA notified when trial has ended 20 June 2016

21. Responsibilities of the Chief Investigator • Only 1 Chief Investigator (CI) per country • Authorised healthcare professional that takes overall responsibility for the conduct of the trial • Application / Amendments • Duties delegated to them by the Sponsor June 2016 21

22. Responsibilities of the Principal Investigator Only 1 Principal Investigator (PI) per site Person who takes responsibility for the initiation and conduct of a study at their site PI can delegate duties outlined in the protocol but remains responsible for them

23. Responsibilities of the Principal Investigator Continued • The Principal Investigator is responsible for the conduct of the • trial and the leadership of the trial team. It is essential that there is clear documented evidence of oversight and involvement in the trial and that the PI is appraised of any issues regarding the trial. • Examples of suitable evidence of oversight: • Completion/Overview of consents • Eligibility assessments • Sign off for completed serious adverse events • Review of safety information • Attendance and availability at monitoring visits • Documented review of incoming data in a timely manner • Review of completed CRF and response to medical queries • Provision of protocol or specialised training to the team. • Regular minuted meetings with trial team

24. Your responsibilities: Ensure the safety and well-being of participants Fulfil the duties delegated to you Report any concerns about study conduct Responsibilities of Individual Researchers

25. Trial Master/Investigator Site File You must ensure that your site file is stored in a secure lockable area and limit access to only those who need to see it Some Sponsors provide an index that they require you to use. UHL R&I have their own CTIMP / NON-CTIMP indexes which can be obtained from the R&I website Not all studies will use all the sections in the index so you can customise the index to suit your requirements. If you are deliberately leaving a section blank because your are not using that section please indicate this on the index and in the relevant section of the site file It is recommended that you file your documents chronologically, with the most recent document uppermost to facilitate ease in locating any requested documents 25

26. General Rules 1 Remove draft documents – may want to keep separately Remove duplicates Document and explain all protocol deviations Maintain confidentiality – numbers not names Logs are essential documents - examples are tracking logs, ID logs etc

27. General Rules 2 Good practice to remove superseded documents from active files and red pen them to ensure they aren’t usable Recall superseded paperwork-who did I give those protocols to? Track Ethics, HRA & Research Office paperwork must be included- file all correspondence Set aside time after patient visits to complete paperwork/filing Do it now!

28. File Notes Use signed and dated file notes to explain important issues on an ongoing basis. Also include study number and title. They provide evidence of when an issue was identified, what was done about it and what was done to stop it happening again (Corrective and Preventative Action, CAPA) Repeated file notes don’t excuse repeated problems!!

29. “If it’s not written down, it didn’t happen, and if you can’t find it within 1 hour it doesn’t exist”

30. Essential Documents Essential documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. Essential documents also serve a number of other important purposes. Filing essential documents at the Investigator/Institution and Sponsor sites in a timely manner can greatly assist in the successful management of a trial by the Investigator, Sponsor and Monitor. These documents are also the ones which are usually audited by the Sponsor’s independent audit function and inspected by the Regulatory Authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of the data collected. (ICH-GCP E6 8.1)

31. EssentialDocuments Filed in Investigator Site File(s) Kept in designated place and maintained by designated person(s) Established at start of trial and maintained throughout Available for audit/inspection (“Inspection Ready”) at all times Archive Minimum 5 years Stored securely, adequately protected, controlled access

32. Examples of Essential Documents • Protocol - This details why and how to conduct trial, and can only be changed by an amendment. All members of the research team should have read and understood the protocol in order to have a thorough working knowledge of the trial. All protocol deviations must be explained, documented and rationale submitted to the Sponsor, REC and Regulatory Authorities. The current approved version of the protocol should be signed and dated by the Principal Investigator and filed in the master/investigator site file. • Investigator Brochure/Summary of Product Characteristics (SPC) - These are a compilation of clinical/non-clinical data on the Investigational Medicinal Product under study. It is the Sponsor’s responsibility to produce an IB and review it at least annually. The trial master/investigator site file must contain clear evidence not only that this review has occurred even when the review concludes that no update is required, but also that this information has been communicated to all relevant parties involved in the trial. If the drug being used in the trial has a marketing authorisation and a SPC, the Sponsor should also ensure that the reference safety information in the IB is consistent with that in the SPC.

33. Examples of Essential Documents cont… • Delegation of Authority Log - This is a record of trial related duties that have been delegated to individual research team members by the Principal Investigator. Everyone who is actively involved in the trial must be named on the log. Each individual on the log must sign and date the log to demonstrate their acceptance of the delegated duties and the Principal Investigator must counter sign each entry to confirm the delegation. The Principal Investigator is ultimately responsible for ensuring the log is completed, but each individual researcher needs to ensure they are named on the log. The log should be completed and maintained prospectively throughout the life of the trial. Current, signed and dated CVs and a valid GCP certificate should be present for anyone named on the log. Evidence of study specific training should also be present • Screening /Enrolment Logs - Screening Log :This is a record of which patients have been approached to take part in the trial. Please be aware that ONLY non-identifiable patient data can be held on this log as at this point the patient has not given their consent for you to hold any of their data. The screening log can record date of birth and initials but should not have hospital numbers, full names, addresses etc. Enrolment Log : This is a record of the patients that have proceeded to give informed consent to participate in the trial and therefore can contain identifiable patient data. Both the screening and enrolment logs should be completed and maintained prospectively.

34. Examples of Essential Documents cont… • Regulatory & Competent Authority Documents - All documents including applications, approvals and correspondence between the trial site and Regulatory/Competent Authorities must be included in the site file. This facilitates the clear audit trail required. • Contracts and Agreements - Contracts must be fully executed and authorised by all parties e.g. Statistical analysis, investigational product supply. Investigators are not authorised to sign on behalf of the sponsor. • Standard Operating Procedures - All Sponsors will provide their own Standard Operating Procedures (SOPs). These cover all aspects of study conduct and detail what the Sponsor expects from all members of the research team. Everyone working on a study must have read these SOPs. In addition there are also Host Standard Operating Procedures. June 2016 34

35. Version Control Repeatedly an audit/inspection finding: Applies to ALL study documentation – protocols, information leaflets, consent forms, data collection forms and advertising media. Updating versions introduces the possibility of errors so needs to be managed carefully . This can be achieved by using footers to document the version number and date . Version control document.

36. ProtocolAmendments At the end of this section you will have an understanding of : Thedifferent types of protocol amendments Who to submit protocol amendments to

37. Protocol Amendments • There are 2 types of amendments: • A substantial amendment is defined as an amendment to the terms of the application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree:   • the safety or physical or mental integrity of the subjects of the trial • the scientific value of the trial   • the conduct or management of the trial   • the quality or safety of any investigational medicinal product used in the trial • A non substantial amendment is a minor amendment which will not affect to any significant degree any of the above

38. Protocol Amendments For all studies the responsibility to decide whether an amendment is substantial lies with the trial sponsor Substantial amendments may need a approval/favourable opinion from the HRA and REC along with authorisation from the MHRA if a CTIMP study. All substantial amendments require Research Office Approval Non-substantial amendments are submitted through the HRA, who will inform the local Research Office. The REC or MHRA do not need to be notified. It is good practice to maintain a record of the submission and subsequent approval For more information see- http://www.hra.nhs.uk/about-the-hra/our-plans-and-projects/assessment-approval, your ‘go to’ person or contact the R&I office

39. Substantial Amendments Examples of substantial amendments are: changes to the design or methodology of the study or to background information   changes to the procedures undertaken by participants significant changes to study documentation such as participant information sheets, consent forms, questionnaires, letters of invitation etc inclusion of a new trial site (not listed in the original application) in a CTIMP Study appointment of a new Principal Investigator at a trial site in a CTIMP Study

40. Non-Substantial Amendments Examples of non-substantial amendments might be: minor changes to the protocol or other study documentation, e.g. correcting errors, updating contact points, minor clarifications  changes in the documentation used by the research team for recording study data changes in the logistical arrangements for storing or transporting samples Further information on amendments can be found on the HRA & MHRA websites

41. Urgent Safety Measures The Clinical Trials Regulations allow for appropriate urgent safety measures to be taken without prior approval in order to protect the subjects of a CTIMP Study against any immediate hazard to their health or safety The main REC and the MHRA must be notified immediately and in any event within 3 days that such measures have been taken and the reasons why. The policy from HRA is that these requirements should apply to all other research with a favourable opinion from a REC The initial notification to the REC should be by telephone. Notice in writing should be sent within 3 days. The notice should set out the reasons for the urgent safety measures and the plan for further action

42. InformedConsent At the end of this section you will: Have an understanding of the GCP requirements of informed consent Gain insight into the added protection for vulnerable groups Be aware of the Mental Capacity Act

43. The Importance of Informed Consent Without fully informed consent: the subject could sue REC/Trust approval may be withdrawn future proposals may not be supported inspection/audit requirements will not be met

44. The Trust has had 2 consecutive major findings in relation to consent in the last 2 MHRA inspections If we don’t improve we will incur a CRITICAL FINDING next time

45. What is InformedConsent? A process by which a subject voluntarily confirms his/her willingness to participate in a trial, after having been informed of all aspects of the trial that are relevant to the subjects decision to participate. Informed consent is documented by means of a written, signed and dated Informed Consent Form. ICH-GCP E6 Document 1.28 (1996)

46. TheProcessof Informed Consent Before any trial related procedures take place It is the PI’s responsibility to ensure that GP letters are sent in a timely manner for all subjects participating in a CTIMP trial

47. Informed Consent PI ultimately responsible for informed consent The role can be delegated by PI provided: Stated up front and approved in writing by ethics committee, host organisation and sponsor Person is appropriately trained and qualified Delegation of duties log completed and signed

48. InformedConsent Everyone involved in the process must be: Appropriately trained and competent to perform their specific role GCP trained Additional training if working with vulnerable groups Current CVs and training records UHL: Consent assessment (non-medics) for each study Able to communicate the information objectively. Subjects must be fully aware of risks and benefits (or not) Familiar with the disease under study/alternative treatments Familiar with the protocol Have adequate time for full discussions Understand the participant’s particular circumstances

49. Informed Consent What does a consent form look like? How should it be completed? Who should complete it?

50. Vulnerable Groups Special protection Should not be included in clinical trials if same results can be obtained using persons capable of giving consent Expected benefit for the patient Trial should relate to condition which that group suffers from As with all studies there should be no incentives or financial inducements “Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.” ICH-GCP E6 1.61