Good Clinical Practice (GCP) A whistle stop tour!

1. Good Clinical Practice (GCP)A whistle stop tour! St George’s University of London, UK Debbie Rolfe Regulatory Assurance Manager, Joint Research & Enterprise Office Joint Research & Enterprise Office Training

2. What is GCP? Good Clinical Practice (GCP) is an international ethical scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.. Joint Research & Enterprise Office Training

3. What is GCP? The objective of ICH GCP is to provide a unified standard for • USA • European Union • Japan To facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. Joint Research & Enterprise Office Training

4. 13 Principles of GCP • Researcher training, education and experience • Freely given informed consent • Accurate data handling and storage • Data Protection and confidentiality • Good Manufacturing Practice • Quality assurance systems ICH GCP Section 2 • Ethical Principles of Declaration of Helsinki • Benefit justifies risk • Rights, safety, wellbeing • Adequate information to support trial • Clear, scientifically sound protocol • Favourable ethics approval • Qualified Chief Investigator Joint Research & Enterprise Office Training

5. What is a clinical trial? ICH GCP 1.13: Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or pharmacodynamic effects of an investigational product and/or to identify any adverse reactions to an investigational product, and/or to study absorption; distribution; metabolism; and excretion of an investigational product with the object of ascertaining its safety and efficacy. Joint Research & Enterprise Office Training

6. Principle 1 • Clinical Trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, that are consistent with GCP and the applicable regulatory requirements Joint Research & Enterprise Office Training

7. DECLARATION OF HELSINKI • Leading international ethical standard 1st adopted in 1964 – 7 revisions current 2013 • The Declaration provides guidance for research on humans, their material and/or their data: • Safeguarding research participants • Adhering to an approved research protocol • Benefits > risks • Full informed consent, including assent where appropriate • Publishing findings • Use of placebos • Post-trial access to treatment Joint Research & Enterprise Office Training Joint Research & Enterprise Office Training

8. Clinical Trials • Phase I: Healthy volunteers/ Oncology patients MTD/DLT • Testing for safety, PK and PD, tolerability • Phase II: Exploratory Selected people with relevant illness • Testing for clinical efficacy • Phase III: Confirmatory Large number of people with relevant illness • Testing against “gold standard” or placebo • Marketing Authorisation • Pre-Clinical • Tissue samples • Computer simulation • In vitro tests • Animal testing - Toxicology • IMPD for Regulatory submission Post Marketing Phase IV: Post marketing surveillance. Wider testing in a more generalised population, reporting further side effects and long-term risks and benefits Joint Research & Enterprise Office Training

9. Principle 2 • Before a trial is initiated, foreseeable risks and inconveniences should be weighed against anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks Joint Research & Enterprise Office Training

10. Principle 3 • Rights , safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society Joint Research & Enterprise Office Training

11. Principle 4 • The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial Joint Research & Enterprise Office Training

12. Principle 5 • Clinical trials should be scientifically sound, and described in a clear, detailed protocol Joint Research & Enterprise Office Training

13. Principle 6 • A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/ Independent ethics committee (IEC) approval/ favourable opinion. Joint Research & Enterprise Office Training

14. Principle 7 • The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, where appropriate, of a qualified dentist. Joint Research & Enterprise Office Training

15. Principle 8 • Each individual in conducting a trial should be qualified by education, training, and experience to perform his or her respective tasks. Joint Research & Enterprise Office Training

16. Role of the IRB/REC • Who are the ethics committee/ Review board? • At least 5 members with at least 1 non-scientific member, at least 1 member independent of trial site or institution can be clinicians, nurses, pharmacists and other interested parties • Ethical approval: • Gives balanced independent view of research following review of the trial protocol, information provided to the subjects, subject recruitment procedures e.g. advertisements, informed consent forms and proposed process and available safety information • Ensures Investigator suitable qualified and experienced • Clear documented approval listing documents and version numbers approved for use ICH GCP: 3.1.1. An IRB/IEC should safeguard the rights, safety and well being of all trial subjects Joint Research & Enterprise Office Training

17. Principle 9 • Freely given informed consent should be obtained from every subject prior to clinical trial participation. Joint Research & Enterprise Office Training

18. Informed Consent “a process by which a participant voluntarilyconfirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the participant’s decision to participate. Informed consent is documented by means of a written, signed and dated consent form” ICH GCP Section 1.28 • Must be obtained before any research related activity occurs • Copy to participant, copy in ISF and original in medical notes • Continuous process throughout the study. • What if consent is withdrawn? Joint Research & Enterprise Office Training

19. Requirements for valid consent • Who should obtain consent? • CI/PI or suitably qualified individual • Must ensure: • Sufficient opportunity to read and consider information • Time given (preferred) >24 hrs • To reflect on implications of participation • To ask questions & discuss with family • Capacity, i.e. consideration of age, maturity, cognitive ability • Illiteracy – use impartial witness • Thumbprint • Name and date of witness entered by witness and signed Joint Research & Enterprise Office Training

20. Adults without Capacity • Mental Illness / Mental Disability / Brain Damage • Country-specific regulations • Legally designated person to give consent for another adult • Hierarchy: • Personal legal representative • Suitable by virtue of relationship • Willing • Professional legal representative • Not connected with study • Primarily responsible for person’s medical care OR • Nominated by relevant health care provider Joint Research & Enterprise Office Training

21. Requirements for valid consent Unconscious Patients • Research should relate directly to life-threatening condition of participant • Legal representative (personal or professional) to give consent • Waiver accepted if allowed by IEC/IRB • Emergency research should be re-consented • Follow-up Joint Research & Enterprise Office Training

22. Assent of Minors • Only research that directly relates to the child’s clinical condition should be conducted • Parent’s signature sufficient in law • Best practice: assent of child (if deemed competent) • Assent is not legally binding,however, favoured by ethics committees • Child should be involved as much as possible – use of age related information sheets • Parental consent should reflect wishes of the child, these may overrule parents’ wishes Joint Research & Enterprise Office Training

23. Inspection Findings • Missing consent forms – not possible to verify subjects had consented • Lack of subject or Investigator signature to demonstrate agreement to participate • Unapproved consent form used • Consent form referencing wrong Patient information sheet • Consent taken by persons not listed on delegation log – therefore no evidence of training to obtain consent Joint Research & Enterprise Office Training

24. Principle 10 • All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification Joint Research & Enterprise Office Training Joint Research & Enterprise Office Training

25. Essential Documents Joint Research & Enterprise Office Training

26. What are Essential Documents? “Essential documents are those which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.” Filing essential documents in a timely manner greatly assists in the successful management of a trial by the investigator, Sponsor and monitor. Normally it will be these documents that are inspected by the regulatory authorities as part of the process to confirm the validity of the trial conduct and integrity of the data collected ICH GCP Section 8 Joint Research & Enterprise Office Training

27. Why Bother? • First thing inspectors, auditors & monitors look at • Organises the paperwork • Saves time • Saves effort • Facilitates organisation of the study Joint Research & Enterprise Office Training

28. Trial Master File • Trial master files should be established at the beginning of the trial BOTH at the Investigator site and at the Sponsor office • Essential documents are generally grouped in 3 stages of the trial (normally where generated) • Prior to Clinical phase • Clinical conduct • Following completion/ trial termination • Description & purpose of each document and whether kept at Sponsor office or Investigator site or both is described in ICH GCP Section 8.2-8.4 • All documents described should be subject to and available for audit by the Sponsor’s monitor and inspection by the regulatory authorities Joint Research & Enterprise Office Training

29. Principle 11 • Confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements Joint Research & Enterprise Office Training

30. Data Protection Directive 95/46/EC • Was created to regulate the progression of personal data within the European Union and is part of the EU privacy and human rights law. • New EU data protection regulation (draft) • To harmonise current data protection laws across the EU member states. • Regulation means it will be directly applicable to all EU member states without need for national implementing legislation. • 2012/0011(COD) Awaiting council 1st reading position • http://www.europarl.europa.eu/registre/docs_autres_institutions/commission_europeenne/com/2012/0011/COM_COM%282012%290011_EN.pdf Joint Research & Enterprise Office Training

31. Investigator Site File • Contact Lists • Protocol and any Amendments • Ethics and Regulatory Approvals • Participant Information Sheets and Consent forms • Agreements and contracts • Delegation & duty Logs • Participant master file – Participant ID log • Data Management • Case Report Forms • Serious Adverse Events • Correspondence and Communication (both Sponsor and Internal Team meetings) • Study specific SOPs & Training logs Joint Research & Enterprise Office Training

32. Protocol A document that describes the objective(s), design, methodology, statistical considerations and organisation of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. ICH GCP 1.44 Contents of a protocol are suggested in ICH GCP Section 6 Joint Research & Enterprise Office Training

33. Document Control • All documents should have: • Version number • Date • Standard numbering system • Ensures only current ethically approved version in use • Format consistent • e.g. v1.1; 27/09/2010 DRAFT • Method/ approved procedure for amending version numbers • Approval and distribution procedures defined Joint Research & Enterprise Office Training

34. Amendments Substantial An amendment to the protocol or any other supporting documentation that is likely to affect to a significant degree the: 1. Safety or physical or mental integrity of the trial subjects 2. Scientific value of the trial • Conduct or management of the trial Non-substantial • Requires notification only (e.g. typos, amending members of research teams except CI & PIs) • Retain all documents in the ISF/TMF – documents that are no longer approved for use MUST be clearly marked as superseded • Pharmacy MUST be included on the circulation list of approved Protocols, updated Reference Safety Information Joint Research & Enterprise Office Training – 21st November 2013 Joint Research & Enterprise Office Training Joint Research & Enterprise Office Training

35. Inspection Findings • Lack of essential docs e.g. IMP shipment receipt, blood sample shipments to central labs • Incomplete trial subject screening lists • Missing source documents • Discrepancies between source data and data reported in Clinical Study Report • Lack of evidence of Sponsor SOP use • Poor document control – documents not superseded/removed from circulation upon update Joint Research & Enterprise Office Training

36. Principle 12 • Investigational products should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. Joint Research & Enterprise Office Training

37. PHARMACY ! • All IMPs (including comparators and placebo) is manufactured in accordance with any applicable GMP and is coded, labelled in a manner that protects the blinding and in accordance with applicable regulatory requirements. • Decoding/unblinding of treatment in case of medical emergency • Storage temperatures, storage conditions e.g. Protect from light, reconstitution fluids and procedures and stability information. • IMP accountability and chain of custody details Sponsors responsibility ICH GCP 5.12-5.14 Recommend to include your Pharmacy department early on! Joint Research & Enterprise Office Training

38. Pharmacy Site File • RSI -IB IMPD or Summary of Product Characteristics (SmPC) • Protocol and Amendments • Submission and approval documentation in accordance with local & regional requirements • Approved label (Annexe 13) Template • Certificate of Analysis • IMP QP release • Instructions for Use • Dose & administration • Approved prescription template & copies of participant prescriptions • Approved prescribers signature samples • Recommended storage conditions • Training log • Delivery notes • Drug accountability forms • Chain of Custody • Treatment Allocation- Participant lists • Drug destruction procedure • Drug destruction log • Code break Procedure • Pharmacy delegation log • Contact Lists • Correspondence & communications Joint Research & Enterprise Office Training

39. Product Accountability ICH GCP Section 5.19 • Should determine: • Storage temperatures • Storage conditions • Storage times • Reconstitution fluids and procedures • Devices for infusion • Site should receive appropriate instructions • Document shipment, receipt, delivery, distribution- dispensing, Subject returned IMP and destruction ICH GCP Section 5.13-5.14 Joint Research & Enterprise Office Training

40. Risk Adaptive Approach ~(UK) • Type A – Routine prescribing on licensed IMPs (or established off-label use supported by published evidence/guidelines) • Type B – licensed IMP – new indication, substantial dose modifications, combinations in which interactions are suspected • Type C – Unlicensed IMPs in any EU MS Joint Research & Enterprise Office Training

41. Principle 13 • Systems with procedures that assure the quality of every aspect of the trial should be implemented. Joint Research & Enterprise Office Training

42. Trial Management Group (TMG) • Every trial should have a TMG • Normally includes individuals who are responsible for the day to day management of the trial • CI • Trial manager • Statistician • Research nurse • Data manager • Role is to: • Monitor conduct and progress of the trial • Ensure that the protocol is adhered to • Take appropriate action to safeguard participants Joint Research & Enterprise Office Training

43. Data Monitoring Committee • aka DSMB, IDMC, DMEC • Role is to: • Interim analyses to monitor the progress of the trial, the safety data, and the critical efficacy endpoints • Recommend to the sponsor whether to continue, modify, or stop • Assess whether there are any safety issues that should be brought to participants’ attention • Should be considered for all trials • DAMOCLES charter • Strongly recommended for blinded studies • Should be the only body that has access to unblinded data • Independent from study AND study team Joint Research & Enterprise Office Training

44. Trial Steering Committee (TSC) • Role is to: • Provide overall supervision of the trial • Ensure that it is being conducted in accordance with the principles of GCP and the relevant regulations • Should agree the trial’s protocol and any protocol amendments • Provide advice to the investigators on all aspects of the trial • The TSC may have members who are independent of the investigators, in particular an independent chairperson Joint Research & Enterprise Office Training

45. Compliance with GCP provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible Joint Research & Enterprise Office Training

46. Safety Reporting Joint Research & Enterprise Office Training

47. Pharmacovigilance (PV) is the process and science of monitoring the safety of medicines and taking action to reduce the risks and increase the benefits of medicines Joint Research & Enterprise Office Training

48. What's it all about? • Collect and manage data on safety of medicines • Interrogate data to detect ‘signals’ (new or changing issues) • Evaluation and decision making with regards to Safety Issues • Pro-active risk management to minimise potential risk associated with medicine use • Acting to protect public health (including regulatory action) • Communication with and informing stakeholders & the public • Audit, both outcomes of actions taken & processes involved Joint Research & Enterprise Office Training

49. Acronyms • AE • Adverse Event • AR / ADR/ADE • Adverse Reaction / Adverse Drug Reaction/Adverse Device Event • SAE/SADE • Serious Adverse Event/Serious Adverse Device Event • SAR/SADR • Serious Adverse Drug Reaction • SUSAR • Suspected Unexpected Serious Adverse Reaction • USADE • Unanticipated Serious Adverse device effect Joint Research & Enterprise Office Training

50. AEs and ARs/ADRs ADE/SADE Any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product • AE: Does notneed to be related to a drug • AR: Related to any dose administered of medicinal product For Non-CE marked devices or CE marked devices used outside the Intended use covered by the CE marking • ADE: Includes any events resulting from insufficiencies or inadequacies in instructions for use, deployment, installation the operation, or any malfunction. It also includes user error or intentional misuse • SADE: Adverse device event has resulted in any consequences characteristic of an SAE Joint Research & Enterprise Office Training