Good Clinical Practice GCP for studies involving Investigational

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

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 E 6 (1996)

Introduction to 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

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

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 the data about the drug/intervention is valid & reproducible Ensure that drugs/interventions developed are safe for patients in the future Give public assurance that the data is credible

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.

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

GCP A Brief History cont. . • • 2016/2017 GCP E 6 (R 2 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

Main Implications of EU Directive 2001 All interventional studies must be performed to same standards GCP 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

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

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

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

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

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

Requirements for setting up a Clinical Trial of Investigational Medicinal Product Identify a Sponsor Health Research Authority approval & Research Ethics Committee favourable opinion Host Research Office confirmation of capacity and capability Conduct trial to GCP guidelines A Sponsor can be an NHS Trust, a University, a Pharmaceutical Company or a Charity 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 Your trial must be conducted to GCP guidelines

Requirements for setting up a Clinical Trial of Investigational Medicinal Product J 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 Eudra. CT number (European Clinical Trials Database) A database which holds details of all CTIMP studies conducted in Europe Are subject to mandatory inspections Usually conducted by the MHRA

Requirements for setting up any Clinical Trial Must collect accurate data Must create clear audit trail Must be aware of safety reporting requirements 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 sufficient time to properly conduct and complete trial within agreed time Must have adequate qualified staff and facilities to safely conduct the trial

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

Quick Question For each study, state which laws, guidelines or frameworks apply and what approvals are required: Trial Law or Framework Approvals 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

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

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

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 Sponsor CI PI Individual Researcher

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 Sponsor CI PI Individual Researcher

Responsibilities of Individual Researchers • Your responsibilities: Ø Ensure the safety and well-being of participants Ø Fulfil the duties delegated to you Ø Report any concerns about study conduct Sponsor CI PI Individual Researcher

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 / NONCTIMP 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

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

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!

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!!

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

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 E 6 8. 1)

Essential Documents • 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 Ø Minimum 5 years Ø Stored securely, adequately protected, controlled access

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.

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.

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 also Host Standard Operating Procedures. June 2016 34

Version Control • Repeatedly an audit/inspection finding: Ø Applies to ALL study documentation – protocols, information leaflets, consent forms, data collection forms and advertising media. Ø 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. Ø Version control document.

Protocol Amendments At the end of this section you will have an understanding of : • The different types of protocol amendments • Who to submit protocol amendments to

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

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-andprojects/assessment-approval, your ‘go to’ person or contact the R&I office

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

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

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

Informed Consent 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

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

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

What is Informed Consent? 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 E 6 Document 1. 28 (1996)

The Process of Informed Consent Introduce study idea Provide written and verbal information Time to consider study and answer questions Agreement to proceed by signed and dated consent form Confirm willingness to continue at each visit Re-consent following amendment to study where relevant to subject’s decision to participate 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

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

Informed Consent 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

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

Vulnerable Groups “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 E 6 1. 61 • 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

Minors in CTIMPs Under the Medicines for Human Use (Clinical Trials) Regulations 2004, a minor is a person under the age of 16 • Hierarchy of Consent Ø The parent or person with parental responsibility in law. Ø A personal legal representative (a person not connected with the study, who is suitable by virtue of their relationship with the minor). Ø Professional Legal Representative (a person not connected with the study, who is either the doctor primarily responsible for the medical treatment of the minor or a person nominated by the relevant healthcare provider NHS Trust). • Can be withdrawn at any time • If the subject/legal representative are unable to read, an impartial witness must be present during the consent discussion and sign and date the consent form

Minors in CTIMPs • Parent or legal representative fully informed of all aspects of trial • Minor should receive information according to their level of understanding • Information given by staff with experience • Minor to give assent where appropriate • Must consider explicit wish of minor • Trial considered by Ethics Committee with paediatric expertise

Minors in Non-CTIMPs • UK law has not been tested as to legal age of consent required for research (as opposed to treatment) • Competence criteria may be applied • Gillick Competency

Incapacitated Adult When we are involving Incapacitated Adults in research we are governed by the following: • CTIMP Studies are governed by Medicines for Human Use (Clinical Trials) Regulations 2004 • All other studies not involving an Investigational Medicinal Product are governed by the Mental Capacity Act 2005 • Hierarchy of consent Ø This would consist of a Personal Legal Representative (a person not connected with the study, who is suitable by virtue of their relationship with the adult). Ø A Professional Legal Representative (a person not connected with the study, who is either the doctor primarily responsible for the medical treatment of the adult or a person nominated by the relevant healthcare provider NHS Trust. Ø For adults with temporary incapacity it is essential that fully informed written consent is obtained from the participant once capacity is regained.

Incapacitated Adult • Consent of legal representative represents presumed will and can be withdrawn at any time • Legal representative fully informed of all aspects of trial • Subject must receive information according to their level of understanding • Must consider explicit wish of subject capable of forming an opinion • Trial considered by Ethics Committee with expertise in relevant area • If the subject/legal representative are unable to read, an impartial witness must be present during the consent discussion and sign and date the consent form

Emergency Situations Where as part of a trial, the treatment needs to be administered urgently to minor or incapacitated adult, time may not allow for written consent to be obtained first from a person with parental responsibility or a personal/legal representative. UK regulations allow for people in these groups to be entered into a trial prior to informed consent being obtained provided that: • Matter of urgency • Not practicable to obtain consent • In accordance with procedure approved by Ethics Committee • Seek consent as soon as practicable. If not given, subject to be withdrawn

Withdrawal Process If a study participant does choose to withdraw there is a process which needs to be followed: There must be documentation of the withdrawal recorded in the medical notes and the enrolment log must be completed (where applicable). Ensure you determine what portion of the study the participant is withdrawing from- e. g. this can be withdrawal from active treatment but agreement to follow up. NB- The investigator can ask the subject their reasons for withdrawing their participation but they do NOT have to give a reason or sign anything to withdraw. No further information can be gathered or retained past the point of withdrawal.

Completion Documentation of a participants study completion must be recorded in their medical notes and Case Report Form. The enrolment log must also be completed. (where applicable) Participants should always be thanked for their contribution and given details of how the study results can be obtained.

Safety Reporting At the end of this section you will understand : • Why all safety data is important • The responsibilities surrounding reporting • Be confident in reporting events • Timeframes

Why collect Safety Data? • Emerging safety profile can be monitored on an ongoing basis • Trials can be amended/stopped • Enables risk vs benefit assessment and ultimately protects patients

Types of events & reactions Adverse Event • “ any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment” Adverse Reaction • “all untoward and unintended responses to an IMP related to any dose administered ” There are no requirements to report these events, but they should be recorded and the subject monitored.

Safety Reporting Serious Adverse Events & Serious Adverse Reactions 1. Results in death 2. Is life-threatening (at the time of the event) 3. Requires (in-patient) hospitalisation or prolongation of existing hospitalisation 4. Results in persistent or significant disability or incapacity 5. Consists of a congenital abnormality or birth defect 6. ”Other important medical condition” Not always used. Medical judgement required as to whether it is serious. It is “an important event that may jeopardise the subject or may require intervention to prevent one of the outcomes listed above • THIS ESCALATES THEM TO…. Serious Adverse Event or Serious Adverse Reaction. These need to be reported to the Sponsor and the Research Office by the research team.

Serious Adverse Event & Serious Adverse Reaction Must be tracked & followed up Record on appropriate form Must involve the Principal Investigator Immediately you become aware but certainly within 24 hours Report to Sponsor/Rese arch Office

SAE reporting requirements • For all studies Sponsored by UHL these should be submitted in accordance with SOP S- 1009 • SAE report form A to be completed for CTIMP studies • SAE report form B to be completed for non-CTIMP studies • For all studies hosted by UHL, SAEs should be submitted in accordance with the Sponsor's SOP

Investigator Responsibilities Causality Assessment Causality assessment decisions must be made by a medically qualified doctor as these decisions require medical and scientific judgement to be used as well as knowledge of the subject concerned. If the investigator is not a medically qualified doctor this task must be formally delegated to a medically qualified doctor who is a member of the research team.

Investigator responsibilities Expectedness Assessments • The reference safety information used for a clinical trial, against which expectedness assessments are made, should be clearly identified in the protocol and specified in the cover letter with the CTA application. • Expectedness decisions must be based purely on the content of the RSI in either the Investigator Brochure or Summary Product of Characteristics • Expectedness is not related to what is an anticipated event within a particular disease.

Investigator Responsibilities • All serious adverse events to be reported to the Sponsor within 24 hours of becoming aware of an event (except those identified as exempt – refer to protocol/IB) • The Principal Investigator is responsible for reviewing and signing off all Serious Adverse Event reports • Follow up the immediate report with a detailed written report • Identify subjects by their initials/study identification number (no personal or identifiable data should be included in any report – this includes supporting documentation)

Investigator Responsibilities • Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations shall be reported to the sponsor according to the reporting requirements and time periods specified in the protocol • For reported deaths of a subject, the investigator shall supply the sponsor and the REC with any additional information requested • An Annual Progress Report is required to be submitted for all studies on the anniversary of the REC favourable opinion/approval Premature Termination or Suspension of Trials • It is the PI’s responsibility to: Ø promptly inform trial subjects and ensure appropriate therapy and follow up is implemented. Ø Provide communication of study termination or suspension to Sponsor, REC and Regulatory Authorities as applicable and to include a detailed written explanation

Safety Reporting SUSAR However, if the serious adverse reaction is unexpected and you suspect it relates to the drug under investigation it is then further escalated to a Suspected Unexpected Serious Adverse Reaction (SUSAR) “an adverse reaction, the nature or severity of which is not consistent with the applicable product information” (ie IB or SPC)” These require expedited reporting to the Sponsor by the research team within 24 hours of becoming aware of the event.

Expedited Reporting of SUSARs to MHRA for CTIMP Studies– Sponsor Timelines • Very strict regulatory timelines apply, compliance is mandatory • Fatal/life threatening SUSARs–initial report must be received at the MHRA within 7 calendar days of becoming aware of the event Ø Further information within 8 calendar days • All other SUSARs need reporting within 15 days • Sponsor must inform MHRA (in the UK), main REC and relevant competent authorities and investigators outside the UK if applicable • It is the Sponsor’s responsibility to report to the MHRA within these time frames

Sponsor Responsibilities Additional requirements • An additional responsibility for the Sponsor with regards to safety reporting is the requirement to ensure research teams conducting CTIMP studies complete an annual Development Safety Update Report (DSURs) on the anniversary of the very first Clinical trial Authorisation for that IMP. • These are then submitted by the Sponsor to the MHRA and the REC.

Drug Accountability Why account for IMP? Drug accountability allows the reconstruction of the trial, put simply it documents what medications were received by the site, what medication was received by the subject; when and where as well as what medication was returned to the Sponsor or destroyed. It facilitates the reconstruction of the disposition of the IMP to demonstrate that subjects received the correct medication, in the correct form and strength according to the protocol

Drug Accountability Responsibilities: • Sponsor provides systems and records • Principle Investigator responsible for: Ø Receipt (shipping notes) & Storage (restricted access, suitable conditions) Ø Prescription (by medic & according to protocol, in a timely manner, IMP usage according to protocol) Ø Allocation (according to randomisation schedule) Ø Dispensing (by qualified person & according to protocol) Ø Temperature monitoring Ø Destruction records (Disposal, return and reconciliation of all IMP) (These may be delegated to a Pharmacist) Ø Ensuring randomisation and blinding procedures are adhered to and documentary evidence is present Ø Promptly documents and reports any premature unblinding to the Sponsor

Drug Accountability/Management Receipt of IMP from Authorised Manufacturer QP Certification Returns/IMP reconciliation return or destruction Prescription Dispensing Return IMP Management Labelling Storage Temperature monitoring accountability logs Randomisation Un-blinding Process

Drug Accountability/Management Temperature monitoring of remotely stored medication: Ø Frequently an audit/inspection finding Ø Remote storage of drugs i. e. ward cupboards Ø Temperatures monitored and recorded but no action taken when excursions occur Ø Min/Max thermometer (calibrated on a regular basis) Ø Locked storage area – restricted access, contact details of research team/pharmacy Ø Temperature, accountability and calibration records/logs

Quality Assurance/Control Types of quality assurance/control: • Policies • Standard Operating Procedures (accessed via R&I website) • Guidelines • Instruction Manuals

Sample Storage and Reporting • Quality Control System to be in place to ensure accurate results • Laboratory Accreditation and Normal Range Values • Results should be reviewed by the PI or delegated individual and signed and dated. If results are out of normal range they should be annotated as clinically significant (CS)or not clinically significant(NCS) • If clinically significant this may require reporting as an adverse event or Serious adverse event

Sample Storage and Reporting • Details of where all samples are stored with contact details of relevant personnel. • Correct storage and temperature monitoring and recording. • Evidence of temperature monitoring must be stored in site file. • Sample Labelling and sample Logs. Samples should be labelled with either Patient study ID or laboratory specific ID if system in place. No patient identifiable data should be recorded on sample or log • Evidence of chain of custody for all samples

CRF, Source Data and Data Entry • Source Data is where the information occurs first e. g. : Ø Hospital notes Ø Lab reports Ø X-rays Ø Coroner’s reports Ø Discharge summaries • Where the CRF is the source this must be agreed in advance and documented • Trial monitor will verify research data against source data

CRF Completion Accurate & legible Minimal abbreviations Complete all fields: ND Not done NK Not known Always use black pen Changes should be dated, initialled and explained (if necessary) Strike through original entry with single line. Do not obscure original entry

Subject Medical Notes • Written confirmation by the PI that the subject meets the required inclusion/exclusion criteria • Trial Identification Sticker on inside cover of medical notes • Copy of Patient Information Leaflet/Informed Consent Form and written confirmation of consent and participation • Copy of GP Letter (soon after study entry) • Documentation of the randomisation process (where applicable) • Title of study and subject number • Visit dates and findings • Concomitant medication/trial medication • Any adverse events • Willingness to continue • Date of next visit

Inspection/Audit/Monito ring “The act by a regulatory authority(ies) of conducting an Inspection Audit Monitoring official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial. ” (ICH-GCP E 6 1. 29) “A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analysed and accurately reported according to the protocol, Sponsor’s standard operating procedures, Good Clinical Practice and the applicable regulatory requirements. ” (ICH-GCP E 6 1. 29) “The act of overseeing the progress of a clinical trial, and ensuring that it is conducted, recorded and reported in accordance with the protocol, Standard Operating Procedures, GCP, and the applicable regulatory requirement(s). ” (ICH-GCP E 6 1. 38)

Who will Audit? • Trial Sponsor or representative – Pharmaceutical company/Contract Research Organisation or noncommercial organisation • Regulatory authority (MHRA/EMEA/FDA) • Host organisation

Audit can check……. • Approvals, Inc. dates and versions • Laboratory normal ranges, reports, procedures etc • Documentation-protocol, Patient Information Sheets (PIS), Informed Consent Forms (ICFs), Investigator Brochure (IB), all correspondence • Personnel-CVs and GCP training plus “peripheral” staff • Drug documentation (Investigational Medicinal Product, IMP)storage, dispensing, tracking (alongside pharmacy file) • Patient details, source data • and anything else re study conduct at site

3 Categories of Finding • Critical Where evidence exists that significant and unjustified departure(s) from applicable legislative requirements has occurred with evidence that: Ø The rights, safety or well-being of trial subjects either has been or has significant potential to be jeopardised, and/or the clinical trial data are unreliable and/or Ø There a number of Major non-compliances across areas of responsibility, indicating a systematic quality assurance failure and/or Ø Where inappropriate, insufficient or untimely corrective action has taken place regarding previously reported Major non-compliances Ø Where provision of the TMF does not comply with regulatory requirements and/or as the TMF is not readily available or accessible, or the TMF is incomplete to such an extent that it cannot form the basis of inspection.

3 Categories of Finding • Major Ø A non-critical finding where evidence exists that a significant and unjustified departure from applicable legislative requirements has occurred that may not have developed into a critical issue, but may have the potential to do so unless addressed. Ø Where evidence exists that a number of departures from applicable legislative requirements and/or established GCP guidelines have occurred within a single area of responsibility, indicating a systematic quality assurance failure. • Other Ø Where evidence exists that a departure from applicable legislative requirements and/or established GCP guidelines and/or procedural requirement and/or good clinical practice has occurred, but it is neither Critical nor Major.

Recent UHL Audit Findings (1) • Consent Ø Inadequate permission for access to study records/notes for research team, sponsor, UHL Trust and/or regulatory authorities Ø Dates and patient names written into consent forms by the consenting investigator, not the patient Ø Ticks instead of initials Ø Forms destroyed after sample analysis Ø Forms missing

Recent UHL Audit Findings (2) • Consent (2) Ø Subject’s initials written by the investigator Ø New versions of the PIL being used prior to REC/Research Office approval Ø Old versions being used after approval Ø No researcher signature Ø Consent taken by people not approved to do so Ø Consent being taken before the REC agreed time to consider the study

Recent UHL Audit Findings (3) • IMP/Pharmacy Ø Pre-signed trial prescriptions and administration logs Ø Staff asked to sign as witnessing drug administration which they hadn’t Ø Subjects being recruited into 2 separate studies using the “same” medication Ø Temperature logs not being maintained or being maintained but no action taken on deviation from acceptable temp range. 22 patients dosed with medication that had not been stored appropriately Ø No process in place for ensuring the most up to date IB or SPC is in the site file (annual review required) Ø Inadequate accountability documentation

Recent UHL Audit Findings (4) • Safety Reporting Ø All final sign offs of the CRF for a 200+ patient study on the same day Ø Protocol stating that AEs would be reported but the CRF not being designed to collect the information Ø Protocol not specifying events exempt from being reported as SAEs Ø Superseded SAE reporting forms being used

Recent UHL Audit Findings (5) • Other Ø Annual reports not completed (on time) Ø Signatures forged on CVs Ø Username and password for secure access to a randomisation system written in the site file Ø Changes in study staff not being communicated or approved Ø Study staff being entered into their own studies Ø Pt identifiable information being viewed by nonauthorised staff (data protection breaches)

Recent UHL Audit Findings (6) • Other Ø Inconsistencies in documentation between the IRAS form and other study documentation – no process to ensure continuity Ø Statistical analysis performed by a specialist registrar but no evidence of their stats training in the site file Ø File notes not signed and dated Ø Delegation log being completed after start of recruitment Ø Master randomisation schedule visible to recruiting investigators

Recent UHL Audit Findings (7) • Other Ø Contracts not being authorised by all parties Ø Investigators signing contracts on sponsor behalf Ø Subjects recruited before Research Office approval Ø Study procedures before consent Ø No temp monitoring for freezers used to store samples Ø Lack of evidence of GCP training Ø Data collection forms/CRFs not version controlled Ø No process for the management of healthy volunteer trials

GCP Certification • Complete an assessment • Give/send it back to us (our details are on the bottom of the second page) • 80% pass mark • There can be 1 to 4 correct answers to each question • Certificate issued-valid for 3 years THANK YOU

Contact Details: Julie James Clinical Trials Monitor & Trainer julie. james@uhl-tr. nhs. uk Aldona Kirkham Clinical Trials Monitor & Trainer aldona. h. kirkham@uhl-tr. nhs. uk Anne Moore Clinical Trials Monitor & Trainer anne. m. moore@uhl-tr. nhs. uk R&I Office Leicester General Hospital Tel: 258 4686

Useful Links… • R & I website http: //www. leicestersresearch. nhs. uk • Twitter: @Leic. Research • UKCRC Regulatory & Governance Advice Service • MHRA Clinical Trials Helpline • Uo. L Research Governance http: //www. ukcrc. org/regulationgovernance ctdhelpline@mhra. gsi. gov. uk http: //www 2. le. ac. uk/colleges/medbiopsych/researchgovernance/ethics Regulatory Agencies • Medicines and Healthcare products Regulatory Agency http: //www. mhra. gov. uk • • Ethics Health Research Authority • ICH GCP • http: //www. hra. nhs. uk http: //www. ich. org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E 6_R 2__ Step_4. pdf

And some more. . Research and Development • NHS Research and Development Forum http: //www. rdforum. nhs. uk/ • NIHR Research Support Services http: //www. nihr. ac. uk/research • NIHR Clinical Research Network http: //www. crncc. nihr. ac. uk/ • INVOLVE - Supporting public involvement in NHS, public health and social care research http: //www. invo. org. uk/