Pe HAEMATOLOGY ‘oS CLINICAL RESEARCH GROUP An Insight into Clinical Research This Guidance has been compiled by Emma Williams & Patricia Carter; Haematology Clinical Research Group, Cancer Trials Unit, University Hospital of Wales. (2018). Principles of ICH GCP Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirements, Before a trial is initiated, foreseeable risks and inconveniences should be /eighed against the anticipated benefit the individual trial subject & society. justify the risks. SUE SHARE, (2018), °:noples of 7 GP [ONLINE] Available st: hips: bing eom/images/saarchview=detallV28ccid=2PLeynuO8id=5ABF7EBOFS2FE22SD02E91 13640705CD946BCB622:hid-O1P 2PLevn VOYKTESyOLOOUEaHaF émediautlentp}0%27%42"elienlayer coma 05 196489421369:2fimages%214 19,20 nnciplesy2boF/2BICH3%20CCP. 1=7208expw= 6609" PRINCIPLES +OF +ich +acp8simid=6060265222267560 15Bselects alexis [accessed 1 May 2015) Good Clinical Practice (GCP) Good Clinical Practice is an international agreement of ethical, scientific and practical standards in which all clinical trials should be conducted. Compliance with these standards provide public assurance that the rights, safety and wellbeing 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. Why do you need GCP training to be involved in clinical trials? ‘Its UK law and everyone involved in a clinical trial should be qualified by education, training and experience to perform his/her respective tasks.GCP training hasn’t always been required, so why is it now? GCP regulations were implemented because of studies resulting in public disasters, serious fraud and abuse of human rights. Studies were also duplicated unnecessarily. Examples: In 1949 war criminals were used as trial participants, without their consent. (Nuremberg trials) Harvard gazette (2018), remy fs ONLINE). ‘Avaliable at hitos:/news harvard edulgazette/story:2003/08hs seb site-gives-access-o-nuremburg-tials-documents! [Accescod 1 May 2018) In 1960's the “Thalidomide disaster” occurred. There was limited testing of Thalidomide as it was wrongly considered to be a mild sedative and helpful for morning sickness. Interestingly, the U.S. FDA refused to approve thalidomide for marketing and distribution as they didn’t think the drug had been tested adequately enough. Experts estimate that the drug thalidomide led to the death of approximately 2,000 children, with serious birth defects in more than 10,000 children, about 5,000 of them in West Germany. Thalidomide Whar is ir? F Thalidomide ss a drug thot was \ reseed rg te ee 190 2 cy iste wardens aslecig pl uritwesase y ‘heught tebe useful for easing ‘morning sickness in pregnont Unfortunately, it had not been ‘ested for use this way Why do T need to know about if? By 1960, thalidomide was found te damage the development of unborn babies, especially if had been tckenin the first four te eight weeks of Pregnancy Is it used now? “Thalidomide s new used as atrestment for lepresy ard bene cance. Tts use heavy regulated, however, to prevent @ repeat of the problems it caused i “The drug ed to the arms or legs of the babies being very short or incompletely ferme last century What regulations de you thik there are ‘egarcing the vse of thalidomide tosy? ‘More than 10,000 babies were affected around Slice share (2012), thavigemide [ONLI Available at hips Iwi sideshsre nel’andymarin/oilogvexsmoler-powerpolnt (Accassed May 201)Evolution of GCP At the end of WW2, the “Nuremberg Trials” occurred, where doctors were prosecuted for using war criminals in clinical trials/studies, without their consent. Following these trials, 10 recommendations were made for how valid and legitimate research should be conducted. These recommendations are known as the “Nuremberg Code”. Its result was the introduction of GCP, evolving into The 13 principles of ICH-GCP we work to today. Declaration of Helsint “The Dedarton cf Hainlisa fo) In 1964 The Declaration of Helsinki was developed. These are a set of ethical principles regarding trials on humans, developed for the medical community frees egg RP the World Medical Association, This is considered to be the keystone ‘eppinonite derdoped forthe medial document on human research ethics. These principles have evolved over the ‘ommurityby the Wold Medial Assocstion, Past 47 years, and was last updated in 2008. * Common document ofhuman research ethics During 1970's and 1980's Japan, UK and European committees developed their own GCP guidelines, resulting in different standard of practice throughout the world, with repetition of clinical trials. This resulted in delays in medication becoming available and increased the costs to the pharmaceutical industry. In 1996 a series of conferences to unify the differing codes of practice occurred. These meetings became known as ‘the “Intemational Conference on Harmonization of Good Clinical Practice”, ICH~GCP. All parties agreed to follow the same code of practice, leading to an internationally recognized, uniformed standard of conducting GCP in clinical trials. ICH—GCP covers all member states within Europe as well as North America, Japan and Australasia. It provides guidance on such issues as: © Research ethics © Being an investigator or sponsor. © Trial protocol and amendments. © Alltrial documentation.The principles of good clinical practice SCIENTIFIC COCO) fesse n isch} Bens PARTICIPANT SAFETY Onn Cy One cup) TEAMWORK Maia @ Chay Parton ops Competency Domains for the Clinical Research Professional Ta ae) ass niien Caner Sry Oyaruenty (GcPs) rT F Oct eer) AND INFORMATICS A Be O UL Pca NICH. (2016). gop [ONLINE ‘Avs inble at: hiio.lvaw mich umich edu/nows/2016/1 O2S/new-nin-poloy-on-gop takes effect jenuary-t [Accessed 1 May 2018),European Regulation on GCP 2001/20/EC-directive made GCP a legal requirement across all European member states. European Commission required that each member state appoint a “Competent Authority” to oversee this implementation and ensure that the directive was completed correctly. in the UK, this competent authority is known as The Medicines and Healthcare products Regulatory Agency (MHRA). This directive became UK law in 2004 under the statutory instrument 2004/1031. ‘Amendment 1, 2005/28/EC, was published in April 2005 by the European Commission and was transposed unto UK law on 29th August 2006 under statutory instrument 2006/1928. ‘Amendment 2 was implemented under statutory instrument 2006/2984 and became law on 12th December 2006 ICH E6 (R2) came into effect on 14% June 2017. Overview: © Certified copies © ALCOAC replaces ALCOA. © Attributable (clear who created record, when) : Legible : Contemporaneous (evidence or test results are recorded as they are observed) : Original : Accurate (correct and true) : Complete. * Sponsor control of investigator CRFs/data and essential documents. ‘© Record location of source documentation - site and sponsor : Trial Master File -change to essential documents and storage system documentation : Requirements for computer validation and electronic records : Sponsor responsibility ~ vendor oversight © Update of ICH principle — (2.13) Systems with procedures that assure the quality of every aspect of the trial should be implemented... “Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be the focus of such systems”. © New requirement for investigator oversight ~ supervising, ensuring qualified, implement procedures to ensure integrity. ‘* Extensive addition of Quality Management requirement for Sponsors. (© Risked based monitoring (RBM) : Central monitoring : Monitoring plans : Monitoring reports : noncompliance Any breach of this legislation is a criminal offence. GCP training is decided by the organization but should be a minimum of every three years. Our requirement is GCP every two years. ‘Regulation of Cliniest Til: Europe & UK @ =s <=, estonia mts CHUK, (2016), gop [ONLINE “hon chou co uiclncal-tials-ccplace- ssIn a nutshell -The 13 principles of ICH-GCP {9p (2016). Core principles of OH GOP [ONLI Avsilable ot: hitpeertrsning co uk/13-core-prin (Accessed 1 Mia, 2078), Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with GCP and the applicable regulatory requirements. 1) Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Deciaration of Helsinki and that are consistent with GCP and the applicable regulatory requirements. 2), Before the trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. 3) The rights, safety and wellbeing of the trial subjects are the most important considerations and should prevail over interests of science and society. 4) The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. 5) Clinical trials should be scientifically sound and described in a clear detailed protocol. 6) Atrial should be conducted in compliance with the protocol that has received prior institutional review board (IRB) / independent ethics committee (IEC) approval/favourable opinion. 7) The medical care given to and medical decisions made on behalf of subjects should always be the responsi of a qualified physician or when appropriate a qualified dentist. 8) Everyone involved in a clinical trial should be qualified by education training and experience to perform his/her respective tasks. 9} Freely given informed consent should be obtained from every subject prior to clinical trial participation. 10) All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification. 111) The confidentiality of records that could identify subjects should be protected, respecting the confidentiality ruled in accordance with the applicable regulatory requirements. 12) IP should be manufactured, handled and stored in accordance with applicable GMP (Good Manufacturing Practice). They should be used in accordance with the approved protocol. 13) Systems and procedures that assure the quality of every aspect of the trial should be implemented. cy and Directives to be aware of © The Data Protection Act 1998, The Act defines eight data protection principles, which apply in various contexts, to ensure that information is processed lawfully. Human Tissues Act 2006 Required for people who collect/store biological samples. ‘Awareness of mental capacity act 2005. GMP: Good manufacturing Guidance. Required for people who receive, store and/or dispense medication. IATA The International Air Transport Association. Required for people who ship/post samples.The ‘Sponsor’ Responsibilities YOU TUBE, (2016), SPONSOR RESPONSIBILITIES [ONLINE] ‘yailabie ct hips wa. youtube comiwaten?v=.SHMOmut Ly [Aecosces 1 Hay 2018) ‘The Sponsor is the company that is sponsoring the experimental clinical research trial. By sponsoring is meant: funding, organizing, initiating, managing and running. Responsibility for: © Pharmacovigilance. Protocol. Patient Information Sheets (PIS)/informed Consent (IC) documentation. Questionnaires methodology/systems. ‘Advertising resources. Protocol training methodology/systems. Data collection methodology/systems. Providing and arranging destruction of drug as agreed by contract. Randomisation, unbinding, allocation of drug methodology/systems. Site selection. Site Qualification Visit (SQV). Training: ‘¢ Investigator Meeting (IM). ‘¢ Site initiation Visit (SIV). ‘¢ Sponsor control of investigator CRFs/data and essential documents, ‘Monitoring. ‘* Risked based monitoring (RBM). © Central monitoring. Monitoring plans. Monitoring reports. Noncompliance. Responsible for monitoring the Site to identify if protocol compliant as per GCP. ‘Any non-compliance identified is recorded as a “Violation” or Deviation”. This may be “Minor”, “Major” or “Critical”. Depending on severity of findings, reporting may be required to Sponsor, MHRA, FDA. ‘The “Bridge” between Sponsor and Investigator. Protocol training, Point of contact for any clarification of protocol requirement, Audits.The ‘Principal Investigator’ Responsibilities Medical care of trial subjects. Must be appropriately qualified. Ensuring there are sufficient patients to enrol to allow for recruitment and proper conduct of the trial Appropriate selection of trial subjects as directed by inclusion/exclusion criteria. Compliance with the protocol: © The investigator must agree to the protocol in writing. In doing this, they confirm understanding of protocol and agree to adhere to every aspect of the protocol in line with GCP. No changes should be made, unless requested in writing and agreed by the Sponsor. The only exception is to maintain patient safety and should be documented, Provide up to date trial information to patient and take informed consent. (See section on informed consent) Information should be both written and verbal Must be familiar with the properties, effects and safety of the Study medication (Investigational Product: IP) Adequate resources to run the study i.e, Site of the trial, facilities and staff: ‘© The trial site must have adequate resources and facilities to ensure patient safety, The Investigator must have adequate time to conduct the trial. The Investigator should ensure that those delegated responsibilities for study procedures are adequately qualified and receive protocol training by supervising to ensure qualified and implement procedures to ensure integrity of data. Pharmacovigilance. Ensure all approvals in place before recruiting to study. Any financial support from the sponsor must be disclosed in writing. Time must be made to facilitate monitoring visits, audits and inspections. Record-keeping and handling of data.MHRA mba (2018), MHRA [ONLINE ‘alae at: http. www mea. gov ok (accessed 1 may 2018) ‘The Medicines and Healthcare Products Regulatory Agency is a UK government body which was set up in 2003 to bring together the functions of the Medicines Control Agency (MCA) and Medicines Device Agency (MDA). The principle aim of the agency is to safeguard the public's health. © Opinion of approval given within 30 days. © ifamended application, within 60 days of receipt of original valid application. ‘© Opinion of refusal or acceptance given within 60 days. Institutional Review Board/Independent Ethics Committee (IRB/IEC) ICH-GCP-Section 3 Institutional Review Boards/ Independent Ethics Committee Safeguards the rights, safety and wellbeing of trial subjects. ‘* Made up of reasonable number of members, who collectively have qualifi evaluate the science, medical aspects and ethics of proposed trial. * They will give an opinion of suitability of proposed trial within 60 days of receipt of valid application. If further information requested, the clock stops until required information is received, © They must give a favourable opinion for trial to proceed. tions and experience to review and Research & Development Its purpose is to: © Scrutinise documents, ensuring a high standard of research governance and assess the risks to the Trust © Help with grant applications and external funding, ‘© Assess the cost to run the study. They will negotiate a contract and bill the Sponsor for work completed. They also take responsibility for getting patients expenses refunded. They assist in data archiving and invoicing companies. © Ensure the UHB achieves the Performance Targets agreed in its contract with the Welsh Assembly Government © They perform internal audits to ensure compliance with GCP with research governance structures being maintained.The Protocol: Clinical Research Protocol |. The protocol is an approved directive of how the Research Trial should be conducted. The trial should be conducted in the same way in every enrolled Site, except for country where specific laws are being contravened, which may lead to amendments in that Country. Each Protocol contains information regarding: © Background & Study rational. Scientific background. * Disease under study. © Other prior and active studies. © Study objectives. © Study Endpoints. Study design ‘Study population. Study drug. ‘Study conduct including inclusion & exclusion criteria. Schedule of events. Study windows. Pharmacovigilance. Study Committees. Statistical and Quantitative analyses. Use of information, Investigator agreement. References, Appendices, Tables. List of abbreviations and glossary of terms. Commercial Trials: ‘Acommercial trial is sponsored by a pharmaceutical company. its purpose Is to get drug licensed for use in a certain context of care. €.g. bxasonib given as maintenance treatment post induction treatment. At time of writing, this drug cannot be given for maintenance treatment outside of the context of a trial Non Commercial Trials: ‘Anon-commercial trial is sponsored by agencies that may not be a pharmaceutical company e.g. MRC (Medical Research Council). Its purpose is to answer a series of questions, for exemple: Which group of treatments works better, Pomalidomide/Cyclophosphamide/Dexamethasone OR Pomalidomide and Dexamethasone? It is more about finding out answers, to inform of best treatment options for the future. The drugs used often have a licence, but they may not be NICE approved. Non-commercial trials often save the NHS money as they are funded by the Sponsor. These trials also give patients access to treatment that might not otherwise be available. 10Conducting the Trial: Green Light — Ready to start: Pre-screen the patient. Review potential patient past medical history. Review of Inclusion / Exclusion criteria ~Is patient suitable? ‘Approach patient, give study chat. Give version controlled Patient Information Sheet (PiS)/Informed Consent (IC) document to patient. ‘Allow patient sufficient time to consider if they want to participate in trial. ‘Answer any questions. Investigator enrols the patient ~ take informed consent (See below). Investigator documents consent procedure in notes. Suggested form (© Patient Initials: __has been given ample time to consider the: __Trial and ask questions. Patient has given written consent using Main PIS/IC Version: __ Dated: ‘The consent forms were signed by Investigator and copies given to patient. ‘© Prepare for patient visits, within the window (time frame) of the protocol. 1Taking Informed Consent, what's involved? Ebates eet tralia stoped Opportunity for questions 20 elements of IC. itis the responsibility of the Principal or Sub Investigator to obtain written informed consent, Before a patient participates in a study they will need to be fully informed about the study. Both the informed consent discussion and the written informed consent form (PIS) and any other written information to be provided to subjects should include explanations of the following: 1) That the trial involves research, 2), The purpose of the trial. 3) The trial treatment(s) and the probability for random assignment to each treatment. 4) The trial procedures to be followed, including all invasive procedures. 5) The subject's responsibilities. 6) Those aspects of the trial that are experimental. 7) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, foetus, or nursing infant. 8) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this. 9) Thealternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks. 10) The compensation and/or treatment available to the subject in the event of trial-related injury. 11) The anticipated prorated payment, if any, to the subject for participating in the trial. 12) The anticipated expenses, if any, to the subject for participating in the trial. 413) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or ‘withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled. 14) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority/ies will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access. 15) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject's identity will remain confidential. 1216) That the subject or the subject's legally acceptable representative will be informed in a timely manner if, information becomes available that may be relevant to the subject's willingness to continue participation in the trial. 17) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury. 18) The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be terminated 19) The expected duration of the subject’s participation in the trial 20) The approximate number of subjects involved in the trial. ‘The Patient Information Sheet (PIS) and Informed Consent (IC) document is always dated and version controlled and reflects the information the patient has been given about the study. If the patient decides to participate, they will sign the IC document. This is the patient giving written permission for them to be used as a trial participant with their decision being based on the information given in this version of the PIS. If the wrong version of PIS is given to the patient, this will mean that the patient has not been fully informed and has therefore not given “Informed” consent even though a version of the consent form has been signed. This can be viewed as a serious breach of GCP, as the rights of the patient to be fully informed about the study, have not been met. ‘As the IC document is proof of informed consent being given by patient to be used as a trial participant, itis imperative that the PIS and IC documentation is correct ice. Correct version PIS/IC document used. Version and date on each header/footer. All pages are present. Site specific information has been included. Correctly completed by the Doctor (and nurse if applicable). Correctly completed by patient (and/or representative if applicable). 2BGlossary of Common Terms ‘NIHR, (2018), Ginseary of o1ms [ONLINE ‘Avalable at: http://www ch govealth.informaton/cihcnia-researchvials-you/lossay-comman-terms [Recessed 1 Mey 2038), Clinical Research Clinical research is medical research that involves people to test new treatments and therapies. Clinical Trial A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioural ‘outcomes. Healthy Volunteer ‘A Healthy volunteer is a person with no known significant health problems who participates in clinical research to test a new drug, device, or intervention. Inclusion/Exclusion Criteria Inclusion/Exclusion Criteria are factors that allow someone to participate in a clinical trial are inclusion criteria. Those that exclude or not allow participation are exclusion criteria. Informed Consent Informed consent explains risks and potential benefits about a clinical trial before someone decides whether to participate, Patient Volunteer ‘A patient volunteer has a known health problem and participates in research to better understand, diagnose, treat, or cure that disease or condition. Phases of Clinical Trials Clinical trials are conducted in “phases.” The trials at each phase have a different purpose and help researchers answer different questions. ‘© Phase I trials — An experimental drug or treatment in a small group of people (20-80) forthe first time. The purpose is to evaluate its safety and identity side effects, ‘© Phase trials — The experimental drug or treatment is administered to a larger group of people (300-300) to determine its effectiveness and to further evaluate its safety ‘© Phase i trials — The experimental drug or treatment is administered to large groups of people (2,003,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments. © Phase IV trials — After a drugis licensed and approved by the FDA researchers trackits safety, seeking more information about its risks, benefts, and optimal use. Placebo ‘A placebo isa pill or liquid that looks like the new treatment but does not have any treatment value from active ingredients, Protocol ‘A Protocol is a carefully designed plan to safeguard the participants’ health and answer specific research questions. Principal Investigator ‘A Principal Investigator is a doctor who leads the clinical research team and, along with the other members of the research team, regularly monitors study participants’ health to determine the study’s safety and effectiveness. Randomization Randomization is the process by which two or more alternative treatments are assigned to volunteers by chance rather than by choice. Single or Double-Blind Studies Single- or double-blind studies (also called single- or double-masked studies) are studies in which the participants do not know which medicine is being used, so they can describe what happens without bias. 4