A Comprehensive and Practical Guide to Clinical Trials PDF
Preview A Comprehensive and Practical Guide to Clinical Trials
A Comprehensive and Practical Guide to Clinical Trials A Comprehensive and Practical Guide to Clinical Trials Edited by Delva Shamley Brenda Wright The Clinical Research Centre at theUniversity ofCape Town, Cape Town, WesternCape Province,South Africa AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1800,SanDiego,CA92101-4495,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Copyrightr2017ElsevierInc.Allrightsreserved. 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Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingand usinganyinformation,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationor methodstheyshouldbemindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhomthey haveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeany liabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceor otherwise,orfromanyuseoroperationofanymethods,products,instructions,orideascontainedinthe materialherein. BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-12-804729-3 ForInformationonallAcademicPresspublications visitourwebsiteathttps://www.elsevier.com/books-and-journals Publisher:MicaHaley AcquisitionEditor:KristineJonesandErinHill-Parks EditorialProjectManager:MollyMcLaughlinandTimothyBennett ProductionProjectManager:Luc´ıaPe´rez CoverDesigner:MatthewLimbert TypesetbyMPSLimited,Chennai,India List of Contributors NickyKramer ClinicalResearchCentre,UniversityofCapeTown,CapeTown, WesternCapeProvince,SouthAfrica WynandSmythe ClinicalResearchCentre,UniversityofCapeTown,CapeTown, WesternCapeProvince,SouthAfrica AnnemieStewart ClinicalResearchCentre,UniversityofCapeTown,CapeTown, WesternCapeProvince,SouthAfrica IngeVermeulen ClinicalResearchCentre,UniversityofCapeTown,CapeTown, WesternCapeProvince,SouthAfrica BrendaWright ClinicalResearchCentre,UniversityofCapeTown,CapeTown, WesternCapeProvince,SouthAfrica xi Foreword All research involving human participants, personal information, or biologi- cal samples must comply with adequate ethical and methodological stan- dards. The need for providing public assurance that the rights, safety, and well-being of research participants are protected, and that data generated are credible, has been widely acknowledged at least since 1964, when the Declaration of Helsinki on the Ethical Principles for Medical Research Involving Human Subjects was first published. The importance of such pub- lic accountabilitywill only keep ongrowingintoday’s context of“globaliza- tion of clinical trials,” where medical research is carried out by commercial and noncommercial actors in a variety of settings in high-, middle-, and low- income countries, with increasingly complex challenges arising particularly in international collaborative research. These challenges include, for exam- ple, the need to engage with the research communities, while fairly sharing the research burdens and benefits; the difficulties to define adequate gover- nance frames for data sharing and for research biobanks; and the exceptional challenges faced when research is carried out in the context of a public healthemergency,as witnessed during the recent Ebola and Zika outbreaks. In such an increasingly complex research environment, skilled and expe- rienced clinicians and scientists are essential to build an efficient research site, but they are not enough. Clinical research teams also need to rely on adequate guidance and expertise in domains that go beyond medical and sci- entific skills. In the first place, they have to master the Good Clinical Practices (GCP) guidelines, which set the international standards for clinical research. In addition, in a competitive environment where medical research is often funded by external donors, they must be able to adequately and timely deal with contractual and administrative issues, as well as to ensure efficient planning and project management. This book, grounded in the experience of a research group based in the South and fed by the experience of international collaborative research, timely addresses these needs. It provides a user-friendly guide to the differ- ent aspects of set-up and management of clinical research. Each chapter is integrated by a set of GCP-compliant forms and templates that may either be used as such, or adapted to the specificities of each study. It will provide an important support to research teams for building and consolidating local research capacity and for successfully conducting individual studies, either xiii xiv Foreword clinical trials with investigational medicinal products or other medical research studies. In addition, while the core-package of essential skills and standards tools becomes available and functional, the investigators will also gainthecapacityandtimetocontextualizestandardtools,todevelopinnova- tive approaches to newly emerging challenges, and to ensure research preparedness for outbreaksor other emergencies. Raffaella Ravinetto Department ofPublic Health Institute ofTropical Medicine Antwerp, Belgium Chapter 1 Introduction to Clinical Trials BrendaWright Chapter Outline WhatIsaClinicalTrial? 1 IRB/IECEthicsCommittees 4 WhyDoWeDoClinicalTrials? 1 Sponsor 4 ClinicalTeam 3 ContractResearchOrganizations 5 StudyParticipant 3 ManagingtheTrial 5 MedicinesRegulatoryAuthorities 3 FurtherReading 9 The purpose of this book is to illustrate and provide guidelines and informa- tion for planning and conducting a successful Clinical Trial from the Project Management perspective. Project Management is the application of planning, knowledge, skills, and technique to execute projects effectively and efficiently. It will also describe the processes from beginning to end, and link these processestokeystakeholdersandGood ClinicalPractice(GCP),allofwhich are critical tothe success ofa trial (Table 1.1and Fig. 1.1). WHAT IS A CLINICAL TRIAL? A Clinical Trial is a prospective biomedical or behavioral research project that involves human volunteers (participants) and/or uses materials of human origin, for example, observed behavior, answers to questions, and/or obtain- ing tissue or specimen samples. WHY DO WE DO CLINICAL TRIALS? Clinical trials are designed to answer a specific research question. They are used to determine if a new biomedical or behavioral intervention is safe, efficacious, and effective. AComprehensiveandPracticalGuidetoClinicalTrials. DOI:http://dx.doi.org/10.1016/B978-0-12-804729-3.00001-8 1 ©2017ElsevierInc.Allrightsreserved. 2 AComprehensiveandPracticalGuidetoClinicalTrials TABLE1.1 WhatIsGoodClinicalPractice? GCPprovidesguidelinesasdefinedbytheICH,aninternationalbodywhichdefines standardsthatgovernmentscantransposeintoregulationsforclinicaltrialsinvolving humans.ThesestandardsarereferredtoasICH-GCPorISO-GCP. Itisastandardforclinicaltrials,whichincludesthedesign,conduct,performance, monitoring,termination,auditing,recording,analysis,reporting,anddocumentationof clinicaltrials.Thesestandardsensurethatthetrialsarescientificallyandethically soundandthattheclinicalpropertiesofthepharmaceuticalproductunder investigationareproperlydocumentedandthedataandreportedresultsarecredible andaccurate.Italsoensuresthattherights,integrity,andconfidentialityoftrial participantsareprotected. GCPguidelinesthereforeprotectthehumanrightsofparticipantsinaclinicaltrialand provideassuranceofthesafetyandefficacyofthenewlydevelopedcompound.These guidelinesalsorequiredetaileddocumentationfortheclinicalprotocol,record keeping,training,andfacilities,includingcomputersandsoftware.Itdefinestheroles andresponsibilitiesofclinicaltrialsponsors,clinicalresearchinvestigators,and monitors.Qualityassuranceandinspectionsensurethatthesestandardsaremet. TheaimofGCPistoprovideInvestigatorsandtheirstudyteamswiththetoolsto protecthumansubjectsandcollectqualitydata. Clinical team/site Contract Study research participant organization Key stakeholders Regulatory Sponsor authorities IRB/IEC ethics committees FIGURE1.1 Keystakeholders. IntroductiontoClinicalTrials Chapter | 1 3 Good Research Questions are: (cid:1) Clear. They are easy to understandand unambiguous. (cid:1) Specific. They are specific enough to understand what constitutes an answer. (cid:1) Answerable. It is clear what data we need, to answer the questions, and how the data will be collected. (cid:1) Interconnected. All the questions are related in some meaningful way, forming a coherent whole. (cid:1) Substantively relevant. They are nontrivial questions that are fundamen- tally worthy of the researcheffort andcost. Some approaches are: (cid:1) To evaluate interventions (drugs, medical devices, etc.) for treating a disease,syndrome, or condition. (cid:1) To evaluate interventions that will identify or diagnose a particular disease or condition. (cid:1) To find methods to prevent the onset or recurrence of a disease or condition (medicine, vaccines,lifestylechanges, etc.). (cid:1) To investigate and identify methods to improve quality of life and comfortfor patients with chronic illnesses. These approaches have to follow GCP guidelines as defined by the International Council for Harmonization (ICH) and subsequently adapted in many countries (Table 1.1). CLINICAL TEAM The Sponsor or its contracted research organization (CRO) will appoint an Investigator Site consisting of the Principal Investigator and his/her Clinical Team who will conduct the clinical trial. In many countries the research team will be provided by a Clinical Trials Unit (CTU), which is based within the institution. On others, a CRO may provide all the research staff. STUDY PARTICIPANT A voluntary, informed person who has read and signed the InformedConsent Document, agreeing to the procedures, etc. he/she will be involved in during a ClinicalTrial. MEDICINES REGULATORY AUTHORITIES In the case of trials involving an investigative medicinal product, regu- latory requirements include approval by a medicines regulatory 4 AComprehensiveandPracticalGuidetoClinicalTrials authority (MRA). The MRA is responsible for ensuring that all clinical trials of both nonregistered medicines, and new indications of regis- tered medicines, comply with the necessary requirements for safety, quality, and efficacy. Applications for clinical trials and for registration of medicines and medical devices are reviewed by a MRA expert com- mittee, which considers among other issues the scientific, medical, and ethical issues of the applications. Reports on the progress of the study are sent to the MRA on a regular basis. Proof of safety, quality, and efficacy must be submitted when applying to the Medicines Control Council (MCC) for approval and registration of a medicine for use in South Africa. In the United States the regulatory body is the FDA (Food and Drug Administration) and in Europe it is the EMEA (European Agency for the Evaluation of Medicinal Products). In South Africa the MCC is the statutory body that regulates the performance of clinical trials and registra- tion of medicines and medical devices for use in specific diseases. See Chapter4,RegulatoryRequirements,formoredetailedinformationregarding International Regulatory submissions. IRB/IEC ETHICS COMMITTEES Approval by an institutional review board (IRB), or ethics board, is neces- sary prior to the conduct of a clinical trial. The IRB should consist of clini- cians, researchers, and members from the community. They play an important role in ensuring that the trial is ethical, and that the welfare and human rights of the participants are protected according to GCP guidelines and the protection of personal information. The IRB inspects the trial for medical safety and protection of the participants involved in the trial, prior toapproval. SPONSOR The Sponsor can be an individual, company, institution, or organization that has the responsibility to initiate and manage the clinical trial. The sponsor may or may not provide the funding. It may be a governmental organization, a pharmaceutical, and biotechnology or medical device company. The clinical trial may also be managed by an outsourced part- ner, i.e., a contract research organization (CRO) or an academic clinical trial unit. National health agencies and academic institutions may offer grants to Investigators who design clinical trials that attempt to answer
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