Principles and Practice of Clinical Research PDF
Preview Principles and Practice of Clinical Research
PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH FOURTH EDITION Edited by J I. G OHN ALLIN F P. O REDERICK GNIBENE L L J AURA EE OHNSON AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1800,SanDiego,CA92101-4495,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Copyright©2018ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical, includingphotocopying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwritingfrom thepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyrightLicensingAgency,canbe foundatourwebsite:www.elsevier.com/permissions. ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthanas maybenotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroadenour understanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusingany information,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethodstheyshouldbe mindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeanyliabilityforany injuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseor operationofanymethods,products,instructions,orideascontainedinthematerialherein. LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN:978-0-12-849905-4 ForinformationonallAcademicPresspublicationsvisitourwebsiteat https://www.elsevier.com/books-and-journals Publisher:MicaHaley SeniorContentStrategist:KristineJones EditorialProjectManager:FentonCoulthurst ProductionProjectManager:KiruthikaGovindaraju Designer:MatthewLimbert TypesetbyTNQBooksandJournals Contents List of Contributors xiii 3. Integrity in Research: Principles for the Conduct of Acknowledgments xv Research Preface xvii MELISSAC.COLBERT,ROBERTB.NUSSENBLATT, MICHAELM.GOTTESMAN 1. A Historical Perspective on Clinical GuidelinesandPrinciples for the Conduct of Research Research 33 JOHNI.GALLIN ScientificIntegrity and Research Misconduct 34 Responsibilities of Research Supervisors and The Earliest Clinical Research 1 Trainees 36 Greek andRoman Influence 2 Data Management, Archiving,and Sharing 36 Middle Agesand Renaissance 2 ResearchInvolvingHumanandAnimalSubjects 38 Seventeenth Century 3 Collaborative and Team Science 39 Eighteenth Century 4 Conflict ofInterest and Commitment 40 NineteenthCentury 7 Peer Review 41 TwentiethCentury and Beyond 11 PublicationPractices, Responsible Authorship, SummaryQuestions 14 and Results Reproducibility 42 References 14 Study Questions 45 Acknowledgments 45 References 45 I Further Reading 46 ETHICAL, REGULATORY 4. Institutional Review Boards AND LEGAL ISSUES JULIASLUTSMAN,LYNNETTENIEMAN Historical, Ethical, and Regulatory 2. Ethical Principles in Clinical Foundations ofCurrent Requirements Research for Research Involving Human CHRISTINEGRADY Subjects 47 Institutional Review Boards 50 Distinguishing Clinical Research From Clinical Researchers andInstitutional Review Clinical Practice 19 Boards 57 Ethics and Clinical Research 20 Evaluation andEvolution of the Current History ofEthical Attention toClinical System of Research Oversight and Research 20 Institutional Review Boards 57 Codes ofResearch Ethicsand Conclusion 59 Regulations 22 SummaryQuestions 59 Research on Bioethical Questions 23 References 59 Ethical Framework for Clinical Research 23 5. Accreditation of Human Research Ethical Considerations inRandomized Protection Programs Controlled Trials 27 ELYSEI.SUMMERS,MICHELLEFEIGE Conclusion 29 SummaryQuestions 29 ABrief History 63 References 30 Principles ofAccreditation 64 v vi CONTENTS Human Research Protection Programs: RegisteringClinicalTrialsatClinicalTrials.gov 116 The ShifttoShared Responsibility 65 Reporting Results toClinicalTrials.gov 118 The Accreditation Standards 66 Using ClinicalTrials.gov Data 120 Steps to Accreditation 70 Looking Forward 121 Value ofAccreditation 70 Conclusion 123 Summary Questions 72 Summary/Discussion Questions 123 References 72 References 123 6. The Regulation of Drugs and Biological 10. Data and Safety Monitoring Products by the Food and Drug PAULG.WAKIM,PAMELAA.SHAW Administration Why Monitor? 127 MOLLYM.FLANNERY,AMYE.McKEE, DIANEM.MALONEY,JONATHANP.JAROW Who Monitors? 128 What toMonitor? 130 Background 73 When and How Often to Monitor? 136 Mission and Terminology 74 Special Topics 137 Drug and Biological Product Life Cycle 76 Summary 138 Compliance 84 Summary Questions 139 Summary 84 Acknowledgments 139 Summary Questions 84 References 139 7. International Regulation of Drugs 11. Unanticipated Risk in Clinical and Biological Products Research THERESAMULLIN STEPHENE.STRAUS Introduction 87 The Reasons 143 Background 88 The Drug 144 Overview ofthe InternationalCouncil on The Target 145 Harmonisation Technical Harmonization The Trials 145 Process 93 Cassandra Revealed 147 InternationalCouncilon Harmonisation Extended Studies 147 GuidelinesMost Relevant toClinical Fialuridine Toxicity 147 Research 95 Reassessing the Preclinical Studies 149 FutureWork inRegulatory Harmonization 98 Research Oversight 149 References 98 The Investigations Begin 150 8. Clinical Research in International Scientific Misconduct 150 Settings: Opportunities, Challenges, The Food and Drug Administration 151 The National Institutes ofHealth 152 and Recommendations The Institute ofMedicine 152 CHRISTOPHERO.OLOPADE,MICHELLETAGLE, The Media 153 OLUFUNMILAYOI.OLOPADE The Congress 154 Introduction 99 The Law 154 Epilogue 155 Challenges 100 Acknowledgments 157 Recommendations 103 References 157 Conclusion 106 Further Reading 158 Summary Questions 106 References 107 12. Legal Issues in Clinical Research 161 9. The Role and Importance of Clinical VALERIEH.BONHAM Trial Registries and Results Databases Introduction 161 DEBORAHA.ZARIN,REBECCAJ.WILLIAMS, Protecting Individual Participant Interests 162 TONYTSE,NICHOLASC.IDE Special Protectionsfor Fetal Tissue, Introduction 111 Human Embryos, and Human Embryonic Background 112 Stem Cells 166 Current Policies 115 Conflict ofInterestand FinancialDisclosure 167 CONTENTS vii Public Transparency: Registration and Development and Importance ofa Study Results Reporting 168 Protocol 204 Recordkeeping and Privacy Protection 168 Equipoise 213 Data Sharing and Individual Consent 171 ManualofOperating Procedures 213 Conclusion 173 Reporting the Results 216 Summary/Discussion Questions 173 Conclusions 217 References 173 SummaryQuestions 217 Acknowledgments 217 13. National Institutes of Health Policy Disclosures 217 on the Inclusion of Women and References 217 Minorities as Subjects in Clinical Research 16. Writing a Protocol JANINECLAYTON,JULIANABLOME ELIZABETHA.BARTRUM,BARBARAI.KARP National Institutesof Health Policy 177 ScientificConsiderations andPeer Review 179 Introduction 219 Role of the Institutional Review Board 180 Regulatory Oversight 219 Challenges toEnrolling Volunteers 181 Writinga Protocol 220 Women of Childbearing Potential,Pregnant Elementsofa Protocol 220 Women, and Children 182 Summary 229 Demographic Trends in Clinical Trial Acknowledgments 229 Participation 183 References 229 What HaveWe Learned? 184 17. Design of Observational Studies Conclusion 186 SummaryQuestions 186 LAURALEEJOHNSON References 186 Introduction 231 Further Reading 187 Ecological (Correlational) Studies 233 14. ClinicalResearch:APatientPerspective Case Reports and Case Series 233 Single Time Point Studies: Cross-sectional JERRYSACHS Studies, PrevalenceSurveys, and The PatienteScientist Partnership 190 Incidence Studies 234 Walking Away: Why Patients Case-Control Studies 236 Refuse toParticipate inClinical Trials 191 Cohort Studies: Retrospective, Prospective, The Trial Begins: Understanding the Patient and Studies Nested Within aCohort 239 Experience 193 Odds Ratios, Risk Ratios,Relative Risks, Understanding the Caregiver 195 and Attributable Risk 242 The Role ofthe Patient Representative 195 Mistakes, Misconceptions, and The Role ofPalliative Care 196 Misinterpretations 243 Managing Difficult News 196 Conclusions 247 Effective Patient Communications: Questions 247 Recommendations and Considerations 197 Acknowledgments 247 The AssertivePatient: Ally in Scientific Disclosures 247 Research 198 References 247 Conclusion 199 Further Reading 199 18. Design of Clinical Trials and Studies II CATHERINEM.STONEY,LAURALEEJOHNSON STUDY DESIGN AND BIOSTATISTICS Design of Clinical Trials 250 The Purposeof Clinical Trials and Clinical 15. Development and Conduct of Studies 250 Studies Understanding the Spectrum ofthe Research Continuum 251 CATHERINEM.STONEY,LAURALEEJOHNSON Clinical TrialDesigns 255 Development and Conduct ofStudies 203 CriticalIssues in Clinical Study Design 258 Howto Choose a Study Design 204 Control Groups 258 viii CONTENTS PlaceboResponses 261 21. Measures of Function and Mistakes and Misconceptions 262 Health-Related Quality of Life Conclusions 266 NAOMIL.GERBER,JILLIANK.PRICE Summary Questions 266 Acknowledgments 266 Introduction toPatient-Reported Outcomes, Disclosures 266 Measuresof Function, and Health-Related References 266 Quality ofLife 303 Further Reading 268 Systematic Reviews 305 Outcomes: Functional Measuresand Patient- 19. The Role of Comparative ReportedOutcomes 306 Effectiveness Research Summary Questions 313 JOEV.SELBY,EVELYNP.WHITLOCK, References 313 KELLYS.SHERMAN,JEANR.SLUTSKY Further Reading 315 Introduction 269 22. Meta-analysis of Clinical Trials AHistory ofComparative Clinical JUNFENGSUN,BRADLEYD.FREEMAN, Effectiveness Research 270 CHARLESNATANSON The Patient-Centered Outcomes Research Institute 271 Techniques ofMeta-analysis 318 The Role ofComparative Clinical Meta-analysisofClinical Trials of Effectiveness Research in the Nation’s Antiinflammatory Agents in Sepsis 321 Medical Research Enterprise 273 Conclusions 323 The Methodsof Comparative Clinical Summary Questions 323 Effectiveness Research 275 References 324 Study Designs for CER Studies 278 EvidenceSynthesis inCER 285 23. Issues in Randomization Building aNational Infrastructurefor the PAMELAA.SHAW,LAURALEEJOHNSON, Conduct ofComparative Effectiveness CRAIGB.BORKOWF Research 287 Conclusions 290 What Is Randomization? 329 References 290 Importance of Randomization 330 History ofthe Randomized Trial 330 Randomization Methods 331 20. Using Large Data Sets for Issues inImplementation 333 Population-Based Health Research Special Considerations 335 Conclusion 337 LEIGHTONCHAN,PATRICKMcGAREY, JOSEPHA.SCLAFANI Summary Questions 338 Acknowledgments 338 Introduction 293 Disclosures 338 What Arethe Original Sources for References 338 These Data? 294 Uses ofSecondary Data inHealth 24. Hypothesis Testing Research 294 LAURALEEJOHNSON,CRAIGB.BORKOWF, Strengths 296 PAMELAA.SHAW Limitations (and Solutions) 297 Surveys 298 Introduction 342 LinkingData Sets 298 Basic Concepts inHypothesis Testing 343 Ethical Considerations 299 Formulation ofStatistical Hypotheses FutureDirectionsandConclusions 300 in the Motivating Examples 345 Summary Questions 300 One-Sample Hypothesis Tests With References 300 Applications to Clinical Research 346 CONTENTS ix Two-Sample Hypothesis Tests With Missing Data 403 Applications toClinical Research 349 Causal Inference inObservational Studies 405 Hypothesis Tests for the Motivating Examples 351 Concluding Remarks 406 CommonMistakes in Hypothesis Testing 353 SummaryQuestions 406 Misstatements and Misconceptions 353 Acknowledgments 407 Special Considerations 354 Disclaimers 407 Conclusion 356 References 407 SummaryQuestions 356 Acknowledgments 357 28. Large Clinical Trials and Disclaimers 357 RegistriesdClinical Research Institutes References 357 ROBERTM.CALIFF 25. Power and Sample Size Calculations Introduction 412 History 412 CRAIGB.BORKOWF,LAURALEEJOHNSON, PAULS.ALBERT Phases ofEvaluation ofTherapies 413 CriticalGeneral Concepts 414 Introduction 359 ExpressingClinical Trial Results 415 Sample Size Calculations for Precision in Concepts Underlying Trial Design 417 Confidence Interval Construction 361 General Design Considerations 420 Sample Size Calculations for Hypothesis Legal and Ethical Issues 422 Tests: One Sample ofData 362 Hypothesis Formulation 427 Sample Size Calculations for Hypothesis PublicationBias 427 Tests: Paired Data 364 Statistical Considerations 428 Sample Size Calculations for Hypothesis Meta-analysis and Systematic Reviews 430 Tests: Two Independent Samples 366 Understanding Covariates andSubgroups 431 Advanced Methodsand Other Topics 368 Therapeutic Truisms 432 Conclusion 369 OperationalOrganization for Large-Scale Exercises 370 Clinical Research 433 Acknowledgments 371 Integration Into Practice 437 Disclaimers 371 Controversies and Personal Perspective 437 References 371 The Future 439 SummaryQuestions 440 26. An Introduction to Survival Analysis References 440 LAURALEEJOHNSON III Introduction 373 Features of Survival Data 374 TECHNOLOGY TRANSFER, Survival Function 375 DATA MANAGEMENT, AND CommonMistakes 380 SOURCES OF FUNDING SUPPORT Conclusion 380 FOR RESEARCH Questions 381 Acknowledgments 381 29. Intellectual Property and Technology Disclaimers 381 Transfer References 381 BRUCEGOLDSTEIN 27. Intermediate Topics in Biostatistics Introduction 448 PAMELAA.SHAW,LAURALEEJOHNSON, Part One: Intellectual Property Generally 448 MICHAELA.PROSCHAN Part Two: Patents andTechnology Transfer 487 Special Topics inTrialDesign 384 Part Three: Technology Transfer Agreements 503 Special Considerations inData Analysis 392 Conclusion 518 Regression to the Mean 394 Brief Glossary ofCritical Termsin Patenting 519 DiagnosticTesting 396 Review Questions 519 Special Considerations inSurvival Analysis 400 References 520
The list of books you might like
