Clinical trials handbook design and conduct

Clinical Trials Handbook Clinical Trials Handbook DESIGN AND CONDUCT Curtis L Meinert Bloomberg School of Public Health The Johns Hopkins University Baltimore, MD A John Wiley & Sons, Inc., Publication Copyright  2013 by John Wiley & Sons, Inc All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002 Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products, visit our web site at www.wiley.com Library of Congress Cataloging-in-Publication Data: Meinert, Curtis L Clinical trials handbook : design and conduct / Curtis L Meinert p cm Includes bibliographical references and index ISBN 978-1-118-21846-4 (hardback) Drugs–Testing–Handbooks, manuals, etc Clinical trials– Handbooks, manuals, etc I Title RM301.27.M45 2013 615.1072 4–dc23 2012015097 Printed in the United States of America 10 Contents Acknowledgments xi Preface xiii On planning xv Explanatory notes, focus, and conventions xvii Abbreviations and designations xxi I General 1 Terminology Definitions Measurement units Trial type Design and flow schematics 13 Design and operating principles 15 Counting and analysis rules 17 Multi-study umbrella name 19 Study name 21 II 10 11 12 13 14 15 16 III 17 18 19 20 21 Design Specifications 25 Objective 27 Specific aims 29 Experimental variable 31 Treatment unit 33 Primary outcome 35 Outcome measures 39 Design synopsis 41 Funding 45 Type of funding initiative 47 Funding: Specifications 49 Funding: Terminology 51 Funding: Type 59 Funding: Initiative 61 v vi CONTENTS 22 Funding: Period 63 23 Funding: Budget 65 24 Funding: Mode 67 IV Treatment Groups/Treatment Administration 69 25 26 27 28 29 30 31 32 33 34 35 36 Study groups 71 Comparison group 73 Study treatments 75 Test treatments 77 Control/comparison treatment 79 Placebo treatment 87 Sham treatment 91 Treatment modality 93 Treatment schedule 95 Treatment compliance measures 97 Protocol overrides 101 Protocol bailouts 103 V Masking 105 37 38 39 40 41 42 43 44 45 Mask/masking: Definitions 107 Masking principles 111 Masking, censoring, and shielding specifications 113 Drug masking procedure 115 Drug packaging and labeling 117 Drug supply 121 Masking safeguards 123 Unmasking treatment assignment 125 Results blackouts 127 VI 46 47 48 49 VII Bias and Variance Control 129 Bias control procedures 131 Stratification 135 Variance control procedures 139 Separations 141 Treatment Assignment/Randomization .143 50 Assignment methods: Fixed vs adaptive 145 51 Treatment assignment: Random vs nonrandom 147 52 Randomization: Complete vs restricted 151 Contents vii 53 Randomization unit 155 54 Randomization: Procedures 157 VIII 55 56 57 58 59 60 61 62 63 IX IRBs and Consents 159 IRBs 161 IRBs: Models and procedures 163 Consent 169 Consent: Checklist 177 Consent: Disclaimers and notifications 181 Consent: Principles and purpose 183 Consent: Process 185 Consent: Types 189 Consent: Questions and answers 191 Enrollment and Followup 195 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 Notation 197 Timing conventions 199 Required approvals, permissions, accesses, and supplies 201 Start-up design 203 Start-up checklist 207 Recruitment design 209 Enrollment goals 211 Enrollment quotas 213 Followup: Terminology 217 Followup: Method 221 Followup: Length 223 Closeout design 225 Missed visit 229 Dropout 231 Loss to followup 235 Study timetable 239 Critical event path analysis 241 Eligibility criteria 243 Exclusions from enrollment 245 Eligibility and exclusions by reason 249 X Sample Size 251 84 Sample size: Design 253 85 Sample size: Specifications 257 viii 86 87 88 89 CONTENTS Sample size: Calculation 259 Fixed vs sequential sample size designs 261 Fixed vs adaptive designs 263 Designed subgroup comparisons 265 XI Data Collection and Processing 267 90 Contact schedule 269 91 Examinations/visits 271 92 Examination/clinic visit schedule 275 93 Data collection 279 94 Data collection: Schedules and procedures 281 95 Data flow 283 96 Data processing procedures 285 97 Laboratory tests 287 98 Readings 289 99 Tissue repositories 293 100 Form design: Principles and procedures 295 101 Time window specifications 299 102 Data entry design 301 103 Data sharing: Internal 307 104 Data sharing: External 311 XII Study Centers 315 105 Center types 317 106 Centers 323 107 Center requirements 325 XIII Investigators/Study Staff 329 108 Investigator requirements 331 109 Clinic staffing requirements 333 110 Research group/Investigators 335 XIV Committees 337 111 Key Committees 339 112 Standing and working committees 341 113 Committee rules and procedures 343 114 Study officers 347 115 Study chair/vice-chair 349 Contents ix 116 Executive committee 353 117 Executive committee members 357 118 Steering committee 359 119 Steering committee members 361 120 Steering committee: Questions, answers, and observations 363 121 Steering committee representation models 367 XV Treatment Effects Monitoring 371 122 Treatment effects monitoring 373 123 Treatment effects monitoring: Purpose 375 124 Treatment effects monitoring: Approach 377 125 Treatment effects monitoring: Masking 379 126 Stopping rules and guidelines 381 127 Treatment effects monitoring: Questions and answers 383 128 Treatment effects monitoring committee 387 129 Treatment effects monitoring committee: Questions and answers 391 XVI Quality Control and Assurance 393 130 Quality control and assurance procedures 395 131 Performance monitoring 399 132 Training procedures 401 133 Assurances and certifications 403 134 Site visiting procedures 405 135 Audit procedures 409 XVII Data Analysis 413 136 Analysis datasets 415 137 Analysis questions regarding study results publications 417 138 Frequentist vs Bayesian analysis 419 139 Final analysis 421 140 Subgroup analysis 423 XVIII Publication/Presentation 425 141 Publication 427 142 Publication policy 429 143 Authorship 431 144 Credits 435 145 Presentation policy 439 x XIX CONTENTS Policies 441 146 Policies 443 147 Publicity policy 445 148 Policy on access to study documents 447 149 Policy on access to study data and results 449 150 Policy on advertising for patients 453 151 Policy on incentive payments 455 152 Policy on payment of patient-related travel expenses 457 153 Ancillary study policy 459 154 Policy on patient-care-related payments 461 155 Policy on conflicts of interest 463 156 Substudy policy 467 XX Adverse Events 469 157 Adverse events 471 158 Adverse event reporting procedures 475 XXI Miscellaneous .479 159 Key study documents 481 160 Design synopsis 483 161 Slide sets 485 162 Study CV 487 163 Study website 489 164 Study history log 491 165 Landmark events and dates 493 166 Registration 495 Appendices 497 appendix Design summaries for selected finished trials 499 appendix Sample design slide sets 517 appendix Template summary worksheet 537 References 551 Index 557 Acknowledgments I wish to thank the people of the Johns Hopkins Center for Clinical Trials for help in producing this document—especially Betty Collison, Jill Meinert, Annette Wagoner, Karen Collins, Mark Van Natta, and Susan Tonascia xi Index Criner GJ, 552 crossover crossover treatment, 103 treatment crossover, 103 Dannenberg AJ, 552 data analysis dataset, 415 bolus data flow, 283 centralized data entry, 301 continuous data flow, 283 data collection site, 317 data coordinator, 333 data dictionary, 307, 311 data dredging, 265, 423 data editing, 285 data element, 285 data entry, 301 data field, 285 data file, 285 data flow, 283 data form, 285 data freeze, 285, 415 data generation, 285 data generation site, 285, 317 data keying, 285 data management, 286 data purge, 286 data query, 286 data record, 286 data sharing, 311 data snapshot, 286 data system, 286 data transcription, 286 data transformation, 286 data use agreement, 311 dataset, 415 deidentified data, 307 dependent double data entry, 301 direct data entry, 301 distributed data entry, 301 double data entry, 301 electronic data form, 301 exploratory data analysis, 265, 423 external data sharing, 307, 312 final data analysis, 421 final dataset, 421 followup data, 217 frozen data, 415 frozen dataset, 415 identified data, 307, 312 independent double data entry, 302 indirect data entry, 302 interim data analysis, 373 internal data sharing, 307, 312 559 keyless data recording, 302 limited use dataset, 312 linkable data, 307 mandated data sharing, 312 masked data analysis, 107 masked data collection, 107 on-line data entry, 302 paper data form, 302 paperless data entry, 302 PC-based data entry, 302 public use dataset, 312 quasi-independent double data entry, 302 real-time data entry, 283 web-based data entry, 302 data analysis exploratory data analysis, 265, 423 final data analysis, 421 interim data analysis, 373 data collection data collection site, 317 editing and processing, 305 masked, 111 masked data collection, 107 data editing rules, 398 data entry considerations, 305 Davis KB, 552 DeAngelis CD, 552, 553 Definitions acknowledgment, 435 active consent, 189 active control treatment, 79 active followup, 217, 221 adaptive study design, 263 adaptive treatment assignment, 145, 263 administrative review, 399 adverse drug experience, 471 adverse drug reaction, 471 adverse event, 471 adverse reaction, 471 adverse side effect, 472 adverse treatment effect, 472 advocacy representation construct, 367 alpha spending function, 383 alternative control treatment, 79 alternative treatment, 79 analysis dataset, 415 ancillary publication, 417, 427 ancillary study, 459 anniversary closing date, 225 appointed study chair, 349 aristocracy representation construct, 367 assent, 169 assent form, 169 560 INDEX Definitions (cont.) assent statement, 169 audit, 409 audit trail, 409 author, 431 author citation, 431 authorship, 431 authorship attribution, 431 award statement, 51 baseline, 271 baseline adaptive treatment assignment, 145 baseline examination, 271 baseline period, 271, 275 baseline results paper, 417 batch number, 117 Bayes’ theorem, 419 Bayesian, 383, 419 Bayesian analysis, 419 best and final offer, 51 best medical judgment control treatment, 79 bias, 131 biased coin treatment assignment, 145 bin number drug system, 117 blacklist, 403 blackout, 127 blind, 107 blister pack, 117 block, 151 block size, 151 blocked randomization, 151 bolus data flow, 283 business office, 51 case report form, 283 censor, 113 center, 317, 325 center director, 331 center representation construct, 367 central IRB, 163 central laboratory, 287 centralized data entry, 301 centralized funding, 51 Certificate of Confidentiality, 181 certification, 403 circuit rider, 405 clinic, 317 clinic coordinator, 333 clinic start-up design, 203 clinical equipoise, 75 clinical research associate, 333 clinical trial, xvii close of followup, 217 closed sequential design, 253 closeout design, 225 closeout examination, 271 closeout followup visit, 225, 271 closeout period, 275 closeout stage, 225 cluster randomization, 155 co-, 331 co-investigator, 331 commercial IRB, 163 common closing date, 225 comparison group, 73 comparison treatment, 73, 79 competitive bid, 51 competitive bidding, 51 competitive funding, 51 competitive initiative, 51 competitive proposal, 51 competitive range, 51 competitive renewal, 52 complete randomization, 151 concealed treatment assignment, 147 concealment, 107 concurrent followup, 217 conflict of interest, 463 consent, 169 consent form, 172 consent process, 185 consent statement, 172 consent, documentation of, 169 consent, elements of, 170 consent, requirement of, 172 consortium funding, 52 consortium funding agreement, 52 consortium funding award, 52 continuous data flow, 283 contract office, 52 contract officer, 52 contract proposal, 52 control treatment, 79 control-assigned group, 71 control-treated group, 71 conventional author, 431 conventional author citation, 431 conventional authorship, 431 cooperative agreement, 52 core funding, 52 corporate author, 431 corporate author citation, 432 corporate authorship, 432 credit, 435 crossover treatment, 103 data collection site, 317 data coordinator, 333 data dictionary, 307, 311 data dredging, 265, 423 data editing, 285 data element, 285 data entry, 301 Index data field, 285 data file, 285 data flow, 283 data form, 285 data freeze, 285, 415 data generation, 285 data generation site, 285, 317 data harvest, 415 data keying, 285 data management, 286 data purge, 286 data query, 286 data record, 286 data sharing, 311 data snapshot, 286 data system, 286 data transcription, 286 data transformation, 286 data use agreement, 311 dataset, 415 debarment, 403 deconsent, 172 deferred consent, 172, 189 deidentified data, 307, 311 deidentify, 307 dependent double data entry, 301 deputy director, 331 design variable, 35 designed subgroup comparison, 265 detectable difference, 257 direct data entry, 301 direct distribution of funds, 52 direct followup, 221 direct funding award, 53 discipline representation construct, 367 disclosure form, 463 distributed data entry, 301 distributed funding, 53 distribution of funds, 53 documented consent, 189 double data entry, 301 double mask, 107 double placebo, 115 dropout, 231 dropout compensation, 232 dropout replacement, 232 drug reaction, 472 efficacy monitoring, 375 elected study chair, 349 electronic data form, 301 endpoint, 39 ex officio, 347 executive committee, 353 expedited review, 161 experimental variable, 31 exploratory data analysis, 265, 423 external data sharing, 307, 312 extramural funding, 53 feasibility study, 203 fee-for-service, 67 fiat study chair, 349 final, 421 final data analysis, 421 final dataset, 421 final treatment result, 421 finder’s fee, 455 fixed sample size design, 254, 261 fixed study design, 263 fixed treatment assignment, 145 fixed-cost, 67 followup, 217, 272 followup cohort, 217 followup compliance, 217 followup data, 217 followup observation, 217 followup period, 217, 223, 275 followup stage, 217 followup study, 217 followup study design, 218 followup visit, 218, 272 form, 295 frequentist, 383, 419 frequentist analysis, 419 frozen data, 415 frozen dataset, 415 frozen state of equipoise, 131 funding agency, 53 funding agreement, 53 funding application, 53 funding award, 53 funding office, 53 funding officer, 53 funding period, 53, 63 funding proposal, 53 funding request, 53 Gantt chart, 241 grant, 53 grant application, 54 grants management office, 54 grants management officer, 54 group randomization, 155 group sequential design, 254 haphazard, 147 haphazardization, 147 harm, 373 head fee, 67 home visit, 272 ideal time window, 299 identified data, 307, 312 implied consent, 189 561 562 INDEX Definitions (cont.) inactive control treatment, 79 incentive, 455 incentive payment, 455 incremental funding, 54, 67 independent double data entry, 302 independent institutional review board, 164 indirect data entry, 302 indirect distribution of funds, 55 indirect followup, 221 indirect funding award, 55 individual randomization, 155 informative censoring, 113 informed consent, 173 insider, 463 insider information, 464 insider trading, 464 institutional review board, 161, 164 interim data analysis, 373 interim followup, 218 interim followup visit, 272 interim look, 373 interim result, 373 internal data sharing, 307, 312 intramural funding, 55 investigational new drug safety report, 472 investigator, 331 investigator-initiated research proposal, 55 involve, 161 jack-up factor, 257 key committee, 339 keyless data acquisition, 302 laboratory, 287 lead center, 164 lead clinic, 203 lead-in period, 97, 203 likelihood principle, 419 likelihoodist, 383, 419 limited use dataset, 312 linkable data, 307 local IRB, 164 local laboratory, 287 loss to followup, 218, 235 losses to followup, 218 lost to followup, 218, 235 lot number, 117 main study, 467 mainline paper, 417, 427 mandated data sharing, 312 mask, 107, 114 masked data analysis, 107 masked data collection, 107 masked randomization, 107 masked reading, 108 masked treater, 108 masked treatment, 108 masked treatment administration, 108 masked treatment assignment, 108 masked treatment effects monitoring, 108, 379 masked treatment effects monitoring committee, 108 masked treatment effects monitoring report, 379 masked trial, 108 masking level, 108 med Id number drug system, 117 minimal risk, 161 minimization, 145 minimum likelihood treatment assignment, 145 missed study visit, 229 mock treatment, 91 modified conventional author citation, 432 modified conventional authorship, 432 modified corporate author citation, 432 modified corporate authorship, 432 monitor, 409 more than minimal risk, 162 multi-study, 19 multi-study structure, 353 multicenter study, xvii multiple placebo, 115 natural history study, 427 negative control treatment, 80 nil treatment, 80 nil treatment control, 80 noncompetitive proposal, 55 noncompetitive renewal, 55 nonconcurrent followup study, 218 nonrequired followup visit, 272 null treatment, 80 number adaptive treatment assignment, 145 officers of the study, 347 on-line data entry, 302 open sequential design, 254 open treatment assignment, 147 oral consent, 173 outcome, 40 outcome adaptive treatment assignment, 146 outcome event, 40 outcome measure, 40 outcome variable, 40 overrepresent, 213 paired treatment design, 33 paper data form, 302 paperless data entry, 302 parent center, 164, 317 parent IRB, 164 parent study, 467 Index passive consent, 189 passive followup, 218, 221 patient contact schedule, 269 patient mail contact, 269 patient telephone contact, 269 PC-based data entry, 302 performance monitoring, 399 performance monitoring committee, 399 performance monitoring report, 399 performance review, 399 permissible time window, 299 permuted block, 151 PI representation construct, 367 pill count, 97 pilot study, 204 placebo, 87 placebo control, 87 placebo effect, 80, 88 placebo group, 88 placebo lead-in period, 88 placebo patient, 88 placebo period, 88 placebo reactor, 88 placebo treatment, 88 placebo treatment effect, 88 placebo washout, 88 placebo-assigned, 89 placebo-assigned group, 89 placebo-assigned patient, 89 placebo-control treatment, 89 placebo-controlled trial, 89 placebo-treated, 89 placebo-treated group, 89 placebo-treated patient, 89 play-the-winner treatment assignment, 146 positive control treatment, 80 post-closeout followup visit, 272 post-treatment followup, 218 post-trial followup, 219 post-trial followup stage, 219 power, 257 presentation, 427, 439 primacy, right of, 308 primary outcome, 35 primary outcome measure, 35 primary outcome variable, 35 primary publication, 417, 427 primary result, 427 principal investigator, 331 prospective followup, 219 protocol bailout, 103 protocol deviation, 101 protocol override, 101 protocol violation, 101 pseudorandom, 147 563 public repository, 293 public use dataset, 312 publication, 427 quality assurance, 395 quality control, 395 quasi-independent double data entry, 302 quasirandom, 147 quota, 213 quota requirement, 213 quotification, 213 random, 147 randomization, 148 randomization unit, 155 randomized controlled trial, xvii reading center, 289 real-time data entry, 283 recompete, 55 recompetition, 55 reconsent, 173 record audit, 409 recruitment quota, 213 reference group, 73 registration, 495 regular followup visit, 219, 272 renewal, 55 reportable event, 472, 475 reported event, 476 repository, 293 representation construct, 368 representativeness, 214 request for application, 56 request for proposal, 56 required followup visit, 219, 272 research, 162 research contract proposal, 56 research grant, 56 research grant application, 56 research grant proposal, 56 research group, 335 resource center, 318 restricted randomization, 151 results blackout, 127, 308 results paper, 417 retrospective followup, 219 rotating study chair, 349 run-in period, 97, 204 safety monitoring, 375 safety report, 473 satellite center, 318 scheduled followup, 219 scheduled study visit, 272 secondary paper, 417 secondary publication, 427 sequential design, 254 sequential sample size design, 255, 261 564 INDEX Definitions (cont.) serious adverse drug experience, 473 shakedown period, 97, 204 sham, 91 sham effect, 91 sham procedure, 91 sham treatment, 91 shield, 114, 127 signed consent, 173 single masked, 108 single placebo, 115 site visit, 405 sponsor, 56 sponsor-initiated research proposal, 56 sponsoring agency, 56 standard treatment, 73, 80 standing committee, 341 start-up patients, 204 steering committee, 359 stopping boundary, 381 stopping guideline, 381 stopping rule, 381 stratification, 135 stratification variable, 135 stratify, 135 study center, 318 study center director, 332 study chair, 349 study chair external, 349 study chair internal, 349 study clinic coordinator, 333 study clinic monitor, 405 study curriculum vitae, 487 study examination, 272 study group, 71 study officers, 347 study physician, 333 study result, 417 study treatment, 75 study vice-chair, 349 study visit, 272 subcontract, 57 subcontractor, 57 subgroup, 265, 423 subgroup analysis, 265, 423 subgroup comparison, 266, 423 subgroup treatment difference, 423 subgrouping, 266 subgrouping cutpoint, 266, 424 subgrouping variable, 266, 424 submission, 57 substudy, 467 test patients, 204 test treatment, 77 test-assigned group, 71 test-treated group, 71 time window, 299 trace control treatment, 80 trace treatment, 80 tracer substance, 97 treating physician, 333 treatment application and adjustment followup visit, 272 treatment assignment ratio, 146, 151 treatment assignment stratum, 152 treatment assignment visit, 272 treatment cessation, 103 treatment change, 103 treatment compliance, 98 treatment compliance measure, 98 treatment crossover, 103 treatment effects monitoring, 373 treatment group, 71 treatment lag, 257 treatment modality, 93 treatment period, 276 treatment protocol suspension, 103 treatment schedule, 95 treatment suspension, 104 treatment switch, 104 treatment termination, 104 treatment unit, 33 treatment variable, 31 treatment-related bias, 132 treatment-related feedback bias, 132 treatment-related selection bias, 132 trial, trial-proper, 204 trial-proper patient(s), 204 triple-mask, 109 type I error, 257 type II error, 257 umbrella study name, 19 underrepresent, 214 understudy, 214 unexpected adverse drug experience, 474 uninformative censoring, 114 unmask, 109 unscheduled followup, 219 unscheduled followup visit, 272 urn model, 146 urn model randomization, 146 urn model treatment assignment, 146 Vancouver Convention, 432 vanguard patients, 204 variance, 139 web-based data entry, 302 withdrawal, 232 witnessed consent, 189 working committee, 341 Index DeMets DL, 552 Department of Health and Human Services, 552 design adaptive study design, 263 clinic start-up design, 203 closed sequential design, 253 closeout design, 225 design variable, 35 designed subgroup comparison, 265 fixed sample size design, 254, 261 fixed study design, 263 followup study design, 218 group sequential design, 254 open sequential design, 254 paired treatment design, 33 sequential design, 254 sequential sample size design, 255, 261 deviation/deviate protocol deviation, 101 Diabetic Retinopathy Study, 53, 552 Dickson WJ, 554 Diggle P, 552 Drazen JM, 552, 553 drug adverse drug experience, 471 adverse drug reaction (ADR), 471 bin number drug system, 117 blister pack, 117 drug reaction, 472 investigational new drug safety report, 472 med Id number drug system, 117 serious adverse drug experience, 473 unexpected adverse drug experience, 474 Dunnett CW, 552 Dupont WD, 419, 552 Eastwood S, 551 Edmiston WA, 551 Edwards AWF, 552 effect masked treatment effects monitoring, 108 placebo effect, 80 sham effect, 91 treatment effects monitoring, 373 error type I error, 257 type II error, 257 event adverse event, 471 FDA related terms adverse drug experience, 471 adverse drug reaction (ADR), 471 adverse side effect, 472 blacklist, 403 565 drug reaction, 472 investigational new drug safety report, 472 safety report, 473 serious adverse drug experience, 473 sponsor, 56 unexpected adverse drug experience, 474 Fisher L, 552 Fitch LL, 551 followup active followup, 217, 221 close of followup, 217 closeout followup visit, 225, 271 concurrent followup, 217 direct followup, 221 followup, 217, 272 followup cohort, 217 followup compliance, 217 followup data, 217 followup observation, 217 followup period, 217, 223, 275 followup stage, 217 followup study, 217 followup study design, 218 followup visit, 218, 272 indirect followup, 221 interim followup, 218 interim followup visit, 272 loss to followup, 218, 235 losses to followup, 218 lost to followup, 218, 235 nonconcurrent followup study, 218 nonrequired followup visit, 272 passive followup, 218, 221 post-closeout followup visit, 272 post-treatment followup, 218 post-trial followup, 219 post-trial followup stage, 219 prospective followup, 219 regular followup visit, 219, 272 required followup visit, 219, 272 retrospective followup, 219 scheduled followup, 219 treatment application and adjustment followup visit, 272 unscheduled followup, 219 unscheduled followup visit, 272 Food and Drug Administration (FDA), 409, 552 Forastiere AA, 552 Forman S, 554 Fost N, 172, 189, 552 Freedman B, 75, 552 Friedman B, 146, 552 Friedman MA, 551 Frizelle FA, 552, 553 566 INDEX funding award statement, 51 best and final offer, 51 centralized funding, 51 competitive bid, 51 competitive bidding, 51 competitive funding, 51 competitive initiative, 51 competitive proposal, 51 competitive range, 51 competitive renewal, 52 consortium funding, 52 consortium funding agreement, 52 consortium funding award, 52 contract office, 52 contract officer, 52 contract proposal, 52 cooperative agreement, 52 core funding, 52 direct distribution of funds, 52 direct funding award, 53 distributed funding, 53 distribution of funds, 53 extramural funding, 53 funding agency, 53 funding agreement, 53 funding application, 53 funding award, 53 funding office, 53 funding officer, 53 funding period, 53, 63 funding proposal, 53 funding request, 53 grant, 53 grant application, 54 grant vs contract, 61 incremental funding, 54, 67 indirect distribution of funds, 55 indirect funding award, 55 intramural funding, 55 investigator initiated, 61 investigator-initiated research proposal, 55 methods of initiation, 61 noncompetitive proposal, 55 noncompetitive renewal, 55 recompete, 55 recompetition, 55 renewal, 55 request for application, 56 request for proposal, 56 research contract proposal, 56 research grant, 56 research grant application, 56 research grant proposal, 56 sponsor-initiated research proposal, 56 subcontract, 57 subcontractor, 57 Gillespie MJ, 552 Glassock R, 555 Glaucoma Laser Trial, 33, 53, 552 Glaucoma Laser Trial Research Group, 33 Godlee F, 553 group control-assigned group, 71 group randomization, 155 subgroup, 265, 423 subgroup analysis, 265, 423 subgroup comparison, 266, 423 subgroup treatment difference, 423 subgrouping cutpoint, 266, 424 subgrouping variable, 424 test-assigned group, 71 Habig RL, 554 Hansen BJ, 551 Hanson RF, 554 Harlan WR, 555 Haug C, 552, 553 Haugh M, 551 Hawk E, 552 Health Insurance Portability and Accountability Act (HIPAA) de-identified data, 307 Heath EI, 552 H´ebert PC, 553 Herman JG, 552 Hersh T, 554 Hightower NC Jr, 554 Hippocratic Oath, 373 Hoey J, 552 Hoffmann AF, 554 Horton R, 551–553 Hunter DW, 551 Hypertension Detection and Follow-up Program, 552 Hypertension Prevention Trial, 553 Ide NC, 555 identification deidentify, 307 linkable data, 307 Ingelfinger FJ, 553 Institute of Medicine, 553 institution commercial institutional review board, 163 institutional review board (IRB), 161, 164 assent, 169 assent form, 169 assent statement, 169 Index central institutional review board, 163 consent, 169 consent form, 172 consent process, 185 consent, requirement of, 172 documented consent, 189 expedited review, 161 finder’s fee, 455 incentive, 455 incentive payment, 455 independent institutional review board, 164 informed consent, 173 involve, 161 local institutional review board, 164 parent institutional review board, 164 renewal, 55 research, 162 International Committee of medical Journal Editors, 553 Kaplan RS, 551 Karnegis JN, 551 Katz J, 553 Kenward MG, 552 Kirk KA, 555 Klimt CR, 553 Knatterud GL, 553 Korn EL, 551 Kotzin S, 552, 553 Kusek JW, 555 Lachin JM, 146, 553–555 Laine C, 552, 553 Lakatos E, 555 Lan KKG, 552 Lasser EC, 554 Lee JY, 555 Leon AS, 551 Levine RJ, 172, 189, 553 likelihood likelihood principle, 419 Lindberg DAB, 555 Long JM, 551 Macular Photocoagulation Study Group, 553 Marks JW, 553, 554 Martin BK, 553 Marusic A, 552, 553 mask/masking blinded, 107 double mask, double masked, 107 mask, 107 mask, masked, 107 mask, masked, masking, masks, 107, 114 masked data analysis, 107 567 masked data collection, 107 masked randomization, 107 masked reading, 108 masked treater, 108 masked treatment, 108 masked treatment administration, 108 masked treatment assignment, 108, 147 masked treatment effects monitoring, 108, 379 masked treatment effects monitoring committee, 108 masked treatment effects monitoring report, 379 masked trial, 108 masking level, 108 principles, 111 shields, 114, 127 single masked, single mask, 108 treatment administration, 111 triple-mask, triple-masked, 109 unmask, unmasked, 109 unmask, unmasked, unmasking, unmasks, 109 Usage note, 107 Matts JP, 551 McCabe MS, 551 McCauley RF, 554 Meier P, 553 Meinert CL, 553 Mekhjian H, 554 model urn model, 146 urn model randomization, 146 Moher D, 551 Moleur P, 551 monitor/monitoring administrative review, 399 efficacy monitoring, 375 interim look, 373 masked treatment effects monitoring, 108, 379 masked treatment effects monitoring committee, 108 masked treatment effects monitoring report, 379 monitor, monitored, monitoring, monitors, 409 performance monitoring, 399 performance monitoring committee, 399 performance monitoring report, 399 performance review, 399 safety monitoring, 375 study clinic monitor, 405 treatment effects monitoring, 373 Montgomery E, 552 Multiple Risk Factor Intervention Trial, 553 568 INDEX National Cooperative Gallstone Study, 553, 554 National Emphysema Treatment Trial, 554 National Emphysema Treatment Trial Research Group, 553 National Heart, Lung, and Blood Institute, 554 National Institutes of Health (NIH), 554, 555 number batch number, 117 Nutton V, 554 Office for Protection from Research Risks (OPRR), 554 office/officer business office, 51 contract office, 52 contract officer, 52 funding office, 53 funding officer, 53 grants management office, 54 grants management officer, 54 officers of the study, 347 office/officer study officers, 347 Okun R, 554 Olkin I, 551 organization desired separations, 141 outcome outcome, 40 outcome adaptive treatment assignment, 146 outcome event, 40 outcome measure, 40 outcome variable, 40 primary outcome, 35 primary outcome measure, 35 primary outcome variable, 35 Overbeke AJPM, 552 patient/person trial-proper patient, 204 Pearce MB, 551 period baseline period, 271, 275 Persantine-Aspirin Reinfarction Study, 554 Pettinger M, 552 Physicians’ Health Study, 554 Piantadosi S, 552 Pitkin R, 551 placebo double placebo, 115 multiple placebo, 115 placebo, 87 placebo control, 87 placebo effect, 80, 88 placebo group, 88 placebo lead-in period, 88 placebo patient, 88 placebo period, 88 placebo reactor, 88 placebo treatment, 88 placebo treatment effect, 88 placebo washout, 88 placebo-assigned, 89 placebo-assigned group, 89 placebo-assigned patient, 89 placebo-control treatment, 89 placebo-controlled trial, 89 placebo-treated, 89 placebo-treated group, 89 placebo-treated patient, 89 single placebo, 115 Pocock SJ, 145, 554 post-stratification vs stratification, 137 power arcsin approximation, 260 definition, 257 normal approximation, 260 Poisson approximation, 260 Prentice RL, 554 probability Bayes’ theorem, 419 likelihood principle, 419 Probstfield J, 555 Program on the Surgical Control of the Hyperlipidemias, 232, 551 proposal competitive proposal, 51 protocol protocol bailout, 103 protocol deviation, 101 protocol override, 101 protocol violation, 101 treatment protocol suspension, 103 publication ancillary publication, 417, 427 baseline results paper, 417 primary publication, 417, 427 publication, 427 results paper, 417 secondary publication, 427 quality control aids, 397 credos, 397 pitfalls, 398 planning aids, 397 requirements, 397 Index Randall OS, 555 random/randomized pseudorandom, 147 quasirandom, 147 random, 147 randomization blocked randomization, 151 cluster randomization, 155 complete randomization, 151 features, 149 group randomization, 155 haphazardization, 147 individual randomization, 155 masked randomization, 107 misconceptions, 149 randomization, 148 randomization unit, 155 restricted randomization, 151 urn model randomization, 146 record record audit, 409 recruitment recruitment quota, 213 Rennie D, 551 research clinical research associate, 333 result final treatment result, 421 interim result, 373 primary result, 427 results blackout, 127, 308 review central institutional review board, 163 commercial institutional review board, 163 independent institutional review board, 164 local institutional review board, 164 parent institutional review board, 164 right primacy, right of, 308 Robbins H, 146, 554 Robertson JA, 172, 189, 552 Robin ED, 554 Roethlisberger FJ, 554 Sahmi P, 553 sample size fixed sample size design, 254, 261 jack-up factor, 257 sequential sample size design, 255, 261 Sanmarco ME, 551 Sawin HS, 551 Schaefer RA, 554 Schlant RC, 554 Schoenfield LJ, 553, 554 Schroeder TV, 552, 553 569 Schultz KF, 551 Shar AO, 552 Shaw L, 554 Shimm DS, 554 side effect adverse drug experience, 471 adverse side effect, 472 safety report, 473 serious adverse drug experience, 473 unexpected adverse drug experience, 474 Simel D, 551 Simon R, 145, 263, 554 Smink Jr RD, 551 Soloway RD, 554 Sox HC, 552, 553 Spece RG, 554 Stamler J, 553, 554 start-up clinic start-up design, 203 start-up patients, 204 test patients, 204 vanguard patients, 204 Stevenson JW, 551 stratification considerations, 136 variable, 136 when to, 136 stratify/stratification stratify, 135 Stroup DF, 551 Studies of Ocular Complications of AIDS, 554, 555 study adaptive study design, 263 ancillary study, 459 feasibility study, 203 fixed study design, 263 followup study, 217 followup study design, 218 main study, 467 missed study visit, 229 multi-study structure, 353 natural history study, 427 nonconcurrent followup study, 218 officers of the study, 347 parent study, 467 pilot study, 204 study center director, 332 study chair, 349 study chair external, 349 study chair internal, 349 study result, 417 study vice-chair, 349 substudy, 467 570 INDEX study index Coronary Drug Project, 117 Glaucoma Laser Trial, 33 Program on the Surgical Control of the Hyperlipidemias, 551 subgroup designed subgroup comparison, 265 subgrouping, 266 subgrouping variable, 266 Systolic Hypertension in the Elderly Program, 53, 554 Taves DR, 145, 555 test test-assigned group, 71 test-treated group, 71 theorem Bayes’ theorem, 419 Thistle JL, 554 Thomas FB, 554 Tonascia S, 553 Toto RD, 555 treatment active control treatment, 79 alternative control treatment, 79 alternative treatment, 79 best medical judgment control treatment, 79 comparison treatment, 73, 79 control treatment, 79 crossover treatment, 103 final treatment result, 421 inactive control treatment, 79 masked treatment, 108 masked treatment administration, 108 mock treatment, 91 negative control treatment, 80 nil treatment, 80 nil treatment control, 80 null treatment, 80 placebo treatment, 88 placebo-control treatment, 89 positive control treatment, 80 post-treatment followup, 218 sham treatment, 91 standard treatment, 73, 80 study treatment, 75 subgroup treatment difference, 423 test treatment, 77 test-treated group, 71 trace control treatment, 80 trace treatment, 80 treatment application and adjustment followup visit, 272 treatment cessation, 103 treatment change, 103 treatment compliance, 98 treatment compliance measure, 98 treatment group, 71 treatment lag, 257 treatment modality, 93 treatment period, 276 treatment protocol suspension, 103 treatment schedule, 95 treatment suspension, 104 treatment switch, 104 treatment termination, 104 treatment unit, 33 treatment variable, 31 treatment-related bias, 132 treatment-related feedback bias, 132 treatment-related selection bias, 132 treatment assignment adaptive treatment assignment, 145, 263 baseline adaptive treatment assignment, 145 biased coin treatment assignment, 145 bin number drug system, 117 cluster randomization, 155 fixed treatment assignment, 145 group randomization, 155 individual randomization, 155 masked treatment assignment, 108, 147 med Id number drug system, 117 minimum likelihood treatment assignment, 145 number adaptive treatment assignment, 145 open treatment assignment, 147 outcome adaptive treatment assignment, 146 play-the-winner treatment assignment, 146 randomization, see also, 148 treatment assignment ratio, 146, 151 treatment assignment stratum, 152 treatment assignment visit, 272 urn model treatment assignment, 146 treatment crossover treatment crossover, 103 treatment design paired treatment design, 33 treatment effect masked treatment effects monitoring, 108, 379 masked treatment effects monitoring committee, 108 masked treatment effects monitoring report, 379 placebo treatment effect, 88 treatment effects monitoring, 373 trial masked trial, 108 placebo-controlled trial, 89 post-trial followup, 219 Index post-trial followup stage, 219 trial-proper, 204 trial-proper patient, 204 Tse T, 555 Tuna N, 551 Tyor MP, 554 Tyroler HA, 555 United States Congress, 555 University Group Diabetes Program, 80, 87, 131, 491, 555 University Group Diabetes Program Research Group, 555 usage note adaptive study design, 263 administrative review, 399 adverse drug reaction (ADR), 471 adverse event, 471 adverse reaction, 471 ancillary study, 459 assent, 169 audit, 409 audit, audited, auditing, audits, 409 author, 431 authorship, 431 authorship attribution, 431 baseline, 271 baseline examination, 271 baseline period, 271, 275 bias, 131 blind, 107 block, 151 censor, censored, censoring, censors, 113 center, 317, 325 clinical equipoise, 75 co-, 331 commercial institutional review board, 163 comparison treatment, 73, 79 competitive bidding, 51 competitive range, 51 competitive renewal, 52 concealment, 107 conflict of interest, 463 consent, 169 contract office, 52 contract officer, 52 control treatment, 79 control-assigned group, 71 control-treated group, 71 data collection site, 317 data dredging, 265, 423 data generation site, 285, 317 dataset, 415 deferred consent, 172, 189 571 design variable, 35 dropout, 231 dropout compensation, 232 dropout replacement, 232 drug reaction, 472 efficacy monitoring, 375 endpoint, 39 ex-officio, 347 executive committee (EC), 353 exploratory data analysis, 265, 423 final, 421 finder’s fee, 455 fixed study design, 263 followup study, 217 frequentist analysis, 419 frozen state of equipoise, 131 funding period, 53, 63 grant, 53 grants management office, 54 grants management officer, 54 haphazard, 147 haphazardization, 147 harm, 373 identified data, 307, 312 implied consent, 189 incentive, 455 incentive payment, 455 informed consent, 173 insider, 463 insider trading, 464 investigator, 331 investigator-initiated research proposal, 55 involve, involved, involving, involves, 161 lead-in period, 97, 203 linkable data, 307 loss to followup, 218, 235 lost to followup, 218, 235 mask, 107 masked randomization, 107 masked treatment assignment, 108 masking level, 108 monitor, monitored, monitoring, monitors, 409 multi-study structure, 353 noncompetitive renewal, 55 outcome, 40 passive consent, 189 PC-based data entry, 302 performance monitoring, 399 performance review, 399 placebo, 87 placebo control, 87 placebo effect, 80, 88 placebo group, 88 placebo patient, 88 572 INDEX usage note (cont.) placebo treatment, 88 placebo treatment effect, 88 placebo-assigned, 89 placebo-assigned group, 89 placebo-assigned patient, 89 placebo-control treatment, 89 placebo-controlled trial, 89 placebo-treated, 89 placebo-treated group, 89 placebo-treated patient, 89 post-treatment followup, 218 presentation, 427, 439 primary outcome, 35 principal investigator (PI), 331 protocol bailout, 103 protocol deviation, 101 pseudorandom, 147 public repository, 293 publication, 427 quality assurance, 395 quality control, 395 quasirandom, 147 quota requirement, 213 quotification, 213 random, 147 randomization, 148 record audit, 409 recruitment quota, 213 registration, 495 regular followup visit, 219, 272 reportable event, 472, 475 reported event, 476 repository, 293 request for application (RFA), 56 request for proposal (RFP), 56 research grant, 56 retrospective followup, 219 run-in period, 97, 204 safety monitoring, 375 sequential sample size design, 255, 261 sham, 91 sham procedure, 91 sponsor-initiated research proposal, 56 standard treatment, 73, 80 start-up patients, 204 steering committee (SC), 359 stopping guideline, 381 stopping rule, 381 stratification, 135 stratify, 135 study center, 318 study group, 71 subcontract, 57 subcontractor, 57 subgroup analysis, 265, 423 substudy, 467 test patients, 204 test treatment, 77 test-treated group, 71 treatment crossover, 103 treatment effects monitoring, 373 treatment protocol suspension, 103 treatment-related feedback bias, 132 triple-mask, triple-masked, 109 underrepresent, underrepresented, underrepresents, 214 understudy, understudied, understudying, understudies, 214 vanguard patients, 204 withdrawal, 232 Van Der Weyden MB, 552, 553 Varco RL, 551 variable design variable, 35 experimental variable, 31 outcome variable, 40 primary outcome variable, 35 stratification variable, 135 subgrouping variable, 266, 424 treatment variable, 31 variance control, 139, 140 reduction, 140 reduction via analysis, 140 variance, 139 Verheugt FWA, 553 visit closeout followup visit, 225, 271 followup visit, 218, 272 home visit, 272 interim followup visit, 272 missed study visit, 229 nonrequired followup visit, 272 post-closeout followup visit, 272 regular followup visit, 219, 272 required followup visit, 219, 272 scheduled study visit, 272 site visit, 405 study visit, 272 treatment application and adjustment followup visit, 272 treatment assignment visit, 272 unscheduled followup visit, 272 Index Weber FJ, 551 Wei LJ, 146, 555 Weinstein WM, 552 West JC, 555 Winau R, 555 Wittes J, 88, 97, 203, 551, 555 Wright JT Jr, 555 Yang VW, 552 Yellin AE, 551 Yusuf S, 555 Zarin DA, 555 Zelen M, 146, 555 573 ... L Clinical trials handbook : design and conduct / Curtis L Meinert p cm Includes bibliographical references and index ISBN 978-1-118-21846-4 (hardback) Drugs–Testing–Handbooks, manuals, etc Clinical. .. states of clinical equipoise.33 Design and methods unique to developmental phase I and II trials are not covered Broadly, randomized trials are of two design types: parallel treatment designs (designs... 11 Design and Flow Schematics 13 Design and flow schematics SLIDE Design schematic: Foscarnet–Ganciclovir CMV Retinitis Trial (FGCRT)86 Location and extent of retinitis Zone or Zone 2, (? ?? 25%)