Fundamentals of Clinical Trials ( PDFDrive )

References 541

53. Food and Drug Administration: Investigational Device Exemption (IDE). http://www.fda.
gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhtransparency/ucm
205697.htm

54. FDA: Guidance for industry and FDA staff: modifications to devices subject to premarket
approval (PMA)—the PMA supplement decision-making process. http://www.fda.gov/down
loads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM270606.pdf

55. FDA: Design considerations for pivotal clinical investigations for medical devices: guidance
for industry, clinical investigators, institutional review boards and Food and Drug Adminis-
tration staff. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidance
Documents/ucm373750.htm

56. Dhruva SS, Bero LA, Redberg RF. Strength of study evidence examined by the FDA in
premarket approval of cardiovascular devices. JAMA 2009; 302:2679–2685.

57. Redberg RF. Sham controls in medical device trials. N Engl J Med 2014;371:892–893.
58. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant

hypertension. N Engl J Med 2014;370:1393–1401.
59. Leon MB, Kornowski R, Downey WE, et al. A blinded, randomized, placebo-controlled trial

of percutaneous laser myocardial revascularization to improve angina symptoms in patients
with severe coronary disease. J Am Coll Cardiol. 2005;46:1812–9.
60. The Intermittent Positive Pressure Breathing Trial Group. Intermittent positive pressure
breathing therapy of chronic obstructive pulmonary disease. A clinical trial. Ann Intern Med
1983;99:612–620.
61. Rome BN, Kramer DB, Kesselheim AS. FDA approval of cardiac implantable electronic
devices via original and supplement premarket approval pathways, 1979-2012. JAMA
2014;311:385–391.
62. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without
an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–
2150.
63. Code of Federal Regulations (21 CFR 600). http://www.accessdata.fda.gov/scripts/cdrh/
cfdocs/cfcfr/CFRSearch.cfm?CFRPart¼600
64. FDA: Biosimilars guidances. http://www.fda.gov/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm290967.htm
65. FDA: Guidance for Industry: clinical pharmacology data to support a demonstration of
biosimilarity to a reference product (draft guidance). http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf
66. ICH guidance on biosimilars: http://www.ich.org/products/guidelines/quality/article/quality-
guidelines.html
67. FDA: Study data submissions to CBER. http://www.fda.gov/biologicsbloodvaccines/
developmentapprovalprocess/ucm209137.htm
68. FDA: Guidance for industry: providing submissions in electronic format—summary level
clinical site data for CDER’s inspection planning: draft guidance. http://www.fda.gov/down
loads/drugs/developmentapprovalprocess/formssubmissionrequirements/ucm332468.pdf
69. Institute of Medicine of the National Academies. Sharing Clinical Trial Data: Maximizing
Benefits, Minimizing Risk. http://www.iom.edu/Reports/2015/Sharing-Clinical-Trial-Data.
aspx
70. FDA: Guidance for industry: providing clinical evidence of effectiveness for human drug and
biological products. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatory
information/guidances/ucm078749.pdf
71. FDA: Guidance for the public and FDA staff on convening advisory committee meetings: draft
guidance. http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm125651.pdf
72. Riveros C, Deschartres, Perrodeau E, et al. Timing and completeness of trial results posted at
ClinicalTrials.gov and published in journals. PLOS Medicine 2013;DOI:10 1371/journal
pmed.1001566

542 22 Regulatory Issues

73. Prayle AP, Hurley MN, Smyth AR. Compliance with mandatory reporting of clinical trial
results on ClinicalTrials.gov: cross sectional study. BMJ 2011;344:d7373 doi: 10.1136/bmj.
d7373

74. Jones CW, Handler L, Crowell KE, et al. Non-publication of large randomized clinical trials:
cross sectional analysis. BMJ 2013;347:f6104 doi: 10.1136/bmj.f6104

75. Saito J, Gill CJ. How frequently do the results from completed US clinical trials enter the
public domain?—a statistical analysis of the ClinicalTrials.gov database. PLoS ONE 2014;9:
e101826. doi:10.1371/journal.pone.0101826

76. Summary of HHS/NIH proposals to enhance transparency of clinical trial results. http://www.
nih.gov/news/health/nov2014/od-19_summary.htm

77. FDA Drug Safety Communication: FDA Study of Medicare patients finds risks lower for
stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared
to warfarin. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm

78. The European Medicines Agency Roadmap to 2010: Preparing the Group for the Future. http://
www.ema.europa.eu/docs/en_GB/document_library/Report/2009/10/WC500004903.pdf

79. Darrow JJ, Avorn J, Kesselheim AS. New FDA breakthrough-drug category—implications for
patients. N Engl J Med 2014;370:1252–1258.

80. Pariser A. Small clinical trials. http://www.fda.gov/downloads/newsevents/
meetingsconferencesworkshops/ucm415213.pdf.

81. Cote´ TR, Kui X, Pariser AR. Comment: Accelerating orphan drug development. Nat Rev Drug
Discov 2010;9:901–902.

82. Frank C, Himmelstein DU, Woolhandler S, et al. Era of faster FDA drug approval has also seen
increased black-box warnings and market withdrawals. Health Affairs 2014;33:1453–1459.

83. FDA: Postmarketing requirements and commitments: introduction. http://www.fda.gov/
Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/

Index

A predicted by baseline measures, 202
Accidental bias. See Bias, accidental regulatory, 272–273
Adaptive design. See Design, adaptive reporting, 266–267
Adaptive randomization. serious, 256
unexpected, 212, 262
See Randomization, adaptive withdrawal studies, 103–104
Adherence Alpha spending functions.

effects on adverse events, 299, 311 See Sequential testing
definition, 412, 414 Alternative hypothesis.
design factors, 300–302
discussing with participants, 312 See Hypotheses
maintaining, 306–311 Analysis
monitoring, 311–314
planning, 300, 304, 309 intention-to-treat, 4, 405, 412,
protocol adherence, 81–83, 86, 415, 443, 490

178, 300, 302 on-treatment, 405, 410, 443, 481, 489
run-in, 301 per protocol, 405, 481
withdrawal, 315 trend adaptive designs, 444–445
Adverse effects/adverse events Ancillary, 53–54, 511
analysis, 266–269 Ascertainment
ascertainment, 257–266 adverse events, 257, 262–267, 269, 273
assessment and reporting, 255–274 bias, 149
avoiding, 80 health related quality of life, 287
classification, 260–262 low adherence effects on, 315
CONSORT statement, 271 outcomes, 54, 62, 81, 242, 245,
data collection, 234–235
definition, 260 417, 465–468
design issues, 52–53 post-study, 473–475
effects on adherence, 299, 311 Audits, 219, 233, 234, 248–250, 469
factorial designs, 106
genetic subgroups, 206 B
identification, 274, 536 Baseline data
meta-analysis, 268–269
monitoring, 67, 349, 352, 354, 356 comparability, 202–204, 484, 487
missing data, 417 definition, 201
post-marketing, 91, 536 measurement, 207–212, 230
testing for imbalance, 204
uses, 201–207

© Springer International Publishing Switzerland 2015 543
L.M. Friedman et al., Fundamentals of Clinical Trials,
DOI 10.1007/978-3-319-18539-2

544 Index

Bayesian nonadherence, 427
data monitoring, 450 sequential methods, 375
methods, 6–8, 391 Classical sequential monitoring.

Belmont Report. See Ethics See Sequential testing
Bias Clinical equipoise. See Equipoise
Close-out
accidental, 92, 124
allocation, 92 transfer of care, 468
ascertainment, 149 visit, 464–465, 469
assessment, 62 Common Rule. See Ethics
estimation, 403 Comparison of survival curves.
experimental, 123
interviewer, 287 See Survival
investigator, 123, 242, 446, 448 Compensatory treatment, 151
publication, 25, 42–43, 223, 269, Competing event issues, 421–422
Compliance. See Adherence
447, 480, 485–487, 514 Concomitant treatment, 3, 151, 488
selection, 92, 93, 123, 124, 128, Concurrent control studies.

132, 216, 446, 447 See Design
Biased coin randomization. Conditional power.

See Randomization, adaptive See Sequential testing
Biomarkers Conflict of interest, 222, 483, 486, 506
CONSORT statement, 160, 271
genetic, 259 Continuous response.
outcomes, 5, 7, 50
personalized medicine, 109 See Response variables
run-in period, 301 Control group
screening for, 242
subgroup, 51 concurrent, non-randomized, 94–95
surrogate outcomes, 9, 62–65, 536 historical, 95–101
Blinding placebo, 31–33
assessment, 487, 488 randomized, 92–94
double-blind design, 150, 152–161 Covariate adjustment
double-dummy, 157, 160 using baseline data, 204, 428–431
open trial, 148 using surrogates, 425–427
protecting, 154–161 Covariate-intervention interaction, 337
reporting, 160–161 Cross-over. See Design
single-blind design, 150 Cutler-Ederer. See Survival, Cutler-Ederer
triple-blind design, 153–154
unblinded (open) design, 150 D
unblinding, 148–149, 158–160 Data analysis
Blindness, 11, 161, 356
Blocked randomization. Conflicts of interest, 33–34
Issues, 403–452
See Randomization, blocked Presentation, 483
Bonferroni. See Multiple testing Randomization process, 128, 136
Data and safety monitoring board.
C
Case-control studies. See Design See Data monitoring committee
Censoring. See also Under survival Databases

bias, 67 dissemination, 472, 473
comparing survival curves, 330–335 electronic health, 243, 244, 249, 465
definition, 323–324 finalization, 464
information loss, 185, 186 historical controls, 95–101
informative, 417, 419, 420, 467 Data collection
Kaplan-Meier, 324–328 data entry, 235, 237
enhancing quality, 348
essential data, 235

Index 545

forms (see Forms) Declaration of Helsinki, 26, 32, 34
guidelines, 233, 234 developing countries, 234
problems, 235–237 emergency settings, 36
verification, 246, 249, 463, financial incentives, 38
guidelines, 26, 34
469, 522, 527 informed consent, 26, 34–41
Data, missing. See Missing data Nuremberg Code, 26, 34
Data monitoring committee privacy and confidentiality, 35, 41
publication bias, 25, 42–43
decision process, 346, 353, 361 surrogate consent, 37
meetings, 347, 349, 378, 379, 390, 507 Ethics review committee, 25, 32,
membership, 346, 507
Data sharing, 274, 470, 472, 493–494, 522 39, 273, 533
Exclusion
See also Dissemination
Declaration of Helsinki. See Ethics from analysis, 405
Design from follow-up, 405
ineligibility, 406–409
adaptive missing data, 138
response adaptive, 114, 115, nonadherence, 303
135–137 Expected number of events,
sample size, 445
trend adaptive, 114, 115, 194, 366, 186, 337, 364
392–395, 444–445 Exponential distribution, 185, 320, 328.

case-control studies, 94, 282 See also Survival
concurrent control studies, 94–95 Extension of follow-up, 65, 166, 366
cross-over, 102–103, 105
double-blind, 148, 150, 152–161 F
factorial, 50, 52, 91, 104–107, 193, Factorial design. See Design, factorial
Falsification of data, 41
423, 502 Fixed allocation, 124–131, 136
hybrid, 91, 107 Follow-up, poststudy, 463, 473–475
large simple trials, 107–109 Forms
Dichotomous response. See Response
Dissemination, 13, 221, 463, 464, 471–473 development, 239
Dose-escalation studies, 6 monitoring, 238
Double-blind design. See Design pretesting, 241
Drop-in, 178, 179, 182, 298, 410
Drop-out, 149, 178, 179, 182, 298, G
Ghost authorship, 43, 482
311, 313, 410 Greenwood’s variance formula,
Drugs
327, 329
coding, 157–158 Group allocation, 106–107
matching, 155–157 Group sequential
quality control, 247–248
alpha spending functions,
E 365, 378–381
Effectiveness trial, 55–56, 298, 302
Efficacy trial, 39, 302 asymmetric boundaries, 384–386
Equipoise, 25, 30, 124, 194, 346, 446 Haybittle–Peto, 375, 376, 384, 385
Lan-DeMets alpha spending
clinical, 25, 30, 194, 346
Equivalence study, 109–113 functions, 365
Ethics methods for monitoring, 375–378
monitoring applications, 381–384
Belmont Report, 26, 34, 510 O’Brien–Fleming, 378, 379
clinical equipoise, 25, 30, 194, 346 Pocock, 375–384, 391
common rule, 34 Guest authorship, 482
conflict of interest, 222
data monitoring, 30

546 Index

H Institutional Review Board (IRB), 25, 29,
Haybittle–Peto group sequential method. 33, 34, 36, 249, 344–345, 510,
521, 523, 524
See Group sequential,
Haybittle–Peto Intention-to-treat (ITT), 4, 299, 405, 408,
Health-related quality of life 411, 412, 415, 443, 481, 490, 491
administration, 285, 287
clinical significance, 290 Interim events, 210
components, 279, 280, 283 IRB. See Institutional Review Board (IRB)
definition, 279 IVRS, IWRS. See Randomization
design, 284–288
interpretation, 279, 286, 288, 292 K
methodology, 284 Kaplan-Meier, 321, 324–329, 331, 337,
outcomes, 279, 281–284, 288–292
pretesting, 284 360, 361, 418–421, 435–437.
primary dimension, 280 See also Under survival
selection of instruments, 288–291
uses, 282–284 L
utility measures, 291–292 Lan-DeMets alpha spending functions.
Historical control studies, 90, 92, 95–101
Hochberg procedure for multiple testing. See Group sequential,
See Multiple testing Lan-DeMets alpha spending
Holm procedure for multiple testing. See functions
Multiple testing Large simple trials. See Design,
Hybrid design. See Design, hybrid Large simple trials
Hypotheses Last observation carried forward.
alternative, 168, 171, 375 See Missing data,
null, 167–171, 188, 189, 193, 269, Last observation carried forward
350–352, 364–365, 375–378, Levels of significance, 166, 374
383, 384, 386–389
one-sided vs. two-sided, 170 M
Mantel Haenszel statistic
I
Imbalance survival analysis, 331–339
two by two tables, 92
baseline, 201–204, 229, 487, 488 Manual of procedures, 15, 238, 470
covariate adjustment, 424 Margin of indifference, 110, 112, 113, 384
randomization, 92, 126, 129, Margin of noninferiority, 111, 442, 444
Masking. See Blinding
131–135, 140 Maximally tolerated dose, 6–8
safety events, 452 Measurement error, 64, 184, 289
subgroups, 432 Medications. See Drugs
Imputation. See Missing data Meta-analysis
Industry modified NIH clinical trials issues, 269, 445–449
methods, 269
model, 344 Minimization allocation, 134
Informative censoring, 467 Missing data
Informed consent imputation, 415, 416
last observation carried forward, 415
changes, 273 missing at random (MAR), 414–417
closeout, 466, 468, 470 missing completely at random
ethics, 26, 28, 29, 32, 34–40
genetics, 82 (MCAR), 415
privacy and confidentiality, 41 Monitoring
quality monitoring, 244
regulatory issues, 522–524, 527, Committee, 30, 66, 67, 148, 153,
273, 307, 343–367, 376–379,
528, 533 389–392, 434, 464, 508, 522, 528
study population, 76, 83

Index 547

interim, 373–395 Phases of trials
procedures, 313, 365, 373, 379, 391 early phase, 3, 5, 9, 16, 523
quality, 343 late phase, 5, 9, 12, 16, 486, 487, 501,
response variables, 106, 153 525, 532, 535
sequential, 356, 365, 378, 382, 383, 385 phase I, 3, 5–7
Multicenter trials phase II, 7–9
conduct, 504–511 phase III, 9–10
globalization, 85, 511–514, 522 phase IV, 9–10
organization, 501, 504, 506–508, 515
reasons for, 501–502 Pilot study, 8, 9, 166, 194, 217, 221, 487
recruitment, 504, 506, 507, 509 Placebo control, 31–33, 45, 152, 155,
Multiple testing
Bonferroni, 490 160, 187, 203, 205, 221, 353,
Hochberg, 440 355–358, 407, 447, 528
Holm, 440 Play-the-winner, 136
Pocock group sequential method.
N See Group sequential
Natural history, 3, 90, 281 Pocock–Simon randomization.
NIH clinical trials model, 344 See Randomization
Nonadherence Population
definition, 74–82
analysis, 410–414 eligibility criteria, 73, 75–78, 83–86
impact on sample size, 111 external validity, 74
Noninferiority generalization, 83–85
analysis, 442–444 heterogeneity, 78
assay sensitivity, 110, 443 homogeneity, 78
constancy assumption, 112 large, simple trials, 77, 78, 82
control group, 110–112 recruitment, 85–86
efficacy imputation, 113 representativeness, 84
interpretation, 113 selection, 75
margin of indifference, 110, 112, 113 Power. See Sample size
margins, 109–113 Pragmatic trial, 4, 29, 56, 83, 91, 108,
Null hypothesis, 167–171, 188, 189, 109, 503, 515, 525, 533
Privacy, 35, 41, 84, 216, 221, 223,
193, 269, 350–352, 364–365, 466, 470, 472, 474, 510,
375–378, 383, 384, 386–389 523, 524
Nuremberg Code. See Ethics Protocol
adherence see Adherence
O adverse events prespecified, 255, 263,
O’Brien–Fleming. See Group sequential, 273–274, 452
baseline factors prespecified, 204
O’Brien–Fleming closeout, 464
Observational studies, 14, 39, 49, 257–259, contents, 15–17, 234–235, 238, 245
defining study population, 75
274, 485, 493 guidelines and registries, 15–17, 161
One-sided vs. two-sided hypothesis. health related quality of life, 287–288
modification, 347, 349, 363
See Hypotheses, one-sided multicenter trial, 502, 506–510
vs. two-sided Per protocol see Analysis, per protocol
Open trial. See Blinding pilot, 194
regulatory, 524–526
P subgroups prespecified, 205, 273, 431
Per protocol analysis. See Analysis, violation, 406
Publication bias, 25, 42–43, 223, 269, 447,
Per protocol 480, 485–487, 514
Pharmacogenetics, 11, 82, 206, 207, 522

548 Index

Q guidelines, 480–484
Quality control interpretation, 484–485
publication bias, 42–43, 485–487
certification, 239–240 Response adaptive randomization.
monitoring, 244–250
Quality of life. See Health-related See Randomization, response
adaptive
quality of life Response variables
Question assessment, 61, 62
combined (composite), 59, 422
adverse event, 52, 61 continuous, 167, 179–183
ancillary, 53–54 dichotomous, 167, 171–179, 319, 320
natural history, 3 discrete, 57, 83
primary, 49–51, 57, 58, 60–62, monitoring, 106, 153
surrogate, 62–65
109, 192, 490 Results, dissemination, 13, 464, 471–473
secondary, 16, 51–52, 61, 202, 403, 490
S
R Safety
Randomization
advantages, 50
adaptive, 131–137 analysis, 267, 451–452
baseline adaptive, 132–133 Committee see Monitoring committee
biased coin (adaptive?), 132 early termination, 353–354
blocked, 126–129, 132 eligibility, 75
fixed allocation, 124–131 ethical issues, 28–29
group allocation, 106–107 hampered by blinding, 153, 158
IVRS, IWRS, 138 importance to primary question, 52
mechanics, 137–138 meta-analysis, 269
Pocock–Simon method, 130, 134, 140 monitoring, 39–40, 343, 345,
response adaptive, 135–137
simple, 125–126 347, 508
two-armed bandit, 136 regulatory considerations, 272–273,
urn design, 132, 133
Randomized control trials, 92–94, 102 519–520
Recruitment reporting, 271
approaches to lagging Sample size
cluster designs, 189–192
recruitment, 229–230 continuous outcome for repeated
conduct, 223–225
contingency plan, 221 measures, 183–184
ethics, 38–39 continuous outcome for
logs, 223
monitoring, 225–228 two independent samples,
planning, 219–221 180–181
problems, 217–219 continuous outcome paired data,
reasons for participating, 216 181–183
recycling subjects, 230 dichotomous outcome for paired
selection of study sample, 216 data, 177–178
sources, 221–223 dichotomous outcome for two
Registration of trials, 16, 480, 483, 524, 535 independent samples, 171–177
Regression toward the mean, 208–209 multiple outcomes, 268, 359, 361,
Repeated confidence intervals. 440, 448
nonadherence adjustment, 178
See Sequential testing noninferiority designs, 110, 111,
Repeated testing for significance, 350–352. 188, 384, 443
parameter estimation, 339
See also Multiple testing time to failure outcome, 184–188
Reporting results

analysis, 489–491

Index 549

Screening informative censoring, 467
effect, 166, 194 Kaplan-Meier, 321, 324–329, 331,
eligibility, 207–208
prescreening, 224 436, 437
recruitment, 215, 217–221 time to failure, time to event, 8
visit, 209
T
Selection bias. See Bias, selection Termination of trial
Sequential testing
examples, 303
alpha spending functions, planning, 463–464
365, 379–381 procedures, 463
Therapeutic misconception, 36
classical, 374–375 Time to failure response, 184.
conditional power, 386–390
repeated confidence intervals, See also Survival
Training
383, 384
statistical methods, 373 ethics, 27, 524
Simple randomization. health related

See Randomization, simple quality of life, 284
Single-blind design. See Blinding interviewer, 287
Statistical methods for data monitoring. multicenter trial, 508–510
pretesting, 241
See Sequential testing, quality assurance, 239–240
statistical methods Triple-blind design. See Blindness
Statistical power, 49, 54, 111, 165, Two-armed bandit randomization.
166, 215, 220, 258, 262,
267, 272, 438, 449 See Randomization
Storage of study material, 463 Type I error, 168, 171, 375, 379,
Stratification
of analysis, 129, 131 381, 384, 388, 390,
of randomization, 129, 131, 433 392–394, 432
Subgroup Type II error, 168, 267, 387, 388
analysis, 51, 52, 108, 201, 205,
207, 235, 271, 273, 355, U
431–438, 446, 449, 480, 490 Unblinded design. See Blinding
definition, 51 Unblinding,
Superiority trials, 30, 55, 91, 111,
113, 298, 414, 442–444, 488 ancillary studies, 511
Surrogate consent, 37 closeout, 464, 468
Surrogate response variable, 62–65 drug coding, 157–158
Survival emergency, 154, 238
analysis methods, 184, 319, 378, 425 inadvertent, 149, 154, 159
comparison of survival curves monitoring committee, 348
Cox Proportional Hazards model, official, 158, 161
339, 427 purposeful, 155
Mantel-Haenszel, 331–339 reporting, 488
medians, 203 serious adverse events, 527
point by point, 329, 330 Urn design randomization.
weighted rank tests, 355, 393, 445
Wilcoxon–Gehan, 333, See Randomization
335, 336
curve estimation, 324 V
Cutler-Ederer, 321, 324 Variability
exponential distribution, 320, 328
Greenwood’s variance formula, cluster, 190
327, 329 estimates, 193–195, 364–365
measurement, 183,

550 Index

Variability (cont.) W
quality control, 235–237 Withdrawal of subjects, 103–104.
reduction, 102–103, 130, 182
sample size parameter, 193–195, 241–242 See also Exclusion
unequal allocation, 169 Withdrawal studies,

91, 103–104