1. No category

INDEX
MA
TE
RI
AL
Adverse effect, 211
Adverse event coding systems, 66–68
Adverse event reporting, 29–30, 42
challenges to, 62–66, 69
in data management, 58
United States versus European
Union, 69
Adverse events (AEs), 211
becoming aware of, 62
challenges to reporting, 65–66
data accuracy/completeness
associated with, 47
in final study clinical report, 68
good clinical practices and, 202
ISO 14155-1 standard and, 149,
155
ISO 14155-2 standard and, 157
in PMA P970029, 167–168, 169, 170
reporting times of, 64–65
resolution of, 63
Adverse events analysis, 64
Agreements, with ISO 14155-1
standard, 154
Allocation of treatments, principles
of, 75
Alternative therapies, critical
literature review and, 10
Alternative therapy risks, in clinical
trial design, 3
Amputation, in LACI study, 82
Analysis datasets, for statistical
analysis plan, 12
CO
PY
RI
GH
TE
D
Abbreviated IDE (A-IDE) devices,
investigational product
applications and, 116
Abbreviations, xi–xii
Abciximab, noninferiority margin
for, 32–33
Absolute risk difference, 211
Absolute values, in outcome tables,
29
ACAS® (Asymptomatic Carotid
Atherosclerosis Study), PMA
P040012 and, 176
Accountability, in medical device
versus drug trial designs, 125
ACCULINKTM Carotid Stent
System, 86, 174
in PMA P040012 study, 175, 176,
177, 181, 186
ACCUNETTM Embolic Protection
System, 163, 175, 176
Accuracy, of data, 47–49
ACE inhibitors, in OPTIMAAL
trials, 30, 31
Active control groups
historic controls versus, 71
in medical device clinical trials, 73
Adjusted analyses, in statistical
analysis plan, 18
Adjustments, in statistical analysis
plan, 16–17
Administration, in medical device
versus drug trial designs, 125
The Design and Management of Medical Device Clinical Trials: Strategies and
Challenges, by Salah Abdel-aleem
Copyright © 2010 John Wiley & Sons, Inc.
221
222
INDEX
Analysis lesion, in PMA P070015,
187
Analyzed data
in clinical trial management, 47
in study management, 49–55
Anatomic conditions, in ARCHeR
studies, 183
Angina, in PMA P970029, 163, 164,
165, 169, 172
Angiographic binary restenosis
(ABR), in PMA P070015, 186,
191
Angiographic data, missing from
SPIRIT trial, 193
Angiographic late loss, in PMA
P070015, 186–188
Angiographic results
from PMA P070015, 192
from SPIRIT III 4.0-mm arm,
195, 196, 197
Angioplasty. See BARI (Bypass
Angioplasty Revascularization
Investigation) trial;
Percutaneous transluminal
angioplasty (PTA)
Angiotensin II Antagonist. See
OPTIMAAL (OPtimal Trial in
Myocardial Infarction with the
Angiotensin II Antagonist
Losartan) trials
Annexes, with ISO 14155-1 standard,
155
Annual reporting requirements, in
medical device and drug
product approval, 118
Anonymity, institutional review
boards and, 209
Anticipated adverse events,
reporting, 63
Anticoagulants, and protocol/
restricting procedural steps,
45–46
Application integrity policy (AIP),
in study management, 48
Approval process, FDA, 128
A priori biological rationale, in
subgroup analysis, 52, 53, 54
ARCHeR Registry study, 80
ARCHeR trials, 176–186
overview of, 174, 175
Arrhythmia, 24
Aspirin, myocardial infarction and,
52
Assay sensitivity, in superiority/
equivalence/noninferiority trials,
32
Associate investigator (AI), in
informed consent documents,
38
Atorvastatin. See CARDS
(Collaborative Atorvastatin
Diabetes Study)
Audits
developing clinical SOPs and, 3
in drug/device product
development, 130–131
Authorized representatives, 211
in CE marking, 147
Background, critical literature
review and, 10
BARI (Bypass Angioplasty
Revascularization Investigation)
trial, 51, 53, 54, 55
Baseline characteristics
of LACI study patients, 84
of SPIRIT III 4.0-mm arm, 194,
195
Baseline data, in CardioWest TAH-t
study, 95
Baseline lesion and vessel
characteristics
in ARCHeR studies, 182–183
in PMA P070015, 190
of SPIRIT III 4.0-mm arm, 194,
195
Baseline patient demographics
in ARCHeR studies, 182–183
in PMA P070015, 190
of SPIRIT III 4.0-mm arm, 194
INDEX
Baseline patient group
characteristics
in HeartMate II LVAS study, 90
in PMA P970029, 170
with historic controls, 96
Belmont Report: Respect for
Persons, 35, 42
bioethics in, 199, 200
ethical guidelines and principles
in, 204–205
institutional review boards and,
208
Benchmarks, for objective
performance criteria, 78
Benefits, of global clinical trials, 139.
See also Risk/benefit analysis
Best-case historic control, LACI
study and, 82
Bias
control groups and, 73
and masking/blinding in clinical
protocols, 13–14
minimization of, 69–70
in missing data analysis, 60
BIMO inspections, in drug/device
product development, 131–132
Binary measures, in statistical
analysis plan, 15
Bioethics. See also Ethics
challenges in, 200–201
in clinical research, 199–210
Biological products, where to report
misconduct related to, 105
Bioresearch monitoring information
system (BMIS), 104
Bioresearch monitoring (BIMO)
program inspection
data audits in, 48
in drug/device product
development, 130–132
Biostatistics, in clinical trials, 44
Biotechnology companies, in study
management, 44
Blame shifting, in detecting
misconduct, 102
223
Blinding
in clinical protocols, 12–14
in medical device versus drug trial
designs, 122
Body surface area (BSA), in
HeartMate II clinical study, 88
Bridge to transplantation (BTT)
CardioWest TAH-t as, 93, 95
HeartMate II LVAS as, 88, 92
Budgeting, of investigator-initiated
clinical trials, 133–134. See also
Costs; Financial disclosure
entries; Funds; Payment
Budgets, for clinical studies, 8
Bypass, in LACI study, 82
CABG interventions, PMA P970029
and, 165, 166
Canadian Cardiovascular Society
classification, PMA P970029
and, 165, 169
Candidate control therapies, in
LACI study, 81
Captopril, losartan versus, 30–31,
31–32
Cardiac Arrhythmia Suppression
Trial (CAST), 24
Cardiac risk factors, in PMA
P970029, 170
Cardiogenic shock, 4
Cardiogenic shock trials, deleting
inclusion/exclusion criteria in,
45
Cardiovascular histories, in
HeartMate II LVAS study, 90
CardioWest total artificial heart, 87
clinical studies of, 93–96
CARDS (Collaborative Atorvastatin
Diabetes Study), early
termination in, 61–62
CARET (beta carotene and alpha
tocopherol) study, early
termination in, 61
Carotid endarthroscopy (CEA),
PMA P040012 and, 176
224
INDEX
Case report forms (CRFs)
data accuracy/completeness
associated with, 47
for foreign clinical sites, 144–145
in study documentation, 49
study statistician and, 20
terms and conditions for, 8–9
Categories, defining, 28
Cause–effect relationships, for
adverse events, 63
Cause of death, in ARCHeR studies,
180
Cell measures/counts, in outcome
tables, 29
CE logo, 211
CE (Conformité Européene)
marking, 146–148, 211
European harmonization and,
147–148
FDA clinical trials versus, 157–160
ISO 14155-1 standard and, 149,
151
process of, 146–147, 148, 158
CE mark standards, xiv, 146–148
in European Union medical
device regulation, 137–138
CE mark studies
challenges of, 137–161
FDA studies versus, 15
purposes of, 160
Center for Biologics Evaluation and
Research (CBER), drug/device
combination products and, 126,
127, 128
Center for Devices and Radiological
Health (CDRH)
ARCHeR studies and, 181–186
drug/device combination products
and, 126, 127, 128
in medical device regulation, 112
PMA P970029 and, 173
Center for Drug Evaluation and
Research (CDER), drug/device
combination products and, 126,
128
Certificate of Confidentiality,
institutional review boards and,
209
Challenges
to adverse event reporting, 62–66,
69
to and within informed consent
forms, 35–41
associated with data accuracy/
completeness, 47–49
bioethical, 200–201
of CE marking, 146, 148
to CE mark studies, 160–161
to clinical study design, 1–42
of clinical trial distribution, 145
to designing statistical analysis
plan, 11–12
of global clinical studies, 137–161
to global harmonization task
force, 142–143
to medical device regulation,
107–135
in medical device versus drug trial
designs, 125–126
posed by drug/device combination
products, 126–129
to reporting adverse events,
65–66
to research contracts, 7, 8
to study management, 43–70
this book and, xiv–xv
to using historic controls, 71–72
Checks, in statistical analysis plan, 18
Chemical action, in drug versus
medical device definitions, 113
Children, consenting by, 40
Circulatory System Devices Panel
approval of HeartMate II LVAS
by, 92, 96
PMA P970029 and, 173
on XIENCE V Everolimus
Eluting Coronary Stent System,
197
Class I (general controls) medical
devices, 114, 119, 137–138, 158
INDEX
Class II (general/special controls)
medical devices, 114, 119,
137–138, 158, 160
Class III (premarket approval)
medical devices, 114, 119,
137–138, 158, 160
Classification, of medical devices,
114, 119, 137–138, 158. See also
ICD-9 (International
Classification of Disease
Version 9) system
Cleveland Clinic, PMA P970029
and, 165
Clinical data, in medical device and
drug product approval, 118
Clinical data managers, study
statistician and, 20
Clinical event adjudication
committee (CEC), in bias
minimization, 70
Clinical investigation plan (CIP)
ISO 14155-1 standard and,
153–154
ISO 14155-2 standard and, 149,
156, 157
Clinical investigations
in EU medical device regulations,
159
ISO 14155-1 standard and, 149,
151
Clinical investigators, in drug/device
product development, 130–131
Clinical personnel. See Personnel
Clinical protocol procedures, patient
compliance with, 46
Clinical protocols. See also Protocols;
Study protocol
adverse event coding systems and,
66
design of, xiii
enrolled subjects and, 7
in informed consent form, 36
investigational devices in, 7
masking/blinding in, 12–14
this book and, xiv–xvs
225
Clinical regulations, medical device
versus drug, 113. See also
Regulations
Clinical research. See also Research
and development
bioethics in, 199–210
criteria for reproducible, 47
Clinical research associates (CRAs)
in fraud prevention, 103
in study management, 44
Clinical research staff. See Personnel
Clinical scientists, this book and,
xiv–xv
Clinical studies. See also Clinical
trials
of CardioWest total artificial
heart, 93–96
challenges of global, 137–161
challenges to designing, 1–42
changing primary outcomes of,
20–22
contract signing for, 8
design and management of, xiii,
xiv–xv
early termination in, 61–62
of HeartMate II LVAS, 88–92
reducing sample sizes of, 25
sample size determination of,
24–25
this book and, xiii–xv
Clinical study teams, in completing
study protocols, 20
Clinical trial designs, commonly
used, 75–77
Clinical trial distribution, of foreign
clinical trials, 145
Clinical trial outcomes, in
CardioWest TAH-t study, 95
Clinical trial records, access to, 57–58
Clinical trials. See also Clinical
studies; Superiority trials
adverse event reporting in, 29–30,
42, 58, 62–66
analysis, design, and management
of, xiii, xiv–xv
226
INDEX
Clinical trials (cont’d)
bias minimization in, 69–70
bioethics in, 199–210
cost-effectiveness of, 43
enrolled subjects in, 7
examples using historic controls,
80
FDA versus CE marking,
157–160
fraud and misconduct in,
99–105
global, 137–161
historic controls for, 71–97
human rights and, 35–41
industry-initiated, 132, 133
investigator-initiated, 132–135
management of, 43–70
of medical devices, 107
medical device versus drug
regulation in, 112–113
meta-analysis studies and, 56–57
multinational, 66
randomization in, 74–75, 75–77
reporting results of, 28–30
risk/benefit analysis in, 3, 41–42
subgroup analysis in, 33–35
WHO GCP principles and, 203
XIENCE VTM Everolimus Eluting
Coronary Stent System,
186–197
Clopidogren, noninferiority margin
for, 33
Cluster randomization trial design,
75
Code of Federal Regulations (CFR)
bioethics and, 205
clinical trial conduct and, 35–36
institutional review boards and,
206
ISO 14155-1 standard and,
152–153
medical device and drug
regulation under, 115, 119
on non-significant risk devices,
111–112
objective performance criteria
and, 79
“short form” signatures and, 41
Coding systems, for adverse events,
66–68
Cohorts
in CardioWest TAH-t study, 93
in HeartMate II LVAS study,
88–89, 90, 91
Co-investigators (CO-PIs), clinical
trials initiated by, 132–135
Columns, in outcome tables, 29
Combination products, drug/device,
126–129
Combined endpoints, 22–23
Common Rule, bioethics and, 205
Communication, in drug/device
combination product
development, 127–128
Comparable groups, randomization
and, 74
Comparable treatments, principles
of, 75
Comparison population, for
CardioWest TAH-t study, 94–95
Competent authority, in CE
marking, 158, 161
Competitive studies, in investigator
selection, 6
Complaints, handling misconduct,
103–104
Completeness, of data, 47–49
Compliance
in data management, 59
implementations of, 46
with study protocols, 46
Compliance classifications, in drug/
device product development, 131
Composite endpoints, 22–23
Comprehension, of informed
consent documents, 37
Confidence intervals (CIs), 211
in clinical research, 26–27, 27–28
in selecting noninferiority margin,
33
INDEX
Confidence limits, 212
Confidentiality
bioethics and, 200, 201
in data management, 58
510(K) medical devices and, 110
institutional review boards and,
209
WHO GCP principles and, 203
Confidentiality breaches, as protocol
deviations, 68
Conflicts of interest, in global
clinical trials, 140
Conformity assessment, 212
Conformity assessment model, in
CE marking, 146–147, 158
Conformity assessment modules, 212
Confounders, in statistical analysis
plan, 17
Consensus, for objective
performance criteria, 78.
See also Transatlantic Inner
Societal Consensus (TASC)
Consent. See Informed consent
entries
Continued access protocol (CAP), in
HeartMate II clinical study, 88
Continuous data, 212
Continuous-scale measurement, in
statistical analysis plan, 16
Contract sign-off, documentation at,
134–135
Contraindication, 212
Control groups, 212
for medical device clinical trials,
73
purpose of, 73
Control group selection, in LACI
study, 81
Control therapies, in LACI study, 81
Cooperation, and masking/blinding
in clinical protocols, 13
Core laboratory, in bias
minimization, 70
Correspondence, in study
documentation, 49
227
Cost-effectiveness, of clinical trials,
43
Cost-effectiveness analysis, 212
Cost reduction, in medical device
and pharmaceutical industries, 2
Costs, of global clinical trials, 139.
See also Budgeting; Budgets;
Financial disclosure entries;
Funds; Payment
Counts, in statistical analysis plan,
15–16
Critical limb ischemia (CLI), LACI
study and, 82–83
Critical trials, design differences in
medical device/drug, 121–124
Crossover trial design, 75, 76
Cultural variations
in European clinical trials, 139–140
in global clinical trials, 141–142
Culture, WHO GCP principles and,
203
Customs, in European clinical trials,
139–140
Data
accuracy and completeness of,
47–49
Data
examining across study sites,
60–62
Data
for BIMO inspections, 132
Data
in changing primary outcomes,
20–21
Data
in clinical trial management, 47
Data
integrity of, 48, 55–56
misconduct related to, 99
in statistical analysis plan, 16, 17
storage in US, 56
Data analysis, in study management,
49–55
Data audits, 48
228
INDEX
Databases
in data management, 58
foreign clinical sites and, 143
with historic controls, 96
using historic controls from, 72
Data collection, for CE mark studies,
161
Data dredging, guarding against,
33–34
Data entry, in data management, 58
Data evaluation, in bias
minimization, 70
Data identifiers, of fraud, 101–102
Data imputation, in missing data
analysis, 59, 60
Data integrity, in study management,
44
Data listings, for statistical analysis
plan, 12
Data management
in clinical trials, 44
fraud and misconduct in, 59
missing data analysis in, 59–60
quality assurance in, 58–59
Data management systems,
responsibilities of, 56
Data managers, study statistician
and, 20
Data Monitoring Safety Board, in
changing primary outcomes, 21
Data Protection Act, ISO 14155-1
standard and, 152
Data quality, 55–56
Data safety and monitoring board
(DSMB)
in bias minimization, 70
in PMA P970029, 167
Data trawling, guarding against,
33–34
Deaths, in ARCHeR studies, 180
Declaration of conformity, 212
Declaration of Helsinki. See Helsinki
Declaration
Deficiencies, BIMO inspections and,
132
Demographics
in ARCHeR studies, 182–183
in PMA P070015, 190
of SPIRIT III 4.0-mm arm, 194
De Novo reclassification, for 510(K)
medical devices, 111
Description, of adverse events, 62
Deviations from protocol
adverse event coding systems and,
66–67
examples of, 67–68
reporting, 68
Deviations reports, adverse event
coding systems and, 67
Device accountability, in medical
device versus drug trial designs,
125
Device-related adverse events,
reporting, 29–30
Devices, in adverse event reporting,
69. See also Investigational
device exemptions (IDEs);
Investigational devices; Medical
device industry; Unanticipated
adverse device effects (UADEs,
UDAEs)
Device sponsor information, for
510(K) medical devices, 109
Device trials, study sites in, 60–62
Diabetes. See also CARDS
(Collaborative Atorvastatin
Diabetes Study)
as inclusion/exclusion criterion, 45
BARI trial and, 51
Diary cards, fraud identified via, 102
Difference, in clinical research, 27
Differential subgroup effects, 34
in statistical analysis plan, 18
Digoxin, 55
Directive, 212
Directorate General Enterprise, in
CE marking, 147
Disease risks, in clinical trial design, 3
Distribution risks, with foreign
clinical trials, 145–146
INDEX
Documentation
for adverse events, 63–64
BIMO inspections and, 131–132
bioethics and, 201
in CE marking, 147
in changing primary outcomes,
21
at contract sign-off, 134–135
in data management, 59
good clinical practices and, 202
in informed consent process,
39–40
for ISO 14155-1 standard, 153
in study management, 49
Dose dependent, 212
Double-blind studies, 13, 212
in bias minimization, 70
Drug research and development,
clinical trials in, 43
Drugs
clinical trial regulations for,
112–113
combined with medical devices,
126–129
defined, 113
FDA regulation of, 115
global trials of, 138–142
investigational product
applications for, 115
mechanisms of action of, 113, 114
medical device classification and,
114
pathways to product approval for,
115–121
trial design for, 121–124
where to report misconduct
related to, 105
Duke Activity Status Index (DASI)
questionnaire, PMA P970029
and, 166, 169–170
Early termination, in clinical studies,
61–62
Eclipse TMR 2000 Holmium Laser
System, in PMA P970029,
229
164–165, 167. See also
Transmyocardial laser
revascularization (TMR)
Effectiveness, 212
Effectiveness parameters, of
CardioWest TAH-t study, 93
Effectiveness results, in PMA
P970029, 171
Efficacy, in ARCHeR studies, 185
Efficiencies, in medical device and
pharmaceutical industries, 2
Electronic database training, in data
management, 58
EN 540 standards, ISO 14155-1
standard and, 152–153
Encainide, 24
Endpoints. See also Primary
outcomes; Secondary outcomes;
Study endpoints
to be analyzed, 25
in CardioWest TAH-t study, 94,
95–96
challenges to selecting, 11–12,
14–15
changing during studies, 20–22
in clinical trial design, 2, 3, 4
combined, 22–23
composite, 22–23
in FDA PMA cases, 163
features and characteristics of,
14
hard and soft, 21–22
of LACI study, 80, 86
and masking/blinding in clinical
protocols, 14
meta-analysis studies and, 56–57
objective performance criteria
and, 80
of PMA P970029, 165–166
selecting good primary, 15
statistical analysis plan and, 15–17,
18–19
statistical terms to define
measurements of, 25–28
surrogate, 23–24
230
INDEX
Enrolled subjects. See also Subject
entries
bioethics and, 199–200
in clinical trial design, 2
consenting by vulnerable, 40–41
defined, 7
in HeartMate II LVAS study,
88–89, 89–90
in LACI study, 83–85
misconduct related to, 99
protocol deviations among, 67
re-consenting, 40
screening logs for, 4–5
statistical power and number of, 52
study protocol compliance by, 46
terms and conditions for, 8–9
EPISTENT trial, noninferiority
margin for, 32
Equivalence. See Substantial
equivalence
Equivalence hypothesis, in LACI
study, 84–85
Equivalence/noninferiority trial
design, 75, 76–77
Equivalence trials, 30–33, 213.
See also Substantial equivalence
Essential requirements, 213
in CE marking, 146–147, 158
Ethical guidelines and principles,
204–205
World Health Organization,
202–203
Ethics. See also Bioethics; Regional
ethical issues
control groups and, 73
in European clinical trials, 139–140
in informed consent process, 39
with ISO 14155-1 standard, 154,
155
and masking/blinding in clinical
protocols, 13, 14
Ethics committees (ECs)
bioethics and, 200, 201
in global clinical trials, 140
WHO GCP principles and, 203
Europe
FDA studies versus those in, 15
global clinical trials in, 139–140
European Commission, 213
in CE marking, 147
European Directives, CE marking in,
146
European Economic Area (EEA),
213
European Free Trade Area (EFTA),
213
European Standard (EN), in CE
marking, 147
European Union (EU), 213
CE mark standard of, xiv, 146–148
medical device regulation in, 137–
138, 157–158
regional ethical issues in, 140–141
United States versus, 45–46, 69,
137–138, 144–145, 157–160
Evaluation teams, and masking/
blinding in clinical protocols,
12–14
Evidence, critical literature review
and supporting/weighted, 10
Excimer laser atherectomy, in LACI
study, 81
Exclusion, of patients from studies, 4
Exclusion criteria
in CardioWest TAH-t study, 94
deleting, 45
meta-analysis studies and, 56–57
for PMA P970029, 165
Exemptions, from informed consent
form, 41. See also
Investigational device
exemptions (IDEs)
Exempt reviews, by institutional
review boards, 206–207
Exercise treadmill testing, in PMA
P970029, 170–172
Expedited reviews, by institutional
review boards, 207
Experience, in investigator selection,
5–6
INDEX
Exploratory analyses, in statistical
analysis plan, 18
Fabrication, fraud, and misconduct
via, 100–101
False Claims Act, 102–103
False payment claims, 102–103
Falsification, fraud, and misconduct
via, 100–101
FDA PMA cases, xiv, 163–197.
See also Food and Drug
Administration (FDA);
Premarket approval (PMA)
European Union and, 138
HeartMate II LVAS study, 92
using historic controls and, 72–73
FDA TMR studies, this book and,
xiv. See also Transmyocardial
laser revascularization (TMR)
Feasibility studies, for medical
devices, 121
Federal-wide Assurance (FWA),
institutional review boards and,
206
Final study clinical report, adverse
events reported in, 68
Financial disclosure, good clinical
practices and, 202. See also
Budgeting; Budgets; Costs;
Funds; Payment
Financial disclosure requirements,
for 510(K) medical devices,
110
510(K) medical devices, 107
determination of, 108–111
European Union and, 138
premarket approval for, 112,
118–120
Flecainide, 24
Follow-ups
in adverse event reporting, 68
in ARCHeR studies, 181
in handling misconduct claims,
103, 104
historic controls and, 71–72
231
Food and Drug Administration
(FDA), 213
on accessing clinical trial records,
57–58
adverse event coding systems used
by, 66
in adverse event reporting, 69
application integrity policy and,
48
approval of HeartMate II LVAS
by, 92, 96
BIMO program of, 130–132
CE marking versus, 15,
157–160
clinical trial conduct and, 35–36
in clinical trial design, 2–3
contract sign-off and, 135
data audits by, 48
in detecting, correcting, and
preventing fraud and
misconduct, 100
developing clinical SOPs and, 3
drug/device combination products
and, 126–129
European Union and, 138
historic controls and, 71–73, 97
ICF exemptions and, 41
investigational devices approved
by, 7
investigational product
applications and, 115–118, 119
ISO 14155-1 standard and,
150–151
in LACI study, 81, 86
LVADs and TAHs and, 97
medical device and drug
regulation by, 115
medical device development and,
115
medical device regulation by,
107–108, 109–111
in medical device versus drug trial
designs, 123–124, 125, 126
meetings with study sponsors,
129–130
232
INDEX
Food and Drug Administration
(FDA) (cont’d)
on non-significant risk devices,
111–112
PMA P040012 and, 176, 181–186
PMA P970029 and, 166
practice of medicine and, 121
premarket approval by, 112
recommendation on acceptance of
foreign clinical sites, 143
reporting adverse events and,
66
reporting misconduct to, 104–105
in selecting noninferiority margin,
33
sponsor reporting to, 123–124
statistical analysis plan and, 19
this book and, xiv
timing of adverse events and, 65
on XIENCE V Everolimus
Eluting Coronary Stent System,
197
Foreign study sites
conducting global clinical trials in,
143–145
FDA recommendations on
acceptance, 143
Fraud
in clinical trials, 99–105
consequences of, 101
data identifiers of, 101–102
in data management, 59
defined, 100–101
detecting, correcting, and
preventing, 100, 103
entities committing, 101
frequency of, 100
reasons for, 101
this book and, xiv
warning signs of, 101–102
Full reviews, by institutional review
boards, 207–208
Funds, for medical device
development, 115. See also
Budgeting; Budgets; Costs;
Financial disclosure entries;
Payment
Global clinical studies, challenges of,
137–161. See also Global clinical
trials
Global clinical trials. See also Global
clinical studies
operational tips on conducting,
143–145
this book and, xiv
Global harmonization task force
(GHTF), global clinical trials
and, 142–143, 148
Global trial considerations, 138–142
Good clinical practice (GCP)
standards, 213
bioethics of, 199, 201–203
for CE mark studies, 160
in data management, 59
in detecting, correcting, and
preventing fraud and
misconduct, 100, 103
developing clinical SOPs and, 3
in drug/device product
development, 131
guidance principles of, 200–201
World Health Organization and,
202–203
Good laboratory practice (GLP), in
drug/device product
development, 130
Good manufacturing practice
(GMP), bioethics and, 201
Good surrogate endpoints, 24
Groupings, in statistical analysis
plan, 16
Hard endpoints, 21–22
Harmonization, CE marking and,
147–148
Harmonized standards (EN), 213
Heart disease. See CARDS
(Collaborative Atorvastatin
Diabetes Study)
INDEX
Heart failure
left ventricular assist devices and,
86–87
in PMA P970029, 163, 164
HeartMate II LVAS, 87
clinical studies of, 88–92
FDA approval of, 92
overall study patient outcomes,
91–92
primary study objective, 90
study design, 88–89
study overview, 88
study patient population, 89–90
Helsinki Declaration, 35, 42
bioethics in, 199, 200
ethical guidelines and principles
in, 204
foreign clinical sites and, 143
Hemodynamic insufficiency, in
CardioWest TAH-t study, 94
Heterogeneity, in subgroup analysis,
53
HIPAA (Health Insurance
Portability Accountability Act),
ISO 14155-1 standard and,
152
Historical data, pooling of, 78
Historic controls, 213
in CardioWest TAH-t study, 93
challenges to, 71–72
definition of, 77
examples of clinical studies with,
80
in FDA PMA cases, 163
in LACI study, 81–86
for PMA P040012, 175–186
recommendations for, 96–97
selection of, 71–97
this book and, xiv
Holmium laser system, in PMA
P970029, 164–165, 167
Human rights, clinical trial conduct
and, 35–41. See also Bioethics;
Ethics entries
Hypotension, 4
233
Hypotheses, 213
in captopril versus losartan trial, 31
in clinical research, 26
in pivotal trial designs, 75–77
in subgroup analysis, 52, 54, 55
ICAI study
historic controls in, 82
LACI study versus, 83
ICD-9 (International Classification
of Disease Version 9) system, 66
IDE exemptions, investigational
product applications and, 116,
117–118. See also Investigational
device exemptions (IDEs)
Identification, of adverse events,
62–63
ID numbers, in patient screening
logs, 5
Ignorance, misconduct due to, 99
Impossible events, fraud identified
via, 102
Inadvertent deviations, as protocol
deviations, 67
Inclusion criteria
in CardioWest TAH-t study, 93–94
deleting, 45
meta-analysis studies and, 56–57
in PMA P070015, 187
in PMA P970029, 165
Indemnification, in research
contracts, 8, 9
Independent ethics committees
(IECs)
bioethics and, 201
WHO GCP principles and, 203
Independent study core laboratory,
in bias minimization, 70
IND exemptions, investigational
product applications and, 116–
117. See also Investigational
new drugs (INDs)
Industry-initiated clinical trials, 132,
133
contract sign-off for, 134–135
234
INDEX
Inferences, in statistical analysis
plan, 16–17
Information
in adverse event reporting, 62–63
bioethics and, 200, 201
institutional review boards and,
209–210
in using historic controls, 72
WHO GCP principles and, 203
Informed consent
bioethics and, 201
in global clinical trials, 140,
142–143
good clinical practices and, 202
ISO 14155-1 standard and, 153, 154
in medical device versus drug trial
designs, 125
obtaining, 38
protocol deviations in, 68
Informed consent documents
challenges of writing, 37
signatures on, 38
Informed consent form (ICF)
basic elements of, 36
challenges to and within, 35–41
in clinical trial design, 3
developing clinical SOPs and, 3
as documentation, 39–40
ethics in, 39
with ISO 14155-1 standard, 154
misconduct related to, 99
requirement exceptions from, 41
waiver of, 36–37
Informed consent process
clinical trial conduct and, 36
“short form,” 39
Inspections, in drug/device product
development, 131–132
Institutional review board (IRB)
accessing clinical trial records by,
57–58
bioethics and, 200, 201, 205
clinical studies budgets and, 8
consenting by vulnerable subjects
and, 40
contract sign-off and, 135
foreign clinical sites and, 143
good clinical practices and, 202
in informed consent documents,
38, 39
on non-significant risk devices,
111–112
reporting adverse events and, 66
review processes of, 206–210
sponsors and FDA and, 123–124
structure of, 205–206
study subject re-consenting and, 40
timing of adverse events and, 65
WHO GCP principles and, 203
Institutions
contract sign-off and, 135
in fraud prevention, 103
Insurance, in research contracts, 8, 9
Insurance protection, in global
clinical trials, 140
Integrity, of data, 48, 55–56
Integrity hold, 48
Intention-to-treat (ITT) analysis, 214
advantages and limitations of, 50
requirements for, 51
in study management, 49, 50
Interaction effects, in subgroup
analysis, 34
International Conference on
Harmonization (ICH)
bioethics and, 199
foreign clinical sites and, 143
International Organization for
Standardization (ISO). See also
ISO 14155 standard
in CE marking, 147
European Union and, 138
International studies, with historic
controls, 96
Intervention errors, as protocol
deviations, 67
Investigational device exemptions
(IDEs)
in adverse event reporting, 69
decision process for, 116–118
INDEX
foreign clinical sites and, 144
investigational product
applications and, 115–118
for medical devices, 108
for non-significant risk devices,
111–112
sponsors and FDA and, 123–124
Investigational devices
in adverse event reporting, 69
in clinical protocols, 7
Investigational device system,
defined, 7
Investigational new drugs (INDs),
214. See also IND exemptions
investigational product
applications and, 115, 116
sponsors and FDA and, 123
Investigational product applications,
in medical device and drug
product approval, 115–118
Investigational product risks, in
clinical trial design, 3
Investigational products, WHO GCP
principles and, 203
Investigations
ISO 14155-1 standard and, 149,
151
in medical device versus drug trial
designs, 123
Investigative product, critical
literature review and, 10
Investigator brochure
anticipated adverse events in, 63
bioethics and, 201
with ISO 14155-1 standard, 153
Investigators. See also Principal
investigator (PI)
bioethics and, 200, 201
in changing primary outcomes, 21
in clinical trial design, 2
clinical trials initiated by, 132–135
contract sign-off and, 135
in drug/device product
development, 130–131
good clinical practices for, 201–202
235
institutional review boards and,
209
and masking/blinding in clinical
protocols, 12–14
nonmedical persons as, 6–7
selection for studies, 3, 5–7
Ischemic heart disease, 4
ISIS-2 study, multiple testing
problem and, 52
ISO 14155 standard, 148–157.
See also International
Organization for
Standardization (ISO)
future of Part 1, 155
general requirements under,
151–152
new definitions under, 151
Part 1 of, 149–155
Part 2 of, 149, 156–157
purposes of, 148–149
IVUS results, from PMA P070015,
191, 192
Jurisdiction, for drug/device
combination products, 127, 128
Kaplan–Meier survival estimates,
168, 169
Key budget items, in investigatorinitiated clinical trials, 133–134
Key inclusion criteria, in PMA
P070015, 187
Key limitations
of SPIRIT III 4.0-mm arm, 197
of SPIRIT III RCT, 193
Labeling
of drug/device combination
products, 127
in medical device and drug
product approval, 121
Laboratory, in bias minimization, 70
LACI (laser angioplasty for critical
limb ischemia) clinical study,
80–86
236
INDEX
LACI Phase 2 Registry, results of,
83–84
Late lumen loss (LL), in PMA
P070015, 186–187, 188
Left ventricular assist devices
(LVADs), 80
in CardioWest TAH-t study, 95
described, 86–87
Left ventricular assist systems
(LVASs), 87. See also
HeartMate II LVAS
Legally authorized representative
(LAR), in informed consent
documents, 38
Length of time, for medical device
development, 115
Lesion types, in LACI study, 83–84
Literature review
for clinical studies, 9–10
in clinical trial design, 3
in EU medical device regulations,
159
with ISO 14155-2 standard, 156
Logs, patient screening, 4–5
Losartan, versus captopril, 30–31.
See also OPTIMAAL (OPtimal
Trial in Myocardial Infarction
with the Angiotensin II
Antagonist Losartan) trials
Major adverse cardiac events
(MACE)
in PMA P070015, 186, 188,
189–191
with SPIRIT III 4.0-mm arm,
194–196
Malicious intent, misconduct due to,
99
Management. See Data management;
Study management
Marketing, ISO 14155-1 standard
and, 149
Marketing applications, in medical
device and drug product
approval, 118
Masking, 214
in clinical protocols, 12–14
in medical device versus drug trial
designs, 122
Mathematical transformations, in
statistical analysis plan, 16
Mean, 214
in clinical research, 26
Measurements, in statistical analysis
plan, 16
Mechanisms of action, medical
device versus drug, 113, 114
MEDDEV (medical device)
guidelines, ISO 14155-1
standard and, 149, 150–151
MedDRA (Medical Dictionary for
Regulatory Activities) system,
66
Median, in clinical research, 26
Medical care, bioethics and, 201
Medical device clinical trials, control
groups for, 73
Medical device industry, challenges
facing, 2
Medical devices
classification of, 114, 119, 137–138,
158
clinical trial regulations for,
112–113
combined with drugs, 126–129
defined, 113
European Union regulation of,
137–138
FDA regulation of, 115
FDA standards for, 107–108,
109–111
global trials of, 138–142
investigational product
applications for, 115–118
ISO 14155-2 standard for, 156–157
ISO 14155 standard for, 148–157
mechanisms of action of, 113, 114
pathways to product approval for,
115–121
in PMA P970029, 164–165
INDEX
regulation of development of,
107–135
trial design for, 121–124
where to report misconduct
related to, 105
Medical Devices Directive (MDD),
137, 159
Medical Management (MM)
patients, in PMA P970029,
167–173
Medical practice, FDA and, 121
Medicare, clinical studies budgets
and, 8
Medication errors, as protocol
deviations, 67
Medications, in LACI study, 81
MEDWATCH (MedWatch) system,
65–66
Meta-analysis studies, 214
criteria for using, 56–57
critical literature review and, 10
Mild adverse events, 63
Misbranding, in medical device and
drug product approval, 121
Misconceptions, in statistical analysis
plan, 17
Misconduct
in clinical trials, 99–105
in data management, 59
defined, 100–101
detecting, correcting, and
preventing, 100
handling claims of, 103–104
reporting research, 104–105
this book and, xiv
tips for detecting serious, 102
Missing data
avoidance of, 60
in detecting misconduct, 102
handling, 60
in SPIRIT trial, 193
in statistical analysis plan, 16
Missing data analysis, 59–60
Moderate adverse events, 63
Monitoring, in bioethics, 200
237
Monitoring investigations, in medical
device versus drug trial designs,
123
Monitors. See also Bioresearch
monitoring information system
(BMIS); Data Monitoring
Safety Board
in detecting misconduct, 102
with ISO 14155-1 standard, 154,
155
in medical device versus drug trial
designs, 122–123
Morbidity, in PMA P970029, 172, 173
Moricizine, 24
Mortality, in PMA P970029, 172, 173
Multicenter studies, of CardioWest
TAH-t, 93
Multicenter trials, budgets for, 8
Multinational clinical trials,
reporting adverse events and, 66
Multiple databases, with historic
controls, 96
Multiple subgroup testing, 35
Multiple testing problem, in
subgroup analysis, 51–52, 53
Multivariate analysis, of data across
study sites, 61
Mutual recognition agreement
(MRA), 214
Myocardial infarction (MI), 22–23,
24. See also OPTIMAAL
(OPtimal Trial in Myocardial
Infarction with the Angiotensin
II Antagonist Losartan) trials
aspirin and, 52
in women, 54, 55
NASCET® (North American
Symptomatic Carotid
Endarterectomy Trial), PMA
P040012 and, 176
National Commission for the
Protection of Human Subjects
of Biomedical and Behavioral
Research, 205
238
INDEX
National Formulary, in drug versus
medical device definitions, 113
National Institutes of Health (NIH),
BARI trial and, 51
National Research Act
bioethics in, 199
ethical guidelines and principles
in, 204
New drug application (NDA), 214
New York Heart Association
(NYHA), in HeartMate II
LVAS study, 89–90
No blind studies, 13
Noninferiority, defined, 30
Noninferiority margin (M), in
noninferiority trials, 32–33
Noninferiority trial design, 75, 77,
214
Noninferiority trials
defined, 30
selecting noninferiority margin
for, 32–33
superiority trials versus, 30
Nonmedical persons, as investigators,
6–7
Nonrandomized concurrent control,
in medical device clinical trials,
73
Nonrandomized design
of CardioWest TAH-t study, 93
of LACI study, 86
Non-significant risk (NSR) devices,
determination of, 111–112
Normal distribution, in statistical
analysis plan, 17
Normalization, in statistical analysis
plan, 16, 17
Notification of Intent to Market
New Device, in medical device
and drug product approval, 119
Notified body (NOBO), 214
in CE marking, 146–147, 158
Nuremberg Code, 35, 42
ethical guidelines and principles
in, 204
Objective performance criteria
(OPC), 78–80
advantages and disadvantages of,
79
described, 78, 80
determining, 79–80
FDA and, 78, 79
in FDA PMA cases, 163
historic controls and, 97
for PMA P040012, 175, 176
in using historic controls, 72
when to use and not to use, 78–79
Observational study, 214
Odds ratio (O.R.), in clinical
research, 27
Office for Human Research
Protections (OHRB), accessing
clinical trial records by, 58
Office of Combination Products
(OCP), drug/device combination
products and, 127
“Off-label” devices, 121, 214
in adverse event reporting, 69
Open-label clinical trial, 214
OPTIMAAL (OPtimal Trial in
Myocardial Infarction with the
Angiotensin II Antagonist
Losartan) trials, 30–31
Ordinal measurement scales, in
statistical analysis plan, 16
OTW (over-the-wire)
ACCULINKTM Carotid Stent
System, 175, 181, 184
Outcome measure information,
precision of, 29
Outcomes. See also Primary
outcomes; Secondary outcomes;
Study outcomes
from CardioWest TAH-t study, 95
from LACI study, 84–85, 86
from PMA P070015, 191
from SPIRIT III 4.0-mm arm,
196
Outcome tables, in clinical research,
29
INDEX
Outcome variables, in statistical
analysis plan, 16
Outline, for statistical analysis plan,
11–12
Panel review, in medical device and
drug product approval, 118
Parallel trial design, 75–76
Parameters, in statistical analysis
plan, 18
Parametric tests, in statistical
analysis plan, 17
Pathology endpoints, 21–22
Patient demographics, in HeartMate
II LVAS study, 90
Patient enrollment, enhancing via
study criteria relaxation, 45–46.
See also Subject enrollment
Patient outcomes, in HeartMate II
LVAS study, 91–92
Patient population
for CardioWest TAH-t study,
94–95
in clinical trial design, 2
with global clinical trials, 139
in HeartMate II LVAS study,
89–90
with historic controls, 96–97
for LACI study, 80
in missing data analysis, 60
in PMA P970029, 163
Patients. See also Enrolled subjects;
Subject entries
in ARCHeR studies, 182–183
bioethics and, 199–200
in CardioWest TAH-t study, 93–94
control groups and, 73
in HeartMate II clinical study,
88–89
historic controls and, 96
institutional review boards and,
206–210
in LACI study, 81, 83–84, 85–86
and masking/blinding in clinical
protocols, 12–14
239
in PMA P070015, 190
in PMA P970029, 164–173
of SPIRIT III 4.0-mm arm, 194
selection for studies, 3–5
terms and conditions for enrolling,
8–9
Patient screening log, 4–5
Patient withdrawals, missing data
resulting from, 60
Payment, terms and conditions for,
9. See also Budgeting; Budgets;
Costs; Financial disclosure
entries; Funds
Peer-reviewed journals, critical
literature review and, 10
Percentages, in outcome tables, 29
Percent change, in clinical research,
27
Percutaneous transluminal
angioplasty (PTA), in LACI
study, 82, 83
Performance data, for 510(K)
medical devices, 110
Per-protocol (PP) analysis, 214–215
in study management, 49–50
Personnel
BIMO inspections and, 131–132
bioethics and, 201
in clinical trial design, 3
in completing study protocols,
19–20
in detecting misconduct, 102
developing clinical SOPs and, 3
fraud by, 101
in fraud prevention, 103
good clinical practices and, 202
Pharmaceutical companies, in study
management, 44
Pharmaceutical industry, challenges
facing, 2
Pharmacokinetics, 215
Phase I–III trials, for drugs, 121
Pivotal trial designs
commonly used, 75–77
in PMA P070015, 187–188
240
INDEX
Pivotal trials, patient selection for, 4
Placebo, in noninferiority trials, 30
Placebo effect, 215
Placebo groups, in medical device
clinical trials, 73, 74
Planned criteria, in LACI study,
83–84
Planned emergency research, ICF
exemptions for, 41
Planned statistical analyses, in
statistical analysis plan, 18
PMA P040012
ARCHeR trials in, 174, 175
historic controls for, 175–186
study design for, 175
PMA P070015
endpoints of, 186–188
SPIRIT trial designs for, 187, 188,
189, 193
statistical analysis for, 189–197
PMA P970029, 163
adverse events observed in,
167–168
angina improvement in, 169, 172
conclusions drawn from, 173
exercise treadmill testing in,
170–172
inclusion/exclusion criteria for, 165
medical devices in, 164–165
morbidity/mortality in, 172, 173
panel recommendation in, 173
patient enrollment and disposition
in, 167
patient MM to TMR rollover
during, 172–173
potential adverse events in, 169,
170
primary objective of, 165–166
purpose of, 164
quality of life and, 169–170
safety and effectiveness results of,
171
study design for, 164–165
study overview, 165
treatment failure in, 166, 172
Policies
on handling misconduct claims,
103–104
US ethical, 205
Pooling, of historical data, 78
Post hoc analysis, skepticism of, 55
Practice of medicine, FDA and, 121
Precision, of outcome measure
information, 29
Pre-clinical regulations, medical
device versus drug, 113
Predicate “creep,” in medical device
regulation, 112
Predicate device information, for
510(K) medical devices, 109, 111
Premarket approval (PMA). See also
FDA PMA cases
for 510(K) medical devices, 110,
118–120
in medical device and drug
product approval, 118–120
in medical device regulation, 112
of medical devices, 114
Premarket notification submissions,
for 510(K) medical devices,
108–111
Premarket phase, FDA–sponsor
meetings during, 129–130
Previous research experience, in
investigator selection, 5–6
Primary effectiveness endpoint, in
LACI study, 80, 85–86
Primary endpoint results
from SPIRIT III 4.0-mm arm, 195,
196
in PMA P070015, 191
of SPIRIT III 4.0-mm arm, 194, 196
Primary endpoints. See also
Endpoints; Primary outcomes
in CardioWest TAH-t study, 94,
95–96
in FDA PMA cases, 163
in PMA P070015, 186–188
Primary hypothesis, in clinical
research, 26
INDEX
Primary jurisdiction, for drug/device
combination products, 127, 128
Primary mode of action (PMOA)
standard, for drug/device
combination products, 127, 128
Primary objectives
of ARCHeR studies, 176–177
of CardioWest TAH-t study, 93
of HeartMate II clinical study, 88,
90
of HeartMate II LVAS study, 90
of PMA P970029, 165–166
Primary outcomes
CE mark versus FDA, 15
changing during studies, 20–22
of clinical studies, 14
defined, 22
in statistical analysis plan, 17,
18–19
in subgroup analysis, 53
Primary safety endpoint, in LACI
study, 80
Principal investigator (PI)
in adverse event awareness, 62
bioethics and, 200, 201
and clinical trial fraud and
misconduct, 100
clinical trials initiated by, 132–135
in detecting misconduct, 102
good clinical practices and, 202
in informed consent documents,
38
with ISO 14155-1 standard, 153–
154, 154–155
in medical device versus drug trial
designs, 122, 124
reporting of protocol deviations
by, 68
in research contracts, 7
study subject re-consenting and,
40
timing of adverse events and,
64–65
Principles, World Health
Organization GCP, 202–203
241
Privacy
bioethics and, 200
institutional review boards and, 209
Privacy of data, in data management,
58
Procedural success
in PMA P070015, 189–191
with SPIRIT III 4.0-mm arm,
194–196
Procedure changes, as protocol
deviations, 67
Procedure-related adverse events,
reporting, 29
Procedures, in statistical analysis
plan, 18
Product approval, pathways to,
115–121
Products, WHO GCP principles and,
203
Product types, medical device versus
drug, 113
PRoFess trial, noninferiority margin
for, 33
Prospective studies, of HeartMate II
LVAS, 88–89
Protocol compliance,
implementations of, 46
Protocol deviation reports, 67, 68
Protocol deviations/violations
adverse event coding systems and,
66–67
data accuracy/completeness
associated with, 47
examples of, 67–68
reporting, 68
Protocol procedural steps, deleting,
45–46
Protocols, 215. See also Clinical
protocols; Study protocols
in adverse event awareness, 62
for anticipated adverse events, 63
bioethics and, 201
with foreign clinical sites, 144
good clinical practices and, 202
in WHO GCP principles, 203
242
INDEX
PTCA interventions, PMA P970029
and, 165, 166
Publication policy
critical literature review and,
9–10
in research contracts, 8, 9
Pulmonary artery diastolic (PAD)
pressure, in HeartMate II LVAS
study, 90
Pulmonary capillary wedge pressure
(PCWP), in HeartMate II LVAS
study, 89–90
p–value (probability value), 215.
See also Significance levels
in clinical research, 26, 27–28
in statistical analysis plan, 19
in subgroup analysis, 34, 35, 55
Quality, of data, 55–56
Quality assurance
in data management, 58–59
WHO GCP principles and, 203
Quality of life
in HeartMate II LVAS study, 92
in PMA P970029, 169–170
Randomization
advantages and disadvantages of,
74–75
in bias minimization, 70
with historic controls, 96
in LACI study, 81–82
in medical device clinical trials, 73
in medical device versus drug trial
designs, 122
meta-analysis studies and, 56
in pivotal trial designs, 75–77
in PMA P970029 patient MM to
TMR rollover, 172–173
in statistical analysis plan, 16–17
in subgroup analysis, 53
Randomized clinical trials (RCTs),
historic controls and, 71–73.
See also TAXUS RCT trial
design
Randomized control clinical trials,
advantages and disadvantages
of, 74–75
Randomized trial, 215
Raw data, in clinical trial
management, 47
Readability, of informed consent
documents, 37
Recommendations, for study
management, 44
Re-consenting study subjects, 40
Record retention, in medical device
versus drug trial designs, 124
Records
access to, 57–58
fraud identified via, 102
good clinical practices and, 202
WHO GCP principles and, 203
Records inspection, in medical
device versus drug trial designs,
125
Regional ethical issues, of global
clinical trials, 140–141
Regression analysis, of data across
study sites, 61
Regulation. See also Code of
Federal Regulations (CFR);
Regulations
of drug/device combination
products, 128
of EU medical devices, 137–138,
157–158, 158–159
of global clinical trials, 140–141
of investigator-initiated clinical
trials, 132–133
of medical device development,
107–135
of medical practice, 121
Regulations. See also Regulation
medical device classification
related to, 114
medical device versus drug, 113
for medical devices, 108
in medical practice, 121
this book and, xiv
INDEX
US and EU, 144
US ethical, 205
Regulatory agencies
accessing clinical trial records by,
57–58
in adverse event reporting, 69
Regulatory challenges, to using
historic controls, 71–72
Regulatory clearance, under ISO
14155-1 standard, 151–152
Regulatory guidelines
for CE mark studies, 160
compliance with, 2
Regulatory knowledge, misconduct
related to, 99
Regulatory trends, in foreign clinical
trials, 145–146
Reimbursement, subject, 7, 8, 9
Relaxation of study criteria,
enhancing patient enrollment
via, 45–46
Renin-Angiotensin system (RAS),
30
Report forms, terms and conditions
for, 8–9
Reporting
of adverse events, 65–66
of adverse event timing, 64–65
of protocol deviations/violations,
67, 68
of subgroup analyses, 54
Reports, good clinical practices and,
202
Representatives, in CE marking,
147
Reproducible clinical research,
criteria for, 47
Requirements
for CE mark devices, 161
in CE marking, 146–147
for CE mark studies, 160
in EU medical device regulations,
158–159
under ISO 14155-1 standard,
151–152
243
Research and development. See also
Clinical research; Reproducible
clinical research
bioethics in, 199–210
clinical trials in, 43
global clinical trials and, 141–142
meta-analysis studies in, 56–57
study protocol compliance in, 46
Research contracts
challenges to, 7, 8
in clinical trial design, 2
defined, 7–8
Researchers, this book and, xiii,
xiv–xv
Research experience, in investigator
selection, 5–6
Research misconduct, reporting,
104–105
Resolution, of adverse events, 63
Respect, as WHO GCP principle,
203
Responsibilities
in clinical trial design, 3
good clinical practices and
investigator, 202
of institutional review boards,
205–206
Restricting procedural steps,
deleting, 45–46
Revascularization, 22–23. See also
BARI (Bypass Angioplasty
Revascularization Investigation)
trial
Review, of severe and serious
adverse events, 64
Review of literature, for clinical
studies, 9–10
Risk, in drug versus medical device
definitions, 113. See also Risks
Risk/benefit analysis
bioethics and, 200
in clinical trial design, 3, 41–42
WHO GCP principles and, 203
Risk mitigation, in clinical trial
design, 3
244
INDEX
Risks. See also Cardiac risk factors
bioethics and, 200
in clinical trial design, 3
critical literature review and, 10
with foreign clinical trials, 145–146
institutional review boards and,
208–209
WHO GCP principles and, 203
Rows, in outcome tables, 29
RX (rapid exchange) ACCULINKTM
Carotid Stent System, 86, 174
in PMA P040012 study, 175, 176,
177, 181, 184, 186
RX (rapid exchange) ACCUNETTM
Embolic Protection System, 163,
175, 176
Safeguard clause, 215
Safety
in ARCHeR studies, 183–184
bioethics and, 200
in HeartMate II clinical study, 88
in PMA P970029, 171
Safety determination, for CE mark
studies, 161
Safety parameters, in CardioWest
TAH-t study, 93
Sample size determination, of
clinical studies, 24–25
Sample sizes
with ISO 14155-2 standard, 157
reducing, 25
SAPPHIRE® trial, PMA P040012
and, 176
Scale, reporting, 28
Scientific challenges, to using historic
controls, 71–72
Scientists, in global clinical trials, 141–
142. See also Clinical scientists
Screening logs, for patients, 4–5
Secondary endpoints. See Secondary
outcomes
Secondary objectives
in HeartMate II clinical study, 88
of PMA P970029, 165–166
Secondary outcomes
changing during studies, 21
of clinical studies, 14
defined, 22
in statistical analysis plan, 17, 18–19
Sensitive information, institutional
review boards and, 209–210
Sensitivity analysis, of missing data,
60
Sequential trial design, 75, 76
Serious adverse events. See also
Severe adverse events (SAEs)
in ARCHeR studies, 177–181
ISO 14155-1 standard and,
149–150
reporting, 29, 62–63
review of, 64
severe adverse events versus, 63
Seriousness, of adverse events, 62–63
Serious protocol deviations/
violations, adverse event coding
systems and, 66–67
Severe adverse events (SAEs), 63.
See also Serious adverse events
good clinical practices and, 202
with ISO 14155-1 standard, 155
with ISO 14155-2 standard, 157
review of, 64
serious adverse events versus, 63
Severity, of adverse events, 63
“Short form,” signatures on, 41
“Short form” consent process, 39
Signatures
fraud identified via, 102
on informed consent documents,
38, 41
Significance, in clinical research, 26,
28
Significance levels, in statistical
analysis plan, 17, 19
Significant risk (SR) devices,
classification as, 112
Significant treatment effects,
detecting in subgroup analysis,
54, 55
INDEX
Single blind studies, 13
Site data, fraud identified via, 102
Site differences, in bias minimization,
70
Site preparation, for BIMO
inspections, 131–132
Sloppiness, misconduct due to, 99
Soft endpoints, 21–22
Source documents
for adverse events, 63–64
in detecting misconduct, 102
in study management, 49
Source records, fraud identified via,
102
SPIRIT III 4.0-mm arm, 193–197
summary of, 197
SPIRIT III RCT trial, summary of,
193
SPIRIT trial designs, in PMA
P070015, 187, 188, 189, 193
Sponsor information, for 510(K)
medical devices, 109
Sponsors
accessing clinical trial records by,
57–58
bioethics and, 200, 201
in CE marking, 147
in changing primary outcomes, 20,
21
clinical studies budgets and, 8
in clinical trial design, 2
and clinical trial fraud and
misconduct, 99–100
in completing study protocols, 19
critical literature review and, 9–10
developing clinical SOPs and, 3
in drug/device product
development, 130, 131–132
FDA meetings with, 129–130
in FDA PMA cases, 163
foreign clinical sites and, 143
in fraud prevention, 103
global clinical trials and, 138–142
historic controls and, 97
indemnification by, 9
245
insurance carried by, 9
of investigator-initiated clinical
trials, 132–133
in investigator selection, 5–6
with ISO 14155-1 standard, 154,
155
of LACI study, 84, 85–86
medical device regulations and,
108
in medical device versus drug trial
designs, 122, 123–124
study subject re-consenting and,
40
timing of adverse events and, 64,
65
using historic controls and, 72
Sponsor site preparation, for BIMO
inspections, 131–132
SPORTIF trials, noninferiority
margin for, 33
Staff. See Personnel
Standard deviation (SD), 216
in clinical research, 26
Standard error (SE), 216
Standardization, bias minimization
via, 69–70
Standard of care, with historic
controls, 97
Standard operating procedures
(SOPs)
in clinical trial design, 2
development of clinical, 3
ISO 14155-1 standard and, 151
Standards
for global clinical trials, 139
for medical devices, 107–108,
109–111
Standards of care, 215
Statement of similarity, in medical
device and drug product
approval, 119
Statistical adjustments, in statistical
analysis plan, 16–17
Statistical analysis, in subgroup
analysis, 54
246
INDEX
Statistical analysis plan (SAP)
challenges to designing, 11–12
in clinical trial design, 2–3
components of, 17–19
data quality in, 56
p–value in, 19
requirements of, 18–19
study endpoints and, 15–17
this book and, xiv
Statistical inferences, in statistical
analysis plan, 16–17
Statistical methods
in clinical trials, 44
multiple testing problem and,
51–52, 53
power of, 52
in statistical analysis plan, 17
in subgroup analysis, 53, 54
Statistical power problem, in
subgroup analysis, 52
Statistical significance, 216
Statistical terminology, to define
endpoint measurements, 25–28
Statistical tests
randomization and, 74
in statistical analysis plan, 16
in subgroup analysis, 34, 53, 54
Statisticians, in completing study
protocols, 20
Statistics, with ISO 14155-2 standard,
157
Stent thrombosis, in PMA P070015,
192
Stent thrombosis levels of evidence,
in PMA P070015, 187
Strategies
for drug/device combination
product development, 127–128
in statistical analysis plan, 17
Stratification, 216
Stratification factors, in statistical
analysis plan, 16–17
Structured document template, for
statistical analysis plan, 11
Students, this book and, xiii
Study centers, in clinical trial design,
2
Study committees, in bias
minimization, 70
Study completion, terms and
conditions for, 8–9
Study core laboratory, in bias
minimization, 70
Study data, managing, 58–59
Study design, of CardioWest TAH-t
study, 93
Study endpoints, 215. See also
Endpoints
challenges to selecting, 11–12,
14–15
in clinical trial design, 2, 3, 4
describing, 21–22
features and characteristics of, 14
statistical analysis plan and, 15–17
Study management
application integrity policy in, 48
challenges to, 43–70
data accuracy/completeness in, 47
data audits in, 48
integrity holds in, 48
issues in, 43–44
recommendations for, 44
Study outcomes
historic controls and, 77
missing data analysis and, 59
Study power, in missing data
analysis, 59
Study procedures, adverse events
and, 63
Study products
adverse events and, 63
challenges to designing, 11–12
Study protocols. See also Clinical
protocols
in CardioWest TAH-t study,
93–94
in clinical research, 26–28
compliance with, 46
responsibilities of clinical
personnel in, 19–20
INDEX
Study sites
in adverse event awareness, 62
budgeting key items at, 133–134
CE mark, 160
conducting global clinical trials in,
143–145
contract sign-off at, 134–135
examining data across, 60–62
FDA recommendations on
acceptance of foreign, 143
selection for studies, 3, 5–7
Study source documents, in study
management, 49
Study statisticians, in completing
study protocols, 20
Study subjects. See Enrolled
subjects
Study teams, in completing study
protocols, 20
Subgroup analysis, 33–35, 216.
See also Subgroup/subset
analyses
a priori definition of, 53, 54
challenging issues due to, 55
interpreting, 54–55
logistics of, 35
points to consider for, 53
problems with, 51–55
reporting, 54
in study management, 44, 51
Subgroups/subsets
appropriately defined, 52
in statistical analysis plan, 18
Subgroup/subset analyses, in
statistical analysis plan, 18
Subject enrollment. See also
Enrolled subjects
enhancing via study criteria
relaxation, 45–46
in LACI study, 81
in medical device versus drug trial
designs, 121
for PMA P970029, 167
protocol deviations in, 67
terms and conditions for, 8–9
247
Subject injury, in research contracts,
8, 9
Subject injury reimbursement plan,
in research contracts, 7, 8, 9
Subjectivity
in FDA PMA cases, 163
and masking/blinding in clinical
protocols, 13–14
Subject reimbursement, in clinical
studies, 8
Subject replacement, terms and
conditions for, 8–9
Subject reporting, and masking/
blinding in clinical protocols, 13
Substantial equivalence
for 510(K) medical devices, 108,
109, 110–111
in medical device and drug
product approval, 119, 120
Substantive information
requirements, for 510(K)
medical devices, 109
Suggestive treatment effects,
detecting in subgroup analysis,
54
Summary data
for 510(K) medical devices, 110,
119–120
in subgroup analysis, 54
Superiority, defined, 30
Superiority trials, 30–33, 77
Supporting evidence, critical
literature review and, 10
Surrogate endpoints, 23–25, 216
examples of, 23
in FDA PMA cases, 163
problems with, 24–25
Surveillance authorities, 215
SynCardia Systems, Inc., 96
System Organ Class (SOC)
terminology, adverse event
coding systems and, 66
TARGET4 trial, noninferiority
margin for, 32–33
248
INDEX
Target lesion revascularization
(TLR), in PMA P070015, 186,
188
Target vessel failure (TVF), in PMA
P070015, 186, 188, 189, 191
Target vessel revascularization
(TVR), in PMA P070015, 186,
188
TASC types, in LACI study, 83.
See also Transatlantic Inner
Societal Consensus (TASC)
TAXUS RCT trial design, PMA
P070015 and, 188, 189, 190, 191,
192, 193, 194, 195, 196, 197.
See also Randomized clinical
trials (RCTs)
Technical file (TF), 214
Technology
in global clinical trials, 142
in medical device versus drug trial
designs, 122
Terminology
for adverse event coding systems,
66
to define endpoint measurements,
25–28
Term of study, for CardioWest
TAH-t study, 94
Test groups, in medical device
clinical trials, 73
Tests
in clinical research, 26, 27
in statistical analysis plan, 16, 17
Therapeutic effects, detecting in
subgroup analysis, 54
Thrombosis, in PMA P070015, 192
Time to clearance, in medical device
and drug product approval, 118
Time to event, in statistical analysis
plan, 16
Time to market
in medical device and
pharmaceutical industries, 2
medical device development and,
115
Time to transplant/death, in
CardioWest TAH-t study, 95
Timing
of adverse events, 64–65
of FDA–sponsor meetings,
129–130
Tirofiban, noninferiority margin for,
32–33
TMR 2000 Holmium Laser System,
in PMA P970029, 164–165, 167.
See also Transmyocardial laser
revascularization (TMR)
Total artificial heart (TAH) devices,
80, 87. See also CardioWest total
artificial heart
Toxicities, study subject
re-consenting and, 40
Traditional clinical practices, in
global clinical trials, 140
Training, in data management, 58
Transatlantic Inner Societal
Consensus (TASC), on LACI
study, 81, 82, 83
Transmyocardial laser
revascularization (TMR), xiv
in PMA P970029, 164, 165, 166,
167, 168, 169, 170, 171, 172, 173
Treadmill testing, in PMA P970029,
170–172
Treatment
bioethics in, 200
in LACI study, 80
Treatment allocation, principles of,
75
Treatment decisions, and masking/
blinding in clinical protocols,
13–14
Treatment failure, in PMA P970029,
166, 172
Treatment options, in subgroup
analysis, 52
Treatment procedures, in
CardioWest TAH-t study, 94
Trial data, in changing primary
outcomes, 20–21
INDEX
Trial design
commonly used types of, 75–77
historic controls and, 71–73
medical device versus drug,
121–124
in subgroup analysis, 52
Trial outcomes, in CardioWest
TAH-t study, 95
Trial records, access to, 57–58
Trials. See Clinical trials
Triple blind studies, 13
t-test, 216
Two-tailed t-test, 216
Type 2 diabetes. See CARDS
(Collaborative Atorvastatin
Diabetes Study)
Unanticipated adverse device effects
(UADEs, UDAEs), 63
in medical device versus drug trial
designs, 124
ISO 14155-1 standard and, 150
timing of adverse events and, 64–65
Unfavorable anatomic conditions, in
ARCHeR studies, 183
United States. See also Food and
Drug Administration (FDA);
National entries; US entries
ACCULINKTM trials in, 175
CE mark studies versus those in,
15
clinical data storage in, 56
ethical regulations and policies of,
205
European Union versus, 45–46, 69,
137–138, 144–145, 157–160
foreign clinical sites and, 144–145
pivotal PMA P070015 trial designs
in, 187–188
submitting false/fraudulent
payment claims to, 102–103
Units
in outcome measure information,
29
US versus EU, 144–145
249
UNOS IA/IB studies, of HeartMate
II LVAS, 88–89, 90
Unrelated adverse events, reporting,
29–30
US Department of Health and
Human Service, on foreign
clinical sites, 143. See also
United States
US Homeopathic Pharmacopoeia, in
drug versus medical device
definitions, 113
US Pharmacopoeia, in drug versus
medical device definitions, 113
Validation
in data management, 58
of historic controls, 79
with historic controls, 96
Valid statistical tests, randomization
and, 74
Variance, in clinical research, 26
Variation of data, across study sites,
60–62
Ventricular arrhythmia, 24
Ventricular assist devices (VADs),
87
Violations, in CE marking, 148
Violations of protocol, adverse event
coding systems and, 66–67
Violations reports, adverse event
coding systems and, 67
Volume information, in medical
device and drug product
approval, 118
Vulnerable subjects, consenting by,
40–41
Waivers, of informed consent form,
36–37
Websites
on medical device versus drug
trial designs, 126
for reporting misconduct, 104–105
Weighted evidence, critical literature
review and, 10
250
INDEX
Weighted historic control (WHC),
PMA P040012 and, 176
Whistleblowers
in detecting misconduct, 102
false payment claims exposed by,
103
Witnesses, in informed consent
process, 39
Women, myocardial infarction in, 54,
55
World Health Organization (WHO),
good clinical practices and,
202–203
XIENCE VTM Everolimus Eluting
Coronary Stent System, clinical
trial of, 186–197
YAG laser, in PMA P970029,
164–165