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ClinicalTrials: Design, Conduct and Analysis 2nd Revised edition [Kietas viršelis]

4.33/5 (3 ratings by Goodreads)
(Professor, Epidemiology and Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Sleepy Eye, MN)
  • Formatas: Hardback, 720 pages, aukštis x plotis x storis: 254x180x41 mm, weight: 1406 g, 20 line art
  • Serija: Monographs in Epidemiology and Biostatistics
  • Išleidimo metai: 19-Apr-2012
  • Leidėjas: Oxford University Press Inc
  • ISBN-10: 0195387880
  • ISBN-13: 9780195387889
Kitos knygos pagal šią temą:
ClinicalTrials: Design, Conduct and Analysis 2nd Revised editionDidesnis paveikslėlis
  • Formatas: Hardback, 720 pages, aukštis x plotis x storis: 254x180x41 mm, weight: 1406 g, 20 line art
  • Serija: Monographs in Epidemiology and Biostatistics
  • Išleidimo metai: 19-Apr-2012
  • Leidėjas: Oxford University Press Inc
  • ISBN-10: 0195387880
  • ISBN-13: 9780195387889
Kitos knygos pagal šią temą:
Pastovi nuoroda: https://www.kriso.lt/db/9780195387889.html
Raktažodžiai:
First published in 1986, this landmark text is the definitive guide to clinical trials, written by one of the leading experts in the field. This fully-updated second edition continues to be the most authoritative reference text on randomized clinical trials. It contains a wealth of practical information on the design, conduct, and analysis of both single center and multicenter trials. No other book on clinical trials offers as much detail on such issues as sample size calculation, stratification and randomization, data systems design, development of consent forms, publication policies, preparation of funding requests, and reporting procedures.

While the basics of design, conduct, and analysis of clinical trials remain the same, there have been significant changes since the first edition of Clinical Trials was published two decades ago. In this new edition, the author discusses the refinements and improvements made to methods and procedures, changes in the policies and guidelines underlying trials, as well as requirements for registration of trials. He also discusses current practices for data sharing, for gender representation, for treatment effects monitoring, and for ethical standards of clinical trials. The importance of the randomized controlled trial has grown significantly over time and they are now the cornerstone of all evidence-based medicine. Still rich in tables, checklists, charts, and other resources for the trialist, the second edition of Clinical Trials is an indispensable reference for clinicians, biostaticians, epidemiologists, and anyone involved in the design and implementation of a clinical trial.

Recenzijos

The most thorough and informative volume on the subject printed so far. In an extremely systematic way most of the pertinent methodological questions are analysed, and thoughtful guidelines provided....A must for all medium size and larger libraries and for those actively involved in clinical trials. * Pain * 'Comprehensive as most others on the topic are not, and thorough in most respects, the book also contains a glossary, many useful summary appendices, and much practical advice. * British Medical Journal * A good reference for many practitioners of clinical trials... This book has many tables and figures representing the actual data from previous clinical trials, which helps maintain interest for the clinical investigator... The bibliography is particularly well done and includes not only the extensive documentation for the text, but also classic statistical papers... This book would serve as a good reference for anyone engaged in designing, implementing, or conducting a clinical trial. * Journal of the American Medical Association * Covers with great thoroughness the design, execution, and reporting of multicenter and single-center uncrossed trials that have a clinical event as endpoint....Both the authors and the publisher are to be congratulated on the skill with which this complex book was put together...Will be the standard for instruction in and evaluation of controlled clinical trials for years to come. * The Lancet * Scarcely any aspect of the design, organization and analysis of clinical trials is neglected....However, the presentation of the material allows it to be a book both for beginners and for readers already familiar with clinical trials. I believe it would be better to buy Dr. Meinert's book than to acquire an elementary test on clinical trials with the hope of filling the gaps from the literature. * Canadian Journal of Public Health * [ The] checklists and examples provide excellent guidance, and the text would be a valuable resource in the library of even the most experienced clinical investigators. * European Organization for Research and Treatment of Cancer * A large amount of practical information on the design, conduct and analysis of both single centre and multi-centre trials is contained in this volume. * Short Book Reviews * Clearly and logically presents material on each stage of a clinical trial, which should be of interest both to practitioners and to a wider statistical audience. * Royal Statistical Society * This book is a practical manual which would be very useful for anyone about to create a clinical trials office...Recommended to specialist clinical trial centres. * Human Psychopharmacology * This book can be safely recommended for people with a keen interest in randomized clinical trials, with an emphasis on parallel groups. I will to use it with pleasure in my work with research and teaching. * Journal of the Norwegian Medical Association, March 2013 *

PART 1 INTRODUCTION
Chapter 1 Introduction
3(9)
1.1 Clinical trial: Definition
3(1)
1.2 History of clinical trials
4(5)
1.2.1 The Book of Daniel diet trial
4(1)
1.2.2 Avicenna
5(1)
1.2.3 Chance observations
5(1)
1.2.4 Smallpox trials of Lady-Mary Wortley-Montagu and Maitland and of Edward Jenner
6(1)
1.2.5 Uncontrolled observations
6(1)
1.2.6 Lind's scurvy trial
6(1)
1.2.7 The advent of placebos and shams as controls
7(1)
1.2.8 Randomization
7(1)
1.2.9 Great Britain and Sir Austin Bradford Hill
8(1)
1.2.10 Multicenter trials
8(1)
1.2.11 Kefauver-Harris 1963 amendments to the FDA Cosmetic Act of 1938
9(1)
1.2.12 Treatment-effects monitoring
9(1)
1.3 Trials today
9(1)
1.4 Terminology: Conventions and definitions
10(1)
1.5 Focus
11(1)
Chapter 2 The language of clinical trials
12(3)
2.1 Introduction
12(1)
2.2 On the language of relativity
12(1)
2.3 Random: The term
13(1)
2.4 The language of the epidemiologist vs the trialist
13(1)
2.5 Terminology: Recommendations and comments
14(1)
Chapter 3 Types and classes of trials
15(4)
3.1 Introduction
15(1)
3.2 Treatment structure
16(1)
3.3 Sample size design
16(1)
3.4 Masking design
16(1)
3.5 Single-center and multicenter trials
16(1)
3.6 Purpose
16(1)
3.7 Treatment modality
17(1)
3.8 Big and simple trials
17(1)
3.9 Industry trials versus academic trials
18(1)
Chapter 4 The state and nature of trials
19(12)
4.1 Introduction
19(1)
4.2 On assessing the state and nature of trials
19(1)
4.3 Published trials
20(2)
4.4 Gender-specific trials
22(4)
4.5 The Cochrane Library
26(1)
4.6 Registration of trials
27(2)
4.7 Registries of trials
29(1)
4.8 Other state measures
30(1)
Chapter 5 The activities of clinical trials
31(8)
5.1 Stages of activities
34(1)
5.2 Division of responsibilities
34(1)
5.3 Impediments to performance of activities
34(2)
5.3.1 Conflict of responsibilities
34(1)
5.3.2 Inadequate organization
35(1)
5.3.3 Overlap of activities
35(1)
5.3.4 Inadequate time for planning and implementation
35(1)
5.3.5 Inadequate funding
36(1)
5.3.6 Maldistribution of funding
36(1)
5.4 Aids to ensuring orderly transition of activities
36(3)
5.4.1 Phased initiation of recruitment and data intake
36(1)
5.4.2 Ensuring adequate organizational structure
36(1)
5.4.3 Opportunities for design modifications in sponsor-initiated trials
36(1)
5.4.4 Certification as a management tool
37(1)
5.4.5 Realistic timetables
37(1)
5.4.6 Ongoing planning and priority assessment
37(1)
5.4.7 Minimizing overlap of activities
37(2)
Chapter 6 Coordinating and other resource centers in multicenter trials
39(9)
6.1 Introduction
39(1)
6.2 Coordinating centers
39(4)
6.2.1 Activities
39(2)
6.2.2 Standing
41(1)
6.2.3 Location
41(1)
6.2.4 Staffing
42(1)
6.2.5 Relative cost
43(1)
6.2.6 Personnel versus "other expenses"
43(1)
6.3 Study chair and office of the study chair
43(1)
6.4 Central laboratories
44(1)
6.5 Reading centers
45(1)
6.6 Project offices
46(1)
6.7 Support centers
46(2)
Chapter 7 Multi-study networks
48(5)
7.1 Introduction
48(1)
7.2 Examples of networks
49(2)
7.3 Advantages and disadvantages
51(1)
7.4 Modes of creation and funding
51(1)
7.5 Organizational structures
51(1)
7.6 Operating structures
52(1)
Chapter 8 Ethical principles and imperatives in clinical trials
53(5)
8.1 Introduction
53(1)
8.2 Medical research codes
53(1)
8.3 Principles of medical ethics in research
54(1)
8.4 The state of clinical equipoise
54(1)
8.5 The ethics of choice of study treatments
55(1)
8.6 The monitoring imperative
56(1)
8.7 The ethics of disclosures for consents and of conflicts of interest
57(1)
Chapter 9 Objectivity versus competency in clinical trials
58(3)
9.1 Introduction
58(1)
9.2 Objectivity constructs and rules
58(1)
9.3 Ethical limits of imposed objectivity constructs
59(2)
PART 2 DESIGN PRINCIPLES AND PRACTICES
61(88)
Chapter 10 Fundamentals of controlled clinical trials
63(5)
10.1 Introduction
63(1)
10.2 Choice of the test and control treatments
63(1)
10.3 Principles in the selection of the outcome measure
64(1)
10.4 Principles of establishing comparable treatment groups
65(1)
10.5 Principles of masking and bias control
66(2)
Chapter 11 Bias
68(6)
11.1 Introduction
68(1)
11.2 Absolute versus relative truth and bias
69(1)
11.3 Selection and representation biases
69(1)
11.4 Treatment-related biases
70(2)
11.4.1 Treatment-related selection bias
70(1)
11.4.2 Treatment-related feedback bias
70(1)
11.4.3 Treatment-related observation and followup bias
71(1)
11.4.4 Treatment-related analysis bias
72(1)
11.5 Indicators of bias
72(1)
11.6 Bias "fix," avoidance, and prevention strategies
73(1)
Chapter 12 Bias control
74(5)
12.1 Introduction
74(1)
12.2 Randomization
74(1)
12.3 Concealment
74(1)
12.4 Masking philosophy of the trialist
75(1)
12.5 Specificity, training, and surveillance
75(1)
12.6 Separation and isolation of functions
76(1)
12.7 Shielding
76(1)
12.8 Results blackouts
76(1)
12.9 Firewalls
77(1)
12.10 Masked treatment-effects monitoring
78(1)
Chapter 13 Variance control
79(4)
13.1 Introduction
79(1)
13.2 Variance control via design
79(2)
13.2.1 Sample size, number of study clinics, and followup time
79(1)
13.2.2 Randomization unit
80(1)
13.2.3 Randomization design
81(1)
13.2.4 Person as own control
81(1)
13.3 Control via patient selection
81(1)
13.4 Control via execution
81(1)
13.5 Control via analysis
82(1)
Chapter 14 The study treatments
83(6)
14.1 Introduction
83(1)
14.2 Study treatments
83(1)
14.3 Test treatments
84(1)
14.4 Control treatments
84(1)
14.5 Treatment designs
85(2)
14.6 The treatment protocol
87(1)
14.7 Treatment changes
87(1)
14.8 Treatment masking
88(1)
Chapter 15 Outcome measures
89(5)
15.1 Introduction
89(1)
15.2 The primary outcome measure
89(1)
15.3 The design variable
90(1)
15.4 The outcome measure and censoring
90(1)
15.5 Death versus cause of death as outcome measures
90(1)
15.6 Clinical events versus change measures as outcomes
91(1)
15.7 Secondary outcome measures
91(1)
15.8 Surrogate outcome measures
91(1)
15.9 Composite outcome measures
92(1)
15.10 Safety measures
92(1)
15.11 Treatment compliance measures
93(1)
Chapter 16 Sample size and power estimates
94(20)
16.1 Fixed versus sequential sample size designs
95(2)
16.2 Sample size and power calculations as planning guides
97(1)
16.3 Specifications for sample size calculations
97(6)
16.3.1 Number of treatment groups
97(1)
16.3.2 Outcome measure
98(1)
16.3.3 Followup period
98(1)
16.3.4 Alternative treatment hypothesis
98(1)
16.3.5 Detectable treatment difference
99(1)
16.3.5.1 Binary outcome measures
99(1)
16.3.5.2 Continuous outcome measures
99(1)
16.3.5.3 Survival outcome measures
99(1)
16.3.6 Error protection
100(1)
16.3.7 Choice of assignment ratio
100(1)
16.3.8 Losses to followup
100(1)
16.3.9 Losses due to treatment noncompliance
101(1)
16.3.10 Treatment lag time
102(1)
16.3.11 Stratification for control of baseline risk factors
102(1)
16.3.12 Degree of type I and II error protection for multiple comparisons
102(1)
16.3.13 Degree of type I and II error protection for multiple looks for safety monitoring
102(1)
16.3.14 Degree of type I and II error protection for multiple outcomes
103(1)
16.4 Sample size formulas
103(5)
16.4.1 Binary outcome measures
103(1)
16.4.1.1 Fisher's exact test
103(1)
16.4.1.2 Chi-square approximation
103(2)
16.4.1.3 Inverse sine transform approximation
105(1)
16.4.1.4 Poisson approximation
105(1)
16.4.2 Continuous outcome measures
106(1)
16.4.2.1 Normal approximation for two independent means
106(1)
16.4.2.2 Normal approximation for mean changes from baseline
106(1)
16.4.3 Survival outcome measures
106(1)
16.4.3.1 Exponential survival model
107(1)
16.4.3.2 Cox proportional hazard model
107(1)
16.5 Power formulas
108(1)
16.5.1 Binary outcome measures
108(1)
16.5.1.1 Fisher's exact test
108(1)
16.5.1.2 Chi-square approximation
108(1)
16.5.1.3 Inverse sine transform approximation
108(1)
16.5.1.4 Poisson approximation
108(1)
16.5.2 Continuous outcome measures
108(1)
16.5.2.1 Normal approximation for comparison of two independent means
108(1)
16.5.2.2 Normal approximation for mean changes from baseline
108(1)
16.5.3 Survival outcome measures
109(1)
16.5.3.1 Exponential survival model
109(1)
16.5.3.2 Cox proportional hazard model
109(1)
16.5.4 Power simulations
109(1)
16.6 Sample size and power calculation illustrations
109(3)
16.6.1 Illustration 1: Sample size calculation using chi-square and inverse sine transform approximation
109(1)
16.6.2 Illustration 2: Sample size calculation using Poisson approximation
110(1)
16.6.3 Illustration 3: Sample size calculation using Coronary Drug Project design specifications
110(1)
16.6.4 Illustration 4: Sample size calculation for blood pressure change
110(1)
16.6.5 Illustration 5: Sample size calculation using Fisher's exact test
111(1)
16.6.6 Illustration 6: Power calculation based on chi-square and inverse sine transform approximation
111(1)
16.6.7 Illustration 7: Power for design specifications given in Illustration 2 for 1,500 patients per treatment group
111(1)
16.6.8 Illustration 8: Power for design specifications given in Illustration 4 for 150 patients per treatment group
112(1)
16.6.9 Illustration 9: Sample size calculation using an exponential survival model with Lachin generalization
112(1)
16.7 Posterior sample size and power assessments
112(1)
16.8 Software for sample size and power calculations
112(2)
Chapter 17 Randomization
114(14)
17.1 Introduction
114(1)
17.2 Adaptive randomization
115(1)
17.3 Fixed randomization
116(4)
17.3.1 Assignment ratio
116(1)
17.3.2 Stratification
117(2)
17.3.3 Blocking
119(1)
17.4 Construction of the randomization schedule
120(4)
17.5 Documentation of the randomization scheme
124(1)
17.6 Administration of the randomization process
124(4)
Chapter 18 Treatment masking
128(7)
18.1 Introduction
128(1)
18.2 Masking credos
128(1)
18.3 Placebo and sham treatments
129(1)
18.4 Mechanics of treatment masking
129(2)
18.5 Bin-numbering versus medication-numbering systems for treatment masking
131(1)
18.6 Labeling and packaging of masked product
131(1)
18.7 Shipping and supply of masked drug
132(1)
18.8 Maintenance of the treatment mask
133(1)
18.9 Other masking
133(1)
18.10 On reporting masking procedures
133(1)
18.11 On misconceptions about masking
134(1)
Chapter 19 The study plan
135(5)
19.1 Introduction
135(1)
19.2 Objective and specific aims
135(1)
19.3 The treatment design
136(1)
19.4 Composition of the study population
137(1)
19.5 The plan for patient enrollment and followup
138(1)
19.6 The plan for close-out of followup
139(1)
Chapter 20 Data collection considerations
140(9)
20.1 Introduction
140(1)
20.2 Data collection principles
140(1)
20.3 Data map and collection schedule
141(2)
20.4 Factors influencing the clinic visit schedule
143(1)
20.4.1 Introduction
143(1)
20.4.2 Screening and baseline visits
143(1)
20.4.3 Followup clinic visit schedule
143(1)
20.4.4 Visit time-limits
144(1)
20.5 Data requirements by type of visit
144(3)
20.5.1 Baseline data
146(1)
20.5.2 Data needed at followup visits
146(1)
20.6 Data system considerations
147(2)
20.6.1 Paper versus electronic data forms
147(1)
20.6.2 Distributed data entry versus centralized data entry
148(1)
20.6.3 Data-harvesting considerations
148(1)
20.6.4 Centralized versus distributed databases
148(1)
PART 3 EXECUTION
149(72)
Chapter 21 Data collection forms
151(13)
21.1 Introduction
151(1)
21.2 Form layout and production
152(4)
21.2.1 Page layout
152(1)
21.2.2 Paper size and weight
152(1)
21.2.3 Print font and form reproduction
152(1)
21.2.4 Location of instructional material
152(1)
21.2.5 Color coding
153(1)
21.2.6 Form reproduction and assembly
153(1)
21.2.7 Arrangement of items on forms
154(1)
21.2.8 Format
154(1)
21.2.8.1 Items designed for unformatted written, replies
154(1)
21.2.8.2 Items requiring formatted written replies
154(1)
21.2.8.3 Items answered by check marks
155(1)
21.2.9 Location of form and patient identifiers
155(1)
21.2.10 Format considerations for data entry
155(1)
21.3 Considerations affecting item construction
156(1)
21.3.1 Explicit versus implicit item forms
156(1)
21.3.2 Interviewer-completed versus patient-completed items
156(1)
21.3.3 Questioning strategy
156(1)
21.3.4 Single- versus multiple-use forms
156(1)
21.4 Item construction
157(5)
21.4.1 General
157(1)
21.4.2 Language and terminology
157(1)
21.4.3 Items from other studies
158(1)
21.4.4 Closed-versus open-form items
158(1)
21.4.5 Response checklists
158(1)
21.4.6 "Unknown," "don't know," and "uncertain" as response options
159(1)
21.4.7 Measurement and calculation items
159(1)
21.4.8 Instruction items
160(1)
21.4.9 Time and date items
160(1)
21.4.10 Birthdate and age items
160(1)
21.4.11 Identifying items
161(1)
21.4.12 Tracer items
161(1)
21.4.13 Reminder and documentation items
161(1)
21.4.14 Data format glitches
162(1)
21.5 Updates and revisions of study forms
162(1)
21.6 Data flow and entry
162(1)
21.7 Types of study forms
163(1)
Chapter 22 Start-up and maintenance procedures
164(13)
22.1 Introduction
164(1)
22.2 The study name and nickname/acronym
164(2)
22.3 Essential documents
166(3)
22.3.1 Study protocol
166(1)
22.3.2 Study handbook and manual of operations
167(1)
22.3.3 Data collection forms
167(1)
22.3.4 Consent and recruitment documents
167(1)
22.3.5 Investigator's brochure
167(2)
22.4 Training and certification
169(1)
22.5 The start-up checklist
169(3)
22.6 Shakedown procedures
172(1)
22.7 Maintenance procedures checklist
173(4)
Chapter 23 Participant recruitment and enrollment
177(9)
23.1 Recruitment goals
177(1)
23.2 Methods of patient recruitment
177(2)
23.3 Troubleshooting
179(1)
23.4 The patient shakedown process
179(1)
23.5 The ethics of recruitment
179(1)
23.6 Patient consent
180(4)
23.6.1 General guidelines
180(1)
23.6.2 The consent process
180(3)
23.6.3 Documentation of the consent
183(1)
23.6.4 What constitutes an informed consent?
183(1)
23.6.5 Maintenance of consents
184(1)
23.7 Co-enrollment
184(1)
23.8 Randomization and initiation of treatment
185(1)
Chapter 24 Patient followup, close-out, and post-trial followup
186(9)
24.1 Introduction
186(1)
24.2 The treatment and followup schedules
186(1)
24.3 Maintenance of investigator interest and commitment
187(1)
24.4 Maintenance of participant interest
188(1)
24.5 The battle for adherence to treatment
188(1)
24.6 Treatment compliance
189(1)
24.7 Losses to followup
189(2)
24.8 Close-out of patient followup
191(2)
24.9 Termination stage
193(1)
24.10 Post-trial followup
193(2)
Chapter 25 Midcourse changes and coping strategies
195(10)
25.1 Introduction
195(1)
25.2 Changes to the study protocol
195(1)
25.3 Changes in entry criteria
196(1)
25.4 Specimen banking
197(1)
25.5 Addition of new test procedures and changes to existing test procedures
198(1)
25.6 Additional data collection forms
198(1)
25.7 Changes to existing data forms
198(1)
25.8 Numbered policy and procedures memoranda
199(1)
25.9 Addition of study clinics
200(1)
25.10 Departures of study clinics
200(1)
25.11 Transfer patients
200(1)
25.12 Midcourse addition or change of coordinating center
200(1)
25.12.1 Adding a coordinating center
200(1)
25.12.2 Relocation of a coordinating center
200(1)
25.12.3 Change of coordinating center
201(1)
25.13 Change of suppliers and service providers
201(1)
25.14 Equipment changes
201(1)
25.15 Consents, reconsents, updates, and deconsents
201(1)
25.16 Clinical holds, early stops, and shutdowns
202(1)
25.16.1 Clinical holds
203(1)
25.16.2 Early stops
203(1)
25.16.3 Shutdowns
203(1)
25.17 Other changes
203(2)
25.17.1 Funding changes
203(1)
25.17.2 Changes in regulations or requirements and guidelines
204(1)
25.17.3 Changes in study governance or leadership
204(1)
Chapter 26 Adverse events (AEs)
205(5)
26.1 Definitions
205(1)
26.2 Data collection and AEs
205(1)
26.3 FDA IND safety reports
206(1)
26.4 Dissemination of safety reports to IRBs
206(1)
26.5 AEs and consent forms
207(1)
26.6 Treatment-effects monitoring committees and AEs
207(1)
26.7 On the shortcomings of trials for detection of AEs
207(2)
26.8 On off-label use and AEs
209(1)
Chapter 27 Quality assurance
210(11)
27.1 Introduction
210(1)
27.2 Data editing
211(2)
27.3 Record auditing
213(1)
27.4 Replication as a quality-assurance measure
213(1)
27.5 Adjudication
214(1)
27.6 Monitoring for secular trends
215(1)
27.7 Data integrity-assurance procedures
216(1)
27.8 Performance monitoring
216(1)
27.9 Site visiting
217(1)
27.10 Quality-control committees and centers
218(1)
27.11 Query resolution
219(2)
PART 4 DATA ANALYSIS
221(72)
Chapter 28 Basic data analysis and counting principles for primary-results publications
223(5)
28.1 Introduction
223(1)
28.2 The primary data analysis principle and counting rules
223(2)
28.3 Intention to treat (ITT)/analysis by assigned treatment
225(1)
28.4 Analysis by administered treatment/per protocol analysis (PPA)
225(1)
28.5 Analysis by treatment assigned versus treatment received
226(1)
28.6 The order principle of analyses
226(1)
28.7 The principle of parsimony
226(1)
28.8 The baseline rule
227(1)
28.9 Analysis do's and don'ts
227(1)
Chapter 29 Study datasets
228(8)
29.1 Introduction
228(1)
29.2 Development and maintenance of the data system
228(1)
29.3 Data security precautions and protections
228(1)
29.4 Data breach protections
229(1)
29.5 Record storage
230(2)
29.5.1 NIH record retention and access policy
231(1)
29.6 The study database and analysis datasets
232(1)
29.7 Data harvests and freezes
232(1)
29.8 Shared and distributed datasets
233(1)
29.9 The final analysis database
233(1)
29.10 Data sharing and public-use datasets
234(2)
Chapter 30 Basic data analysis procedures
236(12)
30.1 Basic analysis requirements
236(1)
30.2 Basic analytic methods
237(4)
30.2.1 Comparisons of proportions
237(1)
30.2.2 Lifetable (survival) analyses
238(1)
30.2.3 Other descriptive methods
239(2)
30.3 Adjustment procedures
241(3)
30.3.1 Subgrouping
241(2)
30.3.2 Multiple regression
243(1)
30.3.2.1 Linear multiple-regression model
243(1)
30.3.2.2 Logistic multiple-regression model
244(1)
30.4 Basic checking routines
244(1)
30.4.1 Cross-checking
244(1)
30.4.2 Recounting
245(1)
30.4.3 Reprogramming
245(1)
30.4.4 Incubation
245(1)
30.4.5 Destructive data analysis
245(1)
30.5 Questionable practices for publication quality analyses
245(3)
30.5.1 Mixed freeze dates
245(1)
30.5.2 Use of "dirty" data
246(1)
30.5.3 Rule violation
246(1)
30.5.4 Overreliance on p-values
246(1)
30.5.5 Haste
246(2)
Chapter 31 Questions concerning the design, analysis, and interpretation of clinical trials
248(14)
31.1 Introduction
248(1)
31.2 Design questions
248(4)
31.3 Study population questions
252(1)
31.4 Randomization questions
253(1)
31.5 Masking questions
254(2)
31.6 Baseline questions
256(1)
31.7 Treatment administration questions
256(1)
31.8 Patient followup questions
257(1)
31.9 Outcome measure questions
258(1)
31.10 Data integrity questions
258(1)
31.11 Data analysis questions
259(2)
31.12 Conclusion questions
261(1)
Chapter 32 Treatment-effects monitoring
262(12)
32.1 Introduction
262(1)
32.2 History
262(1)
32.3 The monitoring imperative
263(1)
32.4 Trials requiring monitoring
264(1)
32.5 Requirements for adequate monitoring
265(1)
32.6 Monitoring schemes
265(1)
32.7 Objectivity constructs
265(3)
32.7.1 Masking
266(1)
32.7.2 Look restrictions
266(1)
32.7.3 Stopping rules and monitoring bounds
267(1)
32.8 The monitoring body
268(1)
32.9 The monitoring report
269(3)
32.10 Communication linkage
272(1)
32.11 Dealing with stop recommendations
272(2)
Chapter 33 Issues in treatment-effects monitoring
274(14)
33.1 Introduction
274(1)
33.2 Policy issues
274(5)
33.3 Procedural and operational issues
279(6)
33.4 Analysis issues
285(3)
Chapter 34 Subgroup analyses
288(5)
34.1 Introduction
288(1)
34.2 The subgrouping variable
288(1)
34.3 Features of proper subgroup analyses
289(1)
34.4 A priori versus post hoc subgroup analyses
290(1)
34.5 Mandated subgroup analyses
290(1)
34.6 Reporting subgroup differences
290(1)
34.7 Finding subgroup differences in published reports
291(1)
34.8 Interpretation and reproducibility of subgroup finding
292(1)
PART 5 ORGANIZATION AND MANAGEMENT
293(52)
Chapter 35 Funding
295(12)
35.1 Introduction
295(1)
35.2 "Do I really want to do this study?"
296(1)
35.3 Funding issues
296(4)
35.3.1 Sponsor-initiated versus investigator-initiated trials
296(1)
35.3.2 Investigator-initiated versus sponsor-initiated funding request
297(1)
35.3.3 Number of tries at funding
297(1)
35.3.4 Permission to apply for funding
297(1)
35.3.5 Acceptance for review
297(1)
35.3.6 Fixed versus cost reimbursement
298(1)
35.3.7 Effort versus funding
298(1)
35.3.8 Fixed versus unit payment modes of funding study clinics
298(1)
35.3.9 Direct versus indirect costs
298(1)
35.3.10 Direct versus indirect distribution of funds to study centers
299(1)
35.3.11 Patient care costs
300(1)
35.3.12 Study liability insurance
300(1)
35.4 RFPs and RFAs
300(1)
35.4.1 Deadlines and review process
300(1)
35.4.2 Factors to consider when deciding whether to respond
300(1)
35.4.3 The response
301(1)
35.5 The study budget
301(4)
35.5.1 Horseback budget estimates
302(1)
35.5.2 The asking budget
302(2)
35.5.3 Budget justification
304(1)
35.5.4 Budget summaries and analyses
305(1)
35.6 Preparation and submission of the funding proposal
305(1)
35.7 Negotiations and award
306(1)
35.8 Administration
306(1)
35.9 The unit cost of trials
306(1)
Chapter 36 Organizational design and structure
307(7)
36.1 Introduction
307(1)
36.2 Symptoms of organizational problems
307(1)
36.3 Organizing questions
308(1)
36.4 Delineation of functions and responsibilities
308(1)
36.5 Separation of roles and functions
309(1)
36.6 Linkages and interactions of organizational bodies
310(1)
36.7 Due process considerations
310(1)
36.8 Communications structures
311(1)
36.9 Other structural and organizational issues
311(3)
36.9.1 Disclosure requirements for conflicts of interest
311(1)
36.9.2 Pay for voting members of the treatment-effects monitoring and advisory-review committees
312(1)
36.9.3 Review and approval of proposed ancillary studies
312(1)
36.9.4 Publication and internal editorial review procedures
313(1)
36.9.5 Publicity and information access policy issues
313(1)
Chapter 37 Study governance
314(10)
37.1 Introduction
314(1)
37.2 Principal investigator
314(1)
37.3 Study chair
315(2)
37.4 Study officers
317(1)
37.5 Executive committee
318(1)
37.6 Steering committee
318(3)
37.7 Steering committee subcommittees
321(1)
37.8 Research group
321(1)
37.9 Treatment-effects monitoring and advisory-review committee
322(2)
Chapter 38 Study organizational structures and meetings
324(9)
38.1 Introduction
324(1)
38.2 Meeting truisms
324(1)
38.3 Parliamentary procedures
325(2)
38.4 Committee creation and specifications
327(1)
38.5 Meeting agendas and materials
328(1)
38.6 Meeting logistics and arrangements
328(2)
38.7 Staff meetings
330(1)
38.8 Study committees
330(3)
38.8.1 Steering committee
330(1)
38.8.2 Executive committee/study officers
331(1)
38.8.3 Treatment-effects monitoring committee
331(1)
38.8.4 Research group
332(1)
Chapter 39 Regulations, requirements, policies, and guidelines
333(12)
39.1 Introduction
333(1)
39.2 IRB review requirements
334(1)
39.3 Investigator IRB training and certification
335(1)
39.4 FDA regulations, requirements, and rules
336(1)
39.5 Registration requirement
336(1)
39.6 Data-sharing requirements
337(1)
39.7 Authorship requirements
337(1)
39.8 Manuscript deposit requirement
337(1)
39.9 Conflict-of-interest disclosure requirements
338(2)
39.10 NIH guidelines on inclusion of women, pregnant women, children, and ethnic minorities
340(1)
39.11 NIH guidelines on treatment-effects monitoring
341(1)
39.12 Other regulations, requirements, policies, and rules
341(3)
39.12.1 Effort certification
341(1)
39.12.2 Office of Management and Budget (OMB) clearance of data collection forms
342(1)
39.12.3 Health Insurance Portability and Accountability (HIPAA) training
342(1)
39.12.4 Summary reports of adverse events to IRBs of trials with treatment-effects monitoring committees
343(1)
39.12.5 The CONSORT guideline
343(1)
39.13 Budding guidelines
344(1)
39.13.1 Gender by treatment subgroup analysis in publications of trials
344(1)
39.13.2 Requirement for systematic review as prelude to IRB approval of proposed trials
344(1)
PART 6 PUBLICATION
345(40)
Chapter 40 The publication imperative
347(3)
40.1 Introduction
347(1)
40.2 The publication imperative
347(1)
40.3 The realities of meeting the publication imperative
348(1)
40.4 The paper chase
349(1)
40.5 Study CVs
349(1)
Chapter 41 Presentation, publication, information, and data access policies
350(11)
41.1 Introduction
350(1)
41.2 Information constraints during conduct
350(1)
41.3 Publication questions
350(3)
41.3.1 When to publish results?
350(1)
41.3.2 Presentation or publication?
351(1)
41.3.3 Where to publish?
352(1)
41.3.4 What to publish?
353(1)
41.3.5 Journal supplements versus regular Issues
353(1)
41.4 Authorship and internal review procedures
353(4)
41.4.1 Individual versus corporate authorship attribution
354(1)
41.4.2 Who to list as authors?
355(1)
41.4.3 Writing responsibilities
356(1)
41.4.4 Credit rosters
356(1)
41.4.5 Internal review procedures
357(1)
41.5 Information access policy issues
357(4)
41.5.1 Password-protected and public study web sites
357(1)
41.5.2 Access to meeting minutes
358(1)
41.5.3 Access to study data
358(1)
41.5.4 Access to study forms and manuals
359(1)
41.5.5 Inquiries from the press
359(1)
41.5.6 Special analyses in response to criticisms
359(1)
41.5.7 Outside audits
360(1)
Chapter 42 Preparation of study publications
361(8)
42.1 Introduction
361(1)
42.2 Preparatory steps
361(1)
42.3 The target journal
361(1)
42.4 Content suggestions
362(5)
42.4.1 Masthead title
362(1)
42.4.2 Authorship attribution
362(1)
42.4.3 Abstract
362(1)
42.4.4 Introduction
362(4)
42.4.5 Methods
366(1)
42.4.6 Results
366(1)
42.4.7 Discussion
366(1)
42.4.8 Conclusion
366(1)
42.4.9 References
366(1)
42.4.10 Credits and acknowledgments
366(1)
42.4.11 Appendices
367(1)
42.5 Internal review and submission
367(1)
42.6 Electronic submissions
367(1)
42.7 Acceptance and publication
368(1)
Chapter 43 Document and report production
369(9)
43.1 Introduction
369(1)
43.2 Production loci
369(1)
43.3 Word processors
369(1)
43.4 Format-robust electronic files
370(1)
43.5 Master documents
370(2)
43.6 Format and code specifications
372(3)
43.7 Tables
375(1)
43.8 Figures
376(1)
43.9 Slides
376(1)
43.10 Maintenance and updates
377(1)
43.11 Storage and archiving
377(1)
Chapter 44 Reading reports of trials
378(7)
44.1 Introduction
378(1)
44.2 Finding relevant publications
378(1)
44.3 Reading order in results papers
379(1)
44.4 Questions and factors to consider when reading
380(3)
44.5 Valid and invalid criticisms
383(1)
44.6 Desirable characteristics of a critic
383(2)
PART 7 MISCELLANEOUS
385(56)
Chapter 45 Scientific integrity
387(8)
45.1 Introduction
387(1)
45.2 Research misconduct
387(1)
45.3 Office of Research Integrity and Office of Regulatory Affairs
388(1)
45.4 Research misconduct and consequences
389(1)
45.5 Reporting and disposition of suspected cases of misconduct
390(1)
45.6 Practices conducive to inducing data fraud
391(1)
45.6.1 Piece payments
391(1)
45.6.2 Threats of funding cuts because of performance
391(1)
45.6.3 Ranking performance
392(1)
45.6.4 Reward systems
392(1)
45.6.5 Harassment by the data center
392(1)
45.7 When is data fraud data fraud?
392(1)
45.8 Findings of data fraud and data purges
392(1)
45.9 Data fraud detection and prevention practices
393(2)
45.9.1 Data audits
393(1)
45.9.2 Audit trails
393(1)
45.9.3 Study site visits
393(1)
45.9.4 Integrity pledge
393(1)
45.9.5 Integrity discussions
393(1)
45.9.6 Data analysis
393(1)
45.9.7 Proscriptions
393(1)
45.9.8 Mindset
394(1)
Chapter 46 Transgressions of trialists
395(4)
46.1 Introduction
395(1)
46.2 Design transgressions
395(1)
46.3 Enrollment transgressions
396(1)
46.4 Execution transgressions
397(1)
46.5 Analysis transgressions
397(1)
46.6 Publication transgressions
398(1)
Chapter 47 Homogeneity versus heterogeneity in trials
399(5)
47.1 Introduction
399(1)
47.2 The homogeneity mindset of the trialist
399(1)
47.3 On reasons to select and exclude in trials
399(1)
47.4 On selection for variance control
400(1)
47.5 The cost of selectivity
401(1)
47.6 On the use of age, gender, and ethnic group for selection
401(2)
47.6.1 Age
402(1)
47.6.2 Gender
402(1)
47.6.3 Ethnic group
402(1)
47.7 On reasons to favor heterogeneity over homogeneity
403(1)
Chapter 48 Meta-analysis
404(4)
48.1 Introduction
404(1)
48.2 Meta-analyses and systematic reviews
404(1)
48.3 Data displays
405(1)
48.4 Finding meta-analyses and systematic reviews
405(1)
48.5 Systematic reviews as preludes to trials
406(1)
48.6 Real-time meta-analyses
406(1)
48.7 Readings
407(1)
Chapter 49 The University Group Diabetes Program (UGDP)
408(16)
49.1 Foreword
408(1)
49.2 Design
409(1)
49.3 History and criticisms
409(5)
49.4 The tolbutamide mortality results
414(2)
49.5 The phenformin mortality results
416(1)
49.6 The insulin results
416(1)
49.7 Conclusion and discussion
417(2)
49.8 "Lesson" vignettes
419(5)
49.8.1 Trust but verify
419(1)
49.8.2 Organized chaos
420(1)
49.8.3 Seek and ye shall find?
420(1)
49.8.4 Who said you can vote?
420(1)
49.8.5 What do you mean, "The visit is missed"?
421(1)
49.8.6 Let's have our cake and eat it too!
421(1)
49.8.7 The heat in the kitchen
421(1)
49.8.8 Moles
421(1)
49.8.9 The "miracle" treatment
422(1)
49.8.10 Mortality: The unspecified outcome
422(1)
49.8.11 The randomization recipe
422(1)
49.8.12 The best two out of three votes
422(1)
49.8.13 Treatment-effects-monitoring
423(1)
Chapter 50 Training trialists
424(4)
50.1 Introduction
424(1)
50.2 The clinical researcher versus the trialist
424(1)
50.3 Training trialists
424(1)
50.4 The academic trialist
425(1)
50.5 The NIH and the CTSA
425(2)
50.6 Short courses and certificate programs
427(1)
50.7 Training the research team
427(1)
50.8 Educating the public about trials
427(1)
Chapter 51 Comparative effectiveness research (CER) and clinical trials
428(4)
51.1 Introduction
428(1)
51.2 Definitions of CER
428(1)
51.3 Features of CER
429(1)
51.4 Efficacy versus pragmatic trials and CER
429(1)
51.5 Observational studies versus randomized trials and CER
430(1)
51.6 Comments
431(1)
Chapter 52 Readings and reference materials
432(9)
52.1 Introduction
432(1)
52.2 Textbooks
432(2)
52.3 Dictionaries, manuals, and encyclopedias
434(1)
52.4 Codes and guidelines
435(1)
52.5 Examples
436(1)
52.6 Other readings
437(1)
52.7 A reading list of a different kind
437(4)
PART 8 APPENDICES
441(158)
Appendix A Glossary of definitions
443(15)
Appendix B Terminology usage and recommendations
458(4)
Appendix C Medical research codes of ethics
462(4)
C.1 The Nuremberg Code
462(1)
C.2 Declaration of Helsinki (Year 2000 version)
463(3)
Appendix D Teaching questions and answers
466(7)
Appendix E Aids for trialists
473(10)
E.1 The "Mother Test" for trialists
473(3)
E.2 The Treatment-Effects Monitoring Manifesto for Multicenter Randomized Trials
476(1)
E.3 Knowledge Assessment Quiz for Clinic Personnel Starting a Trial
477(5)
E.4 Integrity Assurance Form (Johns Hopkins University Center for Clinical Trials)
482(1)
Appendix F Data items and forms illustrations
483(38)
F.1 Item numbering
483(1)
F.2 Items that indicate presence or absence of a finding or condition
484(2)
F.3 Unnecessary words
486(1)
F.4 Double negatives
487(1)
F.5 Compound questions
487(2)
F.6 Comparative evaluations
489(1)
F.7 Inverted meaning of a "yes" reply
490(1)
F.8 Presence versus absence of a condition
490(1)
F.9 Time references
490(2)
F.10 Direction of response
492(1)
F.11 Leading questions
493(1)
F.12 Vertical versus horizontal response lists
494(2)
F.13 Unit specifications
496(2)
F.14 Precision specifications
498(1)
F.15 Calculation items
499(3)
F.16 Instruction items
502(1)
F.17 Age and birthdate items
503(1)
F.18 Reminder and documentation items
504(1)
F.19 Full-page versus two-column layout
505(4)
F.20 Layout for skip items
509(3)
F.21 Instructional information
512(1)
F.22 Unformatted responses
513(1)
F.23 Formatted responses
514(1)
F.24 Layout for check positions
515(3)
F.25 Field designations and precoded responses
518(3)
Appendix G Randomization illustrations
521(8)
G.1 Illustration 1: Restricted randomization using a table of random permutation
521(1)
G.2 Illustration 2: Unblocked assignments using a table of random numbers
521(2)
G.3 Illustration 3: Blocked assignments using the Moses-Oakford algorithm and a table of random numbers
523(1)
G.4 Illustration 4: Stratified and blocked assignments using the Moses-Oakford algorithm and a table of random numbers
523(2)
G.5 Illustration 5: Sample assignment schedule for the Macular Photocoagulation Study
525(1)
G.6 Illustration 6: Double-masked assignment schedule using the Moses-Oakford algorithm and a table of random numbers
526(1)
G.7 Illustration 7: Sample CDP double-masked assignment schedule
527(2)
Appendix H Activities by stage of trial
529(9)
H.I Design
529(1)
H.II Funding
530(1)
H.III Protocol development
530(2)
H.IV Patient recruitment
532(1)
H.V Treatment and followup
533(2)
H.VI Patient close-out
535(1)
H.VII Termination
536(1)
H.VIII Post-trial followup (optional)
537(1)
Appendix I Sketches of trials: Year 2006 publications in N Engl J Med, JAMA, BMJ, and Lancet
538(21)
Table I.1 Clinical trials published in 2006 in N Engl J Med, JAMA, BMJ, or Lancet, indexed by PubMed publication type
538(1)
Table I.2 PubMed indexing by gender, age, phase, and sponsorship
539(1)
Table I.3 Registration record
539(1)
Table I.4 Reason for publication, authorship format, and number of authors
539(2)
Table I.5 Location of study sites
541(1)
Table I.6 Primary outcome measures and conclusions
541(1)
Table I.7 Number of treatment groups and sample size
541(1)
Table I.8 Number of centers in multicenter trials
542(1)
Table I.9 Design type and unit of randomization
542(5)
Table I.10 Enrollment and followup periods
547(1)
Table I.11 Masking
547(1)
Table I.12 Treatment-effects monitoring
547(1)
Table I.13 Aim, purpose, and modalities tested
547(4)
Table I.14 Other features
551(2)
Trial sketch data collection form
553(5)
Registration data collection form
558(1)
Appendix J Sample study documents
559(32)
1 Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) Study Design Synopsis
560(3)
2 ADAPT CV table of contents
563(1)
3 ADAPT Policy and Procedures Memoranda (PPM); through February 8, 2006
564(3)
4 ADAPT Protocol table of contents (version 1.4; November 19, 2002)
567(2)
5 ADAPT Handbook table of contents (Version 1.1; May 1, 2001)
569(3)
6 ADAPT forms list (as of August 2007)
572(1)
7 ADAPT PPMs 1 through 4
573(6)
8 ADAPT IPPMs 1 through 3
579(3)
9 ADAPT table of contents of December 10, 2004 treatment-effects monitoring committee meeting
582(2)
10 ADAPT Steering Committee meeting materials; August 2, 2005 meeting
584(1)
11 Alzheimer's Disease Anti-inflammatory Prevention Trial Participant Prototype Consent Statement for Enrollment (February 7, 2002; PPM 34)
585(4)
12 ADAPT training meeting; March 1, 2002
589(2)
Appendix K User datasets
591(3)
1 Published literature databases
591(1)
2 Clinical trials registration sites
592(1)
3 Funding databases
593(1)
4 Document repositories
593(1)
5 Other databases
593(1)
Appendix L Abbreviations
594(5)
References 599(30)
Index 629
Curtis L. Meinert, PhD, is a Professor in the Departments of Epidemiology and Biostatistics at the Johns Hopkins Bloomberg School of Public Health. He was founder of the Center for Clinical Trials and served as its director through September 2005. He was a founding member of the Society for Clinical Trials and was Editor of Controlled Clinical Trials from its inception in 1980 through 1993.