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E-grāmata: Clinical Trial Methodology

(University of North Carolina, USA), (Georgia Southern University,USA)
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Clinical Trial MethodologyPalielināt
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"Now viewed as its own scientific discipline, clinical trial methodology encompasses the methods required for the protection of participants in a clinical trial and the methods necessary to provide a valid inference about the objective of the trial. Drawing from the authors courses on the subject as well as the first authors more than 30 years working in the pharmaceutical industry, Clinical Trial Methodology emphasizes the importance of statistical thinking in clinical research and presents the methodology as a key component of clinical research. From ethical issues and sample size considerations to adaptive design procedures and statistical analysis, the book first covers the methodology that spans every clinical trial regardless of the area of application. Crucial to the generic drug industry, bioequivalence clinical trials are then discussed. The authors describe a parallel bioequivalence clinical trial of six formulations incorporating group sequential procedures that permit sample size re-estimation. The final chapters incorporate real-world case studies of clinical trials from the authors own experiences. These examples include a landmark Phase III clinical trial involving the treatment of duodenal ulcers and Phase III clinical trials that contributed to the first drug approved for the treatment of Alzheimers disease. Aided by the U.S. FDA, the U.S. National Institutes of Health, the pharmaceutical industry, and academia, the area of clinical trial methodology has evolved over the last six decadesinto a scientific discipline. This guide explores the processes essential for developing and conducting a quality clinical trial protocol and providing quality data collection, biostatistical analyses, and a clinical study report, all while maintaining the highest standards of ethics and excellence"--Provided by publisher.

Now viewed as its own scientific discipline, clinical trial methodology encompasses the methods required for the protection of participants in a clinical trial and the methods necessary to provide a valid inference about the objective of the trial. Drawing from the authors' courses on the subject as well as the first author's more than 30 years working in the pharmaceutical industry, Clinical Trial Methodology emphasizes the importance of statistical thinking in clinical research and presents the methodology as a key component of clinical research

From ethical issues and sample size considerations to adaptive design procedures and statistical analysis, the book first covers the methodology that spans every clinical trial regardless of the area of application. Crucial to the generic drug industry, bioequivalence clinical trials are then discussed. The authors describe a parallel bioequivalence clinical trial of six formulations incorporating group sequential procedures that permit sample size re-estimation. The final chapters incorporate real-world case studies of clinical trials from the authors' own experiences. These examples include a landmark Phase III clinical trial involving the treatment of duodenal ulcers and Phase III clinical trials that contributed to the first drug approved for the treatment of Alzheimer's disease

Aided by the U.S. FDA, the U.S. National Institutes of Health, the pharmaceutical industry, and academia, the area of clinical trial methodology has evolved over the last six decades into a scientific discipline. This guide explores the processes essential for developing and conducting a quality clinical trial protocol and providing quality data collection, biostatistical analyses, and a clinical study report, all while maintaining the highest standards of ethics and excellence

Recenzijas

This comprehensive text introduces the key areas of clinical trial methodology from the perspective of the biostatistician in the pharmaceutical industry. Throughout, the text benefits from a highly structured and logical flow the arguments made in the book are grounded in many years of practical experience in drug development and at the very least will act as a prompt for in-depth discussion or critical review of ones own perceptions. Clinical Trial Methodology will be of substantial value to early career pharmaceutical industry statisticians. Christopher J. Weir, Pharmaceutical Statistics, 2012

informative discussions of mechanisms such as IND and NDA are unique strengths of this book, distinguishing it from the many other clinical trial texts available. Case studies are presented carefully The authors writing style is disciplined, careful, and informative. this is a helpful and informative book, a nice reference to have for most biostatisticians working on clinical trials. Mithat Gönen, Journal of Biopharmaceutical Statistics, 21, 2011

The book is an excellent overview predicated on the first authors seasoned experiences in designing, analyzing, and communicating the results of clinical trials across a broad number of medical disciplines. A nice introductory feature is the history of drug law and regulation, which helps to frame the subsequent statistical discussion nicely. The real-world examples that dominate the last few chapters are fantastic. There is nothing like a series of examples from an experienced clinical trialist to whet the appetite of those involved in the noble enterprise of medical (and more specifically pharmaceutical) research with the goal of improving the publics health. This book does an admirable job in giving the regulatory and statistical foundations for clinical trials, coupled with real-world examples of how statistical methodology has guided the

Preface xxiii
1 Overview of Clinical Trial Methodology
1(8)
1.1 Clinical Trials
1(1)
1.2 Clinical Trial Methodology
1(3)
1.2.1 Randomization and Control
1(1)
1.2.2 Kefauver-Harris Amendment and Its Impact on Clinical Trial Methodology
2(1)
1.2.3 Categorization of Clinical Trial Methodology
3(1)
1.3 Summary of Clinical Trial Methodology
4(3)
References
7(2)
2 Overview of the Drug Development Process and Regulation of Clinical Trials
9(46)
2.1 Introduction
9(1)
2.2 The Drug Development Process
10(5)
2.2.1 Pre-Investigational New Drug Exemption Application
10(1)
2.2.2 Investigational New Drug Exemption Application
10(1)
2.2.3 Phases of Clinical Trials
11(2)
2.2.4 The New Drug Application
13(1)
2.2.5 Post-FDA NDA Review Activities
14(1)
2.3 History of Drug Regulation
15(8)
2.3.1 The Pure Food and Drugs Act---1906
15(1)
2.3.2 The Sherley Amendment---1912
15(1)
2.3.3 The Food and Drug Administration---1930
15(1)
2.3.4 The Food, Drug, and Cosmetic Act---1938
15(1)
2.3.5 The Durham-Humphrey Amendment Act---1951
16(1)
2.3.6 The Kefauver-Harris Drug Amendments---1962
16(1)
2.3.7 The Fair Packaging and Labeling Act---1966
16(1)
2.3.8 The DESI Review---1970
16(1)
2.3.9 The FDA Package Insert Requirement---1970
17(1)
2.3.10 FDA Review of OTC Products---1972
17(1)
2.3.11 The National Research Act---1974
17(1)
2.3.12 The Medical Device Amendments---1976
17(1)
2.3.13 The Good Laboratory Practices---1978
18(1)
2.3.14 Good Clinical Practice Guidelines---1978
18(1)
2.3.15 Protection of Human Subjects and IRB Standards---1981
18(1)
2.3.16 The Federal Anti-Tampering Regulations---1983
19(1)
2.3.17 The Orphan Drug Act---1983
19(1)
2.3.18 The Hatch-Waxman Act---1984
19(1)
2.3.19 The IND/NDA Rewrite---1983-1987
20(1)
2.3.20 Drugs for Life-Threatening Illnesses---1987
20(1)
2.3.21 Inclusion of Older Patients in Clinical Trials---1989
20(1)
2.3.22 Accelerated Approval---1992
21(1)
2.3.23 The Prescription Drug User Fee Act---1992
21(1)
2.3.24 MedWatch---1993
21(1)
2.3.25 The Food and Drug Modernization Act---1997
21(1)
2.3.26 PDUFA Renewed---1997, 2002, and 2007
22(1)
2.3.27 The Gender Guideline---1993
22(1)
2.3.28 The Demographic Rule---1998
22(1)
2.3.29 Best Pharmaceuticals for Children Act---2002
22(1)
2.3.30 Pediatric Research Equity Act---2003
22(1)
2.3.31 Drug Safety Oversight Board---2005
23(1)
2.3.32 Other Regulations and Guidances
23(1)
2.4 Principles of Adequate and Controlled Investigations
23(3)
2.5 Content and Format of the IND
26(2)
2.6 Content and Format of the NDA
28(7)
2.6.1 Overall Summary
29(1)
2.6.2 Technical Sections
29(3)
2.6.3 Integrated Summaries
32(1)
2.6.3.1 Integrated Summary of Efficacy
32(1)
2.6.3.2 Integrated Summary of Safety
33(1)
2.6.3.3 Integrated Summary of Benefit to Risk
34(1)
2.7 Organizational Structure of the FDA
35(4)
2.7.1 Overview of FDA Responsibilities
35(1)
2.7.2 Centers and Offices of the FDA
35(1)
2.7.3 Center for Biologics Evaluation and Research
36(1)
2.7.4 Center for Devices and Radiological Health
37(1)
2.7.5 Center for Drug Evaluation and Research
37(2)
2.8 The FDA Review Process
39(2)
2.9 Labeling and the Package Insert
41(2)
2.10 Pharmaceutical Company Organization and Role of the Biostatistician
43(2)
2.10.1 Pharmaceutical Company Organization Overview
43(1)
2.10.2 Role of the Biostatistician
44(1)
2.11 Concluding Remarks
45(4)
References
49(6)
3 Ethical Considerations in the Design and Conduct of Clinical Trials
55(18)
3.1 Introduction
55(1)
3.2 History and Evolution of Ethical Considerations in Clinical Trials: Key Milestones
56(5)
3.2.1 The Nuremberg Code
56(2)
3.2.2 The Declaration of Helsinki
58(1)
3.2.3 The Belmont Report
59(1)
3.2.4 21 CFR Parts 50 and 56
60(1)
3.2.5 45 CFR Part 46
60(1)
3.2.6 International Conference on Harmonization on Good Clinical Practices
61(1)
3.3 Independent Review Boards
61(1)
3.3.1 Investigational Review Board
61(1)
3.3.2 Data Safety Monitoring Board
62(1)
3.4 Clinical Trial Ethics: Who Should Practice?
62(5)
3.4.1 Protocol Development
62(1)
3.4.1.1 The Physician
63(1)
3.4.1.2 The Biostatistician
63(1)
3.4.1.3 Regulatory Affairs Expert
64(1)
3.4.2 Clinical Trial Operations
64(1)
3.4.2.1 Investigator and Site Personnel
64(1)
3.4.2.2 Field Monitoring
65(1)
3.4.3 Clinical Data Management
65(1)
3.4.4 Biostatistical Analysis
65(1)
3.4.5 Clinical Trial Study Report
66(1)
3.4.6 Dissemination of Results
67(1)
3.5 Informed Consent, Sample Size and Power
67(2)
3.6 Common Ethical Principles of Various Codes and Regulations
69(1)
3.7 Concluding Remarks
70(1)
References
70(3)
4 Sample Size Considerations in Clinical Trials Pre-Market Approval
73(30)
4.1 Introduction
73(1)
4.2 Phases of Clinical Trials and Objectives
73(2)
4.2.1 Phase I Trials
74(1)
4.2.2 Phase II Trials
74(1)
4.2.3 Phase III Trials
75(1)
4.3 The Clinical Development Plan: Pre-Market Approval
75(1)
4.4 Sample Size Requirements
76(13)
4.4.1 Protocol Objectives as Specific Statistical Questions
76(2)
4.4.2 Endpoints
78(1)
4.4.3 Statistical Methods
79(1)
4.4.4 Statistical Design Considerations
80(2)
4.4.5 Numbers in Phase I Program
82(1)
4.4.6 Numbers in Phase II Program
82(1)
4.4.7 Numbers in Phase III Program
83(1)
4.4.8 Other Sample Size Considerations
83(1)
4.4.8.1 Relative Size of Trials and Detectable Differences
83(3)
4.4.8.2 Three-Arm Efficacy Trial: Dose of New Drug, Placebo, and Dose of Marketed Drug
86(1)
4.4.8.3 Interim Analyses
87(2)
4.5 Examples
89(7)
4.5.1 H2-Receptor Antagonist Duodenal Ulcer SNDA Program
89(2)
4.5.2 Two Identical Studies in the Prevention of NSAID-Induced Gastric Ulceration
91(5)
4.6 Philosophical Issues
96(4)
4.6.1 Axioms of Drug Development
96(1)
4.6.2 Sample Size: Efficacy or Ethical Imperative?
97(1)
4.6.3 Larger versus Smaller Trials
98(1)
4.6.4 One-Sided versus Two-Sided Tests
99(1)
4.6.5 Amalgamation of Phase IIB and Phase III Trials
99(1)
4.7 Concluding Remarks
100(1)
References
100(3)
5 Sequential, Group Sequential, Stochastic Curtailment, and Adaptive Design Procedures in Clinical Trials
103(26)
5.1 Introduction
103(1)
5.2 Sequential Procedures
103(1)
5.3 Group Sequential Procedures
104(12)
5.3.1 Definitions
104(2)
5.3.2 Computational Aspects of the Contributions from Each Planned Interim Analysis to Overall P-Value and Power
106(4)
5.3.3 A Three-Stage, Two-Treatment Trial
110(2)
5.3.4 Application
112(1)
5.3.4.1 Conditional Partitioning of α or α Spending Method
112(1)
5.3.4.2 Pocock's Method
113(1)
5.3.4.3 The O'Brien/Fleming Method
113(1)
5.3.4.4 Minimum Detectable Difference
114(1)
5.3.4.5 Power
115(1)
5.3.5 Summary
115(1)
5.4 Stochastic Curtailment
116(5)
5.4.1 Introduction
116(1)
5.4.2 Methods
117(3)
5.4.3 Application
120(1)
5.5 Adaptively Designed Clinical Trials
121(4)
5.5.1 Introduction
121(1)
5.5.2 Group Sequential Design
122(1)
5.5.3 Sample-Size Reestimation Design
122(1)
5.5.4 Drop-Loser Design
123(1)
5.5.5 Adaptive-Randomization Design
124(1)
5.5.6 Biomarker-Adaptive Design
124(1)
5.5.7 Multiple Adaptive Designs
124(1)
5.6 Concluding Remarks
125(1)
References
126(3)
6 Biostatistical Aspects of the Protocol
129(14)
6.1 The Background or Rationale
129(1)
6.2 Objective
129(1)
6.3 Plan of Study
130(2)
6.3.1 Study Population
130(1)
6.3.2 Study Design
131(1)
6.3.2.1 Type of Study
131(1)
6.3.2.2 Treatment Group Specification and Assignment
131(1)
6.3.2.3 Packaging to Achieve Blinding
131(1)
6.3.2.4 Concomitant Medication
132(1)
6.3.2.5 Procedures
132(1)
6.3.3 Problem Management
132(1)
6.4 Statistical Analysis Section
132(6)
6.4.1 Study Objectives as Statistical Hypotheses
133(1)
6.4.1.1 Primary, Secondary, Safety, or Other Objectives
133(1)
6.4.1.2 Translating Protocol Objectives into Statistical Hypotheses
133(1)
6.4.2 Endpoints
134(1)
6.4.3 Statistical Methods
135(1)
6.4.4 Statistical Monitoring Procedures
135(1)
6.4.5 Statistical Design Considerations
136(1)
6.4.6 Subset Analyses
137(1)
6.5 Administration
138(2)
6.5.1 Review and Consent Requirements
138(1)
6.5.2 Record Keeping
139(1)
6.5.3 Monitoring
139(1)
6.6 Protocol References Section
140(1)
6.7 Concluding Remarks
140(1)
References
140(3)
7 The Statistical Analysis Plan
143(10)
7.1 Introduction
143(1)
7.2 Protocol Objective
143(1)
7.3 Efficacy Data Collected and Protocol Schema
143(1)
7.4 Primary and Secondary Efficacy Endpoints
144(1)
7.4.1 Primary Efficacy Endpoint
144(1)
7.4.2 Secondary Efficacy Endpoints
145(1)
7.5 Objectives, Translated as Statistical Hypotheses
145(2)
7.5.1 Primary Efficacy Objective as a Statistical Hypothesis
145(1)
7.5.2 Secondary Efficacy Objectives as Statistical Hypotheses
145(1)
7.5.2.1 Percent of Patients with Acute Kidney Injury by Study Day 56
146(1)
7.5.2.2 Cumulative Percent of Patients Surviving by Study Day 56
146(1)
7.5.2.3 SOFA Score at Study Day 28
146(1)
7.5.2.4 SOFA Score at Study Day 56
147(1)
7.6 Protocol Design Features
147(1)
7.6.1 Experimental Design
147(1)
7.6.2 Treatment or Intervention Groups
147(1)
7.6.3 Randomization
148(1)
7.6.4 Blinding
148(1)
7.6.5 Number of Patients
148(1)
7.6.6 Number of Protocol Centers
148(1)
7.7 Statistical Analyses
148(3)
7.7.1 Trial Populations for Statistical Analyses
149(1)
7.7.2 Demographics, Baseline Characteristics, Eligibility, and Disposition
149(1)
7.7.3 Efficacy Analyses
150(1)
7.7.3.1 Primary Efficacy Analyses
150(1)
7.7.3.2 Secondary Efficacy Analyses
150(1)
7.7.3.3 Analyses of Generalizability across Subpopulations
151(1)
7.7.4 Interim Analyses
151(1)
7.8 Concluding Remarks
151(1)
References
152(1)
8 Pooling of Data from Multicenter Clinical Trials
153(12)
8.1 Introduction
153(1)
8.2 Multicenter Clinical Trial Experimental Setting
154(1)
8.3 Pre-Study Planning
155(1)
8.4 Multicenter Clinical Trial Conduct
155(1)
8.5 Biostatistical Analysis
156(5)
8.5.1 Design-Based Analysis Strategy
156(1)
8.5.1.1 Weighted Means and Variances
156(2)
8.5.1.2 Inference on Treatment Effect
158(2)
8.5.2 Model-Based Analysis Strategies
160(1)
8.5.2.1 Fixed Center and Treatment Effects: No Interaction or No Significant Interaction
160(1)
8.5.2.2 Center and Treatment as Fixed Effects: Significant Interaction
160(1)
8.5.2.3 Random Center and Fixed Treatment Effects
161(1)
8.6 Concluding Remarks
161(2)
8.6.1 Design-Based Inference
162(1)
8.6.2 Model-Based Inference
162(1)
References
163(2)
9 Validity of Statistical Inference
165(10)
9.1 Introduction
165(1)
9.2 Planning the Investigation
166(4)
9.2.1 Research Question and Endpoints
166(1)
9.2.2 Hypothesis Testing Framework
167(1)
9.2.3 The Number of Subjects
167(1)
9.2.4 Procedures for Conducting the Investigation
168(1)
9.2.5 Data Collection, Computerization, and Quality Assurance
168(1)
9.2.6 Statistical Methods
169(1)
9.3 Conducting the Investigation
170(1)
9.4 Statistical Analyses, Interpretation, and Inference
170(2)
9.5 Reporting Results of Investigations
172(1)
9.6 Concluding Remarks
172(1)
References
173(2)
10 Bioequivalence Clinical Trials
175(54)
10.1 Introduction
175(1)
10.2 Absorption, Distribution, Metabolism, and Excretion (ADME)
175(1)
10.3 Bioavailability
176(2)
10.3.1 Basis for Estimating Bioavailability
176(1)
10.3.2 Relative Bioavailability
177(1)
10.3.3 Absolute Bioavailability
177(1)
10.4 Factors that Affect Bioavailability
178(1)
10.4.1 Formulation or Dosage Form
178(1)
10.4.2 Routes of Administration
178(1)
10.4.3 State of the Biological System
178(1)
10.5 Blood Level Clinical Trials
179(1)
10.6 Bioequivalence
179(3)
10.6.1 Bioavailability Parameters or Endpoints Needed for Bioequivalence
180(1)
10.6.2 Decision Criterion for Concluding Bioequivalence
181(1)
10.7 Design of Bioequivalence Trials
182(17)
10.7.1 The Objective of Bioequivalence
182(1)
10.7.2 Experimental Design Considerations
183(1)
10.7.2.1 The Type of Experimental Design
183(1)
10.7.2.2 Drug Elimination Period
184(1)
10.7.2.3 Times of Collection of Blood Samples
184(1)
10.7.2.4 Specific Experimental Designs
184(9)
10.7.3 Endpoints
193(1)
10.7.4 Sample Size Determination
193(3)
10.7.5 Randomization and Blinding
196(1)
10.7.6 The Statistical Analysis Section
197(1)
10.7.6.1 Computation of Endpoints for Each Subject
197(1)
10.7.6.2 Statistical Analysis of Concentrations and Bioavailability Endpoints
198(1)
10.8 Analysis of Bioequivalence Trials
199(1)
10.9 Analysis of Ratios
200(1)
10.10 Pharmacokinetic Models
201(1)
10.11 Support of Bioequivalence Trials in the Pharmaceutical Industry
202(1)
10.12 Examples
203(12)
10.12.1 Parallel Bioequivalence Clinical Trial of Six Formulations with Sample Size Reestimation
203(1)
10.12.1.1 Background
203(1)
10.12.1.2 Six-by-Six Latin Square Design versus Six-Group Parallel Design
203(1)
10.12.1.3 Sample Size Reestimation
204(1)
10.12.2 Crossover Bioequivalence Trial
204(1)
10.12.2.1 Background and Endpoint Computations
204(2)
10.12.2.2 Test for Differential Carryover Effect
206(3)
10.12.2.3 Inferential Analysis of Bioequivalence: Confidence Interval Approaches
209(4)
10.12.2.4 Inferential Analysis of Bioequivalence: Bayesian Approaches
213(1)
10.12.2.5 Inferential Analysis of Bioequivalence: Two One-Sided Tests
214(1)
10.13 Concluding Remarks
215(1)
Appendix 10.A Bioequivalence Dataset
216(6)
Appendix 10.B R Code with Detailed Annotations
222(4)
References
226(3)
11 Dose and Frequency Determination from Phase II Clinical Trials in Stress Test-Induced Angina
229(20)
11.1 Introduction
229(1)
11.2 Overview of Response Surface Methodology
230(1)
11.3 Full Quadratic Response Surface Model
231(1)
11.4 Phase II Clinical Trial Program in Stress Test-Induced Angina
232(14)
11.4.1 Treatment Groups in the Original Protocols
233(1)
11.4.2 Efficacy Measures
233(1)
11.4.3 Stress Testing and Dosing Considerations
234(1)
11.4.4 Design
234(1)
11.4.5 Model
235(1)
11.4.6 Statistical Analyses
236(1)
11.4.6.1 Data and Descriptive Analyses
236(1)
11.4.6.2 Response Surface Methods Analyses
236(10)
11.5 Concluding Remarks
246(1)
References
247(2)
12 Confirmation of Clinically Optimal Dosing in the Treatment of Duodenal Ulcers: A Phase III Dose Comparison Trial
249(22)
12.1 Introduction
249(1)
12.2 Background
250(1)
12.3 Objective
251(1)
12.4 Designing and Planning the Investigation
252(2)
12.4.1 Blinded Treatment Groups
252(1)
12.4.2 Sample Size Determination
253(1)
12.4.3 Entry Requirements and Assessment Schedule
253(1)
12.4.4 Primary and Secondary Endpoints
254(1)
12.5 Conducting the Investigation
254(1)
12.6 Statistical Analyses
255(9)
12.6.1 Statistical Analysis Methods
255(1)
12.6.1.1 Methods
255(1)
12.6.1.2 Interim Analysis
256(1)
12.6.2 Interim Analysis Results
257(1)
12.6.2.1 Numbers of Patients and Baseline Characteristics
257(1)
12.6.2.2 Distribution of Patients according to Ulcer Size
258(1)
12.6.2.3 Influence of Smoking Status and Ulcer Size on Ulcer Healing
258(2)
12.6.2.4 Cumulative Ulcer Healing
260(1)
12.6.2.5 Generalizability Assessment
261(1)
12.6.2.6 Complete UGI Pain Relief and Ulcer Healing
261(2)
12.6.3 Final Analysis Results
263(1)
12.7 Other Considerations
264(1)
12.7.1 Bioequivalence Trial of Two 400 mg Tablets and One 800 mg Tablet
264(1)
12.7.2 Cimetidine-by-Drug Interaction Trials
264(1)
12.7.3 Study in the Elderly
264(1)
12.8 Innovative Aspects of the Clinical Trial Program
265(2)
12.8.1 Interim Analyses to Drop Placebo Arms
265(1)
12.8.2 Third-Party Blinding during Interim Analyses
265(1)
12.8.3 Trial Objectives as Only Three of Six Pair-Wise Comparisons
266(1)
12.8.4 Giving Up Information on Center Differences
266(1)
12.8.5 Assessment of Type of Monitoring by Treatment Group
266(1)
12.8.6 Association between Ulcer Healing and Smoking Status and Ulcer Size
266(1)
12.8.7 Utilization of Bivariate Graphical Methods
266(1)
12.8.8 Establishing Effectiveness Based on a Subset Analysis
266(1)
12.8.9 Maximum Use of Patients Screened with UGI Pain
267(1)
12.9 Concluding Remarks
267(1)
References
267(4)
13 Pivotal Proof-of-Efficacy Clinical Trials in the Prevention of NANSAID-Induced Gastric Ulceration
271(12)
13.1 Introduction
271(1)
13.2 Rationale
271(1)
13.3 The Protocols
272(2)
13.3.1 Objectives
272(1)
13.3.2 Inclusion Criteria
272(1)
13.3.3 Efficacy Endpoints
273(1)
13.3.4 Sample Size Determination
273(1)
13.3.5 Statistical Methods
274(1)
13.4 Monitoring and Data Management
274(2)
13.5 FDA Meeting
276(2)
13.6 Concluding Remarks
278(2)
References
280(3)
14 Clinical Trials in the Treatment of Alzheimer's Disease Based upon Enrichment Designs
283(28)
14.1 Introduction
283(2)
14.2 Enrichment Design Clinical Trials
285(1)
14.3 Objective
286(1)
14.4 Primary Efficacy Endpoints
286(1)
14.5 Sample Size Determination
287(1)
14.6 Statistical Methods
287(11)
14.6.1 Linear Model Analyses of Primary Efficacy Measures
287(1)
14.6.1.1 Titration Phase
288(3)
14.6.1.2 Double-Blind Phase
291(1)
14.6.1.3 Meta-Analyses of Results across Trials
292(1)
14.6.2 Population Pharmacodynamic/Pharmacokinetic, Nonlinear Mixed Effects Model Analyses
293(1)
14.6.2.1 Objectives
294(1)
14.6.2.2 Requirements of the Model
294(1)
14.6.2.3 Model Parameters
295(1)
14.6.2.4 Model Formulation
295(2)
14.6.2.5 Computational Methods
297(1)
14.7 Results
298(8)
14.7.1 Titration Phase Data
298(1)
14.7.1.1 Detailed Titration Phase Results: Protocol 01
298(4)
14.7.1.2 Titration Phase Results Summary: Protocols 01, 04, and 06
302(1)
14.7.2 Double-Blind Parallel Phase Results Summary: Protocols 01, 04, and 06
302(2)
14.7.3 Data from All Phases, PD/PK Results Summary: Protocols 01, 04, and 06
304(2)
14.8 Concluding Remarks
306(2)
References
308(3)
15 A Clinical Trial to Establish Reduction of CHD Risk
311(26)
15.1 Introduction
311(1)
15.2 Objective
312(1)
15.3 Designing and Planning the Investigation
312(2)
15.3.1 Blinded Treatment Groups
313(1)
15.3.2 Sample Size Determination
313(1)
15.3.3 Entry Requirements
313(1)
15.3.4 Primary Efficacy and Safety Endpoints
313(1)
15.4 Conducting the Investigation
314(1)
15.5 Data Management
315(1)
15.6 Statistical Analyses
315(11)
15.6.1 Methods for Double-Blind Phase
315(1)
15.6.2 Methods for Double-Blind and Open-Label Phases
316(1)
15.6.2.1 Classification Groups
316(1)
15.6.2.2 Data on Major Events
316(8)
15.6.2.3 Inferential Statistical Methods
324(2)
15.7 Results
326(4)
15.7.1 Double-Blind Phase
326(1)
15.7.2 Double-Blind and Open-Label Phases
327(1)
15.7.2.1 Cardiac Endpoints
327(1)
15.7.2.2 All-Cause Mortality
328(1)
15.7.2.3 Cardiac Deaths
328(1)
15.7.2.4 Noncardiac Deaths
329(1)
15.7.2.5 Noncardiac, Noncancer Deaths
329(1)
15.7.2.6 Cancer Deaths
329(1)
15.7.2.7 Cancer Diagnosis
329(1)
15.8 Summary
330(3)
15.9 Concluding Remarks
333(1)
References
334(3)
16 Pivotal Proof-of-Efficacy Clinical Trials in the Treatment of Panic Disorder
337(10)
16.1 Introduction
337(1)
16.2 Design of Pivotal Proof-of-Efficacy Trials
338(4)
16.2.1 Forced Titration Dose-Response Trial: Experimental Design
340(1)
16.2.2 Titration according to Response Trial: Experimental Design
340(1)
16.2.3 Efficacy Endpoints
340(1)
16.2.4 Trial Objectives
341(1)
16.2.4.1 Forced Titration Dose-Response Trial Objective
341(1)
16.2.4.2 Titration according to Response Trial Objective
341(1)
16.2.5 Sample Size Determination
342(1)
16.3 Traditional Statistical Analysis Methods
342(1)
16.4 Overview of Efficacy Results of the Two Trials
343(1)
16.5 Alternative Design and Analysis Strategies
343(2)
16.6 Concluding Remarks
345(1)
References
345(2)
17 Combination Clinical Trials
347(14)
17.1 Introduction
347(1)
17.2 Two-by-Two Factorial Design
348(1)
17.3 Effectiveness of the Combination
348(2)
17.4 Contribution of Components to the Effectiveness of the Combination
350(1)
17.5 Factorial Designs in Other Clinical Development Areas
350(1)
17.6 Example 1: Actifed® in the Treatment of SAR Following DESI Review
351(4)
17.6.1 Design and Randomized Treatment Groups
352(1)
17.6.2 Objective
352(1)
17.6.3 Efficacy Endpoints
352(1)
17.6.4 Sample Size Requirements
352(1)
17.6.5 Statistical Analysis Methods
352(3)
17.7 Example 2: Crossover Trial of Actifed in the Treatment of SAR
355(1)
17.8 Example 3: Parallel Trial of Actifed in the Treatment of the Common Cold
356(2)
17.9 Concluding Remarks
358(1)
References
358(3)
18 Monitoring Clinical Trials for Adverse Events
361(22)
18.1 Introduction
361(1)
18.2 Designing for Safety: Antibiotic Rash Example
361(1)
18.3 Designing for Safety: Hypokalemia Example
362(1)
18.4 Designing for Safety: Hypertensive Rebound Example
362(1)
18.5 Premarket Approval Trials: Designed for Efficacy
363(1)
18.6 Premarket Approval Trials: Quality of Adverse Event Information
364(2)
18.7 Monitoring for Safety
366(1)
18.8 Statistical Methodology: Individual Trial
367(4)
18.8.1 Direct Comparison Methodology
368(1)
18.8.2 Indirect Comparison Methodology
369(1)
18.8.3 Connection between Direct and Indirect Comparison Methods
370(1)
18.9 Example
371(5)
18.9.1 Adverse Event Data from a Clinical Trial
371(1)
18.9.2 The Classical Direct Comparison Confidence Interval Method
372(1)
18.9.3 The Indirect Comparison Confidence Interval Method
373(1)
18.9.4 Computing Significance or Confidence Levels for the Indirect Method
374(2)
18.10 Statistical Methodology: Across Trials
376(1)
18.11 Concluding Remarks
376(2)
Appendix 18.A R Program to Analyze the Data in Table 18.2
378(3)
References
381(2)
Index 383
Karl E. Peace is the Georgia Cancer Coalition Distinguished Cancer Scholar, founding director of the Center for Biostatistics, and professor of biostatistics in the Jiann-Ping Hsu College of Public Health at Georgia Southern University.

Din Chen is the Karl E. Peace Endowed Eminent Scholar Chair in Biostatistics and professor of biostatistics in the Jiann-Ping Hsu College of Public Health at Georgia Southern University.
Biežāk uzdotie jautājumi par e-grāmatām Biežāk uzdotie jautājumi par e-grāmatām
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