Fundamentals of Clinical Trials

by Friedman, Lawrence M.; Furberg, Curt D.; Demets, David L.

• ISBN13: 9780387985862
• ISBN10: 0387985867
• Edition: 3rd
• Format: Paperback
• Copyright: 1998-08-01
• Publisher: Springer Verlag

Summary

This classic reference, now updated with the newest applications and results, addresses the fundamentals of such trials based on sound scientific methodology, statistical principles, and years of accumulated experience by the three authors.

Table of Contents

1 Introduction to Clinical Trials	1	(15)
Fundamental Point	2	(1)
What is a Clinical Trial?	2	(1)
Clinical Trial Phases	3	(3)
Phase I Studies	3	(1)
Phase II Studies	4	(1)
Phase III/IV Trials	5	(1)
Why are Clinical Trials Needed?	6	(1)
Problems in the Timing of a Trial	7	(1)
Ethics of Clinical Trials	8	(2)
Study Protocol	10	(2)
References	12	(4)
2 What Is the Question?	16	(14)
Fundamental Point	16	(1)
Selection of the Questions	16	(4)
Primary Question	16	(1)
Secondary Questions	17	(1)
Adverse Effects	18	(1)
Ancillary Questions, Substudies	18	(1)
Natural History	19	(1)
Large, Simple Clinical Trials	19	(1)
Intervention	20	(1)
Response Variables	20	(7)
Surrogate Response Variables	24	(3)
General Comments	27	(1)
References	28	(2)
3 Study Population	30	(11)
Fundamental Point	30	(1)
Definition of Study Population	30	(7)
Generalization	37	(2)
Recruitment	39	(1)
References	39	(2)
4 Basic Study Design	41	(20)
Fundamental Point	42	(1)
Randomized Control Studies	43	(3)
Nonrandomized Concurrent Control Studies	46	(1)
Historical Controls/Data Bases	47	(4)
Cross-over Designs	51	(1)
Withdrawal Studies	52	(1)
Factorial Design	53	(2)
Group Allocation Designs	55	(1)
Hybrid Designs	55	(1)
Studies of Equivalency	55	(1)
Large Simple Clinical Trials	56	(1)
References	57	(4)
5 The Randomization Process	61	(21)
Fundamental Point	61	(1)
Fixed Allocation Randomization	62	(7)
Simple Randomization	63	(1)
Blocked Randomization	64	(2)
Stratified Randomization	66	(3)
Adaptive Randomization Procedures	69	(6)
Baseline Adaptive Randomization Procedures	69	(3)
Response Adaptive Randomization	72	(2)
Mechanics of Randomization	74	(1)
Recommendations	74	(1)
Appendix	76	(2)
Adaptive Randomization Algorithm	76	(2)
References	78	(4)
6 Blindness	82	(12)
Fundamental Point	82	(12)
Type of Trials	82	(4)
Unblinded Trials	82	(1)
Single-Blind Trials	83	(2)
Double-Blind Trials	85	(1)
Triple-Blind Trials	86	(1)
Special Problems in Double-Blind Studies	86	(6)
Matching of Drugs	87	(2)
Coding of Drugs	89	(1)
Unbinding Trials	90	(1)
Assessment of Blindness	91	(1)
References	92	(2)
7 Sample Size	94	(36)
Fundamental Point	94	(1)
Statistical Concepts	95	(5)
Dichotomous Response Variables	100	(9)
Two Independent Samples	100	(1)
Example	101	(1)
Sample Size Tables for Independent Samples	102	(2)
Power for Independent Samples	104	(1)
Confidence Interval Approach for Independent Samples	105	(1)
Paired Dichotomous Response	106	(1)
Example	106	(1)
Adjusting Sample Size to Compensate for Nonadherence	107	(1)
Example	108	(1)
Sample Size Calculations for Continuous Response Variables	109	(3)
Two Independent Samples	109	(1)
Paired Data	110	(1)
Example	111	(1)
Adjustment for Nonadherence	112	(1)
Sample Size for Repeated Measures	112	(2)
Example	113	(1)
Sample Size Calculations for "Time to Failure"	114	(4)
Sample Size for Testing "Equivalency" of Interventions	118	(1)
Sample Size for Cluster Randomization	119	(3)
Continuous Response	120	(1)
Example	120	(1)
Binomial Response	121	(1)
Example	121	(1)
Estimating Sample Size Parameters	122	(1)
Multiple Response Variables	123	(2)
References	125	(5)
8 Baseline Assessment	130	(10)
Fundamental Point	130	(1)
Uses of Baseline Data	130	(3)
Analysis of Baseline Comparability	131	(1)
Stratification and Subgrouping	131	(1)
Evaluation of Change	132	(1)
Natural History Analysis	132	(1)
What is a True Baseline Measurement?	133	(4)
Balance and Imbalance	137	(2)
References	139	(1)
9 Recruitment of Study Participants	140	(16)
Fundamental Point	141	(1)
Planning	141	(2)
Strategies and Sources	143	(2)
Conduct	145	(2)
Monitoring	147	(2)
Problems	149	(2)
Solutions	151	(2)
Reasons for Participation	153	(1)
References	153	(3)
10 Data Collection and Quality Control	156	(14)
Fundamental Point	157	(1)
Problems in Data Collection	157	(3)
Major Types of Problems	157	(1)
Specific Examples of Variability	158	(2)
Minimizing Poor Quality Data	160	(3)
Design of Protocol and Manual	160	(1)
Development of Forms	160	(1)
Training	161	(1)
Pretesting	162	(1)
Techniques to Reduce Variability	162	(1)
Data Entry	163	(1)
Quality Monitoring	163	(4)
Monitoring of Forms	164	(1)
Monitoring of Procedures	164	(1)
Monitoring of Drug Handling	165	(2)
Audits	167	(1)
References	167	(3)
11 Assessing and Reporting Adverse Effects	170	(15)
Fundamental Point	170	(1)
Determinants of Adverse Effects	171	(7)
Definitions	172	(1)
Ascertainment	172	(2)
Frequency of Events	174	(1)
Length of Follow-up	175	(2)
Individual Susceptibility	177	(1)
Analysis of Nonadherent Participants	177	(1)
Reporting Adverse Effects	178	(2)
Other Issues	180	(2)
Conclusions	182	(1)
References	183	(2)
12 Assessment of Health-Related Quality of Life	185	(19)
Michelle J. Naughton
Sally A. Shumaker
Fundamental Point	186	(1)
Definitions	186	(3)
Primary HRQL Dimensions	187	(1)
Additional HRQL Dimensions	188	(1)
Uses of HRQL	189	(3)
HRQL Indices as Outcome Variables	190	(1)
HRQL as Baseline Covariates	191	(1)
Methodological Issues	192	(6)
Trial Design	192	(1)
Study Population	192	(1)
Intervention	193	(1)
Selection of HRQL Instruments	194	(1)
Modes of Administration	195	(1)
Frequency of Assessment (acute vs. chronic)	196	(1)
Symptom Expression (episodic vs. constant)	197	(1)
Functional Impact (present vs. absent)	197	(1)
Interpretation	198	(1)
Scoring of HRQL Measures	198	(1)
Determining the Significance of HRQL Measures	199	(1)
Utility Measures and Preference Scaling	199	(2)
References	201	(3)
13 Participant Adherence	204	(19)
Fundamental Point	205	(1)
Considerations Before Participant Enrollment	205	(5)
Maintaining Good Participant Adherence	210	(3)
Adherence Monitoring	213	(6)
Special Populations	219	(1)
References	220	(3)
14 Survival Analysis	223	(23)
Fundamental Point	223	(1)
Estimation of the Survival Curve	224	(9)
Kaplan-Meier Estimate	225	(7)
Cutler-Ederer Estimate	232	(1)
Comparison of Two Survival Curves	233	(13)
Point-by-Point Comparison	233	(1)
Comparison of Median Survival Times	234	(1)
Total Curve Comparison	234	(2)
Example	236	(3)
Generalizations	239	(2)
Covariate Adjusted Analysis	241	(2)
References	243	(3)
15 Monitoring Response Variables	246	(38)
Fundamental Point	246	(1)
Data Monitoring Committee	247	(3)
Repeated Testing for Significance	250	(3)
Decision for Early Termination	253	(6)
Decision to Extend a Trial	259	(2)
Statistical Methods Used in Monitoring	261	(14)
Classical Sequential Methods	261	(2)
Group Sequential Methods	263	(3)
Flexible Group Sequential Procedures--Alpha-Spending Functions	266	(3)
Applications of Group Sequential Boundaries	269	(3)
Asymmetric Boundaries	272	(1)
Curtailed Sampling Procedures	272	(3)
Other Approaches	275	(1)
References	275	(9)
16 Issues in Data Analysis	284	(39)
Fundamental Point	284	(1)
Which Participants Should be Analyzed?	284	(13)
Ineligibility	285	(4)
Nonadherence	289	(4)
Poor Quality or Missing Data	293	(3)
Competing Events	296	(1)
Covariate Adjustment	297	(7)
Surrogates as Covariates	299	(2)
Baseline Variables as Covariates	301	(3)
Subgroup Analyses	304	(2)
Not Counting Some Events	306	(1)
Comparison of Multiple Variables	307	(1)
Use of Cutpoints	308	(1)
Meta-Analysis of Multiple Studies	308	(8)
Rationale and Issues	310	(3)
Statistical Methods	313	(3)
Appendix	316	(1)
Mantel-Haenszel Statistic	316	(1)
References	317	(6)
17 Closeout	323	(10)
Fundamental Point	323	(1)
Termination Procedures	323	(3)
Poststudy Follow-up	326	(2)
Data Clean-up and Verification	328	(1)
Storage of Study Material	329	(1)
Dissemination of Results	330	(1)
References	331	(2)
18 Reporting and Interpreting of Results	333	(12)
Fundamental Point	334	(1)
Guidelines for Reporting	334	(1)
Interpretation	335	(1)
Publication Bias	336	(1)
Did the Trial Work as Planned?	337	(3)
How Do the Findings Compare with Results from Other Studies?	340	(1)
What Are the Clinical Implications of the Findings?	341	(1)
References	342	(3)
19 Multicenter Trials	345	(12)
Fundamental Point	345	(1)
Reasons for Multicenter Trials	345	(2)
Conduct of Multicenter Trials	347	(7)
Data Monitoring Committee	349	(1)
Steering Committee	350	(1)
Assembly of Investigators	350	(4)
General Comments	354	(1)
References	355	(2)
Index	357