Fundamentals of Clinical Research: Bridging Medicine, Statistics and Operations Book

Foreword     VII
Acknowledgements     XI
Contents     XIII
Introduction     XIX
Variability of Biological Phenomena and Measurement Errors     1
Phenotypic Variability     1
Temporal Variability     2
Measurement-Related Variability     3
The Measurement     3
Measurement Errors     7
Variability of Diagnostic Tests     10
Summary     13
Distinctive Aspects of a Biomedical Study. Observational and Experimental Studies     14
Distinctive Features of Biomedical Studies     14
The Study Protocol     18
Observational Studies     21
Experimental Studies     23
Summary     27
Observational Studies     28
Basic Designs of Observational Studies     29
Prospective or Cohort Studies     30
Retrospective Studies or Control Cases     36
Sample Size     40
Bias and Confounding     40
Control of Bias in Epidemiology     44
Control of the Phenomenon of Confounding     49
Advantages and Disadvantages of the Different Types of Observational Studies     53
Summary     56
Defining the Treatment Effect     58
From the Single Measurement to the Signal     58
Identification and Quantification of the End-Points (Individual Subject Level)     64
Methodological Characteristics of the End-Point     64
Discriminating between Primary and Secondary End-Points and between Efficacy and Safety/Tolerability End-Points     66
Identification and Quantification of the Signals (Group Level)     69
Statistical Considerations     70
Practical, Regulatory, Marketing and Pharmaco-Economic Considerations     73
Selection and Characterization of the Primary End-Point and Signal: an Example     75
Stage One: Define the Main Therapeutic Level     75
Stage Two: Define the Primary End-Point (Individual Patient Level)     77
Stages Three and Four: Define the Group Indicator, the Signal, and the Threshold of Clinical Relevance (Treatment Group and Study Levels)     79
More Than One Question in the Same Study: the Problem of Multiple Statistical Tests     80
Validation of Measurement Scales     84
Special Types of End-Points     85
Summary     88
Probability, Inference and Decision Making     90
Probability     91
Definitions      91
Probability Distribution and Probability Density Function     92
Normal or Gaussian Distribution     99
Basic Concepts of Inference     100
Hypothesis Testing and Statistical Formulation of the Medical Question     103
Statistical Estimation as the Tool for Evaluation of Clinical Relevance     105
Statistical Inference in the Frequentist and the Bayesian Approaches     106
Two Digressions: Measures of Variability and Likelihood Function     110
Measures of Variability     110
Likelihood Function     114
Frequentist (Classical) Analysis of a Clinical Trial     119
Hypothesis Testing: the Frequentist Solution     120
Estimation of the Effect: the Frequentist Solution     135
Bayesian Analysis of a Clinical Trial     138
Hypothesis Testing: the Bayesian Solution     138
Estimation of the Effect: the Bayesian Solution     144
Some Additional Considerations on the Frequentist and Bayesian Approaches     146
Parametric and Non-Parametric Inference     149
Statistical Decision Making in the Medical Field     150
Evidence-Based Medicine     152
Summary     154
The Choice of the Sample     157
Which Subjects Should Form the Sample?     157
Characteristics of the Patients to be Enrolled in the Study     157
Mechanism of Subject Selection     163
How Many Subjects Should Form the Sample?     164
Statistical Considerations     164
Medical and Practical Aspects     169
Summary     171
The Choice of Treatments     172
Study Treatments     172
How Many Treatments     175
What Treatments     176
Blinding of the Study Treatments     178
Packaging and Logistics     178
Concomitant Treatments     180
Summary     182
Experimental Design: Fallacy of "Before-After" Comparisons in Uncontrolled Studies     183
Experimental Design: Introductory Concepts     183
Before-After Comparison in a Single Group of Subjects     185
Temporal Variations of the Disease     186
Temporal Variations of Staff, Equipment and Environment     188
Statistical Regression Toward the Mean     189
The Basic Principle     189
Areas of Biomedical Experiments Affected by Regression Toward the Mean     191
How to Minimize the Effect of Regression Toward the Mean     193
Learning Effect      195
Psychological Effect     196
The Before-After Design Without Control Group in Oncology     197
Summary     198
Experimental Design: the Randomized Blinded Study as an Instrument to Reduce Bias     200
Introduction     200
Randomization as Antidote Against Selection Bias     203
Definition and Conceptual Framework     203
Types of Randomization     206
Other Methods for Assigning Patients to Treatments     215
Blinding of Treatments as Antidote Against Assessment Bias     216
A Priori Definition of the Statistical Methods and Populations as Antidote Against the Analysis Bias     221
Methods of Statistical Analysis     221
Analysis Populations     222
Comparison Between an Observational and an Experimental Study     224
Summary     227
Experimenta Designs     228
Introduction     228
Parallel Group Design     233
Characteristics     233
Advantages and Disadvantages     233
Conditions of Applicability     234
Variants of the Parallel Group Design     234
Completely Randomized Parallel Group Design     234
Stratified Parallel Group Design      235
Parallel Group Randomized Block Design     239
Balanced Incomplete Block Design     242
Other Designs with Comparison Between Subjects: Dose-Escalation and Dose-Titration     244
Dose-Escalation Design     244
Dose-Titration Design     246
Complete Cross-Over Design     247
Characteristics     247
Advantages and Disadvantages     252
Conditions of Applicability     255
Variants of the Cross-Over Design     256
Variants Based on the Type of Randomization     256
Incomplete Cross-Over Designs     257
Other Designs with Within-Subject Comparisons: Simultaneous Treatments and Single Patient Designs     261
Simultaneous Treatments Design     261
Cross-Over Design on a Single Patient (or "N of 1" Design)     261
Factorial Designs     263
Characteristics     263
Advantages and Disadvantages     268
Conditions of Applicability     270
Split-Plot Design     271
Characteristics     271
Conditions of Applicability     273
Non-Controlled Designs in Phase II Oncology Studies     273
Summary     275
Study Variants Applicable to More than One Type of Design: Equivalence Studies, Interim Analyses, Adaptive Plans and Repeated Measurements     277
Equivalence and Non-Inferiority Studies     277
Characteristics     277
The Statistical Analysis of an Equivalence Study     280
Planning and Implementation Problems     281
Analysis and Interpretation Problems     285
Studies with Interim Analyses and Sequential Designs     287
Definitions and Classification     288
Conditions of Applicability     290
Choice of the End-Points     292
Data Management Issues     293
Statistical Issues and Decision Making Criteria     294
Conflict of Interest and Confidentiality Issues     298
Adaptive (Flexible) Designs     299
Studies with Repeated Measurements     301
Summary     302
The Drug Development Process and the Phases of Clinical sx Research     304
Overview of the Preclinical Development Process     304
The Phases of Clinical Development     308
Introduction     308
Phase I     309
Phase II     311
Phase III     313
Registration Dossier     315
Phase IV      319
Project Management     321
The Phases of Clinical Development for Oncology Compounds     322
Phase I     322
Phase II     323
Phase III     323
Accelerating Clinical Development     325
Summary     327
Areas under the Curve of the Standard Normal Distribution     329
References     331
Analytical Index     337