Encyclopedia of Biopharmaceutical Statistics, Volumes 1 and 2

Encyclopedia of Biopharmaceutical Statistics, Volumes 1 and 2

Third Edition

Cover Image
Published
May 2010
ISBN
9781439822463
Edition
Third
Pages
1493
Size
8 1/2 x 11 in
Format
Hardcover
296 illustrations


Preface

Chapter 1

Acceptance Sampling
In general, acceptance sampling is a statistical tool used to help make decisions concerning whether or not a batch (or lot) of product should be released for consumer consumption or use. Acceptance sampling, which will be discussed in this paper, should …

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Chapter 2

Active Control Trials
An active control is an intervention, such as a drug, a therapy, or a medical device, whose effectiveness has previously been established. Active controls have been used in trials with or without a placebo. For clinical drug trials with a placebo, …

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Chapter 3

Adaptive Design Methods in Clinical Trials
In the past several decades, it has been recognized that increasing spending of biomedical research does not reflect an increase of the success rate of pharmaceutical/clinical research and development. The low success rate of pharmaceutical/clinical …

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Chapter 4

Adaptive Survival Trials
A survival trial is a clinical trial with a time-to-event primary outcome, such as time to death or cure. Typically, survival trials involve a limited recruitment period with staggered entry and are complicated by censoring because of losses to follow-up …

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Chapter 5

Adjustment for Covariates
The techniques of analysis of covariance are employed in three mathematically similar but conceptually very different kinds of problem. Examples of all three kinds arise in connection with the development of pharmaceutical products.

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Chapter 6

Adverse Event Reporting
In order for a chemical intended for use as a medicinal product to be sold for use in humans, research must be carried out to prove that the benefits of the drug outweigh the risks associated with the drug. Clinical studies of planned tests of the drug in …

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Chapter 7

Alpha Spending Function
Clinical trials have become the major standard over the past three decades for evaluating new therapies and medical interventions. In the majority of studies, accruing data are monitored and analyzed at intervals by the sponsor or an independent data …

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Chapter 8

Ames Test
Genetic toxicology tests are among the early studies conducted to assess the safety profile of a compound. A battery of tests, each assessing a different genetic endpoint, is typically performed to thoroughly evaluate a given compound because no single …

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Chapter 9

Analysis of 2 K Tables
Data in 2 × K contingency tables are encountered quite frequently in biomedical, epidemiological, social, and behavioral studies. The variable representing two rows is often called the row variable, whereas the variable representing K columns is called …

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Chapter 10

Analysis of Clustered Binary Data
Clinical trial designs often incorporate binary outcomes (i.e., proportion of responders; success probabilities) or change continuous outcomes into binary outcomes for interpretation purposes. When a subject contributes more than one binary response (…

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Chapter 11

Analysis of Clustered Categorical Data
Social, behavioral, and epidemiological studies are often concerned with multiple discrete indicators that are utilized as responses in lieu of an obvious single measure for an outcome of interest. Sometimes these multiple indicators corresponding to a …

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Chapter 12

Analysis of Heritability
Statistical methods applied to the field of quantitative genetics provide insight concerning the role that nature and nurture play in the development of life forms. Physical traits of organisms depend on genetic as well as environmental influences and …

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Chapter 13

Analysis of Repeated Measures Data with Missing Values: An Overview of Methods
The missing data problem, which persists in much of empirical scientific investigations, is particularly common in repeated measures data. One reason for this is that the same subjects are used repeatedly over time. One of the main goals in dealing with …

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Chapter 14

Analysis of Variance
The analysis of variance (ANOVA) is a statistical method, which originally was developed by R.A. Fisher (1890–1962) for problems in biological studies.2 Since that time, the ANOVA has been used in many different areas and there exist a comprehensive …

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Chapter 15

ANCOVA Approach for Premarketing Shelf Life Determination with Multiple Factors
The stability of a drug substance or drug product is the capacity of the drug substance or drug product to remain within the established acceptance criteria to ensure its identity, strength, quality, and purity for a specified period of time. Regulatory …

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Chapter 16

Assay Development
Assays are utilized in the pharmaceutical industry to characterize drugs and biological products. Assay development is coordinated with pharmaceutical development to furnish the tools necessary to guide the research process. Measures of content, potency, …

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Chapter 17

Assay Validation
Upon completion of the development of an assay, and prior to implementation, a well‐conceived assay validation is carried out to demonstrate that the procedure is fit for use. Regulatory requirements specify the assay characteristics that are subject to …

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Chapter 18

Bayesian Approach to Stability Analysis
Shelf-life or expiration dating period is one of the key components of biopharmaceutical products. The U.S. Food and Drug Administration (FDA) requires that the shelf-life, defined as the time interval during which the potency of a product is expected to …

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Chapter 19

Bayesian Methods in Meta-Analysis
Meta-analysis refers to the collection and subsequent statistical analysis of results from numerous studies. The purpose of a meta-analysis is to arrive at an overall conclusion about an issue of interest based on the available data. Meta-analysis has a …

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Chapter 20

Bayesian Statistics
The Bayesian approach to statistical inference has received increased attention in the scientific community over the past several decades because of the general framework it provides for incorporating new experimental evidence into scientific conclusions. …

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Chapter 21

Bayesian Designs for Phase II Oncology Clinical Trials
Many different designs have been proposed and used for phase II oncology clinical trials. The majority of these are based on frequentist statistical approaches. Bayesian methods provide an alternative to frequentist approaches, allowing for the …

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Chapter 22

Binary 2 × 2 Crossover Trials
Crossover design is a commonly used experimental design for the comparison of treatment effects in clinical trials. By letting subject serve as his or her own control, such design automatically removes subject effect from the comparison. Here we focus on …

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Chapter 23

Bioassay
Finney1 defines a bioassay as an experiment for estimating the potency of a drug, material, preparation, or process by means of the reaction that follows its application to living matters. The emphasis in bioassays is on comparing the potencies of …

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Chapter 24

Bioavailability and Bioequivalence
Bioavailability (BA) is a description of the rate and extent of which a drug when administered in a pharmaceutical dosage form becomes available at the site of pharmacological effect. As is pointed out by Benet,1 defining the criteria in terms of site of …

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Chapter 25

Bioinformatics
Broadly, bioinformatics as a field includes research in genomics, proteomics, computer science, pharmacology, drug discovery, and drug development. This review covers several important areas in bioinformatics including sequence analysis, genomics, …

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Chapter 26

Biologics
The Food and Drug Administration (FDA) has six centers that review products for many uses. These centers are as follows: Center for Biologics Evaluation and Research (CBER)—regulates biologic products (e.g., blood products, vaccines, monoclonal antibodies,…

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Chapter 27

Biomarker in Clinical Trials
What is a biomarker? The National Institutes of Health Workshop1 gave the following definitions. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or …

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Chapter 28

Biopharmaceutics
The biopharmaceutics and biopharmaceutical properties of a medicinal/drug product can be considered as the bridging information between physicochemical, pharmaceutical quality, and biological, pharmacological effects that result in therapeutic as well as …

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Chapter 29

Biosimilarity of Follow-On Biologics
When an innovative (brand-name) drug product goes off patent, pharmaceutical and generic companies may file an abbreviated new drug application (ANDA) for approval of the generic copies of the innovative drug product. In 1984, the U.S. Food and Drug …

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Chapter 30

Blinding
Although randomization is used to prevent bias from a statìstical assessment of the study drug, it does not guarantee that there will be no bias caused by subjective judgment in reporting, evaluation, data processing, and statistical analysis. This …

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Chapter 31

Bootstrap, The
The process of a statistical analysis based on a set of observed data can be briefly described as follows. We believe that the observed data are from a postulated (parametric or nonparametric) model. Unknown quantities in the postulated model are …

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Chapter 32

Bracketing Design
Bracketing is a special term used in stability design. Since the amount of data required to demonstrate the stability characteristics of a product can often be large and expensive to generate, methods to reduce the size of stability studies have been …

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Chapter 33

Bridging Studies
For the marketing approval of a pharmaceutical product, sponsors are required to provide substantial evidence of effectiveness and safety from adequate and well-controlled clinical trials. On the other hand, the U.S. Food and Drug Administration (FDA) …

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Chapter 34

Calibration
When a new pharmaceutical compound is discovered, most regulatory agencies such as the United States Food and Drug Administration (FDA) require that an analytical method or test procedure for quantitation of the active ingredients of the compound be …

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Chapter 35

Canadian Health Products and Food Branch (HPFB) and Therapeutic Products Directorate (TPD)
Health Canada, the Canadian federal department with a mission to help the people of Canada maintain and improve their health, had a major organizational realignment in July of 2000. The former Health Protection Branch (HPB) was divided into several new …

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Chapter 36

Cancer Trials
Owing to the severity of many types of cancer, the critical need for improvement in therapies, and the large amount of research in this area, efficient designs and analyses for cancer clinical trials are of great importance. This review presents the major …

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Chapter 37

Carcinogenicity Studies of Pharmaceuticals
The assessment of the risk of exposure to a new drug in humans usually begins with an assessment of the risk of the drug in animals. It is required by law that the sponsor of a new drug conducts nonclinical studies in animals to assess the pharmacological …

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Chapter 38

Carry‐Forward Analysis
In clinical studies, data are often collected over time. The data collected over a period of time from subjects participating in these studies are referred to as longitudinal data by statisticians and biometricians. In longitudinal studies, each subject …

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Chapter 39

Case-Control Studies, Inference in
In general, giving only the absolute or only the relative benefits does not tell the full story; it is more informative if both researchers and the media make data available in both absolute and relative terms. For individual decisions…consumers need …

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Chapter 40

Center Weighting in Multicenter Trials
Clinical trials comparing treatment therapies are commonly conducted using patients from a number of different sites. The primary motivation for using multiple centers is to enable enrollment of a sufficient number of patients to investigate a hypothesis …

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Chapter 41

Clinical Data Management
Clinical data management (CDM) is the process of collecting and validating clinical information with the goal of converting it into an electronic format to answer research questions and to preserve it for future scientific investigation. As computerized …

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Chapter 42

Clinical Endpoint
A clinical trial is an experiment performed by a health care organization or professional to evaluate the effect of an intervention or treatment against a control in a clinical environment. It is a prospective study to identify outcome measures that are …

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Chapter 43

Clinical Pharmacology
This area of study is fairly broad. The following excerpt from the introduction to The Pharmacological Basis of Therapeutics [1] gives a glimpse at this field of study: “The clinician is understandably interested mainly in the effects of drugs in man. …

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Chapter 44

Clinical Trial Process
Regardless of the setting—whether a research group in an academic or healthcare institution, or a research and development organization in a small venture capital‐based or large multinational pharmaceutical company—there are forces that demand these …

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Chapter 45

Clinical Trial Simulation
In the new era of high technology, the traditional process for medical research and drug development has also evolved to become more time- and cost-effective. Clinical trial simulation, which utilizes the computer to simulate virtual patients in the …

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Chapter 46

Clinical Trial Simulations for Earlier Development Phases
Clinical trial simulation (CTS) is a powerful tool for designing, monitoring, and analyzing clinical trials. In recent years, simulation has been used in pharmacokinetic and pharmacodynamic modeling, assessing cardiologic abnormalities, and optimizing …

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Chapter 47

Clinical Trial Simulations for Later Development Phases
The traditional approach to drug development is a mixture of statistical and ad hoc methods. In many cases, assumptions are often introduced to simplify the problem and fit it into the statistics paradigm. In other cases, ad hoc decisions have to be made …

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Chapter 48

Clinical Trials
The randomized clinical trial (RCT) is broadly considered to be the most effective approach to evaluating a new therapeutic modality and to testing an existing therapy in a new setting. In this article, we provide a broad overview of some general …

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Chapter 49

Cluster Trials
Cluster trials are studies that evaluate interventions delivered to intact social groups or clusters, such as communities, churches, schools, workplaces, and medical practices, while outcomes are measured on members of those groups. Today, cluster trials …

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Chapter 50

Clustered Study Designs: Power Analysis
Power analysis is an important component in the design and planning of modern clinical trials. It provides information for assessing the feasibility of a study to detect some prespecified effect size and for estimating the amount of resources necessary …

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Chapter 51

Combination Drug Clinical Trial
Combination treatments are widely used in medicine. The U.S. Food and Drug Administration’s general policy regarding fixed-dose, combination-dosage form prescription drugs for humans is that two or more drugs may be combined in a single-dosage form when …

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Chapter 52

Comparing Variabilities in Clinical Research
In most clinical trials comparing a test drug and a control (e.g., a placebo control or an active control), treatment effect is usually established by comparing mean response change from baseline of some primary study endpoints assuming that their …

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Chapter 53

Confidence Interval and Hypothesis Testing
Parameter estimation is a primary objective in almost every kind of study, whether it is a clinical trial to evaluate the efficacy of a drug or vaccine, a cohort study of excess risk of disease due to toxic exposure, an epidemiological study of disease …

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Chapter 54

Confounding and Interaction
Confounding and interaction, or effect modification, are most commonly discussed in the epidemiological literature. For epidemiological studies, which are generally prospective or retrospective, nonrandomized studies, the principle of confounding is …

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Chapter 55

Content Uniformity
Content uniformity is a measure of the variation in the amount of active ingredient from one dosage to the next. In a perfect world, every dosage unit would contain exactly the same amount of drug. However, in the real world of manufacturing tablets, …

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Chapter 56

Contract Research Organization (CRO)
Over the years, the pharmaceutical industry has developed a full‐scale capability to carry out research from laboratory discovery to biological screening, animal toxicity studies, formulation, clinical pharmacology, stability, clinical trials, new drug …

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Chapter 57

Correlated Probit Model
Probit models are commonly used to describe the relation between one or more independent variables and a quantal response (e.g., alive or dead; mild, moderate, or severe degree of illness). They are often motivated from the idea of a latent continuous …

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Chapter 58

Cost-Effectiveness Analysis
As resources have become scarcer and public accountability has become greater, health care providers have been forced to reexamine the costs and the benefits of its activities as a step in enhancing their abilities to allocate resources more effectively. …

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Chapter 59

Covariate-Adjusted Adaptive Dose-Finding in Early Phase Clinical Trials
Most methods for sequentially adaptive dose-finding in phase I clinical trials characterize outcome as an indicator YT of toxicity and assume that patients are homogeneous. Dose-finding is based on an algorithm involving (x, YT ) 1,2 or model-based …

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Chapter 60

Crossover Design
“A cross-over trial is one in which individual subjects are given sequences of treatments with the object of studying differences between individual treatments (or subsequences of treatments).”1

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Chapter 61

Cutoff Designs
The randomized design is the preferred method for assessing the efficacy of treatments. Randomization of all subjects should be employed whenever possible. Randomization, in principle, serves at least three important purposes: (i) it avoids known and …

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Chapter 62

Data Mining and Biopharmaceutical Research
Outcomes research requires routine data collection and the examination of information. Physicians should have a prominent role in decisions involving data collection, storage, and retrieval. However, physicians still have difficulty in adequately …

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Chapter 63

Data Monitoring Committees (DMC)
The use of Data Monitoring Committees (DMCs) in clinical studies has proliferated over the past several years for studies sponsored by the pharmaceutical industry. This has led to recent publication of the Food and Drug Administration (FDA) Draft Guidance …

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Chapter 64

Design and Analysis for Demonstrating Disease Modification Effects
In drug development, when the cause or etiology of a disease is known, a suitable treatment can be developed to alter its underlying pathogenic process and thereby abate its symptoms. However, for some chronic illnesses such as rheumatoid arthritis, …

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Chapter 65

Diagnostic Imaging
In drug research and development, diagnostic imaging refers to a variety of new innovative techniques to identify disease or injury via images representing the internal anatomic structure of the human body. Physicians use the resulting images to diagnose …

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Chapter 66

Dose Proportionality
In drug development, it is essential to manage a safe and effective dosing. While a complete pharmacokinetic (PK) profile for all doses is impossible to establish, prediction of PK effects in a certain dose range can easily be made if the compound …

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Chapter 67

Dose Response Analysis in Clinical Trials
A primary objective of clinical trials in the drug development process is the selection of an optimal dose or range of doses forphysicians to prescribe. Dose–response analysis plays an integral role in achieving this objective. Ruberg1 summarizes the …

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Chapter 68

Dose Response Study Design
For every drug that is available at the pharmacy, there is information regarding how much drug should be used by a patient. In many over‐the‐counter drugs, such information may also be available for adults and children separately.

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Chapter 69

Dropout
In clinical studies, the length of time for a study can vary tremendously, ranging from a few days or weeks to possibly a few years. For example, in an osteoporosis trial, to illustrate efficacy, subjects must be followed for two to three years. During …

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Chapter 70

Drug Development
Most of the drugs available in pharmacies started out as a chemical compound or a biologic discovered in laboratories. When first discovered, each new compound or biologic is denoted as a drug candidate. The drug candidate has to demonstrate some …

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Chapter 71

Ecologic Inference
Ecological data (e.g., health-surveillance data such as vital statistics and registry data) are often collected at great expense and therefore should be exploited fully. They are useful for detecting trends in behaviors, health, and disease; for initial …

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Chapter 72

ED50/ED90
Data in which each observation assumes only one of two possible outcomes are called binary. This type of data arises in many situations. One area where binary data are frequently observed is biological assay. Much has been written about the toxicity of …

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Chapter 73

Enrichment Design
In clinical trials, the target population is defined by the inclusion and exclusion criteria. As a result, a screening period is usually conducted for the purpose of identifying the eligible subjects before actually enrolling them into the study. On the …

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Chapter 74

Equivalence Trials
Most of the trials conducted during the developmental stage of investigational pharmaceuticals before filing the New Drug Application (NDA) or Product License Application (PLA) are for demonstration of better efficacy and safety of the test product over …

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Chapter 75

Ethnic Factors
Can efficacy and safety data about an experimental drug or device from a trial conducted in one region be extrapolated to other regions? Will governmental regulatory bodies accept data collected in a region other than its own in support of drug or device …

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Chapter 76

Evaluation of Linearity in Assay Validation
In validation of quantitative analytical laboratory procedures, one of the most important characteristics of the accuracy is the linearity. The ICH Q2A guideline1 defines the linearity of an analytical method as its ability (within a given range) to …

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Chapter 77

Expiration Dating Period
The Food and Drug Administration (FDA) requires that for every drug product on the market, an expiration dating period must be indicated on the immediate container label. The expiration dating period (or shelf-life) is defined as the time interval that …

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Chapter 78

Exploratory Factor Analysis
Factor analysis is a multivariate method concerned with detecting and analyzing patterns based on the correlations among quantitative variables. In factor analysis, a set of measured variables is reduced into a smaller, more manageable set of unobservable …

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Chapter 79

Extra Variation Models
Consider a study where experimental units are clusters and each elemental unit within the cluster is classified into two mutually exclusive categories. If we assume elemental units are independent, the binomial model is appropriate for analyzing the data. …

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Chapter 80

Factor Analysis
Factor analytic methods are among a rich body of literature on statistical methods for multivariate continuous outcomes. The goal of factor analysis is data reduction of multiple measurements into a smaller number of latent outcomes or factors that are …

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Chapter 81

Factorial Designs
Factorial design theory is emerging as a fast, effective way of accumulating knowledge in most major sciences. It has been widely used in agricultural research, quality improvement, and cost reduction. Recently, we have seen its application growing fast …

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Chapter 82

Failure‐Time Model
In many clinical follow‐up studies, the primary endpoint is the time to some event of interest, e.g., time from initial treatment to local recurrence of tumor. Such events are generically called failures. The interval of interest, referred to as failure …

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Chapter 83

False Discovery Rate (FDR)
Multiple testing is a classical problem for many high-dimensional data sets. The breakthrough of technology for image analysis or genomics has given a new interest for this question. A classical application is microarrays. This technology is part of a new …

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Chapter 84

Food and Drug Administration
The Food and Drug Administration (FDA) is a U.S. government agency under the Department of Health and Human Services (DHHS) that plays a complex and important role in the lives of all Americans, as well as in the lives of consumers of many products grown, …

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Chapter 85

Generalizability Probability in Clinical Research
For marketing approval of a new drug product, the U.S. Food and Drug Administration1 (FDA) requires that at least two adequate and well-controlled clinical trials be conducted to provide substantial evidence regarding the effectiveness and safety of the …

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Chapter 86

Generalized Estimating Equation
The Generalized Estimating Equation (GEE, 1,2 ) method is an inferential procedure concerning the marginal mean of a multivariate outcome through regression models. The GEE method is based on assumptions regarding the first two moments, rather than the …

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Chapter 87

Generalized Estimating Equations (GEE) Method: Sample Size Estimation
Often, in controlled clinical trials, subjects are randomized to two treatment groups and evaluated at a baseline and at intervals across a treatment period. For example, in a study on labor pain, 83 women in labor were randomly assigned toapain …

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Chapter 88

Generalized Inference
Generalized test variables (GTVs) and generalized pivotal quantities (GPQs) were proposed by Tsui and Weerahandi,1 and Weerahandi,2 respectively. When the conventional frequenting methods fail to provide satisfactory solutions for hypothesis test or …

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Chapter 89

Genetic Linkage and Linkage Disequilibrium Analysis
Genetic mapping of human traits (phenotypes) aims to identify chromosomal regions that contain genes affecting traits of interest and especially genes that affect human susceptibility to particular diseases. There are many single-gene diseases (e.g., …

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Chapter 90

Global Database and System
Standardization is a generic solution applied in business reengineering. Analysis of the clinical data management, statistical analysis, and reporting processes has identified several elements where standardization would result in time savings. Analysis …

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Chapter 91

Good Clinical Practice
Clinical research is essential for the progress of medical science. Because it involves human subjects, their rights, safety, and well being must be protected, and the research should bring about meaningful results. Good Clinical Practice (GCP) is an …

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Chapter 92

Good Programming Practice
The operation of a biostatistics group in the drug development process is analogous to the process of building a house. Data coordinators prepare building blocks and lay a solid foundation. Statisticians are the architects with overall responsibility for …

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Chapter 93

Good Statistics Practice
Good statistics practice (GSP) in pharmaceutical research and development is defined as a set of statistical principles and/or standard operating procedures for the best biopharmaceuticals practices in design, conduct, analysis, evaluation, reporting, and …

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Chapter 94

Group Sequential Methods
The group sequential procedure (design, monitoring, and analysis) is the most commonly applied form of sequential procedure to facilitate the conduct of interim analysis in the biopharmaceutical field. A primary motivation of a group sequential analysis, …

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Chapter 95

Group Sequential Tests and Variance Heterogeneity in Clinical Trials
In clinical trials, investigators conduct a series of interim analyses of such summary statistics as means and variances in order to decide whether to terminate the trial early. If a treatment is deemed beneficial to patients, it is more ethical not to …

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Chapter 96

Hypotheses and False Positive Rate in Active ControlNon-Inferiority Trials
The purpose of clinical trials in drug development is usually to demonstrate that a new treatment is better than placebo or best supportive care. The hypotheses in such clinical trials involve only one parameter of interest, e.g., treatment effect (…

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Chapter 97

Hypothesis Testing
A common objective of any scientific experiment is to make valid inferences about a parameter (or parameters) of a well‐defined target population, on the basis of a sample of observed values from the population. For example, consider a randomized clinical …

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Chapter 98

Imputation in Clinical Research
Missing values or incomplete data are commonly encountered in clinical research and are studied by many authors. 1,2,3 Basically, the causes of missing values in a study can be classified into two categories. The first category includes thereasons that …

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Chapter 99

Imputation with Item Nonrespondents
In clinical research, an instrument (or questionnaire) consisting of a number of items (or questions) is usually used to quantitate a subject’s behavior and the ability to function in day-to-day activities as perceived by the subject. For example, the …

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Chapter 100

In Vitro Bioequivalence Testing
Bioequivalence testing is considered as a surrogate for the clinical evaluation of the therapeutic equivalence of drug products based on the Fundamental Bioequivalence Assumption that when two drug products (e.g., a brand name drug and its generic copy) …

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Chapter 101

In Vitro Dissolution Profile Comparison
Dissolution test is one of the most important in vitro tests that is used to assure the drug product quality. A dissolution profile comparison and assurance of similar profile is also an important step in assuring product performance in the presence of a …

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Chapter 102

In Vitro Micronucleus Test
Genetic toxicology tests are among the early studies conducted to assess the safety profile of a compound. They are designed to determine whether the compound can interact with DNA and lead to the production of gene mutations or chromosomal breakage. Some …

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Chapter 103

Individual Bioequivalence
The current concept for the assessment of bioequivalence (BE) is based on the Fundamental Bioequivalence Assumption that when two formulations of the same drug product or two drug products (e.g., a brand name drug and its generic copy) are equivalent in …

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Chapter 104

Instrument Development and Validation
A psychometric instrument can provide a standardized and objective means of collecting data on subjective states or events. Literally thousands of such instruments exist, ranging from ad hoc instruments composed by investigators for one time use up to …

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Chapter 105

Integrated Summary Report
There are many reasons to integrate and to summarize all the data from a clinical trial program. Each clinical trial in the program is unique in its objective and design. Some are small safety studies among normal volunteers, while others are efficacy …

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Chapter 106

Intention‐to‐Treat Analyses (ITT)
Randomization of therapy ensures that a therapy assignment is based on chance alone. This means that the baseline characteristics (measured and unmeasured) of the therapy groups should be comparable, with any differences due to chance. Thus, differences …

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Chapter 107

Interim Analysis
By interim analysis, we refer to any analysis, summarization, or presentation of clinical trial data which involves separate results produced according to treatment arm (which may be fully identified or coded, e.g., A/B), and which is produced prior to …

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Chapter 108

International Conference on Harmonization (ICH)
In drug research and development, health authorities in different countries have very similar-although different requirements for approval of the commercial use of drug products. As a result, pharmaceutical companies may repeatedly have to conduct similar …

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Chapter 109

Investigating Quality‐of‐Life in Clinical Trials
In many cases, treatment for cancer cannot cure the disease but can only prolong life. However, treatment comes at a cost. Medications that are potent enough to treat cancer can cause many serious adverse effects. At what point is the toxicity of a drug …

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Chapter 110

IVRS/IWRS for Randomization
The rapid development of the Internet and web browsers as well as computer telephony technology around the turn of the twenty-first century has enabled the automatic interchange of information between a computer and a digital phone or a web-based system. …

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Chapter 111

Kaplan–Meier Estimator
The Kaplan–Meier1 is a nonparametric estimator of distribution function of a time to event variable in the presence of independent censoring. The estimator is also referred to as the Product‐Limit estimator because it was first derived as the limiting …

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Chapter 112

Kappa Coefficients in Medical Research
A “kappa‐type” statistic, generally, is one formed by linearly recalibrating some statistic to have the value zero when the data on which it is based are randomly generated, and one, when the generation is, in some sense, optimal. However, the kappa …

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Chapter 113

Kullback–Leibler Divergence for Evaluating Equivalence
In many applications, we are interested in showing that two independent samples arise from similar underlying populations with distribution functions F and G, respectively. Testing the hypothesis H 0: F = G vs. the alternative H a : F ≠ G is not suitable …

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Chapter 114

Laboratory Analyses
In clinical trials, laboratory analyses may be used to determine the efficacy of a biopharmaceutical product such as in trials evaluating the effectiveness of lipid‐lowering drugs where changes in cholesterol levels would be a primary efficacy endpoint of …

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Chapter 115

Latent Class Analysis
A variable is latent if it cannot be directly measured, but can be inferred through the measurement of other related observable variables. For example, in mental health research, major depression is a latent variable: one cannot directly measure …

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Chapter 116

Lilly Reference Ranges
The Lilly Reference Ranges are updated sets of nonparametric reference intervals and delta limits for routine clinical laboratory analytes designed specifically for use in clinical trials. There are 40 sets of adult reference intervals, 5 sets for each of …

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Chapter 117

Local Influence Analysis
Statistical analyses are usually based on models, which are probabilistic descriptions of the process that generated the data. Very often, models involve some unknown parameters of intrinsic interest. These parameters are estimated using the data and lead …

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Chapter 118

Logistic Regression
Logistic regression is a model intended for situations in which the dependent variable Y consists of a binary (yes/no) outcome and the vector of independent variables or covariates x, as in ordinary linear models, may either be continuous, dichotomous, or …

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Chapter 119

Logistic Regression in Three‐Point Designs
Three‐point designs are frequently used in phase II clinical studies to establish a dose–response relationship before proceeding to larger confirmatory studies. In cases with a binary outcome, a logistic regression model is often adopted. As these studies …

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Chapter 120

Maximum Tolerable Dose for Cancer Chemotherapy
The primary scientific objective of the evaluation of new chemotherapeutic agents in cancer patients during the PhaseI clinical development is to employ an efficient, reliable, yet practical dose-finding design to search the highest dose with an …

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Chapter 121

McNemar’s Test
McNemar’s test is a statistical procedure used to compare two proportions which are dependent or correlated. Percentages or proportions of events resulting from 2 observations made on the same or matched experimental units under 2 different conditions may …

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Chapter 122

Measuring Agreement
Consider the problems of assessing the acceptability of a new or generic process, methodology, and/or formulation in areas of laboratory performance, instrument/assay validation or method comparisons, statistical process control, goodness of fit, and …

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Chapter 123

MedDRA and Its Impact on Pharmaceutical Development
Since its formal commercial introduction in 1999, MedDRA remains granular, containing more than 85,000 terms across the encoding levels (Lowest Level Terms (LLTs) and Preferred Terms (PTs)). The term level used for encoding may vary with the sponsor or …

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Chapter 124

Medical Devices
Medical devices comprise a staggering array of products that include everything from diagnostic tests and monitors, to therapeutic machines and instruments and replacements for failing body parts. They include artificial skin, hips, knees, and breast …

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Chapter 125

Meta-Analysis of Therapeutic Trials
How can a large amount of independent quantitative information on the same question come together in a coherent and meaningful manner? Many researchers have relied on meta-analysis to achieve such synthesis of evidence. Traditional journal review articles …

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Chapter 126

Microarray Gene Expression
A gene consists of a segment of deoxyribonucleic acid (DNA). A DNA molecule is a double-stranded polymer composed of four basic molecular units called nucleotides. The expression of genetic information stored in the DNA molecule occurs in two stages: (i) …

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Chapter 127

Minimization Procedure
Randomized clinical trials are considered as “golden standard” in evaluating a new treatment or therapy. From the name, it is easy to know that the randomization is one of the most important components in a clinical trial. Randomization procedure was …

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Chapter 128

Minimum Effective Dose
Moore1 has pointed out that the difference between a drug and a poison is the dose. To provide an effective and safe treatment of a certain disease, it is extremely important to identify the dosing range of a pharmaceutical product. The lower bound of the …

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Chapter 129

Ministry of Health, Labour and Welfare and Pharmaceutical Administration in Japan
Advances in science and technology and changes in domestic and international situations have made pharmaceutical affairs even more complicated. As the social needs and demands arose, the system of pharmaceutical administration in Japan has been …

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Chapter 130

Missing Values in Repeated Measurement Designs
Repeated measurement designs are popular in clinical trials for studies comparing the efficacy of several noncurative treatments because they can effectively remove within‐subject variances, by taking repeated measurements from each subject with different …

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Chapter 131

Mixed Effects Models
Mixed effect models have been the subject of active theoretical research for about three decades. The increasing availability of software for performing the intensive calculations required to implement mixed effect model methods has made it practical to …

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Chapter 132

Mixed-Outcome Data
Mixed outcomes are ubiquitous in applications in health and medicine, and joint analysis of such outcomes entails specification of models flexible enough to accommodate them. Such joint models are potentially advantageous in several statistical and …

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Chapter 133

MMRM with Missing Data
In clinical research of drug development, missing values in longitudinal data are common due to early drop out. Missing values usually lead to a potential source of bias in data interpretation.1 Therefore the method of handing missing values is critical …

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Chapter 134

Modified Large Sample Method
Linear combinations of variance components are frequently considered when the parameter of interest is individual or gross variability in statistical experimental designs. Because of the lack of an exact confidence interval for a general linear …

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Chapter 135

Multicenter Trials
A multicenter clinical trial is a clinical trial (see Clinical Trials entry) involving more than one clinical center (i.e., study site, investigator, field site, clinic) that is conducted to evaluate the effectiveness of a therapeutic agent according to a …

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Chapter 136

Multicollinearity
The high throughput of data arising from microarrays, or the complete sequence of the human genome has left scientists with a rich and extensive information source. Moreover, the wide availability of software and the increase in computer power have …

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Chapter 137

Multidimensional Data Analysis: An Overview of Penalized Regression Methods
Developments in bio-imaging technology have made it possible to widely use genome-wide experiments to do whole-genome analyses of Single Nucleotide Polymorphism (SNP) patterns, microarray-based gene expression analyses, and modern-mass-spectrometry-based …

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Chapter 138

Multinational Clinical Trial
Multinational clinical trials of investigational drugs or of approved drugs for new indications have become increasingly popular over these past several years. In most cases, they are set up in order to complete the trial more rapidly, particularly when …

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Chapter 139

Multiple Comparisons
Generally, a phase II/III trial involves collecting data for evidence to show the efficacy and safety of an experimental drug. The integrity of this evidence relies heavily on such factors as the design, the patients recruited, the overall conduct of the …

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Chapter 140

Multiple‐Dose Bioequivalence Studies
The purpose of a bioequivalence study is to determine if two products, containing the same amount of therapeutic agent, are sufficiently similar in their rate and extent of drug absorption so that they can be interchangeably used in a patient to produce …

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Chapter 141

Multiple Endpoints
A common problem arising in medical research is that of comparing some groups of patients (for instance, the arms of a clinical trial) based on multiple outcome measures called endpoints, all of which must be considered of primary importance and have no …

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Chapter 142

Multiple-stage Designs for Phase II Cancer Trials
The primary objective of a Phase II cancer trial is to determine if a treatment is “active” or efficacious enough to warrant a definitive Phase III clinical trial. Traditionally, the development of Phase II trial designs has focused on cytotoxic …

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Chapter 143

Multiplicative Intensity Models
Multiplicative intensity (MI) models are used to analyze recurrent event data, where subjects repeatedly experience an event, or events of various types, throughout the study, for example, a certain type of tumor (or different types of tumors) occurring …

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Chapter 144

Multiplicity in Clinical Trials
Multiplicity, loosely defined, refers to multiple inferences that are made in a simultaneous context. For the past two decades, there has been a resurgence of interest in multiplicity issues in clinical trials. 1,2,3,4,5,6,7 Multiplicity arises in almost …

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Chapter 145

Multivariate Meta-Analysis
Meta-analysis is the joint statistical analysis of results from a number of related studies to obtain an overall perspective on an effect or outcome of interest. There are often multiple dimensions to the same outcome and so it is common for outcomes to …

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Chapter 146

Noninferiority Analysis in Active Controlled Clinical Trials
Non-inferiority analysis for comparing a new experimental therapy with a selected active (or positive) control therapy is a difficult and often very controversial subject, 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 particularly when the active controlled …

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Chapter 147

Non-parametric Regression
Non-parametric regression is a fundamental tool in data analysis and provides an effective and simple way of finding data structure. The goal is to recover an unknown function based on sampled data that are contaminated with noise. Hess et al.1 have …

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Chapter 148

Odds Ratio
In epidemiological literature, odds ratio has been frequently used to assess the strength of the association between a binary exposure variable and a binary disease outcome. It was first introduced by Cornfield1 as a measure of relative risk in …

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Chapter 149

Onset of Action
Fast onset of beneficial effect is often a very desirable attribute for a pharmacological agent. The time frame that would constitute fast onset depends on the disorder and the expectation of an effective therapy for the disorder. For analgesics, for …

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Chapter 150

Ordered Multiple Class Receiver Operating Characteristic (ROC) Analysis
Assessment of diagnostic markers for classification and prediction in two-class classification problems is commonly performed with the use of receiver operating characteristic (ROC) curves. The two classes under study are commonly referred to as the …

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Chapter 151

Outlier Detection in Clinical Research
In clinical studies, detection of potential outlying observations is a critical step in the data analysis process before reaching any final conclusion of the study. The presence of outlying observations can affect the results of an analysis. In particular,…

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Chapter 152

P-Values
A p-value is the probability of observing a result as extreme or more extreme than that observed given that the null hypothesis (H0) is true. To be able to calculate a p-value, one thus requires at least three things: a null hypothesis, a probability …

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Chapter 153

P-Values, Evidence, and Multiplicity Considerations for Controlled Clinical Trials
Multiplicity is widespread in clinical trials and is of increasing concern because many trials now aim at multiple objectives of different regulatory and scientific importance. Potential sources of multiplicity in trials include comparison of several dose …

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Chapter 154

Parallel Design
Statisticians involved in clinical research in the pharmaceutical industry encounter design of experiments almost on a daily basis while writing protocols for their clinical studies. At the outset, the primary objective(s) described in the protocols …

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Chapter 155

Patient Compliance
Poor compliance to prescribed medication is a common problem that can have a major impact on the success of routine patient care and on the conduct and conclusions of clinical trials. Reported clinical correlates of poor compliance include increased …

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Chapter 156

Percentile Charts on Correlated Measures
Percentile (or centile) charts are often used in health monitoring, medical screening, and clinical studies. In typical applications, a health professional compares certain physical or medical measurements taken from a particular subject with age-specific …

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Chapter 157

Pharmacodynamic Issues
There are several ways of defining pharmacodynamics. Here are three examples. The branch of pharmacology dealing with the reactions between drugs and living systems.[1]The study of the biochemical and physiological effects of drugs and their mechanisms of …

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Chapter 158

Pharmacodynamics with Covariates
In this entry, we will discuss several univariate statistical methods that are used mostly for Phase III clinical studies for considering explanatory factors other than treatment variable and pharmacodynamic (PD) response. We specify the underlying …

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Chapter 159

Pharmacodynamics with No Covariates
In this entry, we will discuss several univariate statistical methods that are used mostly for Phase III clinical studies for considering one independent and one dependent variable. This entry will serve as a review for biostatisticians and as a utility …

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Chapter 160

Pharmacoeconomics
The evaluation of pharmaceutical and biological products has traditionally focused on considerations of safety and efficacy. Federal regulation requires that studies of safety and efficacy be conducted before a product is approved and marketed, and as a …

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Chapter 161

Phase I Cancer Clinical Trials
The phase I clinical trials represent the first time drugs are given to man and are mainly carried out to establish human toleration. In many phase I clinical trials, the subjects are healthy adult volunteers, while in phase I cancer clinical trials, the …

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Chapter 162

Placebo Effect
Prior to the advent of modern medicine, many medications prescribed as a part of medical practice were subsequently found to be pharmacologically inert. Despite this fact, such inactive medication, often referred to as a “placebo”—which literally means “I …

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Chapter 163

Population Bioequivalence
Bioequivalence studies are conducted to demonstrate equivalence in the bioavailability of the active ingredient in different formulations. The U.S. Food and Drug Administration (FDA) requires pharmaceutical companies to show bioequivalence between …

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Chapter 164

Population PK/PD Analysis
Pharmacokinetics and pharmacodynamics are divisions of pharmacology that study the action of the body on the drug and the action of the drug on the body, respectively. They complete dose titration studies aimed to select rational dosage regimens.

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Chapter 165

Postmarketing Adverse Drug Event Signaling
A sponsor seeking to market a new drug product is required by law to have an application [new drug application (NDA)] reviewed and approved by the U.S. Food and Drug Administration (FDA). The principal requirement of the NDA is that the safety and …

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Chapter 166

Postmarketing Surveillance
Drugs are not approved for general use until they go through an elaborate testing period. The “gold standard” of randomized, controlled trials must be utilized for drugs to be granted approval. However, once a drug is released on the market, it can be …

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Chapter 167

Power
The “power” of a statistical test is the probability of rejecting the null hypothesis when it is false. Closely related to statistical power is the false‐negative rate, which is often referred to as the Type II error or beta error. The false‐negative rate …

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Chapter 168

Prediction Trees
Prediction trees are powerful tools for extracting predictive information from data. Their use is increasingly frequent in biomedical research, as in many other fields of application. The conceptual developments leading to the algorithms now in use …

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Chapter 169

Principal Component Analysis
This article discusses the concepts, analysis, and some biomedical applications of principal components. Originated by Pearson1 and later formalized by Hotelling,2 principal component analysis has become one of the best known techniques of exploratory …

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Chapter 170

Prior Effective Sample Size of a Bayesian Model
Understanding the strength of a prior distribution relative to the likelihood is a fundamental issue when applying Bayesian methods. The processes of formulating a putatively non-informative prior or eliciting a prior from an area expert typically require …

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Chapter 171

Process Validation
The Food and Drug Administration (FDA) defines validation in their 1987 publication Guideline on General Principles of Process Validation 1 as “establishing documented evidence which provides a high degree of assurance that a specific process will …

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Chapter 172

Profile Analysis
For some locally acting drug products, such as nasal aerosols and nasal sprays, bioavailability (BA) and bioequivalence (BE) assessments are complicated because delivery to the sites of action does not occur primarily after the systemic absorption. …

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Chapter 173

Propensity Score Analysis and Its Application in Regulatory Settings
First introduced by Rosenbaum and Rubin,1 the propensity score e(X) for a subject with a vector X of observed covariates is the conditional probability of receiving treatment (Z = 1) rather than control (Z = 0) given X:

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Chapter 174

Proportion of Treatment Effect
A surrogate endpoint of a clinical trial is a surrogate biomarker intended to supplant a clinical endpoint, characteristic, or variable that directly reflects how a patient feels or functions, or how long a patient survives.1 Examples of “true” clinical …

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Chapter 175

Proportional Hazards Regression Model
An objective of many medical studies is the prognostic assessment of time to an event, denoted T, such as the remission of symptoms, the progression of a disease, or the onset of death. Clinical studies can be designed to obtain information concerning …

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Chapter 176

Protocol Development
The goal of this entry is to abstract the guidance published by the European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA) 1,2,3,4,5,6,7 as a convenience for the statistical practitioner faced with the task of describing in the …

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Chapter 177

QT Analysis
Cardiac repolarization is a normal, physiologic process that occurs in man by the outward movement of potassium ions through specific channels in myocardial cell membranes. An undesirable feature of some pharmaceutical agents is their ability to delay …

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Chapter 178

Randomization
Randomization plays an important role in the conduct of clinical trials. Randomization not only generates comparable groups of patients who constitute representative samples from the intended patient population but also enable valid statistical tests for …

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Chapter 179

Rank-Based Robust Analysis for Crossover Design

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Chapter 180

Rank Regression in Stability Analysis
In the pharmaceutical industry, stability study is performed to determine the shelf-life of drug product. It provides the assurance that the capacity of a drug product maintains its identity, strength, quality, and purity before the drug expiration date. …

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Chapter 181

Release Targets
Manufacturers of drug products must demonstrate that their products meet with United States Pharmacopeia specifications before the products can be released for sale. One of the important specifications is the low registered limit (LRL) on drug’s potency. …

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Chapter 182

Reliability
Classical statistical analysis usually assumes that data are measured without error. Yet even in exact sciences such as physics, data are recorded with errors, and these are even more important when data are the result of ratings. One usually …

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Chapter 183

Reproducibility Probability in Clinical Research
For marketing approval of a new drug product, the United States Food and Drug Administration (FDA) requires that at least two adequate and well-controlled clinical trials be conducted to provide substantial evidence regarding the effectiveness and safety …

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Chapter 184

Reproductive/Developmental Studies
Soon after the thalidomide tragedy in the late 1950s and early 1960s, which resulted in over 8000 malformed babies, there has been a great deal of interest in predictive tests of reproductive and developmental effects. The ultimate goal of the studies is …

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Chapter 185

Response-Adaptive Designs
Response‐adaptive designs, or response‐adaptive randomization procedures, are designs that change allocation away from 50/50 based on responses observed so far in the trial. The desired allocation proportion is usually motivated by an ethical …

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Chapter 186

Response-Adaptive Repeated Measurement Designs for Clinical Trials
Drug development is complex and costly. It requires researchers to test the potential of numerous chemical compounds to treat the disease. Use of prior experiences and/or accumulated information can advance the development of clinical trial designs. …

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Chapter 187

Response Surface Methodology
Response surface methodology (RSM) is defined as a collection of mathematical and statistical methods that are used to develop, to improve, or to optimize a product or process. It comprises of statistical experimental designs, regression modeling …

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Chapter 188

Risk Ratio Analysis
As the risk ratio (RR), defined as the ratio of probabilities of developing a disease between the population with exposure and the population without exposure to a risk factor, was introduced,1 the RR has been the most important index to measure the …

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Chapter 189

ROC Curve
In the recent development of diagnostic imaging, the receiver operating characteristic (ROC) curve has become a useful tool to distinguish differences in diagnostic performance. Use of this method enhances the traditional measures, and is now well …

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Chapter 190

Sample Size Calculation Based on Nonparametric Statistics
Sample size calculation plays an important role in clinical research.1 The objective of sample size calculation is to select an appropriate sample size so that not only the Type I error probability can be controlled under the specified level when the null …

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Chapter 191

Sample Size Calculation for Survival Data
Accurate determination of the required sample size for survival studies involves various factors that either are unique to these studies or are not typically considered in nonsurvival studies. These include the survival distributions, censoring …

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Chapter 192

Sample Size Determination
Sample size determination refers to the evaluation of the sample size desired or required for a study during the design stage, before data are collected. A fundamental rule of sample size determination is that the method of evaluation should bebased on …

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Chapter 193

Sample Size Re‐estimation Based on Observed Treatment Difference
Sample size re‐estimation based on an interim treatment difference is an adaptive clinical trial strategy that allows modification of the initially projected total sample size based on an observed treatment difference at an interim stage of a clinical …

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Chapter 194

Screening Design
A “screening design” refers to an experimental design that is applicable when a large number of potential causative factors need to be examined to find the most important few that may have an effect on one or more responses of interest. Screening designs …

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Chapter 195

Selection of Control in Clinical Trials
Why is control necessary in clinical trials? The rationale is being well documented in ICH E‐10 Guidance—Choice of Control Group and Related Design Issues in Clinical Trials.1 First, the control serves as a comparator that allows for discrimination of …

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Chapter 196

Semi-Parametric Time-Varying Regression Models
In biomedical applications, there will often be important time-varying effects. A typical example is a treatment effect that varies over time, and two important examples are where (i) treatment efficacy fades away over time owing to, for example, …

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Chapter 197

Sequential Estimation for the Additive Hazards Rate Model with Staggered Entry
In semiparametric survival studies that include covariates, it is often assumed that covariates have a multiplicative effect on the hazard rate function leading to the famous Cox Proportional Hazard Model (PHM). However, several studies have proved that …

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Chapter 198

Slope Approach for Assessment of Dose Proportionality/Linearity Under a Crossover Design
In pharmaceutical research and development, dose response studies are often conducted not only to assess drug tolerance and safety in Phase I clinical development but also to characterize drug–response curve with respect to efficacy in phase II clinical …

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Chapter 199

Spatio-Temporal Modeling
Spatio-temporal models and related methods of inference have seen considerable development over the past decade primarily due to developments in statistical methodology for modeling spatial data and Bayesian computational methods, as well as accessibility …

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Chapter 200

Specifications
In the pharmaceutical industry, “specifications” usually mean the same thing as “specification limits,” which refer to numerical tolerances within which the measured result for a quality attribute of a dosage form should fall. Specifications may also …

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Chapter 201

SROC Curve
The summary receiver operating characteristic (SROC) curve has been recommended to represent the performance of a diagnostic test, based on data from a meta-analysis. Under a fixed-effect, logit-threshold model, the position of the SROC curve can be …

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Chapter 202

Stability Analysis for Frozen Drug Products
For every drug product in the marketplace, the Food and Drug Administration (FDA) requires that an expiration dating period be indicated on the immediate container label. The expiration dating period is also known as shelf-life. The shelf-life of a drug …

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Chapter 203

Stability Matrix Designs
Stability studies are conducted “to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a retest …

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Chapter 204

Statistical Genetics
Most traits in nature and of fundamental importance to agriculture, biology, and health sciences are complex in terms of their genetic underpinnings. First, these traits are usually controlled by a network of genes that act independently or interactively …

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Chapter 205

Statistical Principles for Clinical Trials
The application of biostatistics in the drug development process is now recognized worldwide as being essential. Over the last 10–20 years, the increasing importance of biostatistical methodology has led to a rapid increase in the biostatistical resources …

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Chapter 206

Statistical Process Control
Statistical process control (SPC) is a collection of tools and techniques used to monitor, to control, and to improve a process. The primary goal of SPC is to achieve process stability and to improve process capability by reducing variability. A process …

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Chapter 207

Statistical Significance
Most controlled clinical trials are performed to demonstrate that a new investigational treatment is superior to a concurrent placebo or to an active control (superiority trials); that a test treatment is not inferior to an active treatment by more than a …

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Chapter 208

Statistical Tests for Biomarker Development with Applications to Genetics Data
Biomarker development usually involves several phases. For example, Pepe et al.1 provided five phases of biomarker development in cancer research including preclinical exploratory studies, clinical assay development, retrospective repository studies, …

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Chapter 209

Structural Equation Model
The structural equation model is a regression approach that allows to estimate a linear regression when independent variables are measured with error. The approach is based on defining latent variables, which represent unobservable true values; thus the …

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Chapter 210

Stuart–Maxwell Test
In clinical trials, categorical data analysis plays a crucial rule due to its broad applications that can be applied to different studies. There are many known test procedures that are used in categorical data analysis. For example, in the 2×2 independent …

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Chapter 211

Subgroup Analysis
Because there are many different segments of the population as a whole and because these different subgroups of the population respond differently to treatment, subject recruitment for randomized, controlled trials is now actively attempting to be fairly …

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Chapter 212

Subject-Treatment Interaction
That the effect of a treatment will vary among subjects is not surprising, nor is it a recent concept. Roses1 provided an 1892 quote by Sir William Osler, “If it were not for the great variability among individuals medicine might as well be a science and …

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Chapter 213

Surrogate Endpoint
In the development of a pharmaceutical product, a crucial step is to conduct clinical trials demonstrating the efficacy and safety of this product. The measurement used to evaluate the effect of the treatment is termed an endpoint. Endpoints used to …

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Chapter 214

Survival Analysis
Survival analysis is the study of time-to-event data. The distinguishing characteristics of such data are well-defined starting and ending points, and examples may be found in such diverse fields as demography, actuarial science, engineering, medicine, …

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Chapter 215

Targeted Clinical Trials
For the traditional clinical trials, clinical endpoints and clinical-pathological signs or symptoms are often used as the inclusion and exclusion criteria for the intended patient population in which the new treatments are evaluated with a concurrent …

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Chapter 216

Test for Ordered Categorical Data
In clinical trials for comparing an active treatment and a standard therapy, the scale for the primary clinical endpoint is recommended to be a continuous measure in order to provide an accurate and reliable assessment. In practice, however, it is …

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Chapter 217

Testing for Qualitative Interaction
In clinical trials involving comparison of two treatment groups, often investigators wish to know whether and how the between-treatment difference varies across patient subsets, which may be defined by prognostic factors such as age, gender, disease …

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Chapter 218

Therapeutic Equivalence
Traditionally, most of the trials conducted by the pharmaceutical industry during phases II and III are aimed at obtaining the necessary evidence for establishing the effectiveness and safety of the new therapeutic entity under development. Consequently, …

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Chapter 219

Titration Design
One of the most critical and challenging tasks in developing a new drug is to determine a dose range that provides an optimal therapeutic risk/benefit ratio in the targeted population. Clinical trials carried out to explore this optimal dose range can be …

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Chapter 220

Toxicological Studies
Toxicology is defined as “the knowledge of harmful effects of chemical substances on living organisms.” The methods of toxicology are used to assess the potential risk of substances to man and animals, in order to avoid adverse effects on health. Quite …

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Chapter 221

Traditional Chinese Medicine—General Consideration
In recent years, as more and more innovator drug products are going off patent, the search for new medicines that treat critical and/or life-threatening diseases has become the center of attention of many pharmaceutical companies. This leads to the study …

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Chapter 222

Translational Medicine: Concepts, Statistical Methods, and Related Issues
In early 2000, the U.S. Food and Drug Administration (FDA) kicked off Critical Path Initiative to assist the sponsors to identify possible causes of the scientific challenges underlying the medical product pipeline problems. The Critical Path …

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Chapter 223

Trend Estimation
In dose-effect data analysis, it is of interest to examine the effect (e.g., desirable effect or adverse effect) of different dosages of a drug or chemical in a system (e.g., an organ or a cell). Knowledge of the relationship between dosage and clinical …

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Chapter 224

Two-Stage Design: Phase II Cancer Clinical Trials
In the early development of a new therapeutic agent, the dose and schedule to be used in subsequent trials is determined through a phase I trial. With traditional cytotoxic agents for cancer treatment, this dose is generally known as the maximum tolerated …

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Chapter 225

USP Tests
United States Pharmacopeia (USP) tests are methods and procedures by which the acceptability of drug substances and drug products are determined and adjudicated. In the United States, the standards published in the United States Pharmacopeia and the …

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Chapter 226

Vaccine Clinical Trials
Clinical trials designed to demonstrate the safety and efficacy of new vaccines have a rich history. In 1954, the largest medical experiment in history tested a vaccine to prevent poliomyelitis, one of the most feared childhood diseases. This was the Salk …

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Chapter 227

Validation of Quantitative and Qualitative Assays
After an assay has been developed in a laboratory and before it can be used in clinical application (such as the diagnosis of a patient’s disease), a rigid clinical validation is carried out to demonstrate that the procedure is fit for use. The clinical …

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Chapter 228

Validity of LOCF
In clinical trials, data are often collected over a period of time from participating patients. In many situations, however, analyses are only based on data from the last time point (the end of the study) or change from the baseline to the last time …

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Chapter 229

Z-Score
The z-score is the most commonly used standard score.1 It is derived from the standard normal distribution with mean value 0 and standard deviation 1. Therefore, a z-score of an observation represents how far a value deviates from the mean value in terms …

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Chapter 230

Zero-Inflated Poisson Distribution
In clinical trials, it is common to observe data that are related to the occurrence of certain events, for example, the number of tumors in cancer trials and the number of erosions in gastrointestinal (GI) safety studies. These counts are usually …

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