Design and Analysis of Clinical Trials

Concepts and Methodologies

Shein-Chung Chow, Jen-Pei Liu

• Publisher: Wiley
• Year: 2013
• ISBN:
  9781118458143
• Edition: 3
• Topic: Mathematics
• Subtopic: Probability & Statistics
• Index: Mathematics

Praise for the Second Edition:

"...a grand feast for biostatisticians. It stands ready to satisfy the appetite of any pharmaceutical scientist with a respectable statistical appetite." —Journal of Clinical Research Best Practices

The Third Edition of Design and Analysis of Clinical Trials provides complete, comprehensive, and expanded coverage of recent health treatments and interventions. Featuring a unified presentation, the book provides a well-balanced summary of current regulatory requirements and recently developed statistical methods as well as an overview of the various designs and analyses that are utilized at different stages of clinical research and development. Additional features of this Third Edition include:

• New chapters on biomarker development and target clinical trials, adaptive design, trials for evaluating diagnostic devices, statistical methods for translational medicine, and traditional Chinese medicine

• A balanced overview of current and emerging clinical issues as well as newly developed statistical methodologies

• Practical examples of clinical trials that demonstrate everyday applicability, with illustrations and examples to explain key concepts

• New sections on bridging studies and global trials, QT studies, multinational trials, comparative effectiveness trials, and the analysis of QT/QTc prolongation

• A complete and balanced presentation of clinical and scientific issues, statistical concepts, and methodologies for bridging clinical and statistical disciplines

• An update of each chapter that reflects changes in regulatory requirements for the drug review and approval process and recent developments in statistical design and methodology for clinical research and development

Design and Analysis of Clinical Trials, Third Edition continues to be an ideal clinical research reference for academic, pharmaceutical, medical, and regulatory scientists/researchers, statisticians, and graduate-level students.

PART I

Preliminaries

CHAPTER 1

Introduction

1.1 WHAT ARE CLINICAL TRIALS?

Clinical trials are clinical investigations. They have evolved with different meanings by different individuals and organizations at different times. For example, Meinert (1986) indicates that a clinical trial is a research activity that involves administration of a test treatment to some experimental unit in order to evaluate the treatment. Meinert (1986) also defines a clinical trial as a planned experiment designed to assess the efficacy of a treatment in humans by comparing the outcomes in a group of patients treated with the test treatment with those observed in a comparable group of patients receiving a control treatment, where patients in both groups are enrolled, treated, and followed over the same time period. This definition indicates that a clinical trial is used to evaluate the effectiveness of a treatment. Piantadosi (1997) simply defined a clinical trial as an experimental testing of medical treatment on human subjects. On the other hand, Spilker (1991) considers clinical trials as a subset of clinical studies that evaluate investigational medicines in phases I, II, and III clinical studies which are the class of all scientific approaches to evaluate medical disease prevention, diagnostic techniques, and treatments. This definition is somewhat narrow in the sense that it restricts the clinical investigation to be conducted by pharmaceutical companies during various stages of clinical development of pharmaceutical entities which are intended for marketing approval. The Code of Federal Regulations (CFR) defines a clinical trial as the clinical investigation of a drug that is administered or dispensed to or used involving one or more human subjects (21 CFR 312.3). Three important key words in these definitions of clinical trials are experimental unit, treatment, and evaluation of the treatment.

1. Experimental Unit. An experimental unit is usually referred to as a subject from a targeted population under study. Therefore, the experimental unit is usually used to specify the intended study population to which the results of the study are inferenced. For example, the intended population could be patients with certain diseases at certain stages or healthy human subjects. In practice, although a majority of clinical trials are usually conducted in patients to evaluate certain test treatments, it is not uncommon that some clinical trials may involve healthy human subjects. For example, at very early phase trials of clinical development, initial investigation of a new pharmaceutical entity may involve only a small number of healthy subjects, say, fewer than 30. Large primary prevention trials are often conducted with healthy human subjects with a size of tens of thousands of subjects. See, for example, Physician’s Health Study (PHSRG, 1989), Helsinki Health Study (Frick et al., 1987), Women’s Health Trial (Self et al., 1988), and Women Health Initiative Study (Women Health Initiative Study Group, 1998).

2. Treatment. In clinical trials a treatment can be a placebo or any combination of a new pharmaceutical identity (e.g., a compound or drug), a new diet, a surgical procedure, a diagnostic test, a medial device, a health education program, or no treatment. For example, in the Physician’s Health Study, one treatment arm is a combination of low-dose aspirin and beta carotene. Other examples include lumpectomy, radiotherapy, and chemotherapy as a combination of surgical procedure and drug therapy for breast cancer; magnetic resonance imaging (MRI) with a contrast imaging agent as a combination of diagnostic test and a drug for enhancement of diagnostic enhancement; or a class III antiarrhythmic agent and an implanted cardioverter defibrillator as a combination of a drug and a medical device for treatment of patients with ventricular arrhythmia. As a result, a treatment is any intervention to be evaluated in human subjects regardless of whether it is a new intervention to be tested or serves as a referenced control group for comparison.

3. Evaluation. In his definition of clinical trials, Meinert (1986) emphasizes the evaluation of efficacy of a test treatment. However, it should be noted that the assessment of safety of an intervention such as adverse experiences, elevation of certain laboratory parameters, or change in findings of physical examination after administration of the treatment is at least as important as that of efficacy. Recently, in addition to the traditional evaluation of effectiveness and safety of a test treatment, clinical trials are also designed to assess quality of life, pharmacogenomics, and pharmacoeconomics such as cost-minimization, cost–effectiveness, and cost–benefit analyses to human subjects associated with the treatment under study. It is therefore recommended that clinical trials should not only evaluate the effectiveness and safety of the treatment but also assess quality of life, utility of biomarkers, pharmacoeconomics, and outcomes research associated with the treatment.

Throughout this book we define a clinical trial as a clinical investigation in which treatments are administered, dispensed, or used involving one or more human subjects for evaluation of the treatment. By this definition, the experimental units are human subjects either with a preexisting disease under study or healthy. Unless otherwise specified, clinical trials in this book are referred to as all clinical investigations in human subjects that may be conducted by pharmaceutical companies, clinical research organizations such as the U.S. National Institutes of Health (NIH), university hospitals, or any other medical research centers.

1.2 HISTORY OF CLINICAL TRIALS

We humans since our early days on earth have been seeking or trying to identify some interventions, whether they be a procedure or a drug, to remedy ailments that afflict ourselves and our loved ones. In this century the explosion of modern and advanced science and technology has led to many successful discoveries of promising treatments such as new medicines. Over the years there has been a tremendous need for clinical investigations of these newly discovered and promising medicines. In parallel, different laws have been enacted and regulations imposed at different times to ensure that the discovered treatments are effective and safe. The purpose of imposing regulations on the evaluation and approval of treatments is to minimize potential risks that they may have for human subjects, especially for those treatments whose efficacy and safety are unknown or are still under investigation.

In 1906, the United States Congress passed the Pure Food and Drug Act. The purpose of this act is to prevent misbranding and adulteration of food and drugs. However, the scope of this act is rather limited. No preclearance of drugs is required. Moreover, the act does not give the government any authority to inspect food and drugs. Since the act does not regulate the claims made for a product, the Sherley Amendment to the act was passed in 1912 to prohibit labeling medicines with false and fraudulent claims. In 1931, the U.S. Food and Drug Administration (FDA) was formed. The provisions of the FDA are intended to ensure that (1) food is safe and wholesome, (2) drugs, biological products, and medical devices are safe and effective, (3) cosmetics are unadulterated, (4) the use of radiological products does not result in unnecessary exposure to radiation, and (5) all of these products are honestly and informatively labeled (Fairweather, 1994).

The concept of testing marketed drugs in human subjects did not become a public issue until the Elixir Sulfanilamide disaster occurred in the late 1930s. The disaster was a safety concern of a liquid formulation of a sulfa drug that caused more than 100 deaths. This drug had never been tested in humans before its marketing. This safety concern led to the passage of the Federal Food, Drug and Cosmetic Act (FD&C Act) in 1938. The FD&C Act extended its coverage to cosmetics and therapeutic devices. More important, the FD&C Act requires the pharmaceutical companies to submit full reports of investigations regarding the safety of new drugs. In 1962, a significant Kefauver–Harris Drug Amendment to the FD&C Act was passed. The Kefauver–Harris Amendment not only strengthened the safety requirements for new drugs but also established an efficacy requirement for new drugs for the first time. In 1984, the Congress passed the Price Competition and Patent Term Restoration Act to provide for increased patent protection to compensate for patent life lost during the approval process. Based on this act, the FDA was also authorized to approve generic drugs only based on bioavailability and bioequivalence trials on healthy male subjects. It should be noted that the FDA also has the authority for designation of prescription drugs or over-the-counter drugs. In the United States, on average, it will take a pharmaceutical company about 10 to 12 years for development of a promising pharmaceutical entity with an average cost between $800 million and $1 billion U.S. dollars. Drug development is a lengthy and costly process. This lengthy process is necessary to ensure the safety and efficacy of the drug product under investigation. On average, it may take more than 2 years for regulatory authorities such as the FDA to complete the review of the new drug applications submitted by the sponsors. This lengthy review process might be due to limited resources available at the regulatory agency. As indicated by the U.S. FDA, they will be able to improve the review process of new drug applications if additional resources are available. As a result, in 1992, the U.S. Congress passed the Prescription Drug User Fee Act (PDUFA), which authorizes the FDA to utilize the user fee financed by the pharmaceutical industry to provide additional resources for the FDA’s programs for development of drug and biologic products. However, the PDUFA must be reauthorized by the U.S. Congress every 5 years. Since its enactment in 1992, this program has enabled the FDA to reduce the average time required for review of a new drug application from 2 years to 1.1 years in 2011. In 1997, the U.S. Congress also passed the Food and Drug Administration Modernization Act (FDAMA) to enhance the FDA’s missions and its operations for the increasing technological, trade, and public health complexities in the 21st century by reforming the regulation of food, drugs, devices, biologic products, and cosmetics. On the other hand, the Biologic Price Competition and Innovation (BPCI) Act passed in 2009 provides an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference biological product.

The concept of randomization in clinical trials was not adapted until the early 1920s (Fisher and Mackenzie, 1923). Amberson et al. (1931) first considered randomization of patients to treatments in clinical trials to reduce potential bias and consequently to increase statistical power for detection of a clinically important difference. At the same time, a Committee on Clinical Trials was formed by the Medical Research Council of Great Britain (Medical Research Council, 1931) to promulgate good clinical practice by developing guidelines governing the conduct of clinical studies from which data will be used to support application for marketing approval. In 1937, the NIH awarded its first research grant in a...