Design and Analysis of Clinical Trials

Concepts and Methodologies
By Shein-Chung Chow Jen-pei Liu

John Wiley & Sons

Copyright © 2004 John Wiley & Sons, Inc.
All right reserved.

ISBN: 0-471-24985-8


Chapter One

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 medical treatment on human subject. 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, the clinical studies being the class of all scientific approaches to evaluate medical disease preventions, diagnostic techniques, and treatments. This definition is somewhat narrow in the sense that it restricts to the clinical investigation 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.

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 only involve a small number of healthy subjects, say fewer than 30. Large primary prevention trials are often conducted with healthy human subjects with size in tens of thousand subjects. See, for example, Physician's Health Study (PHSRG, 1988), Helsinki Health Study (Frick et al., 1987), and Women Health Trial (Self et al., 1988).

Treatment

In clinical trials a treatment can be a placebo or any combinations 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 that it is a new intervention to be tested or serves as a referenced control group for comparison.

Evaluation

In his definition of clinical trials, Meinert (1986) emphasizes the evaluation of efficacy of a test treatment. It, however, 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, impact of genetic factors, pharmacoeconomics, and outcomes research associated with the treatment.

Throughout this book we will 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 pre-existing 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 inflict 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 for 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 pass 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 $350 millions to $450 millions US. 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 two 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 so-called user fee financed by the pharmaceutical industry to provide additional resources for the FDA's programs for development of drug and biologic products. From 1992 to 1997, this program has enabled the FDA to reduce the average time required for review of a new drug application from 30 months to 15 months. 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.

The concept of randomization in clinical trials was not adapted until the early 1920s (Fisher and Mackenzie, 1923). Amerson 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 the 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 clinical trial. At the same time the U.S. National Cancer Institute (NCI) was also formed to enhance clinical research in the area of cancer. In 1944, the first publication of results from a multicenter trial appeared in Lancet (Patulin Clinical Trials Committee, 1944). Table 1.2.1 provides a chronic accounts of historical events for both clinical trials and the associated regulations for treatments intended for marketing approval. Table 1.2.1 reveals that the advance of clinical trials goes hand in hand with the development of regulations.

Oklin (1995) indicated that there are at least 8,000 randomized controlled clinical trials conducted each year whose size can include as many as 100,000 subjects. As more clinical trials are conducted worldwide each year, new service organization and/or companies have emerged to provide information and resources for the conduct of clinical trials. Table 1.2.2 provides a summary of resources available for clinical trials from a web-based clinical trial listing service called CenterWatch.(r) These trials are usually sponsored by the pharmaceutical industry, government agencies, clinical research institutions, or more recently a third party such as health maintenance organizations (HMO) or insurance companies. In recent years clinical trials conducted by the pharmaceutical industry for marketing approval have become more extensive. However, the sizes of clinical trials funded by other organizations are even larger. The trials conducted by the pharmaceutical industry are mainly for the purpose of registration for marketing approval. Therefore, they follow a rigorously clinical development plan which is usually carried out in phases (e.g., phases I, II, and III trials, which will be discussed later in this chapter) that progress from very tightly controlled dosing of a small number of normal subjects to less tightly controlled studies involving large number of patients.

According to USA Today (Feb. 3, 1993), the average time that a pharmaceutical company spends getting a drug to market is 12 years and 8 months. Of this figure, six years and 8 months are spent in clinical trials to obtain the required information for market registration. The FDA review takes 2 years and 6 months. As a result of PDUFA, the review time at the U.S. FDA has been reduced considerably. Table 1.2.3 provides a summary of median review time at the Center for Drug Review and Research (CDER) at the U.S. FDA in 2001. For example, for the 10 drugs receiving priority status, the median review time is only 6 months. The median overall approval time is 14 months. However, it is not surprising that new molecular entities requires about more than 7 months to review. This lengthy clinical development process is necessary to assure the efficacy and safety of the drug product. As a result, this lengthy development period sometimes does not allow the access of promising drugs or therapies to subjects with serious or life-threatening illnesses. Kessler and Feiden (1995) point out that the FDA may permit promising drugs or therapies currently under investigation to be available to patients with serious or life-threatening diseases under the so-called treatment IND in 1987. The Parallel Track Regulations in 1992 allow promising therapies for serious or life-threatening diseases to become available with considerably fewer data than required for approval. In the same year, the FDA published the regulations for the Accelerated Approval based only on surrogate endpoints to accelerate the approval process for promising drugs or therapies indicated for life-threatening diseases.

Continues...


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