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.® 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.
Table 1.2.1 Significant Historical Events in Clinical Trials and Regulations
Year Clinical Trials Regulations
1906 Pure Food and Drag Act (Dr. Harvey Wiley)
1912 Sherley Amendment 1923 First randomization to experiments (Fisher and Mackenzie, 1923)
1931 First randomization of patients to treatments in clinical trials Formation of U.S. Food and Drag Administration (Amberson, et al., 1931) Committee on clinical trials by the Medical Research Council of Great Britain (Medical Research Council, 1931)
1937 Formation of National Cancer Institute and First Research
Grant by National Institutes of Health (National Institutes of Health, 1981)
1938 U.S. Federal Food, Drug and Cosmetic Act (Dr. R. Tugwell) 1944 First publication of results from a multicenter trial (Patulin Clinical Trial Committee, 1944)
1952 Publication of Elementary Medical Statistics (Mainland, 1952) FDA makes designation of Prescription Drag or OTC
1962 Publication of Statistical Methods in Clinical and Amendment to the U.S. Food, Drag, and Cosmetic Act Preventive Medicine (Hill, 1962)
1966 Mandated creation of the local boards (IRB) for Funding by U.S. Public Health Service
1976 Medical Device Amendment to the U.S. Food, Drag Cosmetic Act (1976)
1977 Publications of General Considerations for Clinical Evaluation of Drugs (HEW (FDA), 1977)
1984 Drag Price Competition and Patent Term Restoration Act (Waxman and Hatch, 1984)
1985 NDA rewrite
1988 Publication of Guidelines for the Format and Content of the Clinical and Statistical Section of an Application (FDA, 1988)
1990 Publication of Good Clinical Practice for Trials on Medicinal Products in the European
Community (EC Commission, 1990)
1987 Treatment IND (FDA, 1987)
1992 Parallel track and accelerated approval (FDA, 1992)
Prescription Drag User Fee Act
1997 Publication of Good Clinical Practice: Consolidated Guidelines (ICH, 1996)
U.S. FDA Modernization Act
Table 1.2.2 Summary of Resources for Clinical Trials
Number of Clinical Trials Clinical Investigators Academic Clinical Research Center
Pharmaceutical, Biotechnology, and Medical Device Companies Contract Research Organization (CRO) Companies Provides Services to Clinical Trials Financial and Investment Professionals for Clinical Trials
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