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Drug development prior to 1800 was based almost completely on observational trial and error. The earliest known exception was a controlled drug trial conducted by James Lind in 1747 on an English ship to show the effectiveness of citrus fruit in the treatment of scurvy. Clinical tests, but not concurrent comparative trials, were conducted by Charles Maitland in 1722 in London to show the effectiveness of variolation in preventing smallpox, and a controlled drug trial was conducted by Edward Jenner in London in 1796 to show the effectiveness of material taken from cowpox sores of young milkmaids (later called smallpox vaccine) in preventing smallpox. In 1775, William Withering learned from an elderly woman herbalist in Shropshire, England about her use of the Foxglove plant (whose active ingredient Withering later determined to be digitalis) in treating heart disease, and in 1785 published the results of his treatment of 158 patients with the drug, but he did not conduct a controlled study.

The development of generic therapeutic nanoparticles faces a combination of scientific, patent and regulatory challenges.

Clark C. HavighurstDuke University School of LawPeter Barton HuttCovington & BurlingBarbara J. McNeilHarvard Medical SchoolWilhelmine MillerInstitute of Medicine In April 2000 the Institute of Medicine (IOM) and the Agency for Health-care Research and Quality (AHRQ) jointly hosted a one-day workshopto explore an intriguing and important intersection of medicine and law:the courtroom presentation of science-based medical evidence and exper-tise. This workshop was inspired by a concern that legal uses and inter-pretations of science-based medical evidence, particularly populationstudies and the findings of controlled clinical trials, may diverge sub-stantially from the uses and interpretation of that evidence by the med-ical and health care researchers who produce it and of the practitionersand health plans that use it in making clinical decisions and policies. Recognizing that a preliminary discussion among professions wasneeded even to describe the nature of their differences, the IOM andAHRQ, at the instigation of John M. Eisenberg, director of AHRQ, con-vened about twenty clinicians, epidemiologists, health services r esearchers,health plan executives, practicing and academic lawyers, jurists, andsocial scientists in the field of legal medicine (see appendix for partici-pants). Participants and presenters were asked to formulate empiricalresearch questions concerning both evidence-based medicine (EBM) andjudicial practices that might increase familiarity with, and therefore pro-mote greater reliance on, the use of science-based medical evidence bythe courts. Workshop participants were further asked to identify policy

The Federal Food, Drug, and Cosmetic Act (FD&C Act) establishes substantially different regulatory requirements in the United States for cosmetics and drugs. This chapter traces the history of U.S. regulatory policy for these two categories of products, discusses the application of U.S. law to products that fall within both categories at the same time (i.e., cosmetic drugs), and considers potential strategies for resolving the long-standing concern that the drug provisions of the Act impose overly stringent requirements on cosmetic drugs.

I. INTRODUCTION For almost a century, the Food and Drug Administration (FDA) has regulated nutrients and other dietary supplement ingredients and products1 under the food provisions initially of the Federal Food and Drugs Act of 19062 and now of the Federal Food, Drug and Cosmetic Act of 19383 ("FD&C Act"), as amended. Congress amended the FD&C Act through the Food Additives Amendment of 19584 and the Color Additive Amendments of 1960(5) to strengthen FDA authority over food ingredient safety. In 1976, Congress enacted the Vitamin-Mineral Amendments6 which provides that FDA may limit the contents of dietary supplements only for safety reasons. In 1994, Congress enacted the Dietary Supplement Health and Education Act ("DSHEA")7 to continue the regulation of dietary supplements under the food provisions of the FD&C Act but to replace the food additive provisions with separate safety requirements for dietary supplements and dietary ingredients. Most recently, Congress enacted the Public Health Security and Bioterrorism Preparedness and Response Act of 20028 to provide additional authority to assure the safety of the food supply. This article summarizes the safety requirements applicable to dietary supplements and dietary ingredients under the FD&C Act (as amended by DSHEA and the other statutes referenced above), describes the safety requirements applicable to conventional food, and compares these two overlapping regulatory programs. II. SUMMARY Nutrients and other ingredients intended to supplement the daily diet-whether added to a dietary supplement or to a conventional food product-have been regulated by FDA under the food provisions of the 1906 and 1938 Acts for almost a century.9 The same regulatory requirements have been applied by FDA to these nutrients and related ingredients in whatever type of product they are used. These products have been regulated as drugs only where the labeling or the advertising has specifically represented them for therapeutic use. It is widely and erroneously believed that DSHEA eviscerated the FD&C Act safety requirements for dietary supplements. In fact, DSHEA did not alter the basic food safety provision in the FD&C Act that has since 1906 prohibited any poisonous or deleterious substance in food. For both old (pre-1994) and new dietary ingredients, DSHEA prohibits any significant or unreasonable risk of injury, authorizes an immediate ban of an imminent hazard, and authorizes FDA to impose requirements for good manufacturing practices ("GMPs").10 None of these statutory provisions applies to conventional food. DSHEA excludes old and new dietary ingredients from the food additive provisions of the FD&C Act, but requires that all new dietary ingredients be the subject of a premarket notification submitted to FDA with adequate safety information at least seventy-five days before marketing, unless the ingredient has been present in the food supply as an article used for food and in a form in which the food has not been chemically altered." All of the FD&C Act enforcement provisions apply to both old and new dietary ingredients and dietary supplements.12 DSHEA contains three procedural provisions that are applicable only to dietary supplements. First, DSHEA specifically places the burden of proof in a civil enforcement action relating to the safety of a dietary supplement on FDA.13 This is the same rule that applies in litigated court cases involving conventional food adulteration.14 Second, the court must decide the issue of adulteration of a dietary supplement on a de novo basis.15 This is the standard rule in any case where FDA institutes litigation against a product or company, but it reverses the current rule where a company challenges an FDA regulation.16 Third, FDA must provide a person an opportunity to present both oral and written views at least ten days before the agency refers a matter to the Department of Justice for civil court enforcement. …

Drug regulation in the United States has been the subject of extensive public literature and has been studied more thoroughly than any other aspect of American governmental regulation. Yet it remains mired in criticism and debate that, over the years, have threatened not only the existing regulatory system but also the stability of the American drug industry itself. This article summarizes the history of drug regulation in the United States, discusses the basic structure of the American regulatory system as it exists today, and relates some of the more important controversies that continue to surround this subject.

The first and most important source of new OTC drugs is switch of prescription drugs to OTC status. Other far more marginal sources are new chemical entities, marketed initially as OTC drugs, and new indications for previous OTC drugs. These sources identify an enormous potential for new OTC medicines. The American consumer is now ready and able to properly handle many new OTC drugs that are not yet available. The issue is whether industry, government, and consumers will be able to make the evaluation of OTC drugs proceed as it should to expand the number and kind of OTC drugs available.

D uring the past thirty years, pharmaceutical innovation in the United States has declined dramatically. As a result of the increased time needed for testing and other regulatory requirements, the effective patent life of a new pharmaceutical product has been reduced to less than half of the seventeen-year patent term set by Congress for all inventions. Legislation to restore this lost patent protection is urgently needed to reinvigorate investment in pharmaceutical research. A recent report of the National Academy of Sciences defined “innovation” in the following way: Economists define technological innovation as the initial commercial application of a new product or process. From the standpoint of the industrial firm, the activities leading to innovation involve a long-term investment decision process. This process incorporates the various stages of research, development, capital investment, and commercialization. A firm’s investment in these activities are influenced by the same basic forces that govern outlays on other investment projects. Thus, investments for R&D and innovation will be determined by their perceived profits and risks relative to alternative investment opportunities as well as the cost and availability of funds for investment. In the pharmaceutical industry, innovation is thus best measured by the number of new chemical entity (NCE) drugs approved by the Food and Drug Administration (FDA) for marketing during any particular time. These NCE drugs represent, in the words of the National Academy, “the initial commercial application of a new product or process.”

Since the enactment of the Drug Amendments of 1962, there has been no progress in reform of new drug regulation for three reasons. The recommendations for reform have come from outside FDA, and thus have had no leverage or clout. Congress has no interest in reforming drug regulation. The FDA bureaucracy has no incentive to reform the system. Progress in new drug regulation will therefore be extremely difficult in the future and may not be achievable.

The author examines the evolving university-industry relationships in the biotechnology area, addressing the conceptual basis for such arrangements and the resultant contract issues. He examines the need for development of policies in academia that will accommodate the needs of both government and industry without harming the integrity or institutional objectives of the university. The author then recommends a number of directives for written rules to help achieve these objectives, especially ones relating to patenting and licensing of inventions developed under industrial support.

In 1941 FDA first permitted a new drug application (NDA) to become effective for DES, for use as a human drug. New animal drug applications (NADA's) became effective beginning in 1947 for use of DES as a growth promotant for poultry, cattle, and sheep in animal feed, and later in animal implants. Using the analytical methods available at that time, no residues could be found in the tissues of the animals used for human food.