Unapproved Drugs in the United States and the Food and Drug Administration

Adv Ther (2011) 28(10):842-856. DOI 10.1007/s12325-011-0059-4 REVIEW Unapproved Drugs in the United States and the Food and Drug Administration Alexander Nasr ∙ Thomas J. Lauterio ∙ Matthew W. Davis Received: May 17, 2011 / Published online: September 1, 2011 © The Author(s) 2011. This article is published with open access at Springerlink.com ABSTRACT unapproved and illegally marketed drugs into the approval process, or discontinuing their Despite more than a century of evolving federal manufacture, distribution, and sale. The FDA has legislation, there remain many unapproved been actively pursuing control of unapproved drugs on the United States (US) market. This drugs in recent years, with an approach article reviews the history of drug approval in the concentrating on drug safety to ensure optimal US, beginning with the landmark Pure Food and public health and consumer protection. Drug Act of 1906, through to the development of the US Food and Drug Administration (FDA). Keywords: drug approval; FDA; unapproved The Pure Food and Drug Act of 1906 was the drugs first comprehensive federal legislation covering drug regulation. Intervening legislation, such INTRODUCTION as the Federal Food, Drug, and Cosmetic Act of 1938 and Kefauver-Harris Amendments in 1962, The United States (US) Food and Drug was later instituted. In June 2006, a century after Administration (FDA) has grown over the the development of the FDA as an enforcement past century, from a single, unidentified body, an initiative was undertaken to remove chemist in 1862 in the US Department of unapproved drugs from the marketplace. The Agriculture to the present-day organization Marketed Unapproved Drugs - Compliance dedicated to promoting and protecting Policy Guide outlines enforcement policies public health through the regulation of drugs aimed at efficiently and rationally bringing all and other products within its purview (Figure 1). The Pure Food and Drug Act of 1906 was the first comprehensive federal legislation covering drug regulation. This Alexander Nasr ∙ Thomas J. Lauterio (*) ∙ article reviews the history of drug approval Matthew W. Davis in the US, from the landmark 1906 Act URL Pharma, Inc., Mutual Pharmaceutical Company, through significant intervening legislation Inc., 1100 Orthodox Street, Philadelphia, PA 19124. Email: [email protected] and development of the FDA, culminating Adv Ther (2011) 28(10):842-856. 843 a century later when, in June 2006, the Marketed Unapproved Drugs - Compliance FDA announced an initiative to remove Policy Guide,1 outlines enforcement policies unapproved drugs from the marketplace, designed to efficiently shepherd all such many of which remain illegally marketed. drugs through the approval process. In recent Final guidance for this initiative, the years, the FDA has stepped up its oversight Figure 1. Timeline of the development of the FDA and subsequent regulatory actions.1 ANDA=Abreviated New Drug Application; CDER=Center for Drug Evaluation and Research; DESI=Drug Efficacy Study Implementation; FDA=Food and Drug Administration; GRAS/E=Generally Recognized as Safe and Effective; NDA=New Drug Application; OTC=Over-the-counter. Federal Pure Food & Drug Act: Durham-Humphrey Amendment: OTC drug review: adulteration/misbranding prescription versus OTC monograph process 1906* 1951‡ 1972|| Sullivan decision Prescription Drug Wrap-up 1948 1984¶ 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 Federal Food, Drug, and Cosmetic Upjohn versus Fitch Act: safety preapproval (GRAS/E) 1970 1938† Kefauver-Harris amendments: The Marketed Unaprroved Drugs efficacy preapproval (DESI) Compliance Policy Guide (CDER) 1962§ 2006# *Also known as the Wiley act; changed the government’s handling of the adulteration and misbranding of food and drugs, and supported national food and drug regulation through public advocacy. †Provisions included the ability of the FDA to require evidence of safety for new drugs, determine standards for food, and inspect factories. ‡Created the line between prescription and nonprescription drugs in that dangerous drugs could not be dispensed without a prescription and mandated that prescription drugs bear the following legend: “Caution: Federal law prohibits dispensing without prescription.” §Established the FDA’s control over clinical drug trials and mandated “good manufacturing practices.” ||OTC drugs marketed in accordance with a final monograph do not require approval of a marketing application by FDA. ¶Also known as DESI-2. Drugs are considered to be marketed illegally unless “grandfathered” or not otherwise a new drug. #FDA’s CDER; superseded previous policies of marketing new drugs without approved NDAs or ANDAs. 844 Adv Ther (2011) 28(10):842-856. and continues to actively pursue control of influence of preservatives on human nutrition unapproved drugs, examples of which are in 1902, which extended to the analyses of also presented in this review. proprietary medicines and plant drugs in the following year.3 These actions occurred at a Methods time when the US marketplace was awash with adulterated food, drug, and biologic products. A thorough search of the published literature, Drug makers were able to produce and sell including that available on MEDLINE/PubMed, products that, in today’s marketplace, would be was used to identify the materials referenced in considered adulterated. For example, “Peter’s this manuscript. Specific search terms, including, Specific, The Great Blood Purifier System but not limited to, FDA, history, development, Regulator” was recommended as a treatment compliance, nitroglycerin, thalidomide, for dermatologic diseases and as an alternative colchicine, and DESI, were used to perform the tonic, invigorator, and blood purifier.3 comprehensive search. In addition, archived The label stated little, if any, of the ingredients, files from the FDA were also accessed. yet it was available and sold legally in the US. Another example was morphine-laced HISTORY OF DRUG APPROVAL IN “Mrs. Winslow’s Soothing Syrup” used for THE US teething and colicky babies.3 While Wiley realized the need for The Pure Food and Drug Act of 1906 enforcement and change of this unregulated marketplace, it is widely believed that the 1906 Few federal laws to regulate the sale and “muckraking” novel The Jungle, by the Pulitzer contents of food and pharmaceuticals in the US Prize-winning American author Upton Sinclair, existed prior to the creation of the Pure Food was the final driving force, resulting in a meat and Drug Act, which was signed into law in inspection law and a comprehensive food and 1906 by President Theodore Roosevelt. This drug law.4 Sinclair’s novel exposed conditions act is also known as the Wiley Act, in honor of in the US meat-packing industry and caused a its main advocate, Harvey Wiley, who is often public uproar, which contributed, in part, to the referred to as the “Father of the FDA.” Wiley implementation of the Meat Inspection Act, as was offered the position of Chief Chemist in the well as the Pure Food and Drug Act a few months US Department of Agriculture in 1882. On after publication of the book.5 assuming this role in 1883, he immediately More than 200 laws would eventually follow changed the government’s handling of the the Pure Food and Drug Act of 1906, leading to adulteration and misbranding of food and one of the most comprehensive and effective drugs, and supported national food and drug public health and consumer protection networks regulation by spurring public indignation over in the world. The Bureau of Chemistry enforced the issue. Motivated by his work with Alice the Act until 1927, when it was reorganized Lakey, one million American women wrote to to establish the Food, Drug, and Insecticides the White House in support of the Pure Food Administration, which was renamed the FDA in and Drug Act.2 1931.5 The regulatory emphasis of the bureau Historically, under Wiley’s guidance, the during Wiley’s tenure was foods, because he Bureau of Chemistry began analyzing the believed they presented more of a threat to Adv Ther (2011) 28(10):842-856. 845 public health than adulterated or misbranded permitted to “manipulate statutory protections drugs. After Wiley’s resignation in 1912, more to inappropriately delay competition.” Those attention was focused on drug regulation, who attempt to do so are then reported to the including the so-called “patent medicines.”5 Federal Trade Commission (FTC). An NDA was not required under a “grandfather clause” for The Federal Food, Drug, and Cosmetic Act drugs marketed prior to 1938 that had been of 1938 previously labeled as “Generally Recognized as Safe and Effective (GRAS/E).” They were The next milestone in the evolution of the required, however, to contain the same chemical FDA was the Food, Drug, and Cosmetic (FD&C) composition, indications, and conditions for use Act of 1938, which was passed after a series of as the “grandfathered drug.”5 disreputable incidents involving drug marketing The FD&C Act of 1938 also mandated the claims which resulted in highly publicized listing of active ingredients on the drug label, deaths. One major incident involved the legally and required labeling with adequate directions marketed Elixir Sulfanilamide, which killed for use and warnings. By 1940, the FDA had at least 105 people, including many children, developed more than two-dozen standardized in the spring of 1937.6 Elixir Sulfanilamide, warning statements for different drugs and the first antimicrobial sulfa drug used to treat determined

Load more