CHAPTER

2

CHAPTER OBJECTIVES

Upon completing this chapter, the reader will be able to:

▶  Identify the significant historical events that have shaped the current federal Food, Drug, and Cosmetic Act (FDCA).

▶  Describe the organization of the Food and Drug Administration (FDA).

▶  Distinguish among the definitions of food, drug, dietary supplement, cosmetic, device, label, and labeling.

▶  Recognize the prohibited acts, penalties, and enforcement mechanisms in the FDCA.

▶  Identify the situations that may cause a drug to be adulterated or misbranded.

▶  Differentiate FDCA requirements for prescription drugs from those for over-the-counter (OTC) drugs.

▶  Understand the issues and procedures pertaining to new drug approval.

▶  Describe why there are unapproved drugs on the market.

▶  Understand the regulatory system related to drugs intended to treat serious and life-threatening diseases.

▶  Distinguish biologics from other FDCA products.

▶  Describe the MedWatch program.

▶  Understand the process by which medical devices are regulated under the FDCA.

▶  Describe the legal requirements for manufacturers that advertise prescription drugs to healthcare professionals and consumers.

The federal FDCA (21 U.S.C. § 301 et seq., 52 Stat. 1040 (1938)) provides for the comprehensive regulation of all drugs introduced into interstate commerce. The intent of the law is to protect consumers from adulterated or misbranded foods, drugs, cosmetics, or devices. Under the act, no new drug may be marketed and sold unless it has been proved both safe and effective for its intended use and approved by the federal FDA.

This chapter discusses relevant history, definitions, and provisions of the FDCA related to the development, production, and marketing of products, from the discovery of a new concept by a scientist to the delivery of a therapeutically appropriate product to a pharmacy. In many sections, the reader will note that the applicable law is either cited or summarized first, followed by an explanation of the law from the perspective of the author.

HISTORICAL OVERVIEW OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT

In order to protect public health, governments of nearly every civilization have sought to protect the public from adulterated food products. More modern laws in the United States in the 1800s against the adulteration of foods and drugs were led by two factors: one, advances in analytical chemistry and microscope technology, and two, studies showing the impact of adulterated foods and drugs on human life. One such study in 1850 showed that average life expectancy actually decreased by as many as 7 years over certain periods of time in Boston and New York in part because of adulterated drugs and foods (see Hyman, 2002, Chapter 2).

Our present-day food and drug regulatory system in the United States, represented by the FDCA, has been shaped by several important amendments and events and warrants a brief historical discussion at this point. The purpose of this historical overview is to provide the reader a general background of the act. Many of the amendments and events chronicled here are discussed in greater detail later.

PURE FOOD AND DRUG ACT OF 1906

At the turn of the century, investigative reports revealed widespread food and drug adulteration problems. Most notably, the 1906 novel, The Jungle, by Upton Sinclair, described atrocious adulteration problems in the meat industry. Concern for the risks to public health and safety associated with unsanitary and poorly labeled foods and drugs prompted Congress in 1906 to pass the Pure Food and Drug Act (34 Stat. 768). The law prohibited the adulteration and misbranding of foods and drugs in interstate commerce. It fell short of providing the protection that Congress intended, however, because a 1911 U.S. Supreme Court decision, United States v. Johnson, 221 U.S. 488, held that the misbranding provision in the law did not prevent false or misleading efficacy claims. In Johnson, the manufacturer claimed on the label that the drug was effective against cancer, knowing that this representation was false. The Court ruled that the misbranding provision in the law prevented false statements only as to the drug’s identity (i.e., strength, quality, purity). Some manufacturers, fearing a violation of the labeling provision, simply omitted information from the label because the act did not require the label to list the ingredients, include directions for use, or provide warnings. Moreover, the act failed to regulate cosmetics or devices.

The Johnson decision prompted Congress to amend the Pure Food and Drug Act in 1912 to prohibit false and fraudulent efficacy claims. Even with this amendment, however, the act failed to achieve its purpose. The amendment was difficult to enforce because it required the government to prove fraudulent intent on the part of one who made false statements on the label. By pleading ignorance, violators could escape enforcement.

Despite public awareness that the 1906 law was inadequate, there was no new legislation until 1938. By that time, pressure for a new law had been building for many years. A catalyst for the new law was the sulfanilamide elixir tragedy of 1937. Sulfanilamide was one of the first of the “miracle” anti-infective sulfa drugs marketed. A manufacturer who sought to produce the drug in an elixir form seized upon diethylene glycol as the best solvent. (Diethylene glycol is used today as an industrial solvent and for other industrial uses.) No toxicity tests had been done, despite the fact that little was known about the use of diethylene glycol in humans. The solvent proved to be a deadly poison, and 107 deaths were ultimately attributed to this elixir. The 1906 law had not granted the FDA the authority to ban unsafe drugs, so the FDA had to remove the product on the basis of a technical misbranding violation—that an elixir must contain alcohol, and the product did not.

FOOD, DRUG, AND COSMETIC ACT OF 1938

The FDCA of 1938 (21 U.S.C. § 301 et seq. 52 Stat. 1040), with amendments, forms the nucleus of today’s law. All the amendments and laws described subsequently in this section are amendments to the 1938 act. It provided that no new drug could be marketed until proven safe for use under the conditions described on the label and approved by the FDA. The law also expanded the definitions of misbranding and adulteration used in the earlier act, requiring that labels must contain adequate directions for use and warnings about the habit-forming properties of certain drugs. The 1938 law applies to cosmetics and devices as well. Significantly, however, the act exempted drugs marketed before 1938 from the requirement that new drugs be proven safe before being marketed.

In 1941, the FDCA was amended to allow the FDA to require batch certification of the safety and efficacy of insulin to ensure uniform potency. Because of concern over the quality of penicillin production, the FDCA was amended to allow the FDA to require batch certification of the safety and efficacy of penicillin in 1945. Subsequent amendments extended the certification requirement to other antibiotic drugs or any derivative of an antibiotic drug. (In 1997, the FDAMA eliminated the batch certification requirement for insulin and antibiotics.)

In 1948, the extent of the FDCA’s jurisdiction was challenged in United States v. Sullivan, 332 U.S. 689. The defendant pharmacist contended that federal law did not apply to his acts because his acts affected only intrastate transactions. The U.S. Supreme Court, however, declared that the jurisdiction of the act extends to transactions between the pharmacist and the patient. Therefore, the FDCA applies to drugs held for sale in a pharmacy.

DURHAM-HUMPHREY AMENDMENT OF 1951

The 1938 FDCA required all drugs to be labeled with “adequate directions for use.” When the act was passed, however, many drugs on the market were not safe for use except under medical supervision. These drugs could not meet the “adequate directions for use” requirement. The Durham-Humphrey Amendment (also often referred to as the Prescription Drug Amendment) was enacted in 1951 (65 Stat. 648) to solve this problem. The amendment established two classes of drugs, prescription and OTC, and provided that the labels of prescription drugs need not contain “adequate directions for use” so long as they contain the legend, “Caution: Federal law prohibits dispensing without a prescription.” When dispensed by a pharmacist, inclusion on the label of directions from the prescriber satisfies the “adequate directions for use” requirement. In addition to establishing the two classes of drugs, the amendment also authorizes oral prescriptions and refills of prescription drugs.

FOOD ADDITIVES AMENDMENT OF 1958

After several years of hearings, Congress amended the FDCA to require that components added to food products receive premarket approval for safety (P.L. 85-929). The law also contains an anticancer provision, commonly known as the Delaney Clause, which prohibits the approval of any food additive that might cause cancer.

COLOR ADDITIVE AMENDMENTS OF 1960

In 1960, Congress amended the FDCA to require manufacturers to establish the safety of color additives in foods, drugs, and cosmetics. Under the Color Additive Amendments, the FDA can approve a color for one use but not for others (e.g., external use only). The amendments also contain a Delaney Clause, similar to the one contained in the Food Additives Amendment.

KEFAUVER-HARRIS AMENDMENT OF 1962

In the late 1950s, a popular sedative, thalidomide, was being marketed in Europe. The William S. Merrell Company distributed the drug experimentally in the United States in 1960, but the FDA withheld final approval of the new drug application (NDA) pending additional safety information. In 1961, it was confirmed that the drug had caused a birth defect, phocomelia (seal limbs), in thousands of infants. Because the FDA had refused to allow the marketing of thalidomide in the United States, the number of birth defects caused by the drug in this country was low. Nonetheless, the worldwide disaster caused Congress to enact the Kefauver-Harris Amendment to the FDCA.

This amendment, also called the Drug Efficacy Amendment (76 Stat. 780), strengthened the new drug approval process by requiring that drugs be proved not only safe but also effective. The efficacy requirement was made retroactive to all drugs marketed between 1938 and 1962. The amendment also:

•  Transferred jurisdiction of prescription drug advertising from the Federal Trade Commission (FTC) to the FDA

•  Established the Good Manufacturing Practices (GMP) requirements

•  Added more extensive controls for clinical investigations by requiring the informed consent of research subjects and reporting of adverse drug reactions

MEDICAL DEVICE AMENDMENTS OF 1976

Under the 1938 Act, the FDA had no authority to review medical devices for safety and efficacy before marketing. As a result, the agency resorted to classifying devices as drugs when it deemed appropriate and necessary. Prompted by public safety concerns with certain devices such as the Dalkon Shield, an intrauterine device, Congress amended the FDCA in 1976 to provide for more extensive regulation and administrative authority regarding the safety and efficacy of medical devices. The Medical Device Amendments (MDA) (P.L. 94-295; 90 Stat. 539) require

•  Classification of devices according to their function

•  Premarket approval

•  Establishment of performance standards

•  Conformance with GMP regulations

•  Adherence to record and reporting requirements

ORPHAN DRUG ACT OF 1983

For years, pharmaceutical manufacturers had urged Congress to recognize that the NDA process was too expensive to warrant the development and marketing of drugs for diseases that affect relatively few people. In fact, the FDA acknowledged that between 1973 and 1983 only 10 products were approved for the treatment of rare diseases. In response, Congress passed the Orphan Drug Act (P.L. 97-414) in 1983 to provide tax and exclusive licensing incentives for manufacturers to develop and market drugs or biologicals for the treatment of “rare diseases or conditions” (defined as those affecting fewer than 200,000 Americans). Between the act’s passage and 2013, the FDA approved about 400 orphan drugs and biological products, and 2,700 additional orphan-designated entities have entered the research pipeline. The FDA enacted a final rule on June 12, 2013, clarifying various provisions in the Act (78 Fed. Reg. 35117; 21 CFR part 316).

DRUG PRICE COMPETITION AND PATENT TERM RESTORATION ACT OF 1984

Also called the Waxman-Hatch Amendment, the Drug Price Competition and Patent Term Restoration Act (P.L. 98-417) was enacted in 1984 to streamline the generic drug approval process while giving patent extensions, in certain cases, to innovator drugs. The intent of the law is to make generic drugs more readily available to the public and, at the same time, provide incentives for manufacturers to develop new drugs. The law is the result of intense lobbying and negotiating between generic drug manufacturers and the manufacturers of innovator drugs.

PRESCRIPTION DRUG MARKETING ACT OF 1987

Congress enacted the Prescription Drug Marketing Act (P.L. 100-293) in 1987 in response to growing alarm that a secondary or diversionary distribution system for prescription drugs was threatening the public health and safety and creating an unfair form of competition. This law establishes sales restrictions and recordkeeping requirements for prescription drug samples. It also prohibits hospitals and other healthcare entities from reselling their pharmaceutical purchases to other businesses and requires the state licensing of drug wholesalers.

SAFE MEDICAL DEVICES ACT OF 1990

This act further strengthened the MDA Act of 1976, giving the FDA additional authority especially related to postmarketing requirements and premarket notification and approval, while expediting the premarket device approval process.

THE GENERIC DRUG ENFORCEMENT ACT OF 1992

This act warrants discussion to highlight a scandal that occurred when some FDA staff accepted bribes from generic drug industry personnel in order to facilitate the approval process of certain generic drug products. These individuals were convicted and the scandal prompted Congress to pass this law authorizing the FDA to ban individuals or firms from participating in the drug approval process if convicted of related felonies. The law also imposes severe civil penalties for any false statements, bribes, failures to disclose material facts, and other related offenses.

PRESCRIPTION DRUG USER FEE ACT OF 1992 (PDUFA)

Although the FDA was called on to review an ever-increasing number of drugs for approval, it found Congress unwilling to expand its budget. Instead, the administration and Congress took the approach that private industry should shoulder part of the costs for new drug approval rather than the taxpayers. Thus, Congress passed the Prescription Drug User Fee Act (PDUFA), which requires manufacturers seeking NDAs to pay fees for applications and supplements when the FDA must review clinical studies (P.L. 102-571). The fees provide the FDA with the resources to hire more reviewers to assess these clinical studies and speed up the NDA reviews. PDUFA must be reauthorized every 5 years.

NUTRITION LABELING AND EDUCATION ACT OF 1990 (NLEA)

Capitalizing on increased consumer interest in health and nutrition, the 1980s witnessed many food companies promoting their food products with nutritional claims. Congress enacted the Nutrition Labeling and Education Act (NLEA) (P.L. 101-535) to encourage this trend. The NLEA mandates nutrition labeling on food products and authorizes health claims on product labeling, as long as they are made in compliance with FDA regulations.

DIETARY SUPPLEMENT HEALTH AND EDUCATION ACT OF 1994 (DSHEA)

Dietary supplement manufacturers felt that the NLEA left too much authority with the FDA and unduly restricted the promotion of dietary supplements. As a result, Congress was persuaded to pass the Dietary Supplement Health and Education Act (DSHEA) (P.L. 103-417) to define dietary supplements and permit manufacturers to make certain claims that otherwise would have been illegal under the FDCA. The DSHEA in essence forced the FDA to regulate dietary supplements more as foods than as drugs.

FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT OF 1997 (FDAMA)

FDA critics—which included drug manufacturers, Congress, and consumer groups—believed that the FDA was not efficiently administering its statutory responsibilities and that the FDCA itself produced too burdensome a regulatory system for drug approval. The Food and Drug Administration Modernization Act of 1997 (FDAMA) was passed primarily to streamline regulatory procedures to ensure the expedited availability of safe and effective drugs and devices.

Building on the PDUFA, FDAMA increases the FDA’s public accountability, requires an FDA mission statement to define the scope of its responsibilities, and requires the agency to publish a compliance plan in consultation with industry representatives, scientific experts, healthcare professionals, and consumers. The intent is to eliminate backlogs in the approval process and ensure the timely review of applications. In particular, the FDAMA creates a fast-track approval process for drugs intended for serious or life-threatening diseases, establishes a databank of information on clinical trials, authorizes scientific panels to review clinical investigations, and expands the rights of manufacturers to disseminate unlabeled use information.

The FDAMA also expands the FDA’s authority over OTC drugs and establishes ingredient-labeling requirements for inactive ingredients. States are preempted from establishing labeling requirements for OTC drugs and cosmetics when federal requirements exist. The law also affects the regulation of medical devices in part by mandating priority review for breakthrough technologies in medical devices and allowing the FDA to contract with outside scientific experts for review of medical device applications.

FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT OF 2007 (FDAAA)

Congress passed the Food and Drug Administration Amendments Act in September of 2007 (P.L. No. 110-85) reauthorizing and amending many drug and medical device provisions that were set to expire, while providing the FDA with new funding and significantly more authority over drug safety. The FDAAA allows the FDA broader use of the fees generated from PDUFA, while substantially increasing the fees. In response to postmarket problems with certain drug products, such as Vioxx, which had to be removed from the market because of safety concerns, the law provides the FDA with significantly enhanced responsibilities and authorization to regulate drug safety, including the authority to: mandate labeling changes related to safety, require clinical trial data reporting and registries, require postmarket clinical studies to assess risks, and require companies to implement risk evaluation and mitigation strategies (REMS) when necessary. These features and others of the FDAAA will be described in greater detail later in this chapter.

PATIENT PROTECTION AND AFFORDABLE CARE ACT OF 2010 (ACA)

The Patient Protection and Affordable Care Act (ACA) (P.L. No. 111-148), enacted in March 2010, provided sweeping changes throughout the entire healthcare system. The U.S. Supreme Court has ruled that most of the provisions in the act are constitutional (National Federation of Independent Business v. Sebelius, 132 S. Ct. 2566 (June 28, 2012)). Although the ACA added healthcare law far beyond the FDCA, it bears mentioning in this section on regulatory history because it added provisions to the FDCA and directly and indirectly affected other law related to pharmacy practice.

FDA SAFETY AND INNOVATION ACT OF 2012 (FDASIA)

The primary purpose of the FDA Safety and Innovation Act (P.L. No. 112-144) is to reauthorize PDUFA, which was to sunset in September 2012. The law allows the FDA to continue to collect user fees from manufacturers seeking NDAs or medical device approvals, but also adds new user fees for generic drugs and biosimilars. The law also contains several other provisions directed at reducing drug counterfeiting, blocking the import of adulterated products, detecting and reducing drug shortages, and enhancing the exchange of prescription drug diversion information across state lines. Additionally, the law enables the FDA to inspect foreign drug manufacturers more regularly and requires the agency to target problematic manufacturing sites, whether in the United States or not. Congress anticipates that the law will help bring critical drugs and medical devices to market faster and enhance the availability of generic drugs.

DRUG QUALITY AND SECURITY ACT OF 2013 (DQSA)

Title I of the Drug Quality and Security Act (HR 3204) (P.L. No. 113-54), called the Compounding Quality Act, clarifies and strengthens FDA oversight over pharmacies engaged in the large-scale compounding and shipping of sterile products to other licensed entities. This change in the FDCA occurred in response to a meningitis outbreak that killed over 60 people and injured hundreds of others, and was caused by contaminated drugs compounded by a New England pharmacy. Entities compounding sterile products (known as Outsourcing Facilities under the law) may voluntarily register with the FDA and must comply with current good manufacturing practices (CGMP). The law also removed uncertainty regarding when a product compounded by a pharmacy is exempt from the CGMP, labeling, and new drug approval process. Title II of this law, known as the Drug Supply Chain Security Act, adds “track and trace” requirements for all entities in the chain of distribution of pharmaceutical products. By 2015, manufacturers must provide transaction information to purchasers, who in turn must provide transaction information to subsequent purchasers (e.g., wholesalers and pharmacies). The law also mandates an electronic, interoperable product tracing system by 2023, strengthens wholesaler and third-party logistics licensure requirements, and requires manufacturers to serialize drugs by 2017.

RATIONALE FOR FEDERAL DRUG REGULATION

The primary goal of the Pure Food and Drug Act of 1906 and the succeeding drug-related legislation was the protection of the public welfare. Few can deny that the public should be protected or that government should play a role in the protective effort. Nonetheless, there is a legitimate concern by some that government may go too far in protecting people from the consequences of their own risky choices.

The development of federal drug regulation shows a pattern of increasing government intrusion into the decisions of people who use drugs. The 1906 law was an example of “indirect regulation.” Its purpose was to help people make their own decisions by providing accurate and useful information through appropriate labeling. The 1938 act reinforced the indirect regulation by expanding the labeling requirements, but it also introduced an important piece of “direct regulation” by keeping off the market those drugs that have not met government safety standards. This type of regulation is direct because it makes decisions for people rather than helping them to make decisions for themselves. The 1951 and 1962 amendments increased direct regulation by mandating prescriptions for certain drugs and requiring proof of efficacy as well as safety for drug approval. At present, most of the drugs available cannot be used unless the government has certified them as safe and effective and another person (an authorized prescriber) has decided to permit their use.

Against this background of increasingly paternalistic drug laws, modern-day consumers have developed an independence regarding therapeutic choices and have matured in their ability to make sophisticated decisions for themselves. It is perhaps no coincidence that the Omnibus Budget Reconciliation Act of 1990 (P.L. 101-508), one of the later major federal drug laws, focuses on informed decisions by patients rather than on decisions by government or healthcare providers on behalf of patients. It is perhaps no coincidence that the past several years have witnessed an unprecedented number of drugs switched from prescription status to OTC status. This may signal the beginning of a trend away from direct regulation and back toward indirect regulation, empowering patients to participate actively in healthcare decisions rather than passively accepting therapies decided on by others.

  TAKE-AWAY POINTS

THE FOOD AND DRUG ADMINISTRATION (FDA)

Because primary enforcement of the FDCA is vested in the FDA, it is important to know a little about the agency. The FDA is a component of the Department of Health and Human Services (DHHS), and actual authority for administering the FDCA is really vested with the secretary of DHHS. In fact, until 1988, the secretary appointed the commissioner of the FDA. The act now directs the president to appoint the commissioner with the confirmation of the Senate; however, the commissioner still remains accountable to the secretary. In reality, the secretary has delegated most of the secretary’s authority to the commissioner, who in turn has delegated the majority of authority to various FDA directors. The FDA’s website can be accessed at http://www.fda.gov.

The agency is structured around the concept of the national headquarters, which provides policy and decision making, together with an extensive field force of professionals throughout the country, which provides additional decision making and regulatory enforcement. At the headquarters level, under the Office of the Commissioner, are four offices that oversee the core functions of the agency: the Office of Foods and Veterinary Medicine, the Office of Global Regulatory Operations and Policy, the Office of Medical Products and Tobacco, and the Office of Operations. The Office of Medical Products and Tobacco coordinates and leads scientific and regulatory evaluations and interpretations for drugs, biologics, medical devices, and tobacco products and includes the:

•  Center for Drug Evaluation and Research (CDER)

•  Center for Biologics Evaluation and Research

•  Center for Devices and Radiological Health

•  Center for Tobacco Products

•  Office of Special Medical Programs

•  Office of Combination Products

•  Office of Good Clinical Practice

•  Office of Pediatric Therapeutics

•  Office of Orphan Products Development

The field is divided into five geographic regions with several district offices. The district offices provide inspections and work cooperatively with state and local agencies and provide source information to headquarters.

Because the FDA is an administrative agency, it has rulemaking authority (Section 707 of the FDCA). In fact, the FDA prefers to regulate by regulation if at all possible, but the agency also may pursue a less formal avenue by publishing guidance documents. The purpose of guidance documents is to clarify laws or regulations, to explain how compliance with the laws or regulations may be achieved, and to outline review and enforcement approaches. The FDA has issued several guidance documents, some of which will be referred to in this book. Guidance documents are not legally binding, nor legally enforceable. Nonetheless, these guides represent the agency’s best thinking on a particular subject and should be followed.

Although the FDA is staffed with considerable scientific expertise, it also regularly relies on advice from outside experts in the form of standing advisory committees. Most members of these committees are physicians, but they also include nurses, pharmacists, statisticians, epidemiologists, and other professionals. Members are recruited through the Federal Register and often are nominated by professional organizations and professional schools. The secretary of DHHS makes the final selection of members from the list of nominees. Committee size ranges from 9 to 15 members. Although the FDA is not obligated to follow a committee recommendation, it often does.

  TAKE-AWAY POINTS

DEFINING AND DISTINGUISHING DRUGS FROM FOODS, DIETARY SUPPLEMENTS, DEVICES, AND COSMETICS

THE LAW

Section 201 of the FDCA (21 U.S.C. § 321) provides definitions for the important terms used in the act. Understanding these definitions is critical to understanding the FDCA.

(f) The term “food” means (1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article. (§ 201(f); 21 U.S.C. § 321(f))

(g) (1) The term “drug” means (A) articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any articles specified in clause (A), (B), or (C).

(2) The term “counterfeit drug” means a drug which, or the container or labeling of which, without authorization, bears the trademark, trade name, or other identifying mark, imprint, or device, or any likeness thereof, of a drug manufacturer, processor, packer, or distributor other than the person or persons who in fact manufactured, processed, packed, or distributed such drug and which thereby falsely purports or is represented to be the product of, or to have been packed or distributed by, such other drug manufacturer, processor, packer, or distributor. (§ 201(g); 21 U.S.C. § 321(g))

(h) The term “device” … means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is

(1) recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,

(2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

(3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its principal intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its principal intended purposes. (§ 201(h); 21 U.S.C. § 321(h))

(i) The term “cosmetic” means (1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles; except that such term shall not include soap. (§ 201(i); 21 U.S.C. § 321(i))

EXPLANATION OF THE LAW

Ask people about their perception of a drug and they will likely respond that it is a chemical entity for introduction into the body in one manner or another to improve one’s health. The legal definition of drug (see preceding subsection (g)), however, in the FDCA leaves little doubt that Congress intended the term “drug” to have a much broader meaning than that, broader even than any scientific or medical definition. Note that subsection (g) uses the term “articles” to describe a drug. Articles can include chemical and nonchemical entities, and in fact most anything. Part B of the drug definition addresses products intended for use with diseases, whereas part C recognizes that even products not intended for use with diseases may still be drugs if they make a structure or function claim. For example, a product claimed by a manufacturer to prevent pregnancy may not be a drug under part B (because pregnancy is not a disease) but may be a drug under part C (because preventing pregnancy means that the product intends to affect the function of the body).

The FDA has used the drug definition to its advantage on several occasions by adjudicating an article to be a drug and then removing it from the market for failing to meet the premarket approval required of new drugs. Establishing that an article is a drug, as opposed to a food, dietary supplement, or cosmetic, provides the agency with considerably more authority over the article.

The crucial issue in the determination of whether a product is a drug centers on whether the supplier made a therapeutic or health claim, or a structure/function claim. In other words, was the article intended to diagnose, cure, mitigate, treat, or prevent a disease, or (for articles other than food) was it intended to affect the body structure or function? The fact that a supplier, even in good faith, does not believe that its product is a drug or does not want its product to be a drug has little relevance. If therapeutic or structure/function claims are made, an article is a drug, no matter what disclaimers may be included in the labeling. Thus, a supplier cannot mitigate a therapeutic or structure/function claim for a product by proclaiming that the product is not a drug. For example, assume that a company that manufactures alfalfa pellets for animals decides to produce alfalfa tablets for humans, claiming that the tablets will cure ulcers and other gastrointestinal disorders. The label specifically notes that the tablets are not drugs. On the basis of the therapeutic claims, however, a court is likely to consider the product a drug, even though the manufacturer says it is not, and even though alfalfa by itself is certainly not a drug.

As a distinction, it is the supplier’s intended use of the product that is important, not the purchaser’s intended use. The mere use of an article for therapeutic purposes by purchasers, where the supplier does not intend the product to be used therapeutically or makes no therapeutic claims, does not usually make the product a drug. Health food stores and pharmacies have hundreds of examples of these types of products on their shelves. Similarly, although some hardware stores sell dimethyl sulfoxide as an industrial solvent and some purchasers apply it externally to reduce joint pain, this use does not make it a drug.

In contrast, some products that contain ingredients normally considered drugs might not be classified as drugs. For example, in the case of Action on Smoking and Health v. Harris, 655 F.2d 236 (D.C. Cir. 1980), a public interest group sought to have cigarettes declared drugs on the ground that they contain nicotine. The FDA, however, determined that the drug definition applies only to those brands of cigarettes about which a vendor makes therapeutic claims, and the court supported the FDA’s position. Changing its position in the 1990s, the FDA asserted that nicotine is a drug and that cigarettes and smokeless tobacco are drug-delivery devices. The agency found that tobacco products are intended to satisfy addiction, provide stimulation and tranquilization, and promote weight control. As a result, the FDA issued a regulation in 1996 intended to reduce tobacco consumption among children and adolescents (61 Fed. Reg. 44397). Tobacco manufacturers, retailers, and advertisers challenged the FDA, arguing that the agency lacks authority to regulate tobacco products. In a 5 to 4 decision, the U.S. Supreme Court agreed with the plaintiffs, finding that Congress intended to exclude tobacco from the FDA’s jurisdiction (Food and Drug Admin. v. Brown & Williamson Tobacco Corp., 529 U.S. 120 (2000)). The Supreme Court decision played a role in stimulating Congress to enact legislation in June 2009, known as the Family Smoking Prevention and Tobacco Act (P.L. No. 111-31), granting the FDA authority to regulate tobacco products. The FDA may now regulate the contents of tobacco products, require disclosure of product contents, prohibit certain additives, require more effective warnings, and strictly control or prohibit marketing and sales campaigns, especially those directed at children.

The latest tobacco controversy involves electronic cigarettes and other “vaping” devices. Despite widespread societal concern, research has not yet determined the safety of these products. In 2009, the FDA declared that e-cigarettes were unapproved drug/device combination products, which resulted in their removal from the market. Manufacturers of these products, however, successfully challenged the FDA’s assertion. The U.S. Court of Appeals for the D.C. Circuit found for the manufacturers on the basis that the agency can regulate the products under the 2009 Tobacco Act, and that they are not drugs or devices unless marketed for therapeutic purposes (Sottera, Inc. v. Food & Drug Administration, 627 F.3d 891 (D.C. Cir. 2010)). Subsequently, applying its authority under the Tobacco Act, the FDA proposed a regulation in April 2014 which, if promulgated, would ban the sale of e-cigarettes to those under 18, but would not restrict advertising or online sales (79 Fed. Reg. 23142). Companies would have to warn consumers that nicotine is addictive. They would also have to submit new and existing products for FDA approval; however, they could continue selling the products pending the FDA’s review. Not willing to wait for the FDA to act, in 2015 several states introduced bills to restrict the sale of e-cigarettes.

Although courts interpret the definition of the term “drug” broadly and often defer to the expertise of the FDA, the agency does not always prevail, even in nontobacco cases. In National Nutritional Foods Association v. Mathews, 557 F.2d 325 (2nd Cir. 1977), the FDA was unsuccessful in its attempt to classify vitamins A and D in high dosages as drugs on the basis of a lack of nutritional value and potential toxicity. The court held that nutritional value and toxicity were not relevant to the statutory definition of a drug.

A court will admit evidence of therapeutic intent from sources other than the labeling of the product. Thus, therapeutic claims that the manufacturer made while advertising through any media will be considered evidence that a product is a drug. Moreover, the fact that a product is being marketed as an injection, capsule, or tablet may add evidence of therapeutic intent, despite the absence of therapeutic language in the labeling.

FOODS VERSUS DRUGS

The distinction between food and drug has become an important issue, especially in view of the proliferation and popularity of natural products, dietary supplements, and other “health food” type products. As you likely surmised from the previous discussion, almost any food might be considered a drug if a therapeutic or health claim is made for it under part B of the drug definition. Part C of the drug definition, however, specifically excludes foods. This then raises the question: How is food defined for the purpose of part C? Stated another way, is it the intent of part C to exclude all substances normally defined as foods, regardless of their intended use? Reading the definition of food under subsection (f) is hardly helpful.

This issue was partially answered in the case of Nutrilab, Inc., et al. v. Schweiker, 713 F.2d 335 (7th Cir. 1983) (discussed in the case studies section of this chapter), in which the court considered whether a weight-reduction product known as a starch blocker is a food or drug. The plaintiffs argued the product was a food because it was derived from kidney beans. The court disagreed, finding for the FDA on the basis that the product neither fit the statutory definition of food nor the commonsense definition of food, in that people use food primarily for taste, aroma, or nutritive value. Most likely Congress intended to exclude foods from part C when consumed in their ordinary manner, because when ingested, all foods affect the structure or function of the body in some manner merely because of metabolism. Thus, unless excluded, all foods would become drugs by virtue of part C. Congress did not likely intend to exclude foods that are not intended or consumed for their ordinary purpose.

The FDCA has created at least two special categories of foods, including “special dietary foods” and “medical foods.” Without this legal recognition, the FDA would likely regard articles falling into these categories as drugs because their labeling contains health claims.

Special Dietary Foods

Under the FDCA, special dietary foods include, but are not limited to those supplying a special dietary need that exists by reason of a physical, physiological, pathological, or other condition, including but not limited to the condition of disease, convalescence, pregnancy, lactation, infancy, allergic hypersensitivity to food, underweight, overweight, or the need to control the intake of sodium (21 U.S.C. § 411(3)(A)). Examples of products in this category include infant formulas, artificial sweeteners, and caloric supplements.

Medical Foods

Medical foods include foods formulated for oral or enteral use under the supervision of a physician and that are intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements are established by medical evaluation (21 U.S.C.A § 360ee). Examples of medical foods include foods formulated without the amino acid phenylalanine for phenylketonuria, and folic acid, B₆, B₁₂ combination products for hyperhomocysteinemia. Medical foods must be specially formulated, not naturally occurring, and must provide nutritional requirements that would be impossible for the patient to meet through a normal diet. The FDA guidance, revised in 2013, provides examples of diseases and conditions for which a medical food may be marketed, and examples of labeling statements that would be considered misbranding (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/MedicalFoods/ucm054048.htm).

Nutraceuticals and Functional Foods

Some believe that the FDA should recognize additional classifications of food products such as “nutraceuticals” and “functional foods.” The vague and broad category of nutraceuticals would include any substance that may be considered food or part of food and that provides health or medical benefits, including the prevention and treatment of disease. Such products would include nutrients; genetically engineered foods; some cereals, soups, and beverages; and many fruits and vegetables, because they contain such health-related isolates as vitamins, minerals, and omega-3 fatty acids. Advocates of this product classification contend that the current system deters the development of a substantial number of beneficial food-related products because the FDA could regard the products as drugs.

Another related category of product some would like distinguished by law is one called “functional foods.” These include foods or nutraceuticals that have been fortified or enhanced, often with a dietary supplement, such as drinks with ginseng or kava kava added and foods fortified with calcium. Probiotics are yet another example of products that would likely fall into this category. Probiotics are defined as live microorganisms that when administered in adequate amounts produce healthy results. Currently, the law does not recognize any category of articles as nutraceuticals or functional foods. However, many products that might be considered nutraceuticals or functional foods are regulated as dietary supplements and would likely be exempted from parts of the drug definition, as discussed later.

Health Claims for Foods

There is a contentious history between the FDA and food manufacturers who have made health claims for their products. One controversy arose in the 1980s when studies at the time indicated that the ingestion of psyllium might lower cholesterol levels. Cereal manufacturers whose products contained fibrous psyllium thus proclaimed the value of their products in reducing cholesterol levels. The FDA believed that these claims made the products drugs and warned the cereal manufacturers. OTC drug manufacturers who produced psyllium laxatives also were concerned but for a different reason; their products were regulated as drugs and because of this, they could not promote their products as effective for lowering cholesterol without being charged for misbranding. Thus, they felt the cereal manufacturers had an unfair advantage if the FDA allowed them to label their products with the health claim.

The FDA has continued to struggle with this issue for years, as evidenced by the case of United States v. Undetermined Quantities of an Article of Drug Labeled as Exachol, 716 F. Supp. 787 (S.D.N.Y. 1989). In this case, the manufacturer of a product called Exachol distributed literature proclaiming that the product was useful in the prevention and treatment of coronary disease. As a result, the FDA brought legal action against the company, contending that the product, composed of lecithin, phosphatidyl ethanolamine, phosphatidylcholine, and several other natural products, was a drug on the basis of the therapeutic claims. The manufacturer countered that the product was a special dietary food, not a drug. Deciding for the company, the court found that the FDA permitted some foods to be labeled with appropriate health-related messages. The court noted that the FDA was still trying to determine what types of health-related messages would be appropriate and, while doing so, had allowed manufacturers of other products (e.g., Kellogg’s All-Bran, fish oils) to continue making health claims. Thus, concluded the court, it would be inconsistent for the agency to single out Exachol as a drug while failing to take action against other such products.

This confusion over what health claims would be appropriate for food products and whether they could escape being branded as drugs by sliding into the special dietary food category prompted Congress to enact the NLEA of 1990 (P.L. 101-535) that amends § 403 of the FDCA. In part, the amendment for the first time allowed food labeling to contain a health or disease-prevention claim, but only if the FDA had promulgated a regulation approving the claim and establishing the conditions under which the claim can be used. FDAMA modified the NLEA to permit health claims without the requirement that the FDA must issue a regulation, as long as there is “significant scientific agreement,” as determined by the FDA. Alternately, the FDA will approve a health claim if based on an authoritative statement from certain scientific bodies. Pursuant to the NLEA, the FDA issued regulations for food products in 1993 (58 Fed. Reg. 2478, January 6, 1993; 21 C.F.R. part 101) and for dietary supplements in 1994 (59 Fed. Reg. 395, January 4, 1994; 21 C.F.R. parts 20 and 101).

Even when FDA regulation authorizes a health claim, food manufacturers may still wander over the food/drug line if they exceed the strict limits and restrictions of that regulation. For example, the FDA issued a regulation (21 C.F.R. 101.81) authorizing a health claim associating soluble fiber from whole grain oats with a reduced risk of coronary heart disease. Pursuant to the regulation, the manufacturer may also include a statement that the reduced risk of coronary heart disease occurs by lowering blood total and LDL cholesterol. General Mills labeled its Cheerios Toasted Whole Grain Oat Cereal with the claims: “You can Lower Your Cholesterol 4% in 6 weeks,” and “Did you know that in just 6 weeks Cheerios can reduce bad cholesterol by an average of 4%?”

The FDA issued a warning letter to General Mills in May 2009, contending that these claims indicate that Cheerios is intended for use in lowering cholesterol, and therefore preventing and treating the disease of hypercholesterolemia, thus making Cheerios an unapproved new drug (http://www.fda.gov/ICECI/EnforcementActions/-WarningLetters/ucm162943.htm). The FDA took the position that these claims are separate, stand-alone claims and different from the permissible health claim that General Mills also included on the box; and, even if the claims were part of the permissible claim, they would not qualify because the regulation does not allow attributing any degree of risk reduction for coronary heart disease.

DIETARY SUPPLEMENTS VERSUS DRUGS

The NLEA was not popular among suppliers and consumers of dietary supplements, who feared that the law unduly empowered the FDA to restrict the dietary supplement industry. It is important to recognize that at that time, even though dietary supplements were commonly known by the public by that term and commonly marketed, the law did not recognize dietary supplements as a separate legal class of products and the FDA commonly regulated the products as drugs. After intense lobbying, Congress reacted by passing the DSHEA of 1994 (P.L. 103-417), further amending the FDCA by legally creating the category of dietary supplements and significantly altering the FDA’s authority to regulate dietary supplements. The NLEA and its regulations remain in effect to the extent that they are not specifically contradicted by DSHEA.

Essentially, DSHEA mandates that the FDA regulate dietary supplements more as a special type of food than as drugs. For this reason, the FDA cannot require premarket approval of dietary supplements as it does for drugs. Thus, the manufacturer is responsible for determining if its product is safe and that its claims about the product are substantiated by adequate evidence. Moreover, except for new dietary supplements, the manufacturer does not have to provide the FDA with the evidence upon which it relies to substantiate the product’s safety and efficacy. DSHEA also generally prohibits the FDA from regulating dietary supplements as food additives. Because food additives require premarket approval by the FDA, Congress wanted to ensure that the FDA did not attempt a backdoor approach at requiring premarket approval. Being stripped of premarket approval authority means that the agency must prove that a dietary supplement is unsafe before it can remove the product from the market. Under DSHEA, a dietary supplement is defined as a product that is intended for ingestion, is intended to supplement the diet, and contains any one or more of the following:

•  A vitamin

•  A mineral

•  An herb or other botanical

•  An amino acid

•  A dietary substance for use by humans to supplement the diet by increasing the total dietary intake

•  A concentrate, metabolite, constituent, extract, or combination of the previous (§ 201(ff); 21 U.S.C. § 321(ff))

Nutritional Support (Structure/Function) Statements

DSHEA allows dietary supplement suppliers to make four types of nutritional support statements without fear that the statements would cause the FDA to consider the product to be a drug. These are:

1.  Statements that the product will benefit a classical nutrient deficiency disease as long as it also discloses the prevalence of the disease in the United States

2.  Statements that describe the role of the dietary supplement in affecting the structure or function of the body

3.  Statements that characterize the documented mechanism by which a nutrient or dietary supplement acts to maintain structure or function

4.  Statements describing the general well-being from consumption of a nutrient or dietary ingredient (e.g., “energizer,” “relaxant,” “muscle enhancer”)

DSHEA thus exempts dietary supplements from part C of the drug definition by permitting structure/function claims. For example, a seller could promote that its cranberry tablets increase the acidity of the urine and help to maintain a healthy urinary tract. If, however, the seller made the claim that its product prevents urinary tract infections, this assertion could make the product a drug under part B of the drug definition. Similarly, a seller could not claim a product helps avoid diarrhea associated with antibiotic use but could state that it “helps maintain healthy intestinal flora.” In an attempt to clarify the dividing line between acceptable structure/function claims and disease claims, the FDA enacted a regulation on January 6, 2000 (65 Fed. Reg. 1000; 21 C.F.R. part 101; for more information also see: http://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm2006881.htm).

To make any of these four nutritional support statements, the seller must have substantiation that they are truthful and not misleading, and the label of the product must contain the disclaimer, “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” Also, the manufacturer must notify the FDA within 30 days if it makes one of the permitted statements.

Health or Disease Claims

As discussed, DSHEA greatly restricts the FDA’s premarket authority over dietary supplements and exempts dietary supplements from part C of the drug definition. DSHEA does not generally exempt supplements from part B of the drug definition, and the issue of whether suppliers can make health or disease claims without risking their product becoming a drug is complicated. DSHEA does allow manufacturers to make limited health claims for dietary substances that describe the relationship between a food substance and a disease, such as “folic acid may reduce the risk of neural tube birth defects” and “calcium may reduce the risk of osteoporosis.” In order to make these claims, however, the FDA must approve the health claim by regulation pursuant to the “significant scientific agreement” standard. By 1999, the FDA had approved approximately 11 health claims by regulation for foods and dietary supplements, including the claims for folic acid and calcium.

Because the FDA had approved so few health claims, frustrated dietary supplement manufacturers challenged the legality of the FDA’s premarket approval requirement for health claims and the legality of the FDA’s procedure for determining “significant scientific agreement” in a 1999 U.S. Court of Appeals decision, Pearson v. Shalala, 164 F.3d 650 (1999). In Pearson, four dietary supplement manufacturers that had had their health claims rejected by the FDA successfully argued that requiring premarket approval of health claims violates the First Amendment, and that the FDA lacks sufficient criteria for explaining why a health claim does not meet the “significant scientific agreement” standard. The court agreed with the plaintiffs and felt that complete suppression of health claims, unless they are false or misleading, is too restrictive, when disclaimers (e.g., “the evidence is inconclusive that antioxidant vitamins will reduce the risk of certain kinds of cancer”) on the label would accomplish the FDA’s objective. The court of appeals ordered the case remanded back to the district court, whose decision it reversed, with instructions that the FDA articulate clear standards regarding what constitutes “significant scientific agreement.” The FDA declined to appeal Pearson to the Supreme Court.

The Pearson decision ultimately produced a profound change in how the FDA evaluates health claims. The agency now essentially allows two types of health claims, unqualified and qualified, for both foods and dietary supplements. Unqualified health claims (those requiring no disclaimer) are allowed if authorized by the agency by means of a regulation, because the dietary supplement met the significant scientific agreement test. Qualified health claims (those that must contain a disclaimer as pursuant to Pearson) may be made when the claim does not meet the significant scientific agreement test and the claim would be misleading without the qualification. Qualified claims will be allowed only when there is more evidence for the claim than against it. The qualified claim must be truthful and not misleading and it must appropriately indicate the level of scientific support; for example, “Scientific evidence suggests but does not prove” or “Some evidence shows the nutrient may be beneficial, but there is insignificant scientific evidence to prove the effect.” The agency continues to aggressively police manufacturers who make unapproved health claims that it regards as false or misleading. For more in-depth information on health claims for foods and dietary supplements, refer to the FDA Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims – Final at http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm073332.htm.

Dietary Supplements Containing Drugs

On occasion, a dietary supplement may contain a drug, raising the issue of whether the product is actually a drug and not a dietary supplement. The FDCA excludes from the definition of dietary supplement any article that was approved as a new drug, unless prior to its approval it was marketed as a dietary supplement or food (21 U.S.C. § 321(ff) (3)(B)). In the case of Pharmanex, Inc. v. Shalala, 35 F. Supp. 1341 (2001 WL 741419 (D. Utah)), Pharmanex challenged the FDA’s decision that its product, Cholestin, which contained red yeast rice, was a drug and not a dietary supplement. Traditional red yeast rice, which naturally contains small amounts of monacolin K, has been eaten by the Chinese for centuries and is regarded by the Chinese as a health food. On this basis, the manufacturer argued Cholestin is a dietary supplement. The court, however, agreed with the FDA’s determination. The FDA established that Cholestin contained significant amounts of lovastatin, a cholesterol-lowering drug approved by the FDA in 1987, which is derived from and identical to monacolin K. The FDA further proved that Pharmanex carefully manufactured the production of Cholestin to contain high levels of lovastatin not found in traditional red yeast rice. In effect, the agency proved the company was manufacturing and marketing lovastatin, not traditional red yeast rice. Pharmanex retorted that, nonetheless, lovastatin was present in some foods marketed in the United States long before it was approved by the FDA, and therefore it must be considered a dietary supplement. The court, however, agreed with the FDA’s interpretation that traditional red yeast rice does not contain lovastatin at such levels, and that lovastatin itself was not marketed as a dietary supplement, food, or food component prior to 1987.

Safety Issues and Ephedra Products

Because dietary supplements are regulated much as foods rather than as drugs, the FDA can remove a dietary supplement from the market on the basis of public safety only if the agency can prove the product is adulterated (21 U.S.C. § 331(a), (b), (c), (k)). DSHEA provides that a dietary supplement is adulterated if it presents a “significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labeling; and, if no conditions of use are recommended or suggested, then under ordinary conditions of use” (21 U.S.C. § 342(f)(1)).

Pursuant to its application and interpretation of the law, the FDA issued a final regulation in 2004 banning all ephedrine alkaloid dietary supplement (EDS) products (69 Fed. Reg. 6788 (Feb. 11, 2004)). (Note: Ephedrine alkaloids [ephedra] is an extract of the ma huang plant and has been used as a natural medicinal agent in China for centuries. It should be distinguished from OTC drug products with structurally related active ingredients.) This final regulation was the culmination of a long investigative process beginning in the early 1990s when the FDA began receiving adverse event reports suggesting injury and illness associated with the use of EDS products. The administrative record reflecting the regulatory process contains over 133,000 pages of scientific data, expert reviews, comments, and other materials. In addition, the FDA commissioned expert reviews of the scientific evidence and assessed the findings of these expert reviews. After this review, the FDA concluded that, although EDS is promoted to achieve weight loss, enhance athletic performance, and increase energy, its effects are temporary, modest, and generally do not improve health. In contrast, the agency found that EDS increased the risk of serious adverse events including heart attacks, strokes, and death.

The passage of the regulation was hastened after highly publicized accounts of EDS use that led to the death of high profile athletes, such as Korey Stringer of the Minnesota Vikings and Steve Bechler of the Baltimore Orioles. Accounts such as these prompted Congress to issue a resolution that the FDA should immediately remove EDS from the market. Shortly after the enactment of the regulation, however, an EDS manufacturer sued the FDA in federal court in Utah, contending that the regulation was invalid (Nutraceutical Corp. v. Crawford, 364 F. Supp. 2d 1310 (April 12, 2005)). The court ruled for the plaintiff and invalidated the regulation on the basis that the FDA improperly applied a risk-benefit analysis and failed to provide sufficient evidence that EDS poses a significant risk in the dose recommended by the plaintiff. The FDA appealed, resulting in the court of appeals finding for the FDA, reversing the district court’s decision and reinstating the regulation banning EDS products (Nutraceutical Corp. v. Von Eschenbach, 459 F.3d 1033 (10th Cir. 2006)). In a lawsuit against the FDA by another EDS manufacturer (NVE, Inc. v. Department of Health and Human Services, 463 F.3d 182 (3rd Cir. 2006)), the court also sided with the FDA, ruling that plaintiffs could not present additional evidence about EDS, but rather are limited to review of the FDA’s administrative record.

The Dietary Supplement and Nonprescription Drug Consumer Protection Act

The EDS situation prompted Congress to enact serious adverse event reporting requirements for dietary supplement manufacturers in December of 2006 in a law entitled the Dietary Supplement and Nonprescription Drug Consumer Protection Act (P.L. 109–462). This law adds two parallel mandatory serious adverse events reporting systems: one for nonprescription drugs and the other for dietary supplements. Manufacturers, packers, or distributors whose name appears on the label must submit to the Secretary of Health and Human Services (through the MedWatch program described later) any report of a serious adverse event within 15 business days. They also must submit any subsequent medical information received within one year of the initial reported event. Product labeling must include either the supplier’s domestic address or a continuously operating toll-free telephone number so consumers can report serious adverse events. Suppliers also must maintain records related to each report for six years and allow inspection of these records. The FDA published a draft guidance in October 2007 (72 Fed. Reg. 58313–01) to assist the dietary supplement industry in complying with the law. The latest update of the guide was published in 2013 (http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/dietarysupplements/ucm171383.htm).

Criticisms of DSHEA

DSHEA has proven controversial, and critics of the law have identified three major concerns. First, they contend that the law allows the marketing of unsafe dietary supplements and that it prevents the FDA from acting aggressively enough to protect the public. Second, critics are concerned over a lack of consumer information about the dangers of taking many dietary supplements with certain OTC and prescription medications. Most dietary supplement labeling does not warn users of these potential adverse effects. Third, critics argue that dietary supplements lack quality standards for strength and purity because manufacturers are not required to register themselves or their products with the FDA prior to marketing them, and no manufacturing standards exist for dietary supplements. In response to this third concern over quality standards, the FDA issued a final rule in June 2007 (72 Fed. Reg. 34752 (June 25, 2007)) requiring that dietary supplement manufacturers comply with CGMP in such a manner that the products will not be adulterated or misbranded. The regulations also require manufacturers to evaluate the identity, purity, quality, strength, and composition of their products. Dietary supplements containing contaminants or lacking the ingredient they represent would be considered adulterated or misbranded. However, because dietary supplements do not require FDA approval, the FDA will generally not identify products in violation of CGMP before they reach consumers. An investigation by the New York Attorney General’s office released in 2015 found that four out of five of the store-brand dietary supplements it tested from GNC, Target, Walgreens, and Walmart did not contain the active ingredients listed on the labels (http://well.blogs.nytimes.com/2015/02/03/new-york-attorney-general-targets-supplements-at-major-retailers/). The office has issued cease-and-desist letters to the companies demanding they stop selling their store-brand supplements.

Implications of DSHEA for Pharmacists

In light of the decreased government regulation over dietary supplements since DSHEA, pharmacists have an important role in providing accurate product information to patients and assisting them with product selection. If possible, pharmacists should steer patients to products conforming to United States Pharmacopeia (USP) or National Formulary (NF) standards, or at least products in which manufacturers can attest to quality and uniformity standards.

Pharmacists should not promote dietary supplements on the basis of unapproved health or disease claims because this could violate the FDCA. However, it is completely legal for pharmacists to counsel, educate, and provide advice to patients about the use of a supplement product for a disease, and they should do so when appropriate. DSHEA permits pharmacists to display certain publications, such as articles, book chapters, books, and abstracts of peer-reviewed scientific publications, used in conjunction with the sale of dietary supplements. To conform to the law, however, these publications must be reprinted in their entirety; must not be false or misleading; must be presented with other publications, if available, about the product in order to present a balanced view; must be physically separate from the actual product; and must not have appended to them any information by sticker or other method.

DRUGS VERSUS DEVICES

Before the passage of the MDA of 1976 (discussed later in the chapter), the FDA lacked the authority to approve devices for safety and efficacy prior to their commercial distribution. This inadequacy forced the FDA to declare that certain devices were drugs in order to regulate them, which often resulted in litigation. For example, in United States v. Article of Drug Bacto Unidisk, 394 U.S. 784 (1969), the FDA successfully established that antibiotic sensitivity disks fall under the drug definition. In another case, United States v. Article of Drug Ova II, 414 F. Supp. 660 (D.N.J. 1975), the FDA failed to prove that a home pregnancy testing kit is a drug. The court determined that because pregnancy is not a disease, the kit is not a diagnostic test for a disease. The MDA differentiates devices from drugs by stating that a device does not achieve any of its principal intended purposes through chemical action and is not dependent on being metabolized for the achievement of any of its principal intended purposes. The term “device” does include in vitro diagnostic products used to aid in the diagnosis of disease or verification of pregnancy.

When a device is used in conjunction with a drug, the legal distinction becomes less clear. The FDA has stated that many factors may determine whether a product is a device or a drug:

•  Is the product intended to deliver drugs to the patient, but is not prefilled by the manufacturer (e.g., an empty implantable infusion pump)?

•  Is the drug component included solely to make the product safer (e.g., a surgical drape impregnated with antimicrobial agents)?

•  Is the drug component intended to have a therapeutic effect (e.g., an intrauterine contraceptive device that releases a hormone)?

The manufacturer of a drug delivery device must establish that the device and the drug will not have deleterious effects on one another. Although problems of classification still occur, the 1976 device amendment has greatly clarified the distinction between drugs and devices, and has given the FDA significantly more enforcement authority over devices. The MDA’s comprehensive device classification system is discussed later in this chapter.

DRUGS VERSUS COSMETICS

A cosmetic may become a drug if its manufacturer promotes it for a therapeutic purpose, despite the product chemistry. In United States v. An Article … Consisting of 216 Cartoned Bottles, More or Less, “Sudden Change,” 409 F.2d 734 (2nd Cir. 1969), the manufacturer distributed a lotion composed of bovine albumin and distilled water. When applied to the skin and allowed to dry, the lotion left a film that tightened the skin, thus temporarily masking imperfections and making the skin look smoother. The manufacturer’s advertisements claimed that the lotion would “lift out puffs” or give a “facelift without surgery.” The court refused to apply to these claims the standard of what a reasonable consumer would believe, but rather applied the standard of what an “ignorant, unthinking, and credulous” consumer would believe. On the basis of this standard and the manufacturer’s claims, the court found that the lotion was a drug but would cease to be a drug once the claims were discontinued.

On the other hand, in United States v. An Article of Drugs … 47 Shipping Cartons, More or Less … “Helene Curtis Magic Secret,” 331 F. Supp. 912 (D. Md. 1971), the court concluded that such claims as being a “pure protein” and causing an “astringent sensation” would not persuade even ignorant, unthinking, and credulous consumers that the product would alter their appearance. Therefore, this product was not held to be a drug.

LABELS AND LABELING

The FDCA differentiates the definition of label from that of labeling:

(k) The term “label” means a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under authority of this Act that any word, statement, or other information appearing on the label shall not be considered to be complied with unless such word, statement, or other information also appears on the outside container or wrapper, if any there be, of the retail package of such article, or is easily legible through the outside container or wrapper. (§ 201(k); 21 U.S.C. § 321(k))

(m) The term “labeling” means all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article. (§ 201(m); 21 U.S.C. § 321(m))

The term “label,” as the definition indicates, refers to information required on the container or wrapper. The term “labeling” has a far broader application. Although the term labeling includes the label, it also applies to the information “accompanying” the drug, such as the package insert. The legal interpretation of the word accompanying can be important in establishing whether misbranding has occurred. If the literature is deemed to accompany the product, it is labeling. If it is deemed not to accompany the product, it is advertising. The line between labeling and advertising is not always a clear one, leading to controversies.

In United States v. Guardian Chemical Corporation, 410 F.2d 157 (2nd Cir. 1969), the manufacturer discovered that its product, sold for the purpose of cleansing dairy apparatus, also was effective in treating kidney and bladder stones. Ultimately, the company prepared and distributed brochures to the medical profession to promote the product, now named Renacidin, for these purposes. The FDA contended that Renacidin was a drug and that the bottles and the brochures were misbranded because they did not contain the label and labeling information required by law for a drug. The court agreed with the FDA, holding that printed pamphlets or brochures need not be shipped with the article to constitute labeling. They may be sent either before or after the article and still “accompany” it as long as the distribution of the drug and the brochures are part of an “integrated distribution program” to sell the product.

In general, courts have held that information is labeling if the written materials are part of an integrated distribution program, have a common origin and destination, and explain the drug. The distinction between labeling and advertising for prescription drugs may not be that important today because each is subject to regulation by the FDA and must contain all the information approved by the FDA, as discussed later in this chapter.

OFFICIAL COMPENDIA

Part A of the drug definition recognizes particular compendia as legal sources of drug standards. One of these compendia, the United States Pharmacopeia (USP), is published by the United States Pharmacopeial Convention (USPC), an independent, private organization jointly founded in 1820 by physicians and pharmacists of the time, who were concerned that various medicinal ingredients and preparations under the same names differed considerably in potency, quality, and composition. To set uniform standards for these products, the USPC elected scientific experts to publish the USP. It has continued to establish standards ever since.

Although the USPC is a private organization, independent of the FDA, the FDA actively participates in the development and modification of the standards contained in the USP’s monographs, which establish the approved titles, definitions, descriptions, and standards for identity, quality, strength, purity, packaging, stability, and labeling for a drug. The USPC publishes the monographs of many of the drugs marketed in the United States. Before 1980, the USP contained monographs of active ingredients, and the NF contained monographs of inactive ingredients. In 1980, the two books were combined into one compendium, commonly referred to as the USP–NF, which now serves as the official compendium for drug standards in the United States.

The other official compendium stated under the FDCA is the Homeopathic Pharmacopoeia of the United States (HPUS), which has been in continuous publication since 1897. The HPUS defines homeopathy as the “art and science of healing the sick by using substances capable of causing the same symptoms, syndromes, and conditions when administered to healthy people” (http://www.homeopathicdoctor.com). The standards for the homeopathy products contained in the HPUS are established by the Homeopathic Pharmacopoeia Convention of the United States (HPCUS). This is a private, nonprofit organization of scientific experts in homeopathy. Because of the recent resurgence of homeopathy and a resultant need for continuous updates, HPCUS has republished the HPUS since 1988 as the HPUS Revision Service, a loose-leaf binder publication that allows for continual revisions without the need to reprint an entirely new volume.

Under the FDCA, a drug recognized in the USP–NF or HPUS must meet all compendium standards or it will be considered misbranded or adulterated. Similarly, a drug is considered misbranded or adulterated if it is not recognized in the USP–NF or HPUS, yet purports to be so recognized.

  TAKE-AWAY POINTS