Describe the role of the food and drug administration (fda).

Historical Introduction

The Food and Drug Administration (FDA) is an Executive Branch agency within the US Department of Health and Human Services (HHS). Its regulatory obligations include overseeing the safety of about 80% of the domestically produced and imported food in the USA – specifically, all food except meat, poultry, and processed eggs.

Long before the federal government of the USA began to regulate the country's food and drug products, individual states had made independent efforts to regulate them. But despite the threat of punishment for selling adulterated and mislabeled foods, the state laws, including the first-of-its-kind Massachusetts food and drug law passed in 1785, proved unsuccessful in preventing the marketing of violative food products.

It was not until 1906 that the first federal Pure Food and Drug Act was enacted, which made it a federal crime to sell mislabeled or adulterated food, drink, and drugs intended for interstate commerce. This cornerstone legislation of the future Food and Drug Administration was passed following the 1905 publication of Upton Sinclair's provocative novel The Jungle, which exposed the unsanitary conditions in American meatpacking plants, and the public crusade of Dr. Harvey Wiley, the chief chemist of the US Department of Agriculture (USDA) in the late 1800s and early 1900s, to reform the food and drug laws to protect consumers from harmful preservatives and adulterants.

Wiley, who came to be known as the ‘Father of the Pure Food and Drugs Act,’ was appointed as the first administrator of the landmark 1906 legislation. Under Wiley's leadership, the staff at the USDA's Bureau of Chemistry improved upon existing scientific methods for analyzing food and refined legal procedures and inspection methods helpful in enforcing the law.

The first separate federal food and drug agency was established in 1927, and took the name ‘Food and Drug Administration’ in 1931. While the 1906 law laid the agency's foundation, Congress has continued to update the act over the years, ultimately assigning FDA responsibility for assuring the safety of most US food products. The Federal Food, Drug, and Cosmetic Act, signed into law by President Franklin D. Roosevelt in 1938, remains the basic food and drug law of the USA. Three amendments to the 1938 law had important implications for food regulation: the Miller Pesticide Amendment in 1954, the Food Additives Amendment in 1958 (which includes the ‘Delaney Clause’), and the Color Additive Amendments in 1960.

Despite the legal amendments, the overall goal of the federal food law has remained constant: protecting US consumers from adulterated and misbranded food products, whether they are produced domestically or imported into the USA. It is the Food and Drug Administration's responsibility to implement the food and drug laws to protect and promote the health and economic interests of the American public.

Recent statistics from the Centers for Disease Control and Prevention illuminate the enormity of this challenge: foodborne illness, according to CDC, causes approximately 76 million illnesses, 325 000 hospitalizations and 5000 deaths each year in the USA. And in their quest to improve the safety of the US food supply, food scientists and regulators continue to be faced with ever-changing hurdles: for example, US consumers are eating more seafood, fresh produce (especially imported produce), and more ready-to-eat foods, as well as more foods prepared at restaurants and institutional settings such as nursing homes and hospitals. Also, up to 25% of the US population is considered ‘at risk’ for foodborne illness. Vulnerable populations include pregnant women, children, the elderly, and those who are immunocompromised. But perhaps the most perplexing challenge of all comes from evolving bacteria such as new strains of Escherichia coli (E. coli) 0157:H7.

c Examples of Drugs That Have Been Granted Orphan Drug Status

FDA has granted orphan drug status to various drugs to be used for the indications described in the following list. Documents written by FDA reviewers in the approval of all drugs, including orphan drugs, can be found on the FDA’s website using the procedure in footnote (176). The following list identifies the indication, as well as the location (on FDA’s website) of the FDA’s Approval Letter and other documents that supported the FDA’s decision to approve the drug:

Ibrutinib for mantle cell lymphoma (MCL). Documents available on the FDA’s website at November 2013.

Imatinib for chronic myeloid leukemia, a disease characterized by a chromosomal location called, Philadelphia chromosome. Documents available on the FDA’s website at January 2013.

Obinutuzumab for chronic lymphocytic leukemia (CLL). Documents available on the FDA’s website at November 2013.

Afatinib for nonsmall-cell lung cancer where tumors have a deletion in exon 19 of the gene encoding epidermal growth factor receptor or a mutation in exon 21 that involves change of a leucine residue to an arginine residue (L858R). Documents available on the FDA’s website at July 2013.

Velaglucerase alpha for type 1 Gaucher disease. Documents available on the FDA’s website at November 2013.

Glycerol phenylbutyrate for urea cycle disorders. Documents available on the FDA’s website at January 2013.

Cysteamine bitartrate for nephropathic cystinosis. Documents available on the FDA’s website at April 2013.

Riociguat for pulmonary arterial hypertension. Documents available on the FDA’s website at October 2013.

Sapropterin for hyperphenylalaninemia in patients with phenylketonuria. Documents available on the FDA’s website at December 2013.

Elosuflase alpha for Morquio A syndrome, also known as mucopolysaccharidosis IVA. The drug, which takes the form of the enzyme N-acetylgalactosamine sulfatase, replaces an enzyme that is missing in the patient’s body. Documents available on the FDA’s website at February 2014.

2.2.2 What is Fda’s Mission?

FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation (FDA, 2016i). FDA is also responsible for advancing the public health by helping to speed innovations that make medicines more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health. Further, FDA has responsibility for regulating the manufacturing, marketing, and distribution of tobacco products to protect the public health and to reduce tobacco use by minors. FDA’s jurisdiction includes the 50 United States, the District of Columbia, Puerto Rico, Guam, the Virgin Islands, American Samoa, and other US territories and possessions (FDA, 2016j).

I Introduction

FDA’s Warning Letters provide reliable and consistent guidance on substantive and procedural aspects of clinical trials (1). Warning Letters are available on FDA’s website. Please note that FDA inspects pharmaceutical companies, medical device companies, and companies that manufacture foods and dietary supplements, and issues Warning Letters to all of these entities. Where a Warning Letter is sent to a food or dietary supplement company, the complaint usually concerns sanitation, inconsistencies between the package label and regulations in the CFR, and exaggerated health claims on the package label.

Although it is not often that a company fails to comply with the demands in the FDA’s Warning Letters, failure can result in product seizure, debarment, or injunctions (FDA shuts down operations) (2). The consistent nature of FDA’s Warning Letters is ensured by the fact that the draft letters are reviewed, before issue, by the FDA’s Office of Chief Counsel (3,4). The bold font in the Warning Letters was added to emphasize certain phrases, and was not in the original Warning Letters.

FDA Authority

FDA enforcement is authorized in the Food Drug and Cosmetic Act, which allows the FDA to pursue legal actions against a firm that markets products in violation. The recall process, if done correctly, is a way that firms can voluntarily correct violations before FDA legal actions were to take place. FDA has the responsibility to monitor the recall process and to ensure that the firm is providing adequate efforts toward the recall process. However, if the responsible firm does not put forth the efforts to correct violations or institute recalls, the FDA has authority to act. For most products, the FDA does not have the authority to force a firm to institute a recall, they have the authority only to seize a product. However, for a few product classes, the FDA does have the authority to institute a mandatory recall. Statutory provisions authorize mandatory recalls of infant formula (21 USC § 350a(e)-(g)), medical devices (21 USC § 360h(e)), and human biological products (42 USC § 262). The specific requirements for mandatory infant formula recalls are in Subpart E of 21 CFR107. Medical device corrections and removals procedures are codified in 21 CFR Part 806, and mandatory human tissue recall procedures are listed in Subpart D of 21 CFR 1270. Recalls, once initiated, are published in the online weekly FDA Enforcement Report.

Health Claims

Health claims describe a relationship between a food, food component, or dietary supplement ingredient and reducing risk of a disease or health-related condition. A “health claim” definition has two essential components: (1) a substance (whether a food, food component, or dietary ingredient) and (2) a disease or health-related condition. A statement lacking either one of these components does not meet the regulatory definition of a health claim.

FDA has oversight in determining which health claims may be used on a dietary supplement label. Its authority comes from several laws:

NLEA Authorized Health Claims: The Nutrition Labeling and Education Act (NLEA) of 1990, the Dietary Supplement Act of 1992, and the Dietary Supplement Health and Education Act of 1994 (DSHEA) provide for health claims used on labels that characterize a relationship between a food, a food component, dietary ingredient, or dietary supplement, and risk of a disease provided the claims meet certain criteria and are authorized by an FDA regulation. FDA authorizes these types of health claims based on an extensive review of the scientific literature, generally as a result of the submission of a health claim petition, using the significant scientific agreement standard to determine that the nutrient–disease relationship is well established. For an explanation of the significant scientific agreement standard, see the FDA website.

Qualified Health Claims: FDA permits the use of qualified health claims when there is emerging evidence for a relationship between a food, food component, or dietary supplement and reduced risk of a disease or health-related condition. When this is the case, the evidence is not well enough established to meet the significant scientific agreement standard required for FDA to issue an authorizing regulation. Qualifying language is included as part of the claim to indicate that the evidence supporting the claim is limited. Both conventional foods and dietary supplements may use qualified health claims. FDA uses its enforcement discretion for qualified health claims after evaluating and ranking the quality and strength of the totality of the scientific evidence. Although FDA’s “enforcement discretion” letters are issued to the petitioner requesting the qualified health claim, the qualified claims are available for use on any food or dietary supplement product meeting the enforcement discretion conditions specified in the letter. FDA has prepared a guide on interim procedures for qualified health claims and on the ranking of the strength of evidence supporting a qualified claim. Qualified health claim petitions that are submitted to FDA will be available for public review and comment. A listing of petitions open for public comment is at the FDA Dockets Management website. A summary of the qualified health claims authorized by FDA may be found at its website.

1.5.1 Regulatory inspection

FDA has defined “an establishment inspection [as] a careful, critical, official examination of a facility to determine its compliance with laws administered by FDA.”20 More specifically, the inspection examines the organization’s adherence to the concepts of sanitation and GMPs, seeks assurance that all reasonable precautions are being taken to ensure the SISPQ of finished products, and seeks to identify deficiencies as well as to obtain correction of those deficiencies. This inspection can be either comprehensive or directed. The comprehensive inspection covers everything in the organization subject to FDA jurisdiction to determine the organization’s compliance status. The directed inspection covers specific areas to an assigned depth (ibid.).

In the case of a manufacturing site, this inspection will typically inspect the quality system and one of the other five systems of the FDA Quality Systems Approach: facilities and equipment, laboratory controls, production, packaging and labeling, and materials.21 A regulatory inspection can include FDA personnel reviewing records of prior inspections, walking through the facility, examining current records, interviewing employees, etc.

When “deficiencies” are observed, they are reported to management before FDA personnel has left the facility. These Form 483 observations can later become part of an FDA Warning Letter to the management of the organization. At that point, if not earlier, the organization will begin to respond. The response typically includes management’s call for an investigation of each deficiency observed during the inspection. Each investigation will include RCA, and tracking and trending of similar events or situations observed elsewhere or in prior inspections. CAPA will be developed and executed, all within a specified timeline. The remediation may require the revision of an operational SOP.

7.4.1.4.1 “Healthy”

FDA also regulates many other claims. An increasingly more common claim is the term “healthy” and its related variations. FDA has set nutritional parameters on what is considered a “healthy” product,” and, although perhaps imperfect as applied to some foods, this definition has been strictly enforced.yyy An important caveat is that even implied healthy claims, such as that consuming the product is part of a healthy lifestyle, may require the product to comply with FDA’s “healthy” definition (Table 7.2).

Table 7.2. Conditions for the Use of “Healthy” for Individual Food Products

Adapted from: FDA (2013). Appendix B: Additional Requirements for Nutrient Content Claims, Guidance for Industry: A Food Labeling Guide, FDA, January 2013.aaaa

1.6.4 Warning Letters About Caffeinated Alcoholic Beverages

The FDA issued another 27 Warning Letters about caffeinated alcoholic beverages in 2009. Although the FDA approved caffeine as an additive in soft drinks (at concentrations no more than 200 ppm) in the 1950s, the FDA has not approved caffeine at any level in alcoholic beverages. The FDA indicated caffeine is an “unsafe food additive” when mixed with alcohol and allegedly makes the products adulterated under section 402(a)(2)(C) of the FDCA [21 U.S.C. §342(a)(2)(C)]. These Warning Letters indicate caffeine can mask sensory cues of intoxication and may lead to risky behaviors potentially leading to hazardous and life-threatening situations. Based on this evidence, the FDA determined that caffeine use in alcoholic beverages is not GRAS. In discussion with the FDA, major brewers, such as Anheuser-Busch Companies, LLC, and Miller Brewing Co., decided to discontinue Tilt, Bud Extra, and Sparks and agreed not to produce any caffeinated alcohol beverages in the future.

This initiative was updated in 2010 when the FDA and the FTC sent Warning Letters and the Alcohol and Tobacco Tax and Trade Bureau sent notifications to four companies about adding caffeine to alcoholic malt beverages. In addition, an FDA Consumer Health Information notice showed images of some of these beverages and quoted Dr. Joshua M. Sharfstein, FDA’s principal deputy commissioner, as stating: “Consumers should avoid these caffeinated alcoholic beverages, which do not meet the FDA’s standards for safety” (FDA, 2010b).

In addition, the FDA announced a new caffeine initiative in 2013 when they investigated the safety of caffeine in foods targeting children and adolescents. This announcement came shortly after Wrigley’s started promoting a new gum with caffeine and the FDA indicated concerns about the potential cumulative impact of these new caffeinated foods on children and adolescents.

4.11 Enforcement of the color additive requirements

FDA’s enforcement of the color additive requirements is authorized by the Federal Food, Drug, and Cosmetic Act (FFDCA, 2013). The enforcement tools used by the FDA for developing evidence of violations related to color additives include inspecting color additive and food manufacturing firms, screening imported products, and collecting samples for laboratory analysis. Regulatory actions for domestic products include information letters, untitled letters, warning letters, detentions, recalls, seizures, injunctions, prosecutions, and civil money penalties. Regulatory actions for imported products are more limited and include detentions and import alerts. However, adding a manufacturing firm and product to an import alert means the firm and future products have the status of “detention without physical examination” (DWPE) and will always get the FDA’s attention.

The FDA conducts inspections of color additive manufacturers to ensure compliance with labeling, storage, good manufacturing practices, and recordkeeping requirements. During an inspection, FDA investigators cross-reference the lot numbers assigned to the manufacturer’s certified batches with FDA’s certification records to confirm the validity of the lot numbers and check records of disposal of the batches. FDA investigators also collect samples of certified batches for re-analysis by FDA chemists and comparison to the original results.

Both domestic and foreign food manufacturers are subject to FDA inspections. Finished food product labels are examined for product and ingredient declarations. Products may be collected for analysis if they are suspected to contain nonpermitted color additives or appear to be artificially colored but color additives are not declared on their labels. Laboratory analyses can identify permitted and nonpermitted color additives in a product but cannot determine whether any of the color additives have been certified; thus, certification lot numbers must be provided by the product manufacturers in order to demonstrate compliance with that requirement.