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March CE Article
March CPE Article
Evolution of the Federal Legal Framework for Regulation of Medications
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Authors: Joseph L. Fink III, B.S.Pharm., J.D., D.Sc.(Hon.), FAPhA, Professor of Pharmacy Law and Policy and Kentucky Pharmacists Association Endowed Professor of Leadership at the University of Kentucky College of Pharmacy, Lexington.
The author declare that there are no financial relationships that could be perceived as real or apparent conflicts of interest.
Goal: To educate pharmacists and pharmacy technicians about evolution of the federal statutes and regulations related to production and distribution of medications in the U.S. thereby enhancing the readers’ understanding of the legal environment of professional practice.
Universal Activity #0143-0000-21-003-H03-P &T Contact Hour (1.0 CEU) KPERF offers all CE articles to members online at Expires:4/15/2024 www.kphanet.org
Learning Objectives: At the conclusion of this knowledge-based article, the reader should be able to: 1. Distinguish the bases of legal authority to regulate pharmacists, pharmacies and pharmaceuticals between the federal and state governments; 2. Identify the impetus for the 1906 Federal Pure Food and Drug Act; 3.
Identify the impetus for the Federal Food, Drug and Cosmetic Act of 1938; and
Identify the impetus for Kefauver-Harris Amendments of 1963.
Introduction Taken together, when one looks at both federal and state level statutes and regulations, pharmaceuticals are among the most highly regulated products in the U.S. marketplace. They require pre-marketing approval and, if the product presents a potential for abuse, it may have an additional layer of regulation limiting its availability. Authority to regulate medications at the federal level of government comes from the Commerce Clause of the U.S. Constitution: The United States Congress shall have power “to regulate commerce with foreign Nations, and among the several States, and with the Indian Tribes.”1 Having medicinal agents that move across state lines or are composed of ingredients or packaging that did so invokes this provision in the law. At the state level the authority is rooted in what is known as the “Police Power” of state government – the authority to enact and enforce statutes and regulations related to the public health, safety and welfare.
The states possess this authority because of the Tenth Amendment to the Constitution – “The powers not delegated to the United States by the Constitution, nor prohibited by it to the States, are reserved to the States respectively, or to the people.”2 Although, in general, legal restrictions and expectations can emanate from either level of government, this discussion will focus solely on the evolution of regulatory frameworks originating from the federal level. This is not to diminish the impact of statelevel initiatives; rather, pharmaceuticals are principally regulated at the federal level whereas pharmacists and pharmacies are primarily the subject of statutes and regulations emanating from the state level.
Import Drug Act of 1848 The first federal statute directed at protecting U.S citizens from harmful drugs was the Import Drug Act of 1848.3 This Congressional act was directed at prohibiting the importation of adulterated drugs. The motivation for this legislation was that antimalarial medication for U.S. troops fighting the Mexican-American War was found to be grossly adulterated and lacking in potency.
Federal Pure Food and Drug Act of 1906 This next piece of federal legislation is generally regarded as being the principal forerunner of the modern federal food and drug laws. Sometimes this is referred to as the Wiley-Heyburn Act after the two sponsors of the legislation. Impetus for this legislation came from publication of a book, The Jungle, by Upton Sinclair.5 This work focused on the harsh working and living conditions of immigrants in Chicago and awakened the nation to the manifestly unsanitary conditions in food processing and drug manufacturing industries. Lack of purity in those products prompted federal legislative action. This statute, signed into law by President Theodore Roosevelt, prohibited adulteration and misbranding of drugs shipped in interstate commerce. Responsibility for enforcing this legislation was assigned to the Bureau of Chemistry, a part of the U.S. Department of Agriculture. Sherley Amendment of 1912 The Pure Food and Drug Act of 1906 was amended during 1912 to prohibit the seller of a medication from making false or fraudulent claims of efficacy. Impetus for this change was a decision by the U.S. Supreme Court during the prior year in the case of U.S. v. Johnson, a case the federal government lost when it attempted to enforce its interpretation of the 1906 Act related to definition of drug adulteration. The nation’s highest court ruled that the 1906 statute did not prohibit false medical claims; rather, it only addresses false and misleading statements about the ingredients or identity of a drug.6 A local twist on this legislative change is that the bill that was enacted to effect this modification was introduced by Rep. Joseph S. Sherley of Kentucky, a native of Louisville!
Federal Food, Drug and Cosmetic Act of 1938 The next major revision of the legislation came in response to what now is known as the “sulfanilamide incident.” The S.E. Massengill Company of Bristol, Tennessee, marketed Sulfanilamide Elixir with the liquid vehicle for the active ingredient being diethylene glycol. That diluent was suggested by the Chief Chemist of the firm in response to a request from the Marketing Department that a liquid dosage form was needed, especially for pediatric patients. Sulfanilamide was used to treat hemolytic streptococcal infections. The formula for the preparation was finalized but no toxicity tests were conducted. The product was distributed in commerce and it was reported that 107 people died from using this product, many of them children. FDA, the name adopted by the relevant agency during 1930, took steps to pull the product from the market basing its action on what some would call a technical labeling violation – the term elixir was reserved for a product using alcohol for the vehicle, not diethylene glycol. Today we know that diethylene glycol, used as a permanent antifreeze in vehicles, is a deadly poison. That’s why people are cautioned that if they see antifreeze dripping from a vehicle in the driveway it should be promptly cleaned up because it is very sweet and therefore attractive to dogs, with deadly consequences.
This sad story of the deaths from sulfanilamide led Congress to strengthen the statute with amendments requiring that the safety of a product be established before it could be cleared for marketing. These legislative changes also included authorization for inspection of production facilities. Another significant change at this time was that while the FDA was assigned responsibility for oversight of production and marketing of prescription medications, authority to regulate the advertising of non-prescription medications was assigned to the Federal Trade Commission. That dichotomy of jurisdictions continues to this day.
Manufacturing Regulation Changes of 1941 Distribution of sulfathiazole tablets that had become contaminated with phenobarbital during the production process led to nearly 300 deaths. This motivated FDA to make changes in the regulatory scheme for manufacturing and quality control, leading to creation of what are now known as Current Good Manufacturing Practices (CGMP’s).
United States v. Sullivan Decision of 1948 The 1938 amendments included among their prohibitions the Misbranding of Drugs “held for sale after interstate shipment.” A community pharmacist in Columbus, Georgia, had purchased a bottle containing sulfathiazole tablets from an outlet in Chicago, Illinois. That stock bottle bore a label reflecting a warning that the drug product could be toxic. The pharmacist sold twelve tablets in a box that did not bear the warning statement. He was changed with a federal offense for violating the labeling requirement. He was convicted at the trial court level and appealed. The U.S. Court of Appeals reversed his conviction on the basis that the wording of the statute – “held for sale after interstate shipment” –extended only to the first intrastate sale and did not apply to subsequent local sales after some time had lapsed. The government requested that the Supreme Court take up the case and it did, resulting in an opinion written by Justice Hugo Black. He upheld the FDA’s interpretation that such misbranding of the medication was prohibited regardless of when the product was sold and without regard to how many local sales had occurred. The Court’s opinion was that the product continued to be in interstate commerce until “the moment of…delivery to the ultimate consumer” in a terminal transaction. The pharmacist advanced the unsuccessful argument that this interpretation of the statutory language went far beyond the authority granted to the federal government by the Commerce Clause and intruded on the power granted to the states by the Tenth Amendment.8 Durham-Humphrey Amendments of 1951 This legislation was introduced in Congress by two pharmacists elected to serve there at the time –Rep. Carl Durham of North Carolina and Sen. Hubert Humphrey of Minnesota (later to serve as Vice President of the United States!). This legislation attempted to clarify the distinction between those medications requiring a lawfully issued prescription prior to dispensing and those that did not. These legislative changes also authorized prescriptions to be transmitted orally and made it possible for the prescriber to authorize refills at the time of issuance of a prescription.7
Kefauver-Harris Amendments of 1963 During late 1961 another medication-related tragedy began to unfold. Thalidomide, a medication directed at assisting the patient to sleep and sometimes used to treat “morning sickness” in pregnant women, was associated with extremely severe birth defects in thousands of newborns in Europe. The disorder was known as phocomelia (a condition where the arms and leg resemble “seal limbs”) and include youngsters being born with incomplete limbs, both arms and legs in some cases. Those unfortunate circumstances were associated with the mothers having consumed thalidomide while pregnant. While never lawfully completing the review to permit manufacturing and distribution for use in the U.S., the dramatic visual impact of the damages suffered by the children captured the concern of the public that was translated into legislative action. Congress added the mandate that in order to be shipped in interstate commerce a drug product must not only be shown to be safe but also had to have sufficient evidence of effectiveness. The
namesakes of this legislation were Sen. Estes Kefauver of Tennessee and Rep. Oren Harris of Arkansas. The bill was signed into law by President John F. Kennedy. It is sometimes referred to as the Drug Efficacy Amendment.9
Drug Efficacy Study Implementation During 1968, FDA created a program to retrospectively review the effectiveness of medications introduced to the marketplace between 1938 and 1962, an interval when only safety was required to be shown. This change was the result of a study and recommendations from the National Academy of Sciences. These became known as “DESI Drugs”.
Patient Package Inserts Become Required In 1970 the FDA began to require patient package inserts be distributed with certain medications. My memory tells me that the first such product was the Isuprel Mistometer®, an inhalation version of isoproterenol.
Over-the-Counter Drug Review FDA launched this initiative during 1972 to enhance the safety, effectiveness and review the labeling of non-prescription pharmaceuticals. This massive review of hundreds of thousands of OTC products was led by pharmacists on the staff of FDA. To make it more manageable it was approached on a therapeutic category basis.
Tamper-Resistant Packaging Regulations During 1982, FDA enacted regulations to create evidence that an outer container, e.g., box or carton, of a product had been opened earlier. This was done in response to the Tylenol® tampering incident of that year in the metropolitan Chicago area. Seven deaths were the result of a nefarious individual tampering with commercial packaging by adding potassium cyanide to the capsules while on the shelf awaiting sale. Orphan Drug Act of 1983 At the urging of pharmaceutical manufacturers, Congress enacted legislation known as the Orphan Drug Act in 1983.10 Those who did the research and produced the pharmaceuticals pointed out that New Drug Application process that was in place was too onerous and expensive to encourage development of drugs for illnesses suffered by a relatively small number of patients. This initiative was to facilitate such innovations.
Drug Price Competition and Patent Term Restoration Act of 1984 Known variously as the Waxman-Hatch Act (then) or the Hatch-Waxman Act (now), this 1984 legislation authorized FDA to approve marketing of a generic version of an earlier approved brand name medication without the manufacturer conducting expensive and time-consuming studies of safety and efficacy. The legislation, sponsored by Rep. Henry Waxman of California and Sen. Orrin Hatch of Utah, also permitted manufacturers of brand name products to apply to “get back” up to five years of additional patent exclusivity time to replace that lost while awaiting FDA approval.11
Prescription Drug Marketing Act of 1987 The concern being addressed by this legislative action related to diversion of pharmaceuticals out of the traditional system for distribution of these sensitive products that needed assurance of integrity. This legislation created limits on sales of pharmaceuticals, and a special focus was on sales restrictions and recordkeeping for transfer of samples of prescription drugs. Finally, it prohibited hospitals from reselling pharmaceuticals and required that states adopt regulations governing drug wholesalers.12
Prescription Drug User Fee Act of 1992 This legislation adopted in 1992 was designed to address the fact that FDA was receiving an everincreasing number of New Drug Applications for review and, hopefully, approval but Congress was reluctant to increase its budget allocation to cover |23| www.KPHANET.org
that workload. The solution was to pass the cost directly to those who had the potential to reap the financial benefit, the manufacturers. This legislation authorized the FDA to charge fees, known as PDUFA Fees, to manufacturers who sought review of applications to market their products. The legislation contained a provision that this approach –funding from applicants – would need to be reauthorized every five years.13
Food and Drug Administration Modernization Act of 1997 Congress wanted to send FDA a message that it was seeking action by the agency to eliminate a backlog of review of NDA submissions and to bring a more timely approach to their review activities. This legislation, known as FDAMA, authorized the agency to create a “fast-track” process for handling NDA’s for medications proposed to be used for serious or life-threatening diseases. It also created an information databank to compile information about clinical trials and freed to some extent the ability of manufacturers to promote off-label use of their approved products. With regard to OTC products, this legislation set standards for including in product labeling inactive ingredients.14
Drug Facts Label Required for OTC Products In 1999 the FDA created a uniform format for medication information appearing on the packaging or labeling of non-prescription pharmaceuticals. This is referred to as the Drug Facts Label.
FDA Regulation of Tobacco as a Drug During 2000 the U.S. Supreme Court turned down an attempt by FDA to regulate tobacco as a drug. The case was designated Food and Drug Administration v. Brown & Williamson Tobacco Corp. The vote was 5-4.15
Food and Drug Administration Amendments Act of 2007 Congress returned its attention to FDA regulated products with this statute adopted during 2007. This law clarified FDA’s authority to direct that product labeling be changed to enhance safety. It also authorized FDA to mandate that manufacturers could be required to conduct post-approval clinical studies related to product safety, so-called Phase IV Studies. It also authorized the agency to require risk evaluation and mitigation strategies (REMS) communications to enhance patient safety while using selected FDA-approved products.16
FDA Safety and Innovation Act of 2012 This legislation began as an attempt to extend the Prescription Drug User Fee revenue stream for the FDA. It expanded the coverage of that fee approach to generic products and biosimilars. Along the way the legislation picked up other provisions directed at reducing counterfeiting of dosage forms, reducing drug product shortages, reducing the importation of adulterated products, and facilitating sharing of drug diversion information by state agencies across state lines.17
Drug Quality and Security Act of 2013 This legislation amended the Federal Food Drug and Cosmetic Act to clarify that pharmacies may compound custom medications for their patients pursuant to a prescription or in anticipation of a patient-specific prescription. It also created a new category known as “outsourcing facilities” that may do preparation of medication dosage forms for hospitals without having a patient-specific prescription/medication order. It also created a nationwide system used to track pharmaceuticals through the various stages of the supply chain to secure and verify the integrity of the products. This has come to be known as “track and trace.”18
The 21st Century Cures Act of 2016 This statute, sometimes referred to as the “Cures Act”, authorized innovation in clinical trial design to facilitate collecting information needed to prepare submissions to FDA. It also addressed again the idea of facilitating approval of medications to treat certain serious or life-threating conditions.19
Conclusion The history of federal legislative and regulatory action related to assuring the safety and efficacy of medications is replete with examples of action occurring only in response to tragedy. This pattern, seen all too frequently especially with legislative action, is that a tragedy occurs and then there is a legislative response as opposed to anticipating negative events. More recent changes have taken a somewhat more pro-active approach and we can only hope that this will continue. (1906).
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8. 221 U.S. 488 (1911).
21 U.S.C. §353(b).
332 U.S. 689 (1948).
More than a few of these legislative and regulatory changes have brought more requirements for the pharmacist that can be onerous but it’s important to “keep your eye on the ball” – the ultimate objective is protecting the patient and enhancing chances for a positive outcome. And that’s what pharmacy is all about anyway. 9.
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Disclaimer: The information in this is intended for educational use and to stimulate professional discussion among colleagues. It should not be construed as legal advice. There is no way such a brief discussion of an issue or topic for educational or discussion purposes can adequately and fully address the multifaceted and often complex issues that arise in the course of professional practice. It is always best advice for a pharmacist to seek counsel from an attorney who can become thoroughly familiar with the intricacies of a specific situation and render advice in accordance with the full information. 12.
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17. 76 Stat. 780.
P.L. 97-414.
P.L. 98-417.
P.L. 100-293.
P.L. 102-571.
P.L. 105-115.
529 U.S. 120 (2000)
P.L.110-85.
P.L. 112-144.
References 1.
U.S. Constitution, Art. I, Sec. 8, Cl. 3. 18. P.L. 113-54.
U.S. Constitution, Amendment X. 19. P.L. 114-255.
9 Stat. 237.
34 Stat. 768.