Legal and Regulatory Issues in Self-Care Pharmacy Practice PDF
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Mount Holyoke College
Martha M. Rumore
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This document details the legal and regulatory framework for nonprescription drugs in the U.S. Specifically, it discusses the history of nonprescription drug regulation, regulatory approval processes, and relevant legal changes, including recent changes due to the CARES Act. It covers safe use, labeling, adverting, potential liability, and future trends within the field of self-care pharmacy practice.
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9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary APhA OTC - The Practitioner’s Role in Self-Care PREVIOUS You have access | APhA OTC - The Practitioner’s Role in Self-Care Legal a...
9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary APhA OTC - The Practitioner’s Role in Self-Care PREVIOUS You have access | APhA OTC - The Practitioner’s Role in Self-Care Legal and Regulatory Issues in Self-Care Pharmacy Practice https://doi-org.uri.idm.oclc.org/10.21019/aphaotc-practition.legal-issues Authors: Martha M. RumoreMartha M. Rumore Abstract The unit offers a current summary of the legal and regulatory framework for nonprescription drugs in the United States. A brief history is provided of nonprescription drug regulation. The unit then describes the sweeping changes to the 50-year-old regulatory processes for nonprescription drugs as a result of the 2020 Coronavirus Aid, Relief, and Economic Security Act (CARES Act). Focusing on these changes, the unit explores current and proposed legal and regulatory changes in nonprescription drugs and aids professional judgment in use of these agents in self-care pharmacy practice. Overview I. History of Self-Care Therapeutics II. Regulatory Approval Process a. Pathways to Nonprescription Status b. Prescription-to-Nonprescription Switch c. Nonprescription Products with an ACNU III. Safe Use of Nonprescription Drugs a. Adulteration and Misbranding b. Adverse Drug Reaction Reporting c. Labeling d. Packaging e. Advertising IV. Third class of drugs a. De facto third class of drugs https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 1/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary V. Miscellaneous Topics Related to Nonprescription Drugs a. Abuse b. Cosmeceuticals c. Compounding d. Homeopathic Drugs e. Dietary Supplements f. Direct-to-Consumer Diagnostic Tests VI. Professional Liability Related to Nonprescription Drugs a. Liability for Drug Information b. Product Liability VII. Future Trends in Nonprescription Drugs This unit examines the legal and regulatory aspects of the manufacturing, distribution, labeling, and marketing of nonprescription drug products in the United States. Theories of civil liability, negligence, and breach of warranty also are discussed. The relationship between drug regulation and responsibility for proper drug use in the United States is complex. A pharmacist practitioner must be aware of the regulatory paradigm for nonprescription drugs in the United States, as well as the civil and professional obligations that arise from recommendations on use of these drugs in consumer self-care. Staying aware of the dynamic and frequently changing myriad of legal and regulatory issues in self-care pharmacy practice is essential for effective communication across the continuum from patients to elected representatives. Nonprescription and prescription drugs are regulated differently, but both are held to high standards for safety and efficacy. Nonprescription medications are actively and stringently regulated by the U.S. Food and Drug Administration (FDA) and the Federal Trade Commission (FTC). For pharmacists and other health care providers, familiarity with these regulations is essential for framing the most helpful responses to patients’ questions and concerns about the self-care products they use. Reflecting formal usage in pharmacy practice, the term nonprescription replaces over-the- counter (OTC) throughout APhA OTC. However, historically and in many publications, as well as in common parlance, these designations are used interchangeably. History of Self-Care Self-care has evolved over many decades. The era of patent medicines, sometimes referred to as nostrums, or “snake oils,” often involved exaggerated promises of benefit, as well as purely fraudulent claims of efficacy. Since the late 20th century, self-care therapeutics has become a multi-billion-dollar industry and involves standard and novel nonprescription therapeutic agents with proven health benefits and cost savings for self-reliant consumers. https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 2/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary In 1906, the Pure Food and Drugs Act1 prohibited adulteration and misbranding, which forced many patent medicines off the market. Shortly afterwards, the Harrison Narcotic Act2 of 1914 required prescription-only status for opium and other narcotics. However, this law exempted patent medicine manufacturers if their products contained less than threshold amounts of opium and proved difficult to enforce. In 1938, the Food, Drug & Cosmetic Act (FDCA)3 mandated safety standards for foods, drugs, and cosmetics, with further standards established in 1951 by the Durham-Humphrey Amendment.4 Before enactment of the Durham-Humphrey Amendment, the manufacturer determined whether a product would be sold as a prescription or nonprescription drug. Confusion ensued, with some manufacturers of a particular product marketing the drug as a nonprescription medication and other manufacturers of the same drug specifying prescription-only status. FDA did not maintain a list of prescription medications, and the manufacturer’s interpretation of FDA regulations of prescription versus nonprescription status was often arbitrary. If FDA disagreed with a product status determination, its sole recourse for remedy was to sue the manufacturer for misbranding.5 Many nonprescription products were marketed without approved New Drug Applications (NDAs) and deemed “grandfathered” drugs, which were allowed to remain on the market. In 1937, ingestion of a preparation of sulfanilamide using diethylene glycol as a solvent (sold as “Elixir of Sulfanilamide”) resulted in the deaths of more than 100 people from kidney failure. At that time, the toxicity of diethylene glycol was unknown, and the product was sold OTC. This tragic event in 1937 prompted the passage of the 1938 FDCA, but regulations did not clarify when a medication should be available without a prescription, and thus confusion continued until the passage of the Durham-Humphrey Amendment in 1951. This amendment provided the statutory basis for two classes of drugs in the United States: prescription and nonprescription. The amended FDCA mandated nonprescription availability as the default status for FDA-regulated products in the absence of a medical need to restrict distribution. The next legislation that affected nonprescription drugs was the Kefauver-Harris Drug Amendments of 1962, which required proven efficacy for marketed products, including nonprescription drugs.6 To address this requirement, a review of prescription drugs was undertaken through a Drug Efficacy Study Implementation (DESI) program. Subsequently, in 1972, FDA instituted the “OTC Review” process, described later in the unit (see “The Nonprescription Drug Review Process”). In 1990, the Nutrition Labeling and Education Act (NLEA) standardized labeling for food products. In 1994, the Dietary Supplement Health and Education Act (DSHEA) defined and regulated dietary supplements. During the time period from the NLEA in 1990 until the DSHEA in 1994, substantial lobbying effort was focused on defining the term ‘dietary supplement’ as a hybrid between food and drug that remained available to consumers without a prescription. This topic is covered in further detail later in the unit. A timeline for legislation impacting self-care is found in Figure 1. https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 3/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Figure 1: Timeline for legislation impacting self-care In 1991, FDA created the Division of Nonprescription Drug Products within the Office of Drug Evaluation in the Center for Drug Evaluation and Research (CDER). FDA has issued more than 35 guidance documents for nonprescription medications. Although not legally enforceable, these directives describe FDA’s current opinion on a topic and should be viewed simply as recommendations. A listing of guidance documents pertaining to nonprescription drugs, with brief content summaries, is presented in Table 1. Table 1: FDA Guidance Documents Document Description Over-the-Counter Monograph Order Assists in preparation of OMORS for submission to FDA under §505G of Requests: Format and Content (2023) the FD&C Act; format and content of information to be provided. Formal Meeting between the Food and Discusses formal processes for the three meeting types: X, Y, and Z. Drug Administration and sponsors or requestors of over-the-counter monograph drugs (Draft) (2022) Policy Regarding Certain New Dietary Reiterates premarket safety notification requirements for new dietary Ingredients and Dietary Supplements ingredients and future enforcement discretion. Subject to the Requirement for Premarket Notification (Draft) (2022) Drug Products Labeled as Homeopathic Describes FDA’s risk-based approach for enforcement and regulatory (2022) actions based on 6 different categories. Assessing User Fees Under the Over-the- Establishes a requirement for OTC manufacturers and contract Counter Monograph User Fee Program manufacturers to pay user fees for Tier 1 and Tier 2 activities. (2022) Providing Over-the-Counter Monograph Describes the electronic drug registration and listing system. Introduces Submissions in Electronic Form (2022) the CDER NextGen Portal and the OTC Monograph@FDA Portal. Quantitative Labeling of Sodium, Adds phosphorus to the list of ingredients to be disclosed on the label if Potassium and Phosphorus for Human content is greater than 5 mg per dosage unit. Over-the-Counter and Prescription Drug Products (Draft) (2022) https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 4/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Document Description Statement of Identify and Strength- Clarifies the statement of identity required for labeling and Content and Format of Labeling for circumstances which FDA intends to exercise enforcement discretion. Human Nonprescription Drug Products (Draft) (2022) Best Practices for Developing Identifies best practices for naming nonprescription products, including Nonproprietary Names for Human those switched from prescription status. Nonprescription Drug Products (Draft) (2020) Maximal Usage Trials for Topically Applied Describes need for maximal usage trials to support an FDA Active Ingredients Being Considered for determination that a topically applied product for OTC use is GRASE. Inclusion in an Over-the-Counter Monograph: Study Elements and Considerations (2019) Self-Monitoring Blood Glucose Test Describes performance studies required for validation of sterility and Systems for Over-the-Counter Use (Draft) disinfection tests for FDA approval to enhance infection control with (2018) these devices. Innovative Approaches for Presents two additional approaches for FDA approval of additional Nonprescription Drug Products (Draft) conditions for OTC products when the DFL alone is not sufficient for this (2018) purpose. Policy Regarding Quantitative Labeling of Explains that FDA will use enforcement discretion for probiotics labeled Dietary Supplements Containing Live in colony-forming units rather than weight. Microbials (Draft) (2018) Enforcement Policy—OTC Sunscreen Drug Explains FDA’s enforcement approach and certain products and claims Products Marketed Without an Approved (e.g., prevents skin cancer) for which it will no longer exercise Application (2018) enforcement discretion. Drug Products Labeled as Homeopathic Refers to FDA’s enforcement priorities for homeopathic drugs, none of (Draft) (2017) which have undergone FDA approval or OTC Review. Gluten in Drug Products and Associated Includes voluntary gluten labeling statement for oral OTC drug Labeling Recommendations (Draft) (2017) products (including those applied inside the mouth or near the lips) and its placement outside the DFL. Child-Resistant Packaging Statements in Provides labeling recommendations regarding child-resistant Drug Product Labeling (Draft) (2017) packaging statements. Recommended Statement for Over-the- States that FDA will not take enforcement action against aspirin Counter Aspirin-Containing Drug manufacturers who include imagery (e.g., heart image, Products Labeled With Cardiovascular electrocardiography graphic) if the label includes a statement advising Related Imagery (2017) patients to consult with their health care provider before using the product for cardiac indications. Recommended Warnings for Over-the- Provides recommendations for label warnings about serious skin Counter Acetaminophen Containing Drug reactions on acetaminophen products. Products and Labeling Statements Regarding Serious Skin Reactions (2017) https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 5/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Document Description Nonprescription Sunscreen Drug Provides further details regarding processes FDA will use to determine if Products- Format and Content of Data a sunscreen is GRASE. Submissions (2016) Nonprescription Sunscreen Drug Details the quality/manufacturing, clinical/nonclinical, and post- Products- Safety and Effectiveness Data marketing safety data needed to establish that a sunscreen is GRASE. (2016) Self-Monitoring Blood Glucose Test Provides guidance for 510(k) submissions for blood glucose test systems Systems for Over-the-Counter Use (2016) for home use by lay persons. Sunscreen Innovation Act: Withdrawal of a Two pieces of guidance regarding processes FDA will use to determine 586A Request or Pending Request & if a sunscreen is GRASE and should be added to the OTC sunscreen 586C(c) Advisory Committee Process drug monograph. (2016) Organ-Specific Warnings: Internal Covers alternative allowable language for acceptable liver warnings for Analgesic, Antipyretic, and Antirheumatic products in view of the fact that some IAAA products have maximum (IAAA) Drug Products for Over-the- daily doses of acetaminophen of 0.5%–1%) 1991 https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 16/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Purpose/Class of Drug Drug Namec Year of Switch Hydrocortisone 1979 Cold sores Abreva (docosanol) 2000 Decongestant Afrinol Repetabs (pseudoephedrine, timed-release) 1982 Oxymetazoline 1976 Pseudoephedrine 1976 Xylometazoline 1976 Dental rinse Acidulated phosphate fluoride 1980 Sodium fluoride; stannous fluoride 1980 Emergency contraception Plan B One Step (levonorgestrel) 2009 Plan B (levonorgestrel) 2006 Expectorant/decongestant Mucinex D ER Tablet 2004 Mucinex DM ER Tablet 2004 Mucinex ER Tablet (guaifenesin) 2002 Hair regrowth Rogaine Extra Strength (minoxidil) 1997 Rogaine (minoxidil) 1996 Laxative MiraLax (polyethylene glycol) 2006 Ocular vasoconstrictor/decongestant Lumify (brimonidine tartrate) 2017 Zaditor (ketoprofen) 2006 Naphcon A, Opcon A, Ocuhist (pheniramine/naphazoline) 1994 Vasocon A (antazoline phosphate/naphazoline) 1994 Ocuclear (oxymetazoline HCl) 1986 Oral anesthetic Dyclonine HCl (solution, suspension, lozenge) 1982 Overactive bladder Oxytrol for Women (oxybutynin) 2013 Overdose Narcan (naloxone hydrochloride, 4mg nasal spray) 2023 Pediculicide Nix (permethrin) 1990 Sklice (ivermectin lotion 0.5%) 2020 https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 17/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Purpose/Class of Drug Drug Namec Year of Switch Poison ivy protection Ivy Block (bentoquaram) 1996 Pregnancy Prevention Opill (norgestrel) tablet 0.075 mg 2023 Sleep aid Advil PM (ibuprofen/diphenhydramine) 2005 Diphenhydramine (HCl and monocitrate) 1982 Doxylamine succinate 1978 Smoking cessation Commit (lozenge) 2002 Nicotrol TD 2002 Nicorette (gum) 1996 Nicotrol, Nicoderm CQ (patch) 1996 Sunscreen Anthelios SX (Ecamsule/avobenzone/octocrylene) 2006 Topical analgesic Voltaren (diclofenac sodium gel) 2020 Topical antifungal Lamisil Derm Gel 2006 Lotrimin Ultra (butenafine HCl) 2001 Lamisil AT (terbinafine HCl) 1999 Lotrimin AF (clotrimazole) 1989 Miconazole 1982 Weight loss aid Alli (orlistat) 2007 a Complete listing (most current to October 31,2023) can be found at https://www.fda.gov/about- fda/center-drug-evaluation-and-research-cder/prescription-over-the-counter-otc-switch-list. b There were no switches from January 1, 2018, through December 31, 2019. c When a brand name is listed, the switch was affected using the NDA process. Key: NDA, new drug application; PPI, proton pump inhibitor. In 1984, ibuprofen for the treatment of pain was among the first products to be switched to nonprescription status. Some drugs that have been available as nonprescription products have been returned to prescription status, such as metaproterenol sulfate. FDA itself initiated the switch for metaproterenol—a decision that was met with great opposition from physicians and pharmacists.27 FDA considered that self-diagnosis and self-treatment https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 18/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary of asthma with nonprescription metaproterenol could delay physician visits in patients with asthma. Furthermore, a nonprescription product cannot require routine medical examinations or laboratory testing, and it was for this reason that FDA returned metaproterenol to prescription status. However, exceptions exist for grandfathered drugs— that is, those available before the FDCA of 1938. This exception is also precisely the reason that Asthmanefrin (racepinephrine) is available OTC for temporary relief of mild respiratory symptoms of bronchial asthma. An additional requirement for nonprescription status is that the condition must be one that a patient can self-diagnose, thus preventing products like acyclovir for genital herpes or statins for hypercholesterolemia from being switched to nonprescription status.28 Additional issues for acyclovir pertained to the development of resistance to the drug. Similarly, histamine type 2 receptor (H2) blockers cannot be labeled for use with ulcers, because the patient’s symptoms may mask the presence of gastric cancer.29 In some countries, products are available OTC that are available by prescription only in the United States. For example, oral contraceptives are classified as nonprescription drugs in Mexico, Europe and some Latin American countries. At least one manufacturer has received FDA approval for a nonprescription birth control pill. In July 2023, FDA approved the first daily oral contraceptive for nonprescription use to prevent pregnancy. The pill, which is expected to be available in early 2024, is a progestin mini pill that may carry a lower risk of blood clots in comparison with estrogen products, although with lower efficacy than estrogen products. There are two types of prescription-to-OTC switches. In a full switch, a formerly prescription drug is only available OTC, while a partial switch involves the switching of only some indications to OTC, whereas others remain available by prescription only. An example of a full switch is naloxone nasal spray, which is no longer available by prescription. In making the full switch to OTC status, the FDA advisory panel noted that removing the prescription barrier to naloxone access is expected to save lives. For a full switch, a proof-of-efficacy supplement to an NDA is required, whereas an entirely new NDA must be submitted for a partial switch. Additional efficacy studies may be required when the nonprescription population differs from the population used to support the original NDA (e.g., with ibuprofen, for which the nonprescription indications include pain, fever, and dysmenorrhea but the prescription indications are osteoarthritis and rheumatoid arthritis). Label comprehension studies may also be required. However, comparative studies with other agents are not required. In some cases (e.g., ibuprofen, naproxen), a partial switch for nonprescription status occurs whereby some doses fall under nonprescription status, whereas others retain prescription status. In other instances, two different preparations of a product at the same dose may be found on the market as both prescription and nonprescription products (e.g., loperamide 2 mg capsules). In such cases, the prescription and nonprescription versions may not resemble each other in appearance. Additionally, the indications may differ between the nonprescription and prescription versions (e.g., proton pump inhibitors are nonprescription drugs for heartburn but are prescription-only medications for peptic ulcer disease). https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 19/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Nonprescription Drug Product With an Additional Condition for Nonprescription Use On June 28, 2022, FDA proposed a rule to establish requirements for a nonprescription drug product that has an additional condition for nonprescription use (ACNU).30 The rule would make it easier for pharmaceutical companies to switch products from prescription only to nonprescription status, while retaining the prescription version option for patients. The rule would establish an ACNU for certain prescription products for which FDA has found that the OTC Drug Facts Label alone is not sufficient to ensure that the consumer can appropriately self-select and use a drug product in a nonprescription setting. This rule can be viewed as analogous to the Risk Evaluation and Mitigation Strategies (REMS) for prescription drugs, which enabled approval of certain prescription drugs with known safety issues for use in patients with additional requirements for use. An applicant may submit an NDA (not a supplement) or ANDA referencing the original NDA application or Reference Listed Drug (RLD). Applications using the 505(b) (2) route, in which the NDA includes information to demonstrate that the proposed drug is safe and effective, but at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use, would be permitted as well.31 These applications would be based on additional consumer studies proposing an ACNU that a consumer must successfully fulfill to obtain the nonprescription drug product. For example, in the case of different drug products with the same active ingredient, dosage form, strength, route of administration, and indication, one product may be made available as a nonprescription drug product with an ACNU, and the other product may be made available only by prescription. In addition to the application requirement, the rule would establish additional labeling and post-marketing reporting requirements for a nonprescription product with an ACNU. Failures of the ACNU would be reportable to FDA. Traditionally, OTC products have been used for acute self-limiting conditions. With this proposed rule, FDA has indicated flexibility in allowing for OTC use of certain prescription medications for chronic conditions or communicable diseases. An ACNU is one or more FDA-approved conditions that an applicant of a nonprescription drug product must implement to ensure appropriate self-selection or appropriate actual use, or both, by consumers of the nonprescription drug product. For example, an applicant could propose an ACNU which, to purchase the nonprescription product, requires a consumer to respond with specific answers to a set of questions on a self-selection test available through a smartphone application or an automated telephone response system. The expansion of consumer access to drugs products in a nonprescription setting clearly impacts patient autonomy, and this effect has the potential to improve public health. Additionally, the proposed rule could confer enormous potential for the pharmaceutical industry to expand use of prescription products as OTC drugs. While FDA anticipates cost savings to patients switching from a prescription product to a nonprescription product with an ACNU, this effect may be mitigated by the exclusion of OTC drugs from coverage https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 20/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary by payers, requiring patients to pay for such drugs out-of-pocket; it remains unknown whether payers will provide reimbursement for OTC drugs or whether the cost will simply shift to patients. Certainly, payers will benefit from a reduced number of claims filed for prescription reimbursements or the costs of medical visits. The ultimate impact of FDAs proposed rule change regarding OTC drugs on community pharmacy also remains uncertain. However, FDA did not adequately consider the essential role that pharmacists play as medication experts during development of the proposed rule. There has been considerable debate over the last few decades about creating a third class of drugs that would not require a prescription or be available freely OTC, but which would instead be kept behind the counter and require a pharmacist’s consultation upon purchase. These debates reignited again in 2012, when FDA held a hearing about a third class of drugs positioned as an expanded nonprescription drug class under the FDAs Nonprescription Safe-Use Regulatory Expansion (NSURE) Initiative.32 The rule proposed by FDA refers to the 2012 hearing, but it does not mention NSURE, pharmacist oversight, or any counseling requirements; indeed, the proposed rule contains few mentions of pharmacists in any capacity. The impact of the proposed rule on community pharmacies that stock relevant products will be significant, as consumer demand may be massive for some products, such as statins for hypercholesterolemia. Pharmacies may have kiosks to aid in addressing this demand or require consumers to complete questionnaires, view videos, take assessment quizzes, etc. Operationally, multiple kiosks in a pharmacy, inventory with different brands of the same drug, and the responsibility for ensuring that the kiosk/technology function properly are issues requiring further consideration and discussion with pharmacy stakeholders. The significant monetary and personnel requirements associated with coordinating multiple kiosks or technology platforms may not be feasible for community pharmacies. Some states prohibit the sale of drugs via kiosks, which may cause the ACNU to conflict with some states’ laws. Numerous outstanding questions and details which carry implications for the practice of pharmacy should be addressed prior to adoption of the proposed rule by FDA. For example, it remains an open question whether the rule will permit sale of the proposed OTCs with ACNUs in any location or limit their sale to pharmacies where there is a pharmacist present. Moreover, it has not been determined whether the proposed products with ACNUs should be available OTC or behind the counter only; there is no mention of this consideration in the proposed rule, and OTCs are sold in many different venues, including dollar stores and gas stations. In addition, it has not been determined whether the pharmacy/pharmacy profession could secure the establishment of a third class of drugs based on FDA’s proposed rule. Certainly, the proposal has important ramifications for prescription volume. FDA is currently reviewing close to 200 comments regarding the proposed rule, and essential stakeholders must be engaged throughout the process of determining and establishing the proposed paradigm.33 Safe Use of Nonprescription Drugs https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 21/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Adulteration and Misbranding A nonprescription drug is adulterated if it contains a substance that may make the product harmful to consumers under customary conditions for use; if it contains any filthy, putrid, or decomposed substance; if its container is composed of a harmful substance; or if it is manufactured or held under unsanitary conditions. All nonprescription drug manufacturing must adhere to good manufacturing practices (GMPs). Failure to follow GMP requirements may result in adulteration of a nonprescription drug preparation.34 A nonprescription medication is considered misbranded if its labeling is false or misleading, if it does not bear the required labeling information, or if the container is made or filled in a deceptive manner. Labeling refers to all labels and other printed, written, or graphic matter on or accompanying a product. FDA is authorized to inspect nonprescription drug manufacturing facilities, in a capacity similar to its enforcement powers regarding prescription drugs.35 It can then use administrative enforcement tools such as issuing warning letters or requesting a product recall, or it may seek judicial enforcement by means of a civil injunction, criminal penalties, or product seizure. FDA can request, but not mandate, a recall of nonprescription drug products.36 Although the CARES Act reforms provide FDA authority to declare an “imminent hazard to public health,” that only pertains to removal of a drug from a monograph, which still requires a 45-day comment period. CARES does not give FDA authority to demand a recall of a nonprescription drug product. However, if a manufacturer fails to recall a product pursuant to such a request, FDA may apply other enforcement options such as injunction, seizure, or criminal prosecution.37 Once a manufacturer agrees to recall a product, FDA conducts a health hazard evaluation (HHE), classifies the recall, as described next, and notifies the manufacturer of the classification.36 Three recall categories are defined. For a Class I recall, a reasonable probability exists that the use of, or exposure to, a violative product will cause serious adverse health consequences or death. For a Class II recall, use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences, or the probability of serious adverse health consequences is remote. For a Class III recall, use of, or exposure to, a violative product is not likely to cause adverse health consequences. Additionally, a recall can extend to the manufacturer, wholesale, retail, or consumer level. Depending on the class or level of recall, the manufacturer’s notification can be to direct accounts, such as wholesalers, or to pharmacies, or to the general public by way of the FDA website or media coverage. For recalls at the consumer level, the patient may return the nonprescription product to the place of purchase for a refund. Pharmacists can advise patients about the recall and recommend alternative products to replace the recalled product. Additionally, in the event of a recall, manufacturers provide a toll-free number for consumers to obtain additional information. FDA has a recall audit program to ensure that the recall has been effective.36,37 For example, in 2011 FDA mandated changes to dosing instructions for many pediatric (infants and children) acetaminophen products. Immediately upon this 2011 https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 22/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary labeling change, acetaminophen products then in the stream of commerce became ineligible for sale, and they were subject to a recall owing to their nonmonograph status. Adverse Drug Reaction Reporting As patients turn more and more to nonprescription medications, despite the efforts to encourage the reporting of adverse drug reactions (ADRs), excluding health care professionals and relying on consumers/patients for reporting ADRs often results in falsely low numbers of ADR reports. Underreporting is at least partially attributable to the concise and abbreviated safety information found in prescription drug labeling, which may prevent consumers from effectively recognizing ADRs. For example, older adults taking 10 or more medications together with multiple nonprescription products have a higher likelihood of drug interactions and ADRs. Additional reasons for underreporting of ADRs include failure of patients to read the Drug Facts labeling, the false belief that nonprescription medications carry little risk, and lack of patient awareness about the authority responsible for receiving ADRs. In 2004, the dietary supplement ephedra (i.e., ma huang) was linked to stroke, arrhythmias, and death, and the product was banned from the U.S. market. Importantly, the incident prompted regulations mandating reporting of serious adverse events for dietary supplements and nonprescription drugs.38 The 2006 Dietary Supplement and Nonprescription Drug Consumer Protection Act mandated reporting of serious ADRs by dietary supplement and nonprescription drug manufacturers.39 Before this act, ADR reporting was required only for nonprescription drugs marketed pursuant to an NDA or ANDA. Manufacturers should notify FDA of all serious ADRs (Table 5) by submitting an Individual Case Safety Report (ICSR) on FDA form 3500A, together with a copy of the medication label, via either mail or telephone-transmitted facsimile (fax), within 15 business days of receipt. The ADR may also be reported online using the MedWatch reporting form. Consumers may report adverse reactions from nonprescription products using the MedWatch online form or by mail or fax using FDA form 3500B or at www.safetyreporting.hhs.gov. For nonprescription products approved under an NDA or ANDA, the requirements are the same as for prescription products approved under these applications—that is, 15-day, periodic, and annual reports of both serious and nonserious ADRs. All ADR reports must be retained by the manufacturer for a 6-year period. For prescription products, labeling warnings often are included in the prescribing information to inform prescribers even when a causal relationship has not been definitively established; however, only clearly documented, clinically significant, and important warnings are required for nonprescription products.39 Table 5: Defining Criteria for Serious Adverse Events Death Life-threatening https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 23/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Hospitalization (initial or prolonged) Disability or permanent damage Congenital anomaly/birth defect Required intervention to prevent permanent impairment or damage (including device placement) Other serious important medical events (e.g., allergic bronchospasm requiring treatment in an emergency department; seizure that does not result in hospitalization) The Dietary Supplement and Nonprescription Drug Consumer Protection Act also requires that a manufacturer of nonprescription products marketed under a monograph review process must place “responsible person” contact information (i.e., domestic address or phone number) on its labels for consumer reporting of ADRs. The responsible person is defined as the manufacturer, packer, or distributor whose name appears on the label. A toll-free number must be included with nonprescription products marketed pursuant to an NDA or ANDA. One of the improvements in the CARES Act section 505G pertains to FDA’s ability to rapidly respond to safety issues. Since 2004, thousands of reports of adverse events and emergency department visits for infants under two have occurred for certain nonprescription cough and cold drugs.22 A 2007 Citizen’s Petition requested changes to the monograph for these products to limit their use for children under 6. The Cough Cold OTC Monograph was not amended by FDA through rulemaking, and while manufacturers voluntarily removed infant products from the market and relabeled products to state “do not use in children under 4 years of age,” the changes were not mandatory. The CARES Act requires FDA to evaluate the cough and cold monograph under 21 C.F.R. Part 341 as GRASE with respect to children under age six and revise the monograph, as appropriate, to address children under age six through the new administrative order process.22 ADRs have led to various FDA actions, including requiring additional warnings, MedWatch Safety Alerts (e.g., for methemoglobinemia resulting from benzocaine sprays, gels, or liquids applied topically or to gums), category reclassification (e.g., from I to II), request for a recall, or market removal (e.g., of phenylpropanolamine).40 Throughout 2023, FDA issued a number of FDA Safety Alerts that were prompted by ADRs reported for nonprescription eye drops. Eye infections that could result in partial vision loss or blindness were reported following the use of eye drops produced under insanitary conditions.41 In 2019, FDA warned against use of previously owned test strips (e.g., for glucose or international normalized ratio) and those not authorized for sale in the United States. These products are often sold online.42 Labeling Nonprescription drug labeling is regulated by FDA and is just as important as product labeling for prescription drug products. Labeling for nonprescription drug products is the ‘Drug Facts’ and any insert accompanying the product. New label technology permits manufacturers to incorporate multiple pages into label designs. https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 24/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary FDA reviews nonprescription drug labels for products marketed under an NDA. Nonprescription products must be labeled with adequate directions for patient use, with accommodation for persons with low-level reading comprehension, without the need for medical consultation. The labeling must be “likely to be read” and “likely to be understood” by the “ordinary individual.” All labels must be in English. However, manufacturers may include a toll-free number for Spanish-speaking consumers to call with inquiries. Since 1999, the content and format requirements for nonprescription drug labeling have been standardized and specific.43 FDA has even provided guidance on font size for the label, which must be in 6-point type or larger.44 The label must appear on the outside container or wrapper, or may be included on the immediate container label if the packaging does not include an outside container or wrapper, and begins with a Drug Facts panel. It must further include active ingredient(s), purpose(s), use(s), warning(s), directions, other information, inactive ingredients, and frequently asked questions (if relevant).45 Inactive ingredients must be listed in alphabetical order and appear on the outside container. Flavors and fragrances may be listed as “flavors” and “fragrances,” respectively.45 Trade secret ingredients may be listed as “and other ingredients.” Incidental ingredients present at insignificant levels need not be identified, unless the omission would constitute a failure to reveal a material fact.45 (See Figures 2, 3, and 4.) Figure 2: Drug Facts labeling outline. (Source: Reference 44.) https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 25/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Figure 3: Drug Facts labeling sample 1. (Source: Reference 44.) https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 26/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Figure 4: Drug Facts labeling sample 2. (Source: Reference 44.) Drug Facts warnings may include, but are not limited to, the following specific phrases and topics: “for external/rectal/vaginal use only”; Reye syndrome warning; allergic reaction warning; flammability warning; choking warning; alcohol warning; sore throat warning; dosage warning; “do not use” warning; “ask a doctor if you have”; “ask a doctor or pharmacist before you use”; “stop use and ask a doctor if”; pregnancy/breastfeeding warning; “keep out of reach of children”; and “contains phenylalanine.” Drug Facts rules detail how to group warnings and how to include them in bullet-point lists. In addition, other rules specify what information should appear on the principal display panel, which is defined as “that part of the label that is most likely to be displayed, presented, shown, or examined under normal and customary conditions of display for retail sale.”46 The labeling permitted for each nonprescription ingredient is detailed in the monograph. Minor changes are permitted, provided that the content is truthful and the language not misleading. Additionally, repackagers of nonprescription products must comply with the same labeling requirements as those for manufacturers. FDA acts if label claims are false or misleading, and FDA jurisdiction extends to all labels and labeling in any media, including websites and social media.47 NDA ingredients are not found in the monograph, because only the NDA filer is eligible to market these products. Therefore, no rationale exists for https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 27/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary providing information for other manufacturers, because they must still go through the ANDA process once the patents expire. Manufacturers of nonprescription products must warn of foreseeable risks. A voluntary “Flag the Label” program adopted by nonprescription drug manufacturers alerts consumers of changes in currently marketed products or labels. Significant changes are defined as (1) expansion or limitation of the claims, (2) modification of the dosage level, (3) change in active ingredients or directions for use, (4) new warnings or contraindications, and (5) any other significant new information. The “flag” should be carried on the label for at least 6 months after such a change is made. An example is product line extensions, that is, new products with altered features such as flavors, ingredients, or dosage forms. Line extensions for which product names share the same root name with a suffix or other modifier are prone to patient confusion and errors. FDA reviews and approves proposed trade names for nonprescription products that are approved under the NDA or ANDA process. When products are switched from prescription-to-nonprescription status, the product may keep its name or use a new name. For partial switches, such as when only one strength formulation is switched to nonprescription status, a new name is usually selected for the nonprescription version. A “Flag the Label” warning is also required when there is a change in active ingredients, such as the replacement of kaolin and pectin with bismuth subsalicylate in the antidiarrheal Kaopectate. Some monographs (e.g., for antacid, antiflatulent, topical antifungal, antiemetic, and cough and cold products) contain professional labeling for health care professionals that is not included in the nonprescription drug labeling for consumers. Professional labeling is available in the nonprescription monograph. For example, the professional labeling in the monograph for nonprescription antiflatulence products contains additional indications for postoperative gas pain or use in endoscopic examination.48 There is a requirement for quantitative labeling of the sodium and potassium content of nonprescription drugs.49,50 If the amount of sodium or potassium in a product (active and inactive ingredients combined) is less than 5 mg, it does not need to be reported. FDA recently issued guidance clarifying the sodium and potassium labeling requirement further based on dosage and adding phosphorus.51 For example, if the total dosage is 2 tablets and each contains 4 mg of phosphorus, then the total phosphorus would need to be included in the labeling under “Other Information.” Packaging Packaging of nonprescription products is also highly regulated by FDA. Regulations have defined two forms of packaging: tamper-resistant and tamper-evident. There is no feasible method for producing tamper-proof packaging. https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 28/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Most oral, nasal, otic, ophthalmic, rectal, and vaginal nonprescription medications can only be provided in tamper-resistant packaging as required under the Federal Anti- Tampering Act and related regulations52,53 Tamper-resistant refers to a feature of the product packaging that is developed and created to prevent access to the product. Tamper-evident packaging is identified and characterized by features that make previous unauthorized access to the product easily detectable by the prospective consumer. Exceptions include dermatologics, dentifrices, and insulin. Tamper-resistant packaging is defined as “an indicator or barrier to entry which if breached or missing can reasonably be expected to provide visible evidence to consumers that product tampering has occurred.”52 This requirement was in response to the 1982 case of tampering with and adulteration of Extra Strength Tylenol capsules, which resulted in several deaths in Chicago. A tamper- resistant warning statement is required on the package and must be clearly visible to alert consumers. The tamper-resistant warning statement must also advise consumers not to purchase the product if the tamper-evident features are breached or missing. Nonprescription products must bear an expiration date, which is determined by appropriate stability testing. However, a nonprescription product is exempt from this requirement if its label does not specify any dosage limitations and if the medicine is stable for at least 3 years. Under the Poison Prevention Packaging Act (PPPA),54 child-resistant packaging is required for some nonprescription products commonly available in the home, such as aspirin, acetaminophen, ibuprofen, and methyl salicylates, and for any product switched from prescription-to-nonprescription status.55 The complete list of products that require child- resistant packaging may be found at 16 CFR §1700.14. The Consumer Product Safety Commission (CPSC) has authority for enforcement of the PPPA. Manufacturers have the option of offering one size of a product with a non–child-resistant closure. The label for this product must specify “this package for households without young children.” However, if that size happens to be the most popular size (e.g., bottles of 100 tablets), the manufacturer also must market that size in child-resistant packaging. For nonprescription drugs approved via an application (e.g. NDA, ANDA), FDA reviews data related to container closure systems. However, FDA does not approve or review individual products under the monograph system and therefore, does not review data related to container closure systems. Although no process has been defined for ensuring that such nonprescription products meet CPSC standards for child-resistant packaging, manufacturers that have data to demonstrate this safety feature may include a child- resistant packaging statement (e.g. “child-resistant package” or “this package is child- resistant”) on the labeling. Advertising https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 29/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary The U.S. Government closely regulates advertising of medicinal products to ensure public health and safety. The FTC regulates advertising of nonprescription drugs, devices, and dietary supplements and prohibits false advertisements, which are defined as those that are misleading in a material respect.56 There is no “fair balance” requirement for benefits versus warnings or contraindications. Advertisements must be supported by the level of data in the manufacturer’s files that the ad wording communicates. For example, if the advertisement states that “pharmacists and doctors recommend” the product, then tests, recommendations, and/or studies must substantiate this statement. A “reasonable basis” standard is applied, meaning that a manufacturer must have objective evidence to support a claim before running an advertisement.57,58 In Warner Lambert Co v. FTC, the claims for Listerine in the prevention, cure, and symptomatic alleviation of the common cold were found not to be substantiated, and the company was required to stop running the original advertisement and run corrective advertisements.59 In addition to corrective advertising, in other cases the FTC has required a manufacturer to conduct at least two clinical trials to substantiate advertising claims.58 The National Advertising Division of the Council of the Better Business Bureaus investigates complaints from consumers, competitors, or other parties regarding the truth and accuracy of nonprescription drug advertisements and may escalate the matter to the attention of the FTC. Additionally, a manufacturer may file private lawsuits against competitors for false claims in advertising, packaging, and labeling through Section 43(a) of the Lanham Act.60 FDA has indirect authority over advertising of nonprescription drugs. Advertising claims not included in OTC Review monographs may be subject to agency regulatory action under the misbranding provisions of the FDCA.61 Additionally, the FTC is empowered to issue cease-and-desist orders against false, deceptive, or misleading advertisements of nonprescription drugs. FDA and the FTC often act in tandem in reviewing nonprescription drug promotion and have issued joint warning letters to companies that their advertising violates both the FDCA and the FTC Act. Third Class of Drugs A little over a decade after passage of the Durham-Humphrey Amendment, various organizations began to advocate for an additional or third class of medications. This intermediate class of drugs would be available without a prescription, but a pharmacist would be required to be involved with the sale. The two-tier system of prescription and nonprescription status in the United States is unique. While the availability of an intermediate or third class of drugs in the United States could be expected to be of considerable benefit for the quality and costs of health care, the United States and South Africa remain the only two countries without such a third class of drugs. https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 30/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Should the FDA Proposed Rule not be revised to include the role of pharmacists, there is little likelihood for the establishment of a third class of drugs in the United States. However, U.S. policy regarding nonprescription drugs continues to mature. The unique education, training and expertise of pharmacists should be recognized and fully endorsed as resources that can be exploited to improve the access, quality, and cost of nonprescription drugs available to U.S. consumers. Although this maturing process is too slow for some stakeholders, progress forward is cautious, but continued. The benefits of a third class of drugs is obvious when the medication has a potential for abuse, requires closer monitoring, or is a first-in-class agent for a new indication. Aside from the economic interests of the opposers, FDA has been reluctant to establish a third drug class, citing reasons that the current two-class system works and stating that evidence that a third class would improve public health is insufficient for action.62 However, these arguments are insufficient, because, as discussed below, strong evidence indicates that a de facto third class of drugs would have a tremendous positive impact on public health. Since 2006, emergency contraception products for women have been nonprescription. At least one oral contraceptive product has been approved for nonprescription use. Studies have shown that women in the United States strongly desire access to oral contraceptives without a prescription, that women can accurately identify contraindications to use of oral contraceptives with simple checklists, and that access to nonprescription contraception products would increase use, with consequent reductions in unintended pregnancy rates.63 Currently, oral contraceptives are available from pharmacists in many states (e.g., Tennessee, Washington) and Washington, D.C., under collaborative practice agreements with licensed prescribers and in other states (e.g., Oregon, California) through direct pharmacist prescribing.64 However, oral contraceptives remain classified as prescription products in these scenarios, with pharmacists given additional authority to initiate access to these products via protocol or to prescribe them directly. Although California has no age restrictions, in Oregon female patients younger than 18 years of age must have a previous prescription from a physician or pharmacist. Alternatively, oral contraceptives could be a candidate for expanded access via a third class of drugs with pharmacist’s using a checklist to screen appropriate patients. De Facto Third Class of Drugs Certain prescription-status products are already supplied to patients without a prescription, but consumer access to them is restricted; these products are specifically available only “behind the counter” when a patient expressly asks a pharmacist for them, thereby creating a de facto third class of drugs. This group includes a small number of exempt narcotic combination products placed in Schedule V (e.g., codeine, available without a prescription in several states such as Oklahoma and Washington),65 https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 31/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary pseudoephedrine (see Colds and Allergy), NPH and recombinant (R) U-100 insulin, syringes, and needles. Federal requirements for Schedule V medications sold without a prescription are found in Table 6. Table 6: Federal Requirements for Schedule V Medications Feature Specific Requirement(s) Schedule V definition Codeine preparations: limited to 200 mg/100 mL or 100 g. Dihydrocodeine, ethylmorphine, opium preparations: limited to 100 mg/100 mL or 100 g. Diphenoxylate: limited to 25 mg/25 mcg atropine sulfate. Diphenoxin: limited to 0.5 mg/25 mcg atropine sulfate. Age and personal Purchaser must be 18 years of age. identification requirement Identification is required when pharmacist does not know purchaser. Seller requirement Dispensed only by pharmacist or intern. Medication limitations Not more than 240 mL (8 ounces) of any such controlled substance containing opium. Not more than 120 mL (4 ounces) of any other such controlled substance. Not more than 48 dosage units of any such controlled substance containing opium. Not more than 24 dosage units of any other such controlled substance may be dispensed at retail to the same purchaser in any 48-hour period. Documentation requirement Bound record book containing: – Purchaser’s name and address – Name and quantity of medication – Date – Name or initials of dispensing pharmacist Stricter law prevails No state or local law requires a prescription to dispense. Another example of voluntary restricted access is that for dextromethorphan, a cough suppressant. Although dextromethorphan is not a Schedule V medication, it is an opioid derivative with psychoactive properties and potential for abuse. Accordingly, drug manufacturers and retailers have imposed state-specific voluntary age restrictions on its purchase, making the drug far less available to young users looking for a hallucinogenic “high.”66 https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 32/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Additionally, in an increasing number of states, pharmacists have been given prescriptive authority to dispense a limited number of prescription-only products without a medical prescription. The first state to allow this provider role was Florida, where pharmacists can prescribe medications listed on a state formulary that consists of fluoride- or lindane- containing products, some topical anti-infectives, antihistamines and decongestants, and products recommended by an FDA advisory panel for transfer to nonprescription status but pending FDA action.67,68 Currently, six states—Montana, New Mexico, North Carolina, North Dakota, Oregon, and California—give pharmacists midlevel practitioner status, allowing them to initiate and modify drug therapy pursuant to a collaborative practice agreement with a physician.69 In California, the professional scope of practice for pharmacists was expanded to include the following70: Prescribing nicotine replacement therapy, which normally requires a prescription Prescribing medications for travel health purposes (e.g., scopolamine patches) Mandating tests to monitor and maintain drug therapy for patients with comorbid conditions such as diabetes, hypertension, and hyperlipidemia Other states are considering similar legislation. Pharmacists, who constitute the most accessible health professional interface between the community and the health care system,71 are ideally positioned to provide overdose education and to expand access to naloxone. In March 2023, FDA approved the first nonprescription naloxone nasal spray. However, strengths other than 4 mg and other formulations such as injectables remain available by prescription only. Naloxone products that come in higher doses and other forms of the drug for which more safety data is still needed, such as those that come in glass vials and ampoules, must be prescribed or dispensed via protocols, for example. Newer nasal spray opioid reversal products such as nalmefene remain available by prescription only. Alternatively, these products could be made available ‘behind the counter’ in the United States if a third class of drugs is established. “Other Topics” In a unit on legal and regulatory issues for self-care, it is important to include several topics that fall into the “miscellaneous” category. The contemporary topics covered in the next several sections, including OTCs, cosmeceuticals, compounding, homeopathic OTCs, dietary supplements and direct-to-consumer diagnostic testing, are important for pharmacists, but they do not necessarily fit into the standard concepts associated with nonprescription drugs. Many of these areas seem to lay outside the definition and concept of a nonprescription drug, especially in cases where stakeholders may exceed regulatory allowances for the safety and efficacy of nonprescription drugs. Pharmacists should be prepared to receive questions from consumers or other health care providers about these topics. https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 33/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Abuse of Nonprescription Medications A list of nonprescription medications that have been abused, along with legislative and regulatory initiatives to curb such abuse, is presented in Table 7. Pharmacists have a key role to play in protecting the public from the risks inherent in abuse of nonprescription medications. Table 7: Anti-Abuse Measures for Various Nonprescription Medicationsa Medication Effect(s)/Use Legislative/Regulatory Action Dextromethorphan Dissociative effects; altered Many products reformulated to omit ingredient; in mental status; intoxication some states, behind-the-counter sale only (e.g., New York, Utah) Pseudoephedrine (also Precursor used in Combat Methamphetamine Epidemic Act of 2005 applied to ephedrine, but manufacture of (logbook of sales; limits daily purchase amounts to sale limits differ) methamphetamine 3.5 g, with 30-day limit of 9 g and mail order 30-day limit of 7.5 g) Schedule V in some states (Illinois, Iowa, Kansas), Schedule III in others (Oregon, Mississippi)b Class V Controlled Opioid abuse See Table 5 Substances (e.g., cough syrups) Laxatives Anorexia; electrolyte imbalances; gastrointestinal complications Loperamidec Cardiotoxicity; ventricular None arrhythmias; QT and QRS prolongation Nonprescription Intoxication; stimulant None antihistamines; effects including euphoria dimenhydrinate and hallucinations aDEA’s Office of Diversion Control website provides more detailed information regarding sale limits and recordkeeping requirements: https://www.deadiversion.usdoj.gov/pubs/manuals/pharm2/appendix/appdx_g.htm. bSource: U.S. Department of Justice Drug Enforcement Administration. Combat Methamphetamine Epidemic Act 2005. Title VII of USA Patriot Improvement Reauthorization Act of 2005. Pub L No. 109– 177. 109th Congress. March 9, 2006. Available at: http://www.deadiversion.usdoj.gov/meth/index.html. cSource: U.S. Food and Drug Administration. Drug Safety Communication: FDA warning about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium) https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 34/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary including abuse and misuse. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm504617.htm. Accessed February 6, 2023. Key: DEA, Drug Enforcement Agency. From Cosmetic to Drug: Crossing the Line Enacted on December 29, 2022, the Modernization of Cosmetics Regulation Act (MoCRA) is a major overhaul of FDA’s current regulatory framework for cosmetics.72 Since 1938, FDA’s authority over cosmetics has been less comprehensive than its authority over other FDA- regulated products and limited to adulteration and misbranding provisions of the FDCA73, the PPPA, and the Fair Packaging and Labeling Act.74 MoCRA adds requirements for manufacturer registration, premarket notification (but not approval), ingredient safety testing (including adequate safety substantiation product and ingredient listing), mandatory allergen labeling, GMPs, and ADR reporting.72 Mandatory ADR reporting is limited to infections or “significant disfigurement,” such as “serious and persistent rashes, second- or third- degree burns, significant hair loss, or persistent or significant alteration of appearance, other than as intended, under conditions of use that are customary or usual.”72 MoCRA grants FDA mandatory recall authority.72 In an early opinion, FDA stated that some cosmetics are also nonprescription drugs. Such products must meet the regulatory requirements (including labeling and packaging) for both cosmetics and drugs. Additionally, many legal precedents are in place for products that cannot be categorized conveniently as a cosmetic or drug—so-called cosmeceuticals75 Early cases involved wrinkle removal products for which the product claims included strong therapeutic implications.76,77 Other cases involve cosmetic product claims that establish the product as intended to treat or prevent disease or otherwise affect the structure or functions of the human body. Often it is not the ingredient used in a product, but rather the content of labeling claims, that determines whether the product is considered a cosmetic or a drug; potentially problematic examples include claims that products will restore hair growth, reduce cellulite, treat varicose veins, or regenerate cells. The mere presence of ingredients at low or inactive levels below those specified in an OTC Review monograph is not sufficient to cause a cosmetic to be categorized as a drug. Examples of cosmetic products that also may be drugs are listed in Table 8. Table 8: Cosmetics That Also May Be Drugs Topical antimicrobial products (e.g., soaps containing antimicrobials) Skin protectants Sunscreen products Antiperspirant products Skin-bleaching products https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 35/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Nail hardeners Teeth whiteners with bleach Indoor and oral tanning preparations Hormone creams Eye wrinkle creams Wrinkle eradicators or antiaging creams If a cosmetic is also a drug, the active ingredients must be listed first, followed by other ingredients, except flavors and fragrances, in descending order of predominance, on the product package. The “principal display panel” on the label must include the net quantity, name and place of the manufacturer, the declaration of ingredients, and any warning statements. Specific content that determines when a cosmetic should be classified as a drug includes (1) claims to cure, mitigate, treat, or prevent a disease; (2) claims to effect major changes in the structure of the body, or in a major bodily function; and (3) presence of a compendium-listed ingredient intended to serve medicinal purposes.78 Compounding Nonprescription Drugs At one time, nonprescription products were routinely compounded as needed. Although explicit guidelines on compounding nonprescription medications are lacking, and the pharmacy compounding provisions of the Food and Drug Modernization Act of 1997 do not directly address nonprescription drugs, pharmacists should rely on guidance established for compounding prescription medications. Pharmacists should not compound any medication for nonprescription use that is intended to be used pursuant to a prescription or one that has not been approved for nonprescription use. Additionally, as with prescription medications, pharmacists should not compound large quantities of nonprescription medications that are essentially copies of commercially available nonprescription drugs.79 A summary of regulatory requirements for nonprescription drugs is presented in Table 9. Table 9: Summary of Nonprescription Drug Regulations Feature Component(s) Labeling Drug Facts format Regulated by FDA Inactive ingredients in alphabetical order ADR reporting Required for both OTC Review monograph-approved and NDA-approved nonprescription drugs https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 36/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Feature Component(s) Manufacturing GMPs Advertising Regulated by FTC Packaging Tamper-resistantChild-resistant Marketing By NDA By monograph route Key: ADR, adverse drug reaction; FDA, U.S. Food and Drug Administration; FTC, Federal Trade Commission; GMPs, good manufacturing practices; NDA, New Drug Application. Nonprescription Homeopathic Drugs Homeopathy is a system of alternative medicine based on the practice of treating symptoms of a disease with substances that produce symptoms of the disease in healthy subjects (i.e., on the basis of the principle “like cures like”). Nonprescription homeopathic preparations are regulated by FDA as drugs80 and must have a therapeutic indication for a self-limiting, self-diagnosable condition. FDA has not reviewed any products labeled as homeopathic under the OTC Review process for drugs, because these agents are categorized as a separate entity and FDA has deferred consideration of them.81 Homeopathic products and ingredients do not go through any FDA approval process, nor are they subject to any nonprescription monograph approval. They are governed by the Homeopathic Pharmacopoeia of the United States (HPUS) and its supplements, which are produced by the Homeopathic Pharmacopoeia Convention of the United States.82 The same criteria under the FDCA for a determination of nonprescription or prescription status apply to homeopathic products. The regulatory framework for marketing is found in FDA’s Compliance Policy Guide (CPG), specifically, CPG 7132.15. Labeling of homeopathic products includes the word “homeopathic” in addition to a “Drug Facts” box, which could result in confusion that the products are approved by FDA. However, the ingredients are listed in terms of dilution (e.g., 1X, 6X, 2C)—a clear difference from conventional product labeling. Homeopathic product dosing is covered in Common Complementary and Integrative Health System Modalities, along with efficacy concerns. These products must comply with display panel requirements, but they are exempt from expiration dating. Advertising of these products is regulated by the FTC. Homeopathic drugs were not included in either the DESI or the Nonprescription Drug Review and have https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 37/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary never been required to show safety or efficacy before marketing. However, nonprescription homeopathic drugs cannot be marketed for conditions that require a prescription. Manufacturers must register with FDA, list their products, and adhere to GMPs.83 More recently, FDA is taking a closer look at homeopathic products. In 2015, a public hearing was held evaluating FDA’s regulatory framework, including labeling, safety and enforcement policies, and mechanisms and means of improving such policies going forward. The homeopathic industry has grown, safety issues have emerged, and many cases of poison exposure related to homeopathic products are reported annually by the American Association of Poison Control Centers.84 In a 2022 guidance, FDA stated that subsequent to enactment of CARES, no GRAS/E determinations will be made for homeopathic drug products under section 505G, because section 505G does not apply to homeopathic drug products.85 Because at this time no homeopathic drug products have been determined by FDA to be GRAS/E, all homeopathic drug products remain subject to the premarket approval requirements. FDA has now reexamined its enforcement policies and applies a risk-based approach focusing on six categories of products: (1) Products with reported safety issues, (2) products intended for prevention or treatment of life-threatening conditions, (3) products for routes of administration other than oral or topical, (4) products that contain or purport to contain ingredients associated with potentially significant safety concerns, (5) products for vulnerable populations, and (6) products with significant quality issues.85 Dietary Supplements Although often offered alongside nonprescription drug products on pharmacy shelves, dietary supplements are regulated by FDA’s Center for Food Safety and Applied Nutrition as foods, not as drugs. Although dietary supplement claims and nonprescription drug claims have different evidence standards, they may be perceived by the consumer as indistinguishable. However, dietary supplements belong to a separate category that is not tightly regulated. More than 200 million Americans take dietary supplements, and botanical dietary supplements are used by 17.9% of U.S. adults.86 Dietary supplements are regulated under the DSHEA of 1994.87 Under the DSHEA, dietary supplements are defined to include “vitamins, minerals, herb or other botanical, amino acid, a substance which increases the dietary intake of it, or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above.”88 Dietary supplements are not approved by FDA, but they are subject to the adulteration and misbranding provisions of the FDCA and should be manufactured in accordance with GMPs. GMPs are nonbinding on manufacturers, however, and herbal product manufacturers in particular have largely ignored them because of considerable variation in the ingredients for herbal preparations.89 A petition must be filed to market new dietary https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 38/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary ingredients (i.e., those not already marketed before 1994), thus requiring premarket notification but not an evaluation for efficacy or safety. Enforcement of this provision has been problematic, however, with only approximately 170 notices from 1994 to 2012 despite the introduction of thousands of new supplements to the marketplace.83 FDA enforcement activities such as warning letters have recently increased against dietary supplement manufacturers making medical claims. In November 2022, FDA issued warning letters to 7 companies for selling dietary supplements with claims to cure, treat, mitigate or prevent cardiovascular disease.90 FDA has strengthened regulation of dietary supplements by including new 75-day premarket notification requirements for new dietary ingredient (NDI) notification and implementation of a dietary supplement ingredient advisory list.91 The list is intended to quickly alert the public when FDA identifies ingredients that do not appear to be lawfully marketed in dietary supplements. For example, FDA had recently concluded that tetrahydrocannabinol (THC) and cannabidiol (CBD) products are excluded from the dietary supplement definition under §201(ff)(3)(B) of the FDCA.92 Under the DSHEA, labels must bear the term “dietary supplement,” and the quantity of each ingredient must be stated. For a proprietary blend, however, the quantities of each ingredient are not stated; only a net content for the blend is included. Inactive ingredients must be listed in descending order of predominance. The labeling must contain a Supplement Facts panel identifying the dietary ingredient(s) contained in the product. When no daily recommended dose has been established, the dietary supplement may be marketed without this information. Such products also may be marketed in any combination of supplement ingredients (e.g., calcium plus magnesium).93 Although FDA requires that manufacturers verify that every supplement they produce is safe and accurately labeled, the system essentially operates on the honor code. Under DSHEA, a dietary supplement deemed unsafe may continue to be marketed until the courts rule in FDA’s favor.94 Advertising claims in all media are regulated by the FTC. However, FDA is responsible for claims on product labeling. Introduction to Dietary Supplements provides information about proper labeling of dietary supplement products. Dietary supplement manufacturers are subject to GMPs and FDA inspection. Nevertheless, these products often have been found to be tainted with active pharmaceutical ingredients or adulterated with other ingredients, or fail to contain the purported active ingredient, or may be sold at toxic doses.95 The DSHEA requires the government to bear the burden of proof to show that a dietary supplement is either adulterated or misbranded, and each case must be tried de novo. Categories of dietary supplements that often have been found to be tainted include male enhancement supplements,96 herbal products, and weight loss products. FDA’s Medication Health Fraud website (https://www.fda.gov/consumers/protecting-yourself/health-fraud-scams) is a useful resource for information regarding tainted products sold as dietary supplements. Additionally, to improve regulation of dietary supplements, FDA has created an Office of Dietary Supplements Programs. One FDA initiative is unit-of-measure label changes from https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 39/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary international units (IU) to metric units of measure (mcg or mg) for nonprescription vitamins A, D, and E. Also required is the listing of the absolute amounts of vitamins and minerals in metric units in addition to the percent daily value (%DV) on the label.97 Introduction to Dietary Supplements provides a more in-depth look at dietary supplements. Direct-to-Consumer Diagnostic Devices Unlike nonprescription drugs, the in vitro direct-to-consumer tests marketed today are considered devices that may or may not be reviewed by FDA’s Center for Devices and Radiological Health. For example, carrier screening tests, ancestry tests, and low-risk general wellness tests do not require FDA premarket review, whereas cancer predisposition tests, pharmacogenetics tests, and generic health risk tests generally require FDA clearance. Direct-to-consumer tests may be approved via a Premarket Approval (PMA) application or via the 510(k) route, or not at all, depending upon the risk classification.98 A company with 510(k) clearance for a prescription device will need to submit a new 510(k) form to market the product for nonprescription use. Data will be required to show that consumers can use the device and interpret the results without the assistance of a health care professional.99 FDA has created a database of nonprescription in vitro device tests it regulates.100 Point-of-care testing can be self-initiated, as when the patient is responding to symptoms, or prescriber-initiated, as when a sample is taken in the home environment or clinic and returned to be assayed in a laboratory. All point-of-care laboratory testing in pharmacies is subject to regulation by the Centers for Medicare & Medicaid Services as part of the Clinical Laboratory Improvement Amendments (CLIA) program. However, most point-of-care tests conducted in community pharmacies or at health screenings are considered CLIA-waived. To obtain a CLIA waiver, the pharmacy must first obtain a CLIA certificate and then apply for laboratory status at the state level, usually through the state health department. Each state has its own CLIA program and may impose additional requirements or restrictions. Pharmacies with CLIA waivers are still subject to inspection to ensure compliance and must comply with standards set forth in Occupational Safety and Health Administration (OSHA) universal precautions to reduce risk of exposure to blood-borne pathogens. The total number of pharmacies with a CLIA waiver grew from approximately 18% in 2015 to approximately 28% in 2020.101 These community pharmacies with a CLIA waiver can perform CLIA-waived tests such as determination of the international normalized ratio (INR), blood glucose, glycosylated hemoglobin (HbA1c), COVID-19 infection tests, and lipid profile. With the upsurge in pharmacy-based disease state management programs and health screening-related collaborative practice agreements, the number of pharmacies with CLIA waiver status is likely to increase in the future. https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 40/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary Nonprescription Product Liability Most legal cases involving nonprescription drugs are product liability cases brought against manufacturers rather than cases against pharmacies or pharmacists. Although not as common as claims against prescription drugs, incidents involving nonprescription drugs have been the subject of civil litigation. Claims are brought for breach of the Implied Warranty of Fitness102 and for breach of the Implied Warranty of Merchantability.103 Recovery under these legal theories is generally limited to issues related to sale of a product, rather than performance of a service in which a defective product may be involved only incidentally. When the service being performed is a professional service, such as with a pharmacist recommendation for a defective nonprescription product, the courts exhibit a reluctance to impose strict liability without fault. However, the pharmacist may still be liable for negligence and/or intentional misconduct as appropriate to the facts of the case.104 In litigation in which a pharmacist sold the patient camphorated oil instead of castor oil, with subsequent harm to the patient, the court held the pharmacist negligent.105 For the nonprescription drug plaintiff, the first evidentiary hurdle is proof of purchase, which can result in a summary judgment on this threshold issue. The injured party will need to furnish a receipt or other evidence of proof of purchase. Causation is another issue, in that a purchased nonprescription product may sit in the medicine cabinet for months before actual use. It is difficult to prove, with mere plaintiff testimony, proximity in time between use of the product and injury. However, unlike the case of prescription drugs, in which the learned intermediary (the prescriber) is a defense for manufacturers, manufacturer warnings for nonprescription drug products must go directly to the consumer. In Yugler v. Pharmacia & Upjohn Co., the court denied application of the learned intermediary doctrine, even when the provider had initially prescribed prescription Motrin and the patient obtained refills OTC.106 Liability for Advice on Nonprescription Drugs Pharmacists can be sued for malpractice and negligence for inaccurate advice (with liability requiring affirmative misrepresentations) regarding nonprescription drugs that harm the patient. A recommendation for use of a nonprescription product not in accordance with the labeling may increase the risk for liability if the patient is harmed. Additionally, in a case in which a pharmacist recommended a nonprescription product in place of the prescribed one, and the patient was harmed, the court denied the pharmacy’s motion for summary judgment that the patient was “contributory negligent” in ignoring the label directions.107 One high-profile case centering on pharmacists’ advice for nonprescription products is Whiting v. Rite Aid Pharmacy,108 wherein the patient’s estate sued the pharmacist for a recommendation that the patient could safely take phenylpropanolamine and Sudafed. The plaintiff contended that she informed the pharmacist of the patient’s prostate https://pharmacylibrary-com.uri.idm.oclc.org/doi/10.21019/aphaotc-practition.legal-issues 41/44 9/11/24, 11:37 PM Legal and Regulatory Issues in Self-Care Pharmacy Practice | APhA OTC - The Practitioner’s Role in Self-Care | PharmacyLibrary problems. The pharmacist denied that the conversation ever occurred. The plaintiff asserted that the use of the drug exacerbated the patient’s prostate condition, resulting in the need for several surgeries and, ultimately, his death several years later from an unrelated illness. The pharmacy contended that learned intermediary doctrine protects the pharmacist from such liability and that the pharmacist’s duty of care does not require giving adequate advice about nonprescription drugs. Falling under the learned intermediary doctrine is a defense of tort lawsuits stating that the duty to warn of the dangers of a nonprescription product is that of the manufacturer. The court ruled that the learned intermediary doctrine applies only to prescription drugs. Additionally, however, the court was clear with respect to the duty of care for pharmacists.108 “Pharmacists in Utah clearly have duties regarding nonprescription drugs. If a pharmacist answers a customer’s question and offers advice about nonprescription drugs, the pharmacist must advise and act in a non-negligent manner consistent with a reasonably prudent pharmacist’s response to a customer’s question about the safety of a nonprescription drug.” Ingredients in nonprescription drug products change often, and pharmacists should be certain of a product’s ingredients and contraindications before recommending it. The Drug Facts labeling
