Federal Regulation of Medication Production

Function

Although the government passed the first law safeguarding the public from food and pharmaceuticals in 1906, the present-day FDCA was not enacted until 1938. The 1938 law stipulated that drug products not already on the market could not be commercialized until they were demonstrated to be safe. In addition, drug labels were required to include adequate directions for use and appropriate warnings. Several laws and amendments followed to establish the regulatory framework in effect today:

• The Prescription Drug Marketing Act (PDMA) of 1987 regulated the distribution of prescription drug samples and prohibited hospitals and other healthcare facilities from reselling medications to other entities.
• The 1984 Patent Term Restoration Act (PTRA) streamlined the approval process for generic drugs while preserving patent protections for innovator products.
• The Orphan Drug Act of 1983 incentivized drug and biologic manufacturers to develop and market treatments for rare diseases.
• The Kefauver-Harris Amendment of 1962 added a requirement that the efficacy of drug products be proven with substantial evidence and made this requirement retroactive to 1938. Drugs that were on the market before 1938 were exempt.
• The Durham-Humphrey Amendment defined 2 classes of drugs: prescription and over-the-counter (OTC). 
• Under the Prescription Drug User Fee Act (PDUFA) of 1992, manufacturers must pay application fees for NDAs.[5]
• The Dietary Supplement Health and Education Act (DSHEA) of 1994 established the regulatory framework for dietary supplements and mandated that the FDA regulate them more like foods than medications.
• The Food and Drug Administration Modernization Act (FDAMA) of 1997 streamlined regulatory procedures to expedite the availability of medications and devices and established a fast-track process for medications intended to treat serious or life-threatening conditions.
• The Food and Drug Administration Amendments Act (FDAAA) of 2007 gave the FDA greater authority to oversee drug safety, including the requirement of Risk Evaluation and Mitigation Strategies (REMS) when appropriate.
• Among other measures, the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 introduced user fees for generic drugs and biosimilars.
• The Drug Quality and Security Act (DQSA) of 2013 simplified laws governing pharmacy compounding, introduced track-and-trace requirements for prescription medications, and established a new category of sterile compounding entities known as "outsourcing facilities."
• The Cures Act of 2016 facilitated and expanded the drug development and approval systems, enabling other patients to experience data collection along the way.[6]

The FDCA's principal purpose is to safeguard the public, but there is a trend toward indirect control rather than direct regulation.

Issues of Concern

In the 1980s, when an NDA was approved for a new chemical entity, market exclusivity provided the innovator product with 5 years of protection from generic competition. In other words, the FDA generally did not accept certain generic drug applications for 5 years following approval of the innovator product. In cases where a new drug has clinical significance, the FDA may also grant 3 years of exclusivity regarding the investigations. The FDA, however, previously had the authority to approve additional Abbreviated New Drug Applications (ANDAs) for other drugs. Although the FDCA allows generic companies to obtain regulatory approval for medications by submitting an ANDA, relatively few generic drugs were on the market in the early 1980s. The US Congress looked into the matter and found that innovator companies could make it difficult for generic companies to submit ANDAs under preexisting patent and regulatory law. The regulatory pathway for ANDA approval was erratic and ambiguous. The Patent Term Restoration Act (PTRA) of 1984, also known as the Hatch-Waxman Act, was enacted in retaliation. The PTRA, however, led to various controversies.[7]

Practitioner Controversy

The legislation permits approval of generic drugs that demonstrate bioequivalence to the reference product. Bioequivalence is generally established when the 90% confidence intervals for the ratios of key pharmacokinetic parameters, including maximum concentration (Cmax) and area under the concentration-time curve (AUC), fall within an accepted regulatory range of 80% to 125% of the reference product. Some physicians expressed concern that differences among generic formulations could result in clinically meaningful variation in drug exposure; however, the FDA has maintained that approved generic products that meet bioequivalence standards are expected to be therapeutically equivalent.

• In public pronouncements, the FDA addressed this concern by stating that the statistical approach in question would not permit such a variation.
• When evaluating data on generic medications authorized between October 1984 and September 1986, the FDA stated that the mean variation in absorption between generic and innovator drugs was only 3.5%, which should not result in clinical disparities among patients.
• Nonetheless, several medicinal items are still the subject of debate.[8]

The statute also sparked debate about whether physicians could prescribe and dispense a generic drug product if the innovator drug product obtained exclusivity. For instance, when the original brand propranolol has commercial exclusivity for a particular indication, can a pharmacist legally substitute generic propranolol for post-myocardial infarction? Since this is the use of an approved drug (the generic medicine) for an off-label reason, the basic answer to this issue is "yes."

Manufacturer Controversy

The PTRA has resulted in several highly contentious drug manufacturing practices. Although several of these activities have existed since the act’s inception, they have drawn renewed attention from Congress and the public in recent years because of the expiration or impending expiration of numerous bestselling drug patents.

One such method involves an innovator manufacturer creating an "authorized generic" version of its brand-name product just before the patent expires or is successfully challenged by a generic competitor. Because generic and brand-name prescription drugs are alike and thus approved under the NDA, the innovator manufacturer may create the generic and compete with a generic manufacturer that has submitted an ANDA with a successful paragraph IV certification. As a result, the 180-day market exclusivity is less valuable to the generic manufacturer, and the innovator company retains market share that it would otherwise lose.[9]

Another point of contention is the 30-month stay of ANDA approval that follows when the patent holder files a patent infringement lawsuit against the generic firm. Many innovator manufacturers, according to critics, have been accused of filing patent litigation to obtain the benefits of a 30-month stay despite having weak legal claims. Although subsequent legislation has restricted this practice, some manufacturers have used multiple patent claims or related litigation strategies to extend delays in generic market entry.

Generic Drug Labeling Controversy

The PTRA stipulates that a generic drug's labeling must generally be the same as that of the innovator drug (21 USC §355(j)(2)(A)(v)), a requirement that has generated considerable legal and regulatory debate. For example, in Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493 (D.C. Cir. 1996), Bristol-Myers Squibb retained exclusivity rights to an indication approved through a supplemental application for one of its drug products for three years.

A generic manufacturer subsequently submitted an ANDA for a generic version of the product. Bristol-Myers argued that the ANDA should be denied because the law requires generic labeling to be identical to that of the innovator product, which, according to the company, would not be possible while the protected indication remained subject to exclusivity. However, the court concluded that this interpretation was inconsistent with the statutory framework and purpose of the Hatch-Waxman Act. The court determined that a generic product could be approved with labeling that omitted indications protected by exclusivity, provided that the remaining labeled uses satisfied applicable regulatory requirements. Accordingly, the omission of protected indications from generic labeling did not preclude approval of the ANDA. The court further reasoned that adopting Bristol-Myers' interpretation could allow innovator manufacturers to repeatedly obtain exclusivity for new indications and substantially delay generic competition.[10]

PLIVA, Inc. v. Mensing, 564 U.S. 604 (2011), marked another important development in the debate surrounding generic drug labeling. In this case, the plaintiffs alleged injury resulting from an adverse effect of a medication and argued that the generic manufacturer had a duty to strengthen its warning label. Under FDA regulations, a Changes Being Effected (CBE) supplement allows a brand-name manufacturer, under certain circumstances, to strengthen safety warnings before receiving prior FDA approval. In Wyeth v. Levine, 555 U.S. 555 (2009), the Supreme Court held that a brand-name manufacturer could have strengthened its warning label through the CBE process and therefore could be subject to state-law failure-to-warn claims. However, in PLIVA v. Mensing, the Court determined that generic drug manufacturers generally may not unilaterally change labeling that must remain consistent with the reference listed drug's labeling. Consequently, the Court ruled that state-law failure-to-warn claims against generic manufacturers were preempted by federal law.[11]

Clinical Significance

Since the passage of the FDCA, clinical efficacy, as demonstrated through rigorous scientific and clinical evaluation, has played a significant role in the development of federal protocols governing drug approval and regulation.[12] 

• An applicant must provide evidence under section 505(d) demonstrating that a drug is safe and effective when seeking approval of an NDA.
  • Animal and clinical (human) investigations are required as supporting evidence.
• Section 505(a) prohibits the distribution of any new drug unless it has received FDA approval.
  • Section 505(i), which permits the FDA to exempt a medication from certain NDA requirements for clinical research, avoids this seemingly conflicting position. The maker must file a Notice of Claimed Investigational Exemption for a New Drug, commonly known as an Investigational New Drug (IND) application, to obtain this exemption.
• The producer could then perform clinical tests of its IND unless the FDA places the IND on clinical hold.
• Filing of an IND follows the applicant's lengthy preclinical inquiry. The petitioner determines that the drug has potential value and appears reasonably safe for initial testing in humans based on laboratory studies and animal testing.[13]

Biological products provide a useful example of FDA regulation. These products have been under federal oversight since the Biologics Control Act of 1902 and are currently regulated under both the FDCA and the Public Health Service Act (PHSA).[14]

• To be considered interchangeable, the applicant must demonstrate that the biosimilar is expected to produce the same clinical result as the reference product in any given patient and, for products administered more than once, that switching between products does not increase safety risks or reduce effectiveness compared with continued use of the reference product.[15]
• Biologics are medical products derived from living organisms or their components and are used to prevent, diagnose, or treat diseases and medical conditions.
• The Biologics Price Competition and Innovation Act (BPCIA) of 2009 established an abbreviated regulatory pathway for FDA approval of biosimilar and interchangeable biological products.[16]
• Biosimilarity refers to the absence of clinically meaningful differences between a biological product and its reference product in terms of safety, purity, and potency.

Other Issues

The term "drug" has a broad interpretation under the FDCA, encompassing any article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, or for affecting the structure or function of the body. Various legal disputes may arise from such interpretations.[17]

• Depending on its intended use, a cosmetic may be classified as a drug, and courts have often evaluated consumer perception and product claims when making this determination.
• Some products are classified as both cosmetics and drugs.
• Foods are not classified in Part C of the substance specification, raising the question of what constitutes food for the purposes of Part C.
• If they are marketed to meet specific nutritional requirements associated with a disease or condition and are used under medical supervision, medical foods are generally regulated as foods rather than drugs.[18] 

• If a food product makes unauthorized disease treatment claims, it may be regulated as a drug. Certain health claims may be permitted when supported by significant scientific agreement and authorized by the FDA.

• Dietary supplements were described and developed by the DSHEA as a distinct product category. 
• Without violating Part C of the medication definition, a substance that fits the legal description of a dietary supplement can make 4 kinds of nutritional support claims. 
• If the claim meets the substantial scientific consensus requirement, a substance that fits the legal meaning of a dietary supplement may make an “unqualified” health or disease claim without being classified as a drug, provided the FDA accepts the claim through regulation. 
• Even if the claim does not satisfy the substantial scientific consensus test, a substance that fits the legal meaning of a dietary supplement may make a “qualified” health or disease claim if it is not deceptive.[19] 
• If a dietary supplement was authorized before the prescription, dietary supplement products containing medications are almost certainly classified as drugs. 

• As illustrated by the ephedra case, the FDA may remove a dietary supplement from the market if it determines that the product presents a significant or unreasonable risk of illness or injury under DSHEA.
• The 2006 Dietary Supplement and Nonprescription Drug Consumer Protection Act requires manufacturers, packers, and distributors of dietary supplements and nonprescription drugs to report serious adverse events to the FDA.
• DSHEA has been criticized for establishing a predominantly postmarketing regulatory framework for dietary supplements, which places greater responsibility on the FDA to identify and address safety concerns after products enter the marketplace. Critics have argued that this approach may limit the agency's ability to proactively evaluate potentially unsafe products before they are marketed.
• Since 2007, dietary supplement manufacturers have been required to comply with current Good Manufacturing Practices (CGMPs) to help ensure the identity, purity, strength, and composition of their products.[10][16]
• The distinction between drugs and medical devices may occasionally be complex because some products share characteristics of both categories. In general, classification depends on the product's intended use and primary mode of action. Medical devices are regulated separately under the Medical Device Amendments (MDA), which expanded the FDA's authority to oversee their safety and effectiveness.
• The United States Pharmacopeia (USP) and the Homeopathic Pharmacopeia of the United States (HPUS) are official compendia under the FDCA. 

• The USP establishes drug regulations, and the HPUS regulates homeopathic products. 
• Homeopathic drug products are subject to the FDA's risk-based enforcement approach, with regulatory attention focused on products that may pose greater risks to public health.[20]

Direct-to-consumer (DTC) prescription drug advertising emerged in the 1980s and remains a topic of debate.[21][22][23] Supporters argue that DTC advertising may improve patient awareness of medical conditions, encourage treatment-seeking behavior, and improve adherence to prescribed therapies. Some have suggested that pharmacists may benefit from increased opportunities to provide medication-related education and counseling.

Critics argue that DTC advertising may increase healthcare expenditures, create inappropriate demand for prescription medications, contribute to patient misunderstanding of benefits and risks, and potentially affect the patient-provider relationship.[24][25][26]

Enhancing Healthcare Team Outcomes

The FDA has a voluntary reporting system called MedWatch that enables healthcare professionals and consumers to report serious adverse events, product use errors, and product quality problems involving pharmaceuticals, biologics, medical devices, dietary supplements, and cosmetics. The AccessData web platform includes an official reporting form (FDA Form 3500) that may be completed online. Pharmacists are among the healthcare professionals who frequently submit adverse event reports and are encouraged to report product quality concerns, including incorrect labeling, foreign particulate matter, improperly manufactured dosage forms, abnormal color or taste, and suspected stability issues.[27]

The FDA stresses interprofessional responsibility by encouraging healthcare professionals to report suspected adverse events, product quality issues, and medication or device errors. The Food and Drug Administration Amendments Act (FDAAA) of 2007 expanded postmarketing safety surveillance activities and enhanced mechanisms for collecting safety information from both healthcare professionals and patients.[28]

The FDA encourages practitioners to file reports, emphasizing that submission of a report does not establish causality and is neither a legal claim nor an admission that an adverse event, quality issue, or error occurred. The identities of practitioners and patients are kept confidential. In addition to reports involving drugs, biologics, and medical devices, the FDA encourages reporting of clinically significant adverse events associated with dietary supplements, including products containing vitamins, minerals, and other nutritional ingredients.[28] The FDA also evaluates serious adverse events associated with foods and food additives when appropriate. The MedWatch program facilitates safety reporting and provides access to product safety information through the FDA's official website.[27][29]

Nursing, Allied Health, and Interprofessional Team Interventions

Although FDCA §301 is largely self-explanatory, pharmacists should pay particular attention to several provisions.

A pharmacist is prohibited from manufacturing, selling, holding for sale, or dispensing a counterfeit drug under Section 301(i)(3). Counterfeit pharmaceuticals remain a significant concern in the United States. This section outlines the responsibilities of pharmacists and pharmacies in maintaining the integrity of the drug supply chain and ensuring the authenticity of products that are purchased and dispensed.[30]

Pharmacists who repackage or relabel prescription or over-the-counter medications must pay particular attention to Section 301(k). A pharmacist may be subject to regulatory action if a relabeled product fails to comply with applicable FDA labeling requirements. Pharmacists should verify that relabeled products contain all required information consistent with applicable federal and state regulations.[31]

Recognizing and appropriately managing recalled products is also an important responsibility of pharmacists. Because recalled products may be adulterated, contaminated, or misbranded, dispensing such products may violate the FDCA and expose patients to harm. In the event of patient injury, pharmacists may also face potential civil liability.[31][32][33]

A drug is considered misbranded if it is offered under the name of another drug pursuant to Section 502(i)(3) of the FDCA. The concept of misbranding under Sections 502(i)(2) and 502(i)(3) is closely related to the FDCA definition of a counterfeit drug under Section 201(g)(2). A pharmacist who dispenses a generic drug while inaccurately labeling it as a brand-name product may violate both misbranding and counterfeit drug provisions. Likewise, dispensing a placebo while representing it as a specific drug product may violate multiple FDCA provisions.

Professional labeling is intended primarily for healthcare professionals and should be interpreted within the context of appropriate clinical judgment. Pharmacists play an important role in helping patients understand medication information and may provide counseling consistent with applicable laws, regulations, and standards of practice. Physicians, pharmacists, and other healthcare professionals may utilize FDA-approved labeling when making treatment decisions.

Although pharmacists may recommend certain over-the-counter products for uses not specifically described in the product labeling, they should do so based on sound clinical judgment, available evidence, and applicable standards of care, recognizing that inappropriate recommendations may expose patients to harm and create potential liability concerns.

The FDAAA directed the FDA to develop and maintain publicly accessible resources containing prescribing information, safety communications, REMS, medication safety information, and other drug-specific safety updates.[34]

In 2009, the FDA released a risk communication strategic plan recognizing the importance of effectively communicating risks associated with FDA-regulated products to healthcare professionals, patients, and consumers. Pharmacists were identified as an important audience for receiving and disseminating safety information.[35]

Due to the distinct regulatory framework established by DSHEA, pharmacists play an important role in helping patients evaluate dietary supplements and related products. Whenever possible, pharmacists should direct patients toward products that comply with recognized quality standards, such as USP or National Formulary (NF) standards, or products supported by appropriate quality assurance practices.

Pharmacists should avoid promoting dietary supplements based on unsubstantiated health or disease claims that may be inconsistent with FDA regulations. However, pharmacists may educate patients regarding the available evidence, potential benefits, limitations, and risks associated with dietary supplements and their use in specific disease states. DSHEA also permits the distribution of certain scientific publications related to dietary supplements, provided applicable legal requirements are met.[36]

Nurses, pharmacists, physicians, and other healthcare professionals should collaborate to promote safe medication use, support regulatory compliance, identify and report adverse events through programs such as MedWatch, educate patients regarding FDA-regulated products, and facilitate evidence-based decision-making. Effective interprofessional communication and coordination help enhance patient safety and optimize therapeutic outcomes.