NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
Amanda E. Miller ; Samar Nicolas .
Last Update: June 20, 2023 .
The Federal Food and Drug Administration (FDA) oversees and manages all medication disbursement in the United States. The Food, Drug, and Cosmetic Act (FDCA) of 1906 was the first federal law to establish the FDA as the main regulatory body for all medications in the United States. This role became more complex with the Durham-Humphrey Amendment of 1951 and the Food and Drug Administration Modernization Act of 1997 (FDAMA).
These acts defined the two classes of federally regulated medications: OTC and prescription medications. Ultimately, these acts established the criteria for labeling a medication as a prescription drug, with the following requirements:
The use of such a drug is safe only under the supervision of a licensed practitioner due to its toxicity or method of use.
All drugs categorized as prescription medications are subject to the new drug application (NDA) approval process under the FDAMA.
The FDA is responsible for ensuring that all medications on the market, both over-the-counter (OTC) and prescription, are distributed safely [21 C.F.R.§ 205]. The FDA has the power to impose any restrictions on medications that are deemed unsafe for public consumption. This role is defined in Title 21 of the Code of Federal Regulations, as well as the Controlled Substances Act of 1971 (CSA) [21 C.F.R.§ 1306 2022; 21 U.S.C.§ 801 2018]. Title 21 defines prescription and OTC drug labeling and distribution.
The CSA is responsible for categorizing all medications into schedules. This CSA also sets the requirements to prescribe, dispense, store, and dispose of medications. Furthermore, this Act was expanded with the Combat Methamphetamine Epidemic Act of 2005 (CMEA).
Finally, the FDA instituted the Poison Prevention and Packaging Act of 1970 (PPPA) to protect the public and particularly children. This law established the required safety precautions that must be taken when dispensing medications to protect children under the age of 5 years from accidental poisoning [16 CFR § 1700].
This federal law is monitored and enforced by the Consumer Products Safety Commission (CPSC) under the guidance of the FDA. This article describes the federal regulations regarding medication disbursement and describes the provider’s role in properly prescribing, filling, and monitoring medications.
Food, Drug, and Cosmetic Act of 1938
The FDA has been regulating all medications in the United States since 1906. The federal Food, Drug, and Cosmetic Act of 1938 (FDCA) further expanded this role. Under the FDCA, drugs are recognized as any non-food substance intended to be used for diagnoses, cures, treatments, or disease prevention. They are intended to affect bodily structure or function [21 U.S.C.§ 321].
The FDCA defines two main classes of medications: OTC and prescription medications. Prescription medications are drugs that require a prescription and specific labeling and directions to be deemed safe. These drugs are limited to disbursement solely by prescription because they are considered habit-forming, toxic, carry a potential for harm, or their approval under the FDA is limited [21 U.S.C.§ 321].
Furthermore, the Durham-Humphrey Amendment established guidelines for all pharmacists dispensing prescription medications. These guidelines require a written or oral prescription by a licensed practitioner, a refill to be authorized by a licensed prescriber, and all prescription medication dispensing to be overseen by a prescriber. Additionally, prescription drugs must be labeled with the statement "Caution: Federal law prohibits dispensing medication without a prescription."
Non-prescription medications, also known as OTC medications, are drugs deemed safe and effective for public consumption without a provider's consult or approval [21 U.S.C.§ 321]. Supplements were later added to the Act as a separate category of "drugs" with separate regulations from OTC and prescription drugs. The FDA classifies dietary supplements as "food" products [21 U.S.C.§ 341]. These products cannot claim to manage or cure a disease and must contain a printed statement on the label stating, "These claims and statements have not been evaluated or approved by the FDA" [21 U.S.C.§ 343].
The FDCA was also responsible for explaining the rigorous new drug approval process, which must be completed before any new drug comes to market. This process is lengthy, with numerous steps that must be completed before the drug progresses to approval [21 U.S.C.§ 355]. The drug approval process begins by conducting laboratory and animal studies of the drug. These studies evaluate the drug's pharmacology and potential toxicities.
If the drug shows limited toxicity in animal studies, it progresses to step two of the approval process. In step 2, the manufacturer submits an investigational new drug (IND) application to the FDA. The IND must include pre-clinical data, proposed drug use, safety data from animal studies, and the proposed plan for human studies. Once the FDA approves the IND, the drug enters the final step of the process.
The final step details the four phases of human clinical trials. Phase 1 monitors a small group of healthy human subjects to gain information on the toxicological, pharmacokinetic, and pharmacologic properties of the drug. If Phase 1 successfully determines the drug's safety in humans, the drug enters Phase 2.
Phase 2 includes a larger sample of human subjects with a disease or symptom the drug claims to treat. In Phase 2, the drug may be compared to another treatment for the disease or symptom or a placebo. This phase provides information on drug efficacy and dosing and continues monitoring adverse effects. Once the drug has an established efficacy with minimal serious side effects, it advances to Phase 3.
Phase 3 studies different dosages of the drug in large patient groups in several geographic locations. Typically, in Phase 3, patients receive the study drug along with other medications. This phase is imperative for a drug's approval. If the drug passes Phase 3, it is placed on file with the FDA and undergoes thorough review. If the FDA determines the drug as safe and effective, the manufacturer can start the sale of the drug, and Phase 4 begins.
In Phase 4, the manufacturer is responsible for monitoring the drug safety, efficacy, interactions, long-term risks and benefits, and optimal use information. The manufacturer must continue to monitor the drug as long as it is on the market and submit reports to the FDA yearly or sooner if there are updates on the drug's safety or use [21 U.S.C.§ 355].
In 1979, the FDCA described various categorizations for drugs when used in pregnancy [21 U.S.C.§ 379]. In 2015, under the FDCA, the FDA changed its guidance to require specific warnings to be placed in all drug packaging to alert patients about the drug's safety in pregnancy. This is known as the Pregnancy Lactation and Labeling Final Rule (PLLR) [21 U.S.C.§ 201]. This rule eliminated the previous A through D and X pregnancy risk categories. The PLLR mandates that the drug's package information states the risks of using that drug during pregnancy and lactation and the safety of the drug in males and females of reproductive age [21 U.S.C.§ 201]. Risk statements are based on data from relevant sources and research material [21 U.S.C.§ 201].
The drug packaging must also include information on the drug's maternal/fetal risk estimates, dose adjustments in pregnancy and postpartum, the drug's presence in breast milk, and the drug's possible effect on labor and delivery [21 U.S.C.§ 201]. In addition to informing patients of the risks and overall safety of a drug's use during pregnancy and lactation, the PLLR assists healthcare providers in making safe prescribing decisions and provides them with more information for patient counseling.
Controlled Substances Act of 1971
The Controlled Substances Act (CSA) is the titular law detailing how prescription drugs are categorized, stored, inventoried, and dispensed. The CSA established the "scheduling" of drugs to include all prescription medications [21 U.S.C.§ 812].
The Schedules range from I to V, indicating the potential for the drug to be addictive. Schedule I drugs have the highest potential for abuse or addiction and do not have an acceptable medical use in the United States. Marijuana, lysergic acid diethylamide (LSD), and heroin are Schedule I drugs. Drugs in Schedules II have a high potential for abuse but less than Schedule I. Hydrocodone and methadone belong to Schedule II. Schedule III drugs have a potential for abuse but are less so than Schedule II. Anabolic steroids and ketamine belong to Schedule III. Drugs in Schedule IV and V drugs have a lower potential for abuse than Schedules I, II, and III, and the risk of abuse with Schedule V is less than that with Schedule IV. Phenobarbital is an example of a Schedule IV drug. Drugs in Schedule V consist of preparations that contain limited amounts of narcotics, such as an antitussive with a maximum of 200 mg of codeine per 100 mL.
Most cold medications, cough preparations, and antidiarrheals fall into Schedule V if they contain codeine. With these schedules in place, the FDA and Drug Enforcement Agency (DEA) are able to monitor the sale, distribution, and dispensing of all controlled substances in the United States [21 U.S.C.§ 812].
In addition to creating five medication schedules, the CSA established guidelines on how the DEA monitors and manages the storage, transfer, disposal, and dispensing of controlled drugs. This Act also detailed the registration and maintenance of all pharmacies that register with the DEA to dispense controlled medications [21 U.S.C.§ 827].
Under the CSA, a pharmacy should keep records of all controlled substances that the pharmacy purchases, receives, stores, and distributes. The pharmacy should store these records in a safe and secure location for a minimum of 2 years. These records must document the name, dosage, quantity, and dates of purchase/receipt of all controlled drugs [21 U.S.C.§ 825]. Each pharmacy is required to complete a thorough inventory after registering with the DEA and document a physical count of all controlled substances that the pharmacy possesses.
This inventory is released to the DEA, and the pharmacy must conduct a new count once every two years to ensure that there is no impropriety [21 U.S.C.§ 826]. Pharmacies must report theft or impropriety to the DEA within one business day of discovering the discrepancy[21 U.S.C.§ 841].
Prescriptions for controlled substances must only be issued for legitimate medical purposes by a professional practitioner. Pharmacists should exercise sound professional judgment to determine the prescription's legitimacy [21 U.S.C.§ 832]. To comply with the CSA, the pharmacy must ensure that a valid prescription is on file before dispensing a controlled drug. Valid written and electronic prescriptions must include the date the prescription was written, the patient's full name and address, and the practitioner's full name, address, DEA number, and signature. The prescription must also include the drug name, strength, quantity prescribed, directions for use, and the number of refills [21 U.S.C.§ 829].
According to the CSA, any substance that is a Schedule II drug can only be prescribed for a maximum 30-day supply per prescription at a time[21 U.S.C.§ 829]. For medications in Schedules III to V, a maximum of 5 refills is authorized within a 6-months of issuing the prescription. After six months, the prescription expires, and a new prescription is needed.
Under federal law, a prescription for a controlled substance may only be issued by a physician, dentist, veterinarian, or mid-level practitioner [21 U.S.C.§ 823]. Mid-level practitioners are DEA-authorized practitioners other than those specified above or those who require the supervision of another practitioner. Although this fact is established in the CSA, prescriptive authority is determined at the state level.
Poison Prevention and Packaging Act of 1970
The Poison Prevention and Packaging Act of 1970 (PPPA) was instituted by the federal government to protect children under the age of 5 years from accidental poisoning. This Act enforces labeling requirements and child-safe packaging [16 CFR § 1700.15]. Although this Act is enforced on the federal level, the Consumer Products Safety Commission (CPSC) monitors compliance rather than the FDA. The Commission ensures that all medications be placed in specific packaging to curb the incidence of accidental child poisoning [16 CFR § 1700.2]. Safety labeling must be placed on all packaging, whether or not the prescription is secured with a child-resistant cap.
The main provision that has been instituted since the passage of the PPPA is the use of safety caps on all prescriptions. Under the PPPA, all new prescriptions must have a child-resistant cap unless the prescriber or the patient specifies one is unnecessary. A provider may request that a prescription be filled without a child-resistant cap, but it is only for specific medications and subsequent refills. Ultimately, the patient decides whether a child-resistant cap is placed on their prescription. Additionally, there are a few medications that are exempt from the requirements of the PPPA. Some examples include sublingual nitroglycerin, chewable aspirin, oral contraceptives, and aerosol inhalation products [16 CFR § 1700.14].
Combat Methamphetamine Epidemic Act of 2005
The Combat Methamphetamine Epidemic Act of 2005 (CMEA) was designed to regulate OTC sales of ephedrine and pseudoephedrine, among other drugs, due to their use in the production of illegal drugs such as methamphetamines [21 USC § 801 sec. 701]. The CMEA created "scheduled listed chemical products" (SLCP), which was a master list of any product marketed under the Food, Drug, and Cosmetic Act that contained ephedrine or pseudoephedrine that would eventually be regulated under this act.
The CMEA was also pivotal in establishing requirements for record-keeping, reporting lost or stolen items, and proof of identity upon purchase. The seller of any drug containing ephedrine or pseudoephedrine is now required to document the sale, as well as the purchaser, the amount of product sold, and the date/time of sale. These records were to be kept at a central location for a minimum of two years. The seller is now responsible for reporting theft or loss of items containing ephedrine or pseudoephedrine to the DEA within fifteen days of the inciting event.
The final provision under the CMEA instituted a proof of identity requirement for purchasing any products containing the materials above. The purchaser had to prevent a valid picture ID and was subsequently placed into a database to monitor for "pharmacy shopping" activity. To date, there is mixed evidence as to the effectiveness of state and federal laws in curbing the production and sale of methamphetamine products.[1]
Food, Drug, and Cosmetic Act
The FDCA is a piece of federal legislation on which all medication regulation laws are based. This pivotal law established safety guidelines for the manufacturing and distributing of all medical drugs and devices. This law allowed the federal government to regulate pharmaceuticals and medical devices, enforce these safety guidelines nationwide, and prevent drug manufacturers from peddling false or unproven claims.
The FDA was able to counteract unsafe drugs from entering the U.S. market by instituting strict labeling and packaging laws under the FDCA. Before implementing the FDCA, manufacturers were not required to list the medication's ingredients on the label or describe the expected effects or adverse events associated with the drug. Now, under the FDCA and enforcement by the FDA, patients and practitioners know the ingredients of the medication and the possible side effects associated with it.
Additionally, the FDCA established guidelines for the manufacturing and distribution of new drugs as well as the safety requirements that must be met in a series of clinical trials before the drug is available to the public. Clinical trials serve the public by regulating medications at every step of the process to ensure that every approved drug is safe and would not cause undue harm to the patient.
After thalidomide was widely used by pregnant women and caused numerous fetal and newborn defects, the FDA amended the FDCA to require all drug manufacturers to evaluate the drug's safety in pregnancy. Eventually, the FDCA propelled medicine within the United States into the 20th century safely.
Controlled Substances Act
The CSA determines how prescription drugs are categorized, distributed, and stored safely. The CSA created a method to categorize medications based on their safety, purpose or method of use, and abuse or addiction potential. Founding a scheduling system to categorize drugs helped the FDA and DEA regulate controlled substances on the market. By monitoring controlled substances, the DEA was able to track the production and distribution of medications with the potential for abuse and regulate prescribing practices of these medications.
The CSA requires specific information on written and electronic prescriptions for controlled substances and specifies the practitioners authorized to issue these prescriptions. Prescribers must include their DEA number on the prescription to facilitate the DEA's ability to regulate the type and quantity of drugs being prescribed by each practitioner. It is at the discretion of the DEA when and if to audit a practitioner's prescription records.
The CSA improved safety measures, established a legal framework for regulating controlled substances, and curbed addiction and death from overdose.
Poison Prevention and Packaging Act
Prior to the PPPA, accidental poisonings via household goods and medications were the highest cause of injury to children five years and under in the United States. This fact led the FDA to implement the PPPA and give oversight and enforcement duties to the CPSC.
The PPPA made the packaging of controlled substances and medications safer for children five years and under by mandating a child-resistant cap on prescription bottles. Few medications were exempt from this rule, mainly due to the patient's need to easily access these medications during a medical emergency.
The PPPA also allows patients to request a non-child-resistant cap on their prescription bottle from the pharmacy. Since its implementation in 1970, the PPPA has led to a decrease in child injuries, with data showing an 80% decline in poisoning fatality among children five years and under from 1972 to 2020.
Combat Methamphetamine Epidemic Act
The CMEA was established to decrease the use of OTC pseudoephedrine in producing illegal drugs, such as methamphetamines. Before the CMEA, several OTC products contained large amounts of pseudoephedrine and were easily accessible to the public.
Since the enforcement of the CMEA, the availability of these OTC products has decreased dramatically. Now, patients must purchase all pseudoephedrine-containing products from behind the pharmacy counter and present their photo identification for pharmacy records. There is a limit on the amount of pseudoephedrine-containing products that may be purchased daily and monthly.
This process allows the FDA to identify a pattern of "pharmacy shopping" if purchasers visit multiple pharmacies to obtain as many ephedrine-containing products as is permitted. The CMEA established a strict punishment for manufacturing methamphetamines, which may result in up to 20 years in prison per offense.
Drug Dispensing to Improve Patient Care
One crucial aspect of patient care affected by these federal regulations is how patients obtain their drugs from local pharmacies. Local pharmacies are critical in ensuring medications are dispensed safely and labeled correctly.[2]
Pharmacists' counseling on medication use falls under state rather than federal law. Since the federal government has not established a national, standardized disbursement practice for pharmacists, the standard of care and medication counseling may not be consistent among patients receiving care from different pharmacists nationwide. There have been numerous studies, as recent as 2021, analyzing the effect that direct drug disbursement from local pharmacies has on patients' clinical and economic outcomes.[3]
These studies show that pharmacist counseling has a positive outcome on the patient's clinical and financial well-being, regardless of the amount of time spent counseling on medication safety.[3]
Conscientious Objection
Another concern when discussing medication dispensing is the conscientious objection, which means that a healthcare provider opposes a legal healthcare treatment, procedure, or medication due to a religious or ethical reason.[4]
Recently, most objections were directed to administering legal abortifacient or birth control medications. Although state laws differ to the extent of what pharmacists may do in leu of dispensing these medications, most states require pharmacists to ensure patients get their medications somewhere else by transferring the prescription to another pharmacy.[5] Some pharmacists may struggle in referring patients to other pharmacies because the patient will eventually receive these medications.[5]
After multiple cases of pharmacist misconduct in Idaho and Washington, pharmacists went to the federal government requesting further protections for providers and their right to apply conscientious objections. As a result, in 2018, the Department of Health and Human Services established a "Conscience and Religious Freedom Division." This division enforces existing federal laws, protecting healthcare workers' rights when enacting a conscientious objection. However, the formation of this division did not require any change to the existing state laws regarding conscientious objection.
Although the federal government is willing to enforce the reasonable objection of prescription medications by providers, individual states regulate alternative measures providers must take to ensure patients receive their medications. [Level 5]
Prescriptive Authority
Prescriptive authority refers to the ability of healthcare providers to prescribe specific medications, including controlled substances. Although prescriptive authority refers to a provider's role in prescribing and dispensing legal drugs as described in Title 21, the regulation of this authority does not fall under the federal government's purview. Instead, prescriptive authority is regulated by each state's government.[6]
In every state within the United States, all physicians holding an MD or DO degree have full prescriptive authority. However, there have been some legal disparities between states regarding providing prescriptive authority to other certified providers, such as registered nurse practitioners (NPs) and physician assistants (PAs). In some states, these providers may only prescribe certain medications under the supervision of a licensed clinician.[7]
In other states, these providers can prescribe some medications but not controlled substances, and in other states, they have full prescriptive authority at the same level as doctors.[7][6] Recently, a group of providers petitioned the FDA for defined federal regulations on prescriptive authority in order to globally protect a provider's ability to prescribe medications. The FDA has not yet taken a stance on federal prescriptive authority legislation. For now, regulating prescriptive authority remains at the state level.
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Disclosure: Amanda Miller declares no relevant financial relationships with ineligible companies.
Disclosure: Samar Nicolas declares no relevant financial relationships with ineligible companies.
