2.3 Federal Food, Drug, and Cosmetic Act

The FDCA Framework

The Federal Food, Drug, and Cosmetic Act (FDCA) of 1938, codified in 21 USC §§ 301 et seq. and administered by the Food and Drug Administration (FDA), is the foundation of U.S. drug regulation. It requires that a drug be safe, effective, and properly labeled before it enters interstate commerce, and it gives FDA the authority to inspect manufacturers, seize adulterated or misbranded products, and pursue criminal penalties. For the PA MPJE, the FDCA matters because it governs drug approval, labeling, compounding, and the prescription/OTC distinction that pharmacists apply every day.

Prescription vs. OTC: Durham-Humphrey (1951)

Before 1951, the 1938 Act required drugs to be labeled with "adequate directions for use" but did not clearly distinguish prescription from OTC products. The Durham-Humphrey Amendment of 1951 (Public Law 82-215) amended FDCA § 503(b) (21 USC § 353(b)) to create a legal distinction that still structures pharmacy practice:

• Prescription ("legend") drugs — Drugs that, because of toxicity or potential for harm, cannot be safely used without professional supervision. They must bear the federal legend "Rx only" (or, per the 2018 redesign, the symbol "Rx" in a defined format) and may be dispensed only on a licensed practitioner's order. Refills are limited to the number authorized by the prescriber.
• OTC drugs — Drugs that are safe and effective for use without professional supervision. They must bear adequate directions for lay use on the label.

Note that the federal "legend" language was updated by the FDA Reauthorization Act of 2017 to replace the words "Rx only" on packaging with the symbol "Rx," but the underlying prescription-vs-OTC distinction is unchanged.

FDA Drug Approval Pathways

Bioequivalence for Generics

An ANDA must demonstrate that the generic product is bioequivalent to the RLD — meaning the rate and extent of absorption fall within FDA-defined confidence intervals (typically 80–125% for AUC and Cmax). An AB-rated generic is considered therapeutically equivalent and may be substituted for the brand under state substitution laws (in PA, unless the prescriber writes "dispense as written" or marks "brand medically necessary").

Special Regulatory Pathways

• REMS (Risk Evaluation and Mitigation Strategy) — FDCA § 505-1. FDA may require a REMS when it determines that risk management beyond labeling is necessary to ensure benefits outweigh risks. Components may include a Medication Guide, a communication plan, and Elements to Assure Safe Use (ETASU) such as prescriber certification, patient enrollment, restricted distribution, or monitoring (e.g., isotretinoin's iPLEDGE program, clozapine's REMS).
• Accelerated approval — FDCA § 506. Allows approval of drugs for serious or life-threatening illnesses based on a surrogate endpoint reasonably likely to predict clinical benefit. The sponsor must conduct post-approval confirmatory trials; FDA may withdraw approval if confirmatory evidence is lacking.
• Orphan drug — FDCA § 526. Grants special status (7 years of market exclusivity, tax credits, and grant support) to drugs treating rare diseases or conditions (prevalence <200,000 in the U.S.). Orphan exclusivity blocks FDA approval of another sponsor's same drug for the same orphan indication for 7 years.
• Pediatric exclusivity — FDCA § 505A. A sponsor that conducts FDA-requested pediatric studies may receive an additional 6 months of marketing exclusivity added to the end of any patent or exclusivity that would otherwise expire. This is a high-yield MPJE fact.
• Priority review / fast track / breakthrough therapy — procedural expeditions that shorten FDA review time but do not lower the approval standard.

Misbranding and Adulteration

• Misbranding (FDCA § 502) — A drug is misbranded if its labeling is false or misleading, lacks required directions for use, lacks adequate warnings, is not labeled with the established name and ingredient statements, or is packaged or labeled in violation of FDA regulations. A prescription drug dispensed without a valid prescription or with inadequate labeling is also misbranded.
• Adulteration (FDCA § 501) — A drug is adulterated if it contains filthy, putrid, or decomposed substances; is prepared, packed, or held under unsanitary conditions; deviates from compendial quality standards (USP); or is a compounded drug that does not meet USP <795>/<797> standards where required. A drug that fails potency or purity specifications is also adulterated.

Both misbranding and adulteration trigger FDA enforcement: seizure, injunction, civil penalties, and (for knowing or willful violations) criminal prosecution.

Compounding: 503A vs. 503B

The FDCA divides human drug compounding into two statutory categories, both relevant on the PA MPJE because PA's compounding regulations at 49 Pa. Code §§ 27.601–27.606 (finalized June 22, 2019) incorporate federal standards and current USP <795> (nonsterile), <797> (sterile), <800> (hazardous drugs, effective Nov 2023), and <825> (radiopharmaceuticals).

Section 503A — Traditional Compounding

• Compounding by a licensed pharmacist within a state-licensed pharmacy or federal facility;
• Based on a patient-specific prescription or in anticipation of occasional, limited quantities based on documented historical prescribing patterns;
• Exempt from NDA/ANDA approval, adequate-directions-for-use labeling, and DSCSA product tracing requirements, provided the drug is not on FDA's "demonstrable difficulties for compounding" (DDC) list;
• Must comply with USP <795>/<797>/<800> and state board of pharmacy regulations;
• May not compound a product that is essentially a copy of an approved drug, or a product that was withdrawn for safety reasons.

Section 503B — Outsourcing Facilities

• A facility that compounds drugs without patient-specific prescriptions and may distribute them to healthcare facilities for office use (not for direct dispensing to patients);
• Must register with FDA as an outsourcing facility;
• Must comply with current Good Manufacturing Practice (cGMP) under 21 CFR Parts 210 and 211;
• Exempt from NDA/ANDA approval and DSCSA product tracing, but subject to FDA inspections, adverse-event reporting, and labeling requirements;
• May compound drugs on FDA's 503B bulks list (substances that are not on the DDC list).

Common MPJE Traps on the FDCA

1. ANDA vs. NDA — An ANDA requires bioequivalence to the reference listed drug, not independent efficacy trials; this is what makes generics cheaper to bring to market.
2. Interchangeable vs. biosimilar — A biosimilar is highly similar to the reference biologic; an interchangeable biologic may be substituted for the reference product without prescriber notification, much like a generic for a small-molecule drug. Not all biosimilars are interchangeable.
3. Pediatric exclusivity — 6 months added to existing exclusivity or patent term, in exchange for conducting FDA-requested pediatric studies. A frequent MPJE answer choice.
4. 503A requires patient-specific prescriptions; 503B may compound for office use without patient-specific prescriptions, but must follow cGMP and register with FDA.
5. Misbranding vs. adulteration — Misbranding concerns labeling and packaging; adulteration concerns the drug's physical quality, potency, or manufacturing conditions. A mislabeled but otherwise pure drug is misbranded, not adulterated.