Over-the-counter (OTC) human drugs adorn the shelves of many retail outlets in the U.S., including pharmacies, grocery stores, and convenience stores. OTC drugs do not require a written prescription from a medical professional, making them highly accessible. Though there are similarities in the regulations the U.S Food and Drug Administration (FDA) enforces for both prescription drugs and OTC drugs, there are also significant differences. The most noteworthy difference is the ability for companies to market an OTC Drug using an OTC Drug Monograph. This pathway allows companies to market certain OTC drugs without further FDA approval, so long as the drug complies with an existing monograph.

Keep reading to learn about FDA’s regulations for OTC human drugs, including registration, listing, and marketing requirements.

Drug Establishment Registration

All establishments engaged in the manufacturing, repacking, relabeling, or salvaging of a drug product for commercial distribution are required to register with FDA, unless exempt. (21 CFR 201.17). Drug establishment registration informs FDA which facilities are engaging in manufacturing activities of drug products either in the U.S. or offered for import into the U.S.

For a U.S. based establishment, registration includes the facility’s DUNS number, manufacturing facility address, business operation details, and establishment contact information. Non-U.S. based establishments must also include information for their U.S. Contact and U.S. Importer(s).

Drug companies must register with FDA within five days of introducing their drug product into commercial distribution. After registering, FDA will assign the establishment an FDA Establishment Identification (FEI) number and the site becomes subject to inspection.

Establishments must update their registration annually between October 1^st and December 31^st. The update should include changes to the contact information, the company name, and/or the establishment address. If there are no updates to the registration information, the establishment must submit a No Change Notification. Establishments must also update their registration before shipping to the U.S. when importer information has changed or when a new importer has been added.

Product Listing

Most registered drug establishments must list all of their drug products to let FDA know what drug products are in commercial distribution, who manufacturers each drug product, and what drug products a label distributor distributes. Product listings must be assigned a National Drug Code (NDC) number and must include labeling in Structured Product Labeling (SPL) format.

Establishments exempt from listing requirements include contract testing laboratories, contract assemblers, and manufacturers, repackers, salvagers, or relabelers of Type B or C medicated feeds.

Listings must be updated if there is a change to the company name, DUNS number, or artwork that does not require a new NDC number assignment. Additionally, listings must be verified every year between October 1st and December 31st. If there are no changes, the company must submit a Blanket No Change Certification to FDA.

Marketing Regulations

OTC human drugs must meet established standards for safety and effectiveness, be manufactured according to current good manufacturing practices (cGMPs), and comply with the labeling content and format requirements. These products can be regulated through an OTC Drug Monograph or a New Drug Application (NDA)

OTC Drug Monographs

OTC drugs that conform to an existing OTC Drug Monograph follow acceptable ingredients, doses, formulation, and labeling requirements that are specified for a drug already on the market. In this sense, OTC Drug Monographs serve as a “recipe book” for drug companies, allowing the drug to be marketed without further FDA clearance as long as it adheres to the monograph.

Monographs specify the active ingredients that an OTC drug product can contain. An OTC drug product containing ingredients that comply to the standards established in the corresponding OTC monograph for formulation, labeling, and testing is considered to be “generally recognized as safe and effective” (GRASE) and does not require specific FDA approval before marketing.

Applications

If an OTC drug does not adhere to the standards of an OTC Drug Monograph, the sponsor of the drug must submit a New Drug Application (NDA) or an Abbreviated New Drug Application (ANDA) to FDA for approval. FDA must approve the NDA or ANDA before the drug can be marketed.

An OTC drug can be marketed as either a direct-to-nonprescription (direct-to-OTC) or prescription-to-nonprescription switch (Rx-to-OTC switch) drug. For a direct-to-OTC drug, the sponsor can submit an NDA to market a new drug without first receiving approval as a prescription drug. An Rx-to-OTC switch refers to an approved prescription drug that eventually receives FDA approval to be marketed as nonprescription.

Proposed Rule

FDA is proposing a rule that could increase options for applicants to develop and market safe and effective nonprescription drug products, by providing consumers with an additional condition for nonprescription use (ACNU). If the rule passes, an applicant would be able to submit a drug application proposing an ACNU for a product “when labeling alone is not sufficient to ensure that the consumer can appropriately self-select or appropriately actually use, or both, a drug product correctly in a nonprescription setting”. Consumers would need to successfully fulfill the ACNU to obtain the drug product without a prescription.