There are more than 250,000 over-the-counter (OTC) products on the market today with wide access to consumers. But after a
series of major OTC drug recalls, regulators and standardsetting bodies seem to be taking a closer look at these readily available
Although industry is familiar with the process by which over-the-counter (OTC) products reach the shelves, many consumers
may not fully understand the difference between regulatory approvals for prescription products and the majority of nonprescription
products. They may not know, for example, that FDA does not perform a prereview of chemistry, manufacturing, and controls
(CMC), labeling, or pharmacokinetics for products regulated under the OTC Monograph System. Unlike prescription products,
OTC drug products may or may not require clinical studies, and manufacturers of OTC monograph drugs are not required to pay
user fees (1). The fact is, OTC drug products have their own rules, and they are approved in various ways depending on when
they are (or were) developed and submitted to FDA for marketing approval.
PHOTO: SHAWN STIGSELL
OTC approvals: a brief history
Before the 1960s and 1970s, OTC drug sponsors were not required to demonstrate drug effectiveness. But in 1962, FDA required
manufacturers to show effectiveness, and in 1972, the agency began what's known as the OTC Monograph System (also called the
OTC Drug Review process), a project that is still underway today. The project involved reviewing in great detail the hundreds
of compounds available to consumers in OTC form and developing FDA monograph requirements for drugs to be considered as generally
recognized as safe and effective (GRAS/E).
All drugs, including OTCs, for human use in the US market must: adhere to current compendial standards; meet labeling requirements
called for in the Code of Federal Regulations (CFR) and in the Federal Food, Drug, and Cosmetic Act; and be manufactured according to cGMPs, which are outlined in 21 CFR Parts 210, 211, and 330 (2). GMP compliance is verified through FDA inspections. Any OTC drug that deviates from a final
monograph is not recognized as GRAS/E and requires an approved application (i.e., a new drug or abbreviated new drug application,
NDA or ANDA) before it can be marketed (3). OTC drugs that meet final monograph requirements do not require an application
Compendial drug quality monographs, or written standards, are published and maintained for the US marketplace by the US Pharmacopeial
Convention (USP) and published in the USP–NF. FDA monographs, which are for conditions for market entry, are published in the CFR. An OTC drug monograph includes requirements for the active ingredient's dosage strength and form as well as for the product's
labeling and final formulation testing (1).
As part of the OTC Drug Review process, FDA ended up restricting in the 1970s the use of some 500 active ingredients that
had previously been on the market because of a lack of sufficient demonstration of effectiveness or lack of general recognition
of safety. To date, the agency has completed a review of more than three-fourths of the original monographs proposed at the
inception of the program, according to FDA spokesperson Lisa Kubaska. Certain OTC medicines can be reviewed again when a monograph
is amended or when a new question of safety or efficacy is raised.
Since about 1984, most new OTC drug products have gone through the NDA/ANDA process for market approval, although companies
can still submit applications to get into the monograph system. Figure 1 provides a full historical timeline of OTC drug regulation.
Figure 1: More than 250,000 OTC products are available to consumers. The following timeline provides a detailed look at at
the history of OTC regulation (Adapted from an FDA online presentation, from Ref. 1.)
Despite the differences in OTC monograph-drug reviews, NDAs and ANDAs for nonprescription products are examined in the same
manner as prescription products. According to FDA, there are 774 OTC products on the market today that were approved by NDA
Another mechanism by which a drug can enter the market as an OTC drug is to undergo a status switch from a prescription drug
to a nonprescription drug. The labeling process for this type of switch is quite complex and described later in this article.