Up Close and Personal

Regulators and standard-setting bodies are re-examining over-the-counter drugs.
May 02, 2011
Volume 35, Issue 5

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 products.

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.

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 approval.

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 USPNF. 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.

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.)
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.

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 or ANDA.

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.