How Medications Gain FDA-Approved OTC Status

W. Steven Pray, PhD, RPh, Joshua J. Pray


The nonprescription marketplace has had an unusually dynamic decade, with many new developments. Patients can purchase a range of nonprescription products that would have been unthinkable 10 years ago. Taken in the aggregate, these changes have altered the face of self-care forever. This article will explore the means by which these changes have come about.

Before 1972, OTC products largely escaped federal scrutiny. Manufacturers were not required to institute research to prove their ingredients' safety or efficacy or that their labels were adequate for self-care. This bureaucratic limbo allowed them to make false and misleading statements and to use ingredients with unproven safety and efficacy. In fact, the 1938 Food, Drug, and Cosmetic (FDC) Act specifically allowed medications marketed before that time to be grandfathered, meaning that a lower standard of evidence would apply to them, a concept that was to have important ramifications for OTC products.

In 1962, the thalidomide tragedy caused Congress to pass the Kefauver-Harris Amendments to the FDC Act, which required that all prescription medications be examined for proof of efficacy. Shortly thereafter, President Kennedy sent the US Senate a request for a review of nonprescription drugs.[1,2] On May 11, 1972, the FDA announced in the Federal Register that it would evaluate the safety and efficacy of all OTC products marketed in the United States up until that date that were not covered by new drug applications (NDAs). The FDA also said it would evaluate all OTC products covered by safety NDAs that were marketed in the United States before Congress adopted the Kefauver-Harris Amendments.[3,4,5,6,7] The agency assumed that the review would take no longer than two to three years.

The FDA wrestled with the overwhelming task of reviewing the 100,000 to 500,000 OTC products estimated to exist at that time. Before then, in prosecuting offending drugs under the 1938 law, the FDA had been forced to work on a case-by-case basis, amassing evidence against each specific product-a process that could take years for a single drug. That approach would be impossible to carry out in the realm of nonprescription products. Regardless of how it proceeded, a wholesale review of OTC products would be the largest single task ever undertaken by the FDA.

The FDA chose a much simpler method of reviewing nonprescription products that would become a model of efficiency for other federal agencies. It became known as the FDA OTC Review Process. The process began with dividing the nonprescription marketplace into categories according to intended therapeutic effect (eg, laxatives, antidiarrheals, and cough medications). Next, the FDA assigned independent panels composed of people knowledgeable in each field to each category of nonprescription products (eg, if the category involved oral care, the panel might include dentists). Each panel had to decide which ingredients were included in its category's products.[8] To have their ingredients included, manufacturers submitted their products to the panels. Once a list of ingredients was complete, the panel examined the existing literature to determine whether those ingredients were safe and effective for that indication. Each panel placed the ingredients into one of three categories. Category I ingredients had evidence of safety and efficacy. Category II ingredients already had evidence of lack of safety or lack of efficacy, or both. Ingredients that lacked clear proof of safety and/or efficacy were placed in Category III. When the panels finished their review, a report explaining the various category assignments appeared in the Federal Register. Based on the panels' evaluations, prudent manufacturers could have reformulated their products at this point to remove all Category II and III ingredients.

Publication of the panel reports in the Federal Register was only the first step in a lengthy process. Manufacturers were given a seemingly inexhaustible amount of time to carry out studies for their unproven ingredients (while still marketing them). For several years, the FDA deliberated over the panel reports and considered new industry studies. Eventually the FDA published a report that gave its evaluation of the ingredients, again placing them into Category I, II, or III. At this point, manufacturers could have reformulated their products to remove all nonprescription ingredients that were not listed in Category I (eg, Category II and III ingredients such as quinine, theophylline, phenylpropanolamine, phenobarbital, ephedrine). They should have reintroduced other ingredients only after the FDA had assigned them safe-and-effective status. Rather than removing non­Category I products from the market, the FDA allowed ingredients lacking proof of safety and efficacy to remain on pharmacy shelves throughout the entire process. Removing such products would have ensured that the public was not exposed to Category II ingredients (already known to be unsafe and/or ineffective), Category III ingredients (lacking data to prove safety and efficacy), grandfathered drugs (for which the manufacturers were to be given the benefit of the doubt), and products for which the manufacturers failed or refused to submit ingredients for governmental review. Had the FDA followed this approach, the public would have been able to select nonprescription products with confidence in their proven safety and efficacy. Rather, decisions to continue marketing these ingredients during the review were left to the manufacturers, which generally chose to keep them on the market.

This situation made the pharmacist's advice compellingly important throughout the time of the FDA OTC Review Process. Informed pharmacists were able to steer patients away from products that did not contain Category I ingredients, explaining their recommendations in terms that patients could understand. Using this decision-making power in the typical community pharmacy became an early opportunity to practice pharmaceutical care throughout the 1970s and 1980s, continuing to the present time.

After lengthy deliberations for each category and the publication of another report (the Final Rule), the FDA finally removed unproven ingredients from the market. Many other ingredients are still undergoing examination and are still being sold, more than three decades since the start of the FDA OTC Review Process, either because the final rule covering them has not appeared or because they escaped scrutiny (eg, phenazopyridine).

The shift of medications from prescription to nonprescription status has also revitalized the OTC marketplace. Status changes are usually initiated through a process involving the NDA, but Claritin is a recent exception. Its switch was initiated by WellPoint, a managed-care company that estimated it could save $45 million a year by cost-shifting to patients who did not have insurance coverage for nonprescription products.[9] They cited a little known regulation dating from the 1950s, referred to as the "switch regulation," that allows any interested party to petition the FDA to change the status of any prescription drug. The regulation had not been employed since 1971, when it was used for dextromethorphan.[8] The company also petitioned for a switch of Zyrtec and Allegra, but the outcomes are not known as of this writing. The drug manufacturers were initially against the switch, as was the Consumer Healthcare Products Association, which emphasized that status changes should be initiated by drug manufacturers.[10] However, Schering later filed a supplemental NDA to switch Claritin, and the status change proceeded through that mechanism.[11] When Claritin arrived in pharmacies, pharmacists who scrutinized its label found that it was contraindicated for self-use without speaking to a physician for patients with liver or kidney disease. This was not highlighted in the launch kit (shelf inserts, balloons, and PA announcements) sent to some locations.

Occasionally, the nonprescription marketplace is the first place a new product is marketed. There is often little warning that a product introduction is imminent. For instance, the poison ivy barrier IvyBlock did not pass through any prescription channels. Similarly, a few months ago a new antismoking lozenge known as Commit debuted. Competition is one reason why the profession is not prepared to counsel on these new products. The company marketing a new product must maintain the utmost secrecy to prevent competitors from discovering marketing plans in advance and developing advertising against them. Unfortunately, this leaves the pharmacist unprepared for the onslaught of new patients hungry for information on the competitive advantages and disadvantages of newly introduced products. This is particularly acute when a first-in-class product such as Rogaine or Nicorette is launched, since all of the circumstances in which a product can be used safely must be committed to memory to facilitate the counseling process.