When you look up a prescription drug like atorvastatin — a cholesterol-lowering medication sold under the brand name Lipitor — in the FDA’s Orange Book, you’ll find a neat grid showing which companies make it, the forms it comes in, and a column called “TE,” short for therapeutic equivalence. That code signals whether a generic is deemed to be interchangeable with the brand-name.
But search for over-the-counter “acetaminophen,” better known as Tylenol, and that column is mysteriously empty. Why?
Drugs have existed long before the Food and Drug Administration (FDA) began evaluating their safety and efficacy. So when Congress tasked the agency with assessing drugs, it had a lot of catching up to do. To make the workload more manageable, explains Randy Hatton, PharmD, a clinical professor of pharmaceutical outcomes and policy at the University of Florida, the FDA focused its efforts on prescription drugs and allowed over-the-counter (OTC) drugs already on the market to continue being sold with limited oversight.
That means we have little data on how well brand-name OTC drugs work, and even less information on how generic OTC drugs compare to their brand-name counterparts.
How Branded and Generic Prescription Drugs Are FDA Approved
In October 1962, Congress passed the Kefauver-Harris Drug Amendments, requiring drug companies to provide substantial evidence to the FDA that a drug was effective before it could be marketed. This evidence comes from clinical trials that demonstrate not only the effectiveness and safety of a drug for humans, but also the rate at which its active ingredients are released into and absorbed by the body, otherwise known as bioavailability
Once a branded prescription drug has been on the market for several years, other drug manufacturers can apply to sell less expensive generic forms of the same drug. Rather than repeating the large, costly clinical trials conducted by the original manufacturer, these companies need only submit bioavailability data to the FDA.
If the generic drug’s bioavailability is close enough to that of the branded drug, the FDA will approve it.
The Beginning of Drug Regulation
When the 1962 amendments were enacted, Dr. Hatton explains, countless drugs were already being sold, forcing the FDA to prioritize which products to evaluate first. Because thousands of OTC medicines were on the market — many of which were made from the same few hundred ingredients — the agency created a separate system that reviewed the active ingredients rather than every individual finished product. As long as an OTC drug uses an active ingredient in a dose and form recognized by the FDA as safe, it can be sold without any further evaluation.
As a result, Dr. Hatton notes, the FDA now lacks bioavailability and bioequivalence data for many of these products.
For instance, because the FDA recognizes acetaminophen as safe, no products on the market that contain it, including the brand name Tylenol, are required to submit data on the bioavailability of different pill, capsule or liquid formulations.
Are OTC Drugs Effective?
Just because an OTC drug is on a pharmacy shelf doesn’t mean it’s effective, especially if it entered the marketplace before modern FDA drug regulations took shape. Phenylephrine, a decongestant found in medications like Sudafed PE, DayQuil, and Mucinex, is still widely sold even though an FDA advisory committee unanimously concluded in fall 2023 that it doesn’t actually relieve congestion.
“We’re at a point now where we need to go back and look at all those old drugs and determine if they should even be in the market,” notes Dr. Hatton.
While the Orange Book may lack information on the effectiveness and safety of your OTC medications, you can check the FDA’s enforcement reports database for ongoing recalls. Drug manufacturers often recall their medications if they discover problems during testing, or if the FDA identifies issues during a facility inspection.
To check these enforcement reports, type the name of your generic drug, then choose “drugs” as the product category. Under the status dropdown, select “ongoing.” If the medication you have appears to be one on the list, consider purchasing a different brand or asking your pharmacist for advice.
