Assume for a moment that you're a manufacturer of a pharmaceutical product, one with recognized benefits but enough potential risks to warrant a Boxed Warning on your product's label. Now here's a question for you: Is your product more likely or less likely to eventually receive a Warning Letter from the US Food and Drug Administration (FDA) if you commit an advertising violation relative to a regularly-labeled product?

If you answered in the affirmative-that is, more likely-you're probably right, says Mark Senak of the public affairs firm Fleishman-Hillard and the author of the popular industry blog Eye on FDA.

In an analysis posted 13 November 2013, Senak took a pool of 282 Warning and Untitled Letters ranging from 2004 through November 2013 that originated from FDA's Office of Prescription Drug Promotion (OPDP) and its differently-named predecessors (i.e. DDMAC).

Senak then divided them into two product categories: Those with and those without a Boxed Warning.

Black Boxes and Letters

Before we get into what Senak found, a brief discussion of Black Box warnings and Untitled and Warning Letters.

A Boxed Warning-also known as a Black Box Warning-is used when a drug has a particularly dangerous risk, such as the risk of death, that regulators want a prescriber and/or end user to be aware of before use. In other cases, the warning is used if there is a serious risk that can be prevented or reduced through appropriate use.

The warnings are so named because they are contained within a prominent black box on the drug's label.

Warning Letters and Untitled Letters, meanwhile, represent different types of warnings from FDA. An Untitled Letter is generally for less-serious offenses, and expresses FDA's opinion that the presentation of certain information is potentially misleading or untruthful. Notably, the letter does not threaten further action, though it leaves open the implication that FDA could, if it really wanted to, issue a Warning Letter later on.

Warning Letters, by contrast, are sent when FDA feels there have been serious violations of federal law or regulations. If satisfactory actions are not taken to remedy a problem identified in the letter, FDA can take legal action against a company.

Comparison Between Warning and Untitled Letters

Of the 282 letters analyzed by Senak, 40 were for products with Boxed Warnings and the remaining 142 were for products with regular labels.

But when the data were broken down further, Senak said he saw a clear trend. "Of the 40 Boxed Warning Letters, 45% of them were Warning Letters while of the 242 regular labels, only 32% were Warning Letters."

In other words, the more serious the inherent concerns are about your product, the more likely it is for FDA to issue you a Warning Letter compared to a product without a boxed warning.

"It stands to reason that when you are dealing with a product with a Boxed Warning in its label, extra care needs to be taken with regard to communications because if there is a violation, it would appear that there is a greater tendency for it to be in the form of a more serious Warning Letter than Untitled Letter," Senak concluded.

Eye on FDA Analysis