To establish a drug product’s effectiveness by “substantial evidence,” the Food and Drug Administration (FDA) has generally indicated that such evidence should consist of two adequate and well controlled clinical investigations.1 Recently, three Notice of Violation (NOV) letters issued by the Division of Drug Marketing, Advertising, and Communications (DDMAC) suggest that the pharmaceutical industry may experience greater difficulty when using results from open-label studies to make claims regarding clinical efficacy in promotional materials. Open-label studies refer to clinical trials where both the investigators and the study participants know the treatment the participant is receiving and are distinguished from blinded studies with a control. Although the agency has not prohibited the use of open-label studies as potential support, these letters collectively reflect DDMAC’s increased scrutiny of study design when determining whether substantial evidence has been provided to support marketing claims regarding the benefit or efficacy of a drug product.

DDMAC’s most recent NOV to a drug company, dated June 17, 2011, addressed the use of an open-label study to support product claims in a flashcard promotion.2 The agency stated that “results from a single open-label study with no control group do not constitute substantial evidence or substantial clinical experience to support these, or any other, efficacy claims.” In addition, DDMAC stated that the efficacy results from the uncontrolled, openlabel trial were inconsistent with the results from the well controlled, doubleblinded, placebo-controlled trials listed in the product’s package insert and, as a result, significantly overstated the product’s effectiveness.  

Approximately six weeks earlier, DDMAC cited another drug company for making misleading comparative claims in certain sales aids and brochures. The agency noted that the company’s only support for claims regarding the superiority of its drug product over similar formulations (but in a different route of administration) was as an open-label trial involving 20 healthy volunteers. DDMAC further indicated that such claims would typically need to be supported by “two adequate and well controlled head-to-head clinical trials comparing appropriate doses and dose regimens of a drug and a comparator drug.”

The two aforementioned letters followed another NOV, dated February 17, 2011, where DDMAC challenged a drug company for making misleading claims of efficacy for its anemia drug. The pharmaceutical company had distributed a direct mailer to physicians, citing results from three randomized, open-label, controlled clinical trials. Specifically, DDMAC cited the company for making claims regarding the product’s efficacy in a subgroup of patients on concurrent erythropoiesis-stimulating agent (ESA) therapy. Noting that the study design failed to stratify the study population into subgroups based on ESA use, the agency concluded that any subgroup analysis based on the current study design would be considered only “exploratory” in nature and not sufficient to constitute substantial evidence to demonstrate any clinical benefit or efficacy.  

Drug companies must remember that DDMAC continues to focus on marketing claims that promote clinical efficacy or make comparative statements and reviews whether such claims are supported by substantial evidence or substantial clinical experience. Companies should be careful when using or relying on open-label studies in promotional materials.