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Summary of DDMAC Enforcement Correspondence
January 2007
In January 2007, FDA’s Division of Drug Marketing, Advertising and Communications (DDMAC) posted one warning letter and two untitled letters on its website.1 The letters addressed the issues below. This summary describes only DDMAC’s allegations. It does not reflect the recipient’s response or analysis by Covington & Burling. A professional print ad for Dyrenium® (triamterene) Capsules suggested that Dyrenium is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The piece included claims suggesting that Dyrenium, by preserving magnesium levels, prevents enhanced lipid peroxidation and accelerated growth response in vessel walls caused by magnesium deficiency. These processes, however, have no relation to Dyrenium’s indicated use for edema. In addition, FDA is not aware of evidence showing that a magnesium deficiency enhances lipid peroxidation and triggers an accelerated growth response in the vessel wall of humans or that Dyrenium can prevent those effects. The study cited as support for this claim is an in vivo study in rats and does not provide evidence that Dyrenium has a favorable effect on lipid peroxidation or growth within vessel walls in humans or that there is any clinical benefit arising from such an effect. FDA is not aware of substantial evidence or substantial clinical experience to support this claim. The ad therefore misleadingly overstated the efficacy of Dyrenium. (WellSpring Pharmaceutical, 12/19/2006) A journal advertisement for Gliadel® Wafer (polifeprosan 20 with carmustine implant) was misleading because it included efficacy and safety data for patients implanted with Gliadel Wafer during initial craniotomy but failed to present the corresponding approved indication for the product. Specifically, it did not explain that Gliadel Wafer is indicated in newly diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation. (MGI PHARMA, 1/29/2007) A professional print ad for Dyrenium® (triamterene) Capsules was misleading because it claimed that Dyremium “[c]orrects or prevents hypokalemia and maintains serum potassium . . . levels more effectively than does potassium supplementation.” A claim of superior effectiveness requires adequate, well-designed head-to-head clinical trials involving a full or maximum tolerated dose of the comparator drug product. Potassium chloride should be dosed according to the individual needs of the patient. In the study cited as support for the comparative claim in the print ad for Dyrenium, 1 DDMAC did not post any letters during the month of December. The WellSpring Pharmaceutical letter is dated December 19, 2006, but it was not posted until January 9, 2007. www.cov.com
however, patients received the same dose of potassium chloride, regardless of their individual needs. The study therefore does not constitute substantial evidence. (WellSpring Pharmaceutical, 12/19/2006) A journal advertisement for Gliadel® Wafer (polifeprosan 20 with carmustine implant) suggested that the particular advantage of Gliadel Wafer, compared to radiation therapy alone, is the avoidance of treatment delay because Gliadel Wafer can be implanted during craniotomy for tumor resection, whereas radiation therapy cannot begin for several weeks following surgery. The claims in the advertisement further implied that early use of Gliadel Wafer provides a clinical benefit during the 14 days from implantation to initiation of traditional radiation therapy and represents the basis for the product’s effectiveness. While FDA acknowledges that Gliadel Wafer has demonstrated a survival benefit compared to radiation alone, the agency is not aware of any evidence that the efficacy of Gliadel Wafer results from the ability to use the product at the time of surgery. The “delay” in the treatment of glioma between surgery and the beginning of radiotherapy referenced in the advertisement is merely the prescribed healing time following surgery. FDA is unaware of any substantial evidence to support the claims in the advertisement implying that the timing of Gliadel Wafer implantation prior to radiotherapy provides a clinical benefit or that, in the absence of Gliadel Wafer implantation, there is a potential for significant disease progression during the period prior to radiotherapy. The reference cited to support this latter claim is an in vitro labelling study using a new method for calculating “potential doubling time” of glioma cells and does not represent substantial evidence. Moreover, the references cited to support the claim that “GLIADEL WAFER WORKS AT DAY 1” discuss only rat and monkey studies and report not on the time to actual glioma cell death but on the release of carmustine (from Gliadel Wafer), which is taken up by surrounding brain tissues, including residual glioma. FDA is unaware of substantial evidence to support an extrapolation that carmustine uptake results in immediate glioma cell death. (MGI PHARMA, 1/29/2007) A professional print ad for Dyrenium® (triamterene) Capsules was misleading because it presented the boxed warning for Dyrenium but failed to present other risk information for the drug, including its contraindications and warnings. By omitting this risk information, the piece misleadingly suggested that Dyrenium is safer than has been demonstrated. (WellSpring Pharmaceutical, 12/19/2006) A wall calendar and dry erase board for Evoxac® Capsules (cevimeline hydrochloride) failed to effectively communicate risk information associated with use of the product. Although risk information was printed on the back of the wall calendar and dry erase board, this information was not visible or accessible to the viewer for two reasons. First, the backs of the calendar and dry erase board were covered with an adhesive, which was protected by an opaque paper backing designed to prevent sticking. The backing covered all of the risk information. Second, once the paper backing was removed and the calendar and dry erase board were adhered to a wall or similar surface, the risk information was hidden from view. Presenting risk information in this manner was not sufficient to ensure that the claims on the front of the materials were truthful and non-misleading. As a result, the pieces misleadingly suggested that Evoxac was safer than has been demonstrated by substantial evidence or substantial clinical experience. Even if the information on the back of the calendar and dry erase board had been accessible, the misbranding would not have been cured because risk information must be disclosed in the same place that effectiveness claims appear, which in this case was the front of the pieces. (Daiichi Sankyo, 1/12/2007) www.cov.com
This information is not intended as legal advice, which may often turn on specific facts. Readers should seek specific legal advice before acting with regard to the subjects mentioned herein. If you have any questions concerning the material discussed in this client alert, please contact the following members of our food & drug practice group: Covington & Burling LLP is one of the world's preeminent law firms known for handling sensitive and important client matters. This alert is intended to bring breaking developments to our clients and other interested colleagues in areas of interest to them. Please send an email to unsubscribe@cov.com if you do not wish to receive future alerts. 2007 Covington & Burling LLP. All rights reserved. www.cov.com

Source: http://www.cov.com/files/Publication/18c884f4-f942-40d4-a3db-34c6345d7cc6/Presentation/PublicationAttachment/2fa61444-5f40-4f6d-b918-425064aa3741/Summary_of_DDMAC_Enforcement_Correspondence%20_January_2007.pdf