DDMAC Gets Aggressive On Downplaying Risk Info, Sends Three Letters In Three Weeks

Materials aimed at patients and professionals targeted in letters to Iroko, Eisai and Shire.

Allegedly downplaying risk information in promotional materials has gotten three drug companies separate warning letters since the beginning of November 2009 from FDA's Division of Drug Marketing, Advertising and Communications, as the agency continues to bear down on drug makers for this failure.

"If people are not getting the message, they're not paying attention," former FDA Associate Chief Counsel Arnold Friede said. He said FDA has had "a very sustained focus" on this area for as long as three years, and issued a draft guidance on the subject in May (Also see "FDA Relies On Cognition Research To Spot Misleading Ads – Draft Guidance" - Medtech Insight, 1 Jun, 2009.). DDMAC regularly sends out warning letters and notices of violation (untitled letters) citing companies for failures in this area, he added.

The most recent warning letter went to Iroko Pharmaceuticals for a dosing sheet it submitted to FDA for its non-steroidal anti-inflammatory drug Indocin (indomethacin) oral suspension. DDMAC sent the other warning letters to Eisai for "serious" violations regarding a marketing document for Dacogen (decitabine), indicated for patients with myelodysplastic syndromes, and to Shire Development for Fosrenol (lanthanum carbonate hydrate) chewable tablets, indicated to reduce serum phosphate in patients with end-stage renal disease.

Dosing Sheet Don'ts

In the warning letter to Iroko, DDMAC said, "The dosing sheet is false or misleading because it omits important risks associated with Indocin OS and omits other material facts associated with the use of the drug. The dosing sheet therefore misbrands the drug in violation of the Federal Food, Drug and Cosmetic Act."

Although the dosing sheet includes information from the boxed warning on the cardiovascular and gastrointestinal risks posed by Indocin OS, it fails to include any other risk information for the drug, "including information about other serious and potentially fatal risks associated with the drug," the warning letter, sent Nov. 17 and posted to the FDA Web site Nov. 20, added.

According to its FDA-approved product labeling, Indocin OS is indicated in the active stages of moderate-to-severe osteoarthritis, ankylosing spondylitis or rheumatoid arthritis, including acute flares of chronic disease. It is also indicated for acute gouty arthritis or painful shoulder (bursitis and/or tendonitis).

The dosing sheet presents a chart with the five indications for Indocin OS and corresponding dosage information for each indication, but omits important information such as instructions to use the lowest effective dose for the shortest duration for each individual patient and to slowly increase the dose if needed, as well as information on the duration of therapy and the need to carefully monitor patients and reduce the dose or discontinue treatment if adverse reactions occur, the warning letter said.

The instruction to "please see accompanying full prescribing information" at the bottom of the dosing sheet "does not mitigate this misleading omission of risk information," the warning letter added. DDMAC requested that Iroko immediately withdraw the allegedly violative promotional materials for Indocin OS and submit a written response by Dec. 2, 2009 including its plans to prevent future use of these materials.

Friede noted that many drug makers have fallen into the trap of thinking that a reference in promotional materials to full prescribing information contained elsewhere relieves them of responsibility to communicate full risk information. He called this idea an "urban myth."

"Risk information must be integrated with efficacy claims," he added. Other tactics such as "picking out the worst thing that could be" and presenting only that information, or "footnoted disclosures in mouse type," are not acceptable, he said.

Overly Broad Claims In Patient Brochure

Shire's "How I Stay On Track" promotional brochure for patients receiving a prescription for Fosrenol had broader problems than Iroko's dosing sheet, in that it not only omitted risk information, it also made unsubstantiated superiority claims, overstated the efficacy and broadened the indication for the drug, a DDMAC warning letter, sent Nov. 5 and posted to the FDA Web site Nov. 13, said.

The brochure omits risk information about Fosrenol, such as recommendations against use in pediatric patients, pregnant women or patients who have acute peptic ulcer, ulcerative colitis, Crohn's disease or bowel obstruction, the warning letter said.

Moreover, the brochure claims that Fosrenol "works like a sponge to soak up phosphorus," and includes a large picture of a sponge to illustrate this, thereby implying that "Fosrenol is more effective than other phosphate binders because it works earlier in the digestive system (i.e., the stomach) than these other binders and therefore binds more phosphorus," a claim not backed up by evidence, the warning letter said.

Further unsubstantiated claims in the brochure are that Fosrenol helps prevent mineral deposition, bone disease, heart disease or death, and an implication that it is that generally appropriate for any patient with hyperphosphatemia when only patients with end-stage renal disease are supposed to get it.

The warning letter adds that DDMAC had previously objected, in an untitled letter dated May 1, 2008, to the dissemination of a notebook and a medical exam light case for Fosrenol that failed to include any risk information as well as the drug's indication and other important information (Also see "FDA Warns Novartis, Shire On Misbranding" - Pink Sheet, 9 May, 2008.).

"We are concerned that you are continuing to promote Fosrenol in a similarly violative manner," the new letter said, and asked Shire to withdraw the brochure from circulation and detail steps it is taking to ensure that such violative promotional materials do not appear again.

"Shire is committed to ensuring that all of our medicines are promoted in compliance with all applicable laws and regulations," the company said. "We are reviewing the letter from FDA and plan to respond by the requested time with our plan of action."

On Nov. 6, Eisai was cited for its document promoting Dacogen, which minimizes risk and "greatly overstates the efficacy," the warning letter said (Also see "Eisai Draws U.S. FDA Warning Letter For Misleading Efficacy and Safety Claims" - Scrip, 18 Nov, 2009.).

Eisai told PharmAsia News the company is fully cooperating with FDA's requests, which include halting distribution of any related promotional material and submitting a written plan to FDA by Nov. 20 on how the company will provide corrections of the misinformation to physicians.

Friede pointed to the stern warning letter sent to Allergan regarding promotional material for the acne medicine Aczone Gel (dapsone) as yet another recent example of this type of DDMAC action (Also see "Inflamed Language: FDA Sends Harsh Warning Letter To Allergan For Acne Drug" - Pink Sheet, 25 Aug, 2009.).

-Martin Berman-Gorvine ([email protected])