Superiority Claims Based On Drug Delivery System Fail DDMAC Test

Shire overreached in claiming that the formulations for its ulcerative colitis drugs Lialda and Pentasa gave them an advantage, FDA says.

FDA objection to Shire's attempt to position its ulcerative colitis drugs Lialda and Pentasa as enjoying a benefit due to their delivery systems could signal a growing agency focus on formulation claims.

FDA's Division of Drug Marketing, Advertising and Communications sent two "untitled letters" citing promotional materials Shire distributed to health care professionals for the two drugs, both of which have mesalamine as their active ingredient - a brochure in the case of Lialda and a "professional core leave behind" in the case of Pentasa.

DDMAC h lately has been focusing on unsupportable commercial claims that a drug's delivery system gives it an advantage. One example was an April 20 untitled letter to Sanofi-Aventis for Eligard (leuprolide acetate), a hormonal treatment for advanced prostate cancer that the company claimed required fewer injections than other drugs, thereby improving patients' quality of life (Also see "Convenience Claims Can Put Companies On Slippery Promotional Ground" - Pink Sheet, 27 Apr, 2010.).

DDMAC spotted the Pentasa promotional piece at the American College of Gastroenterology annual meeting in October 2009, but "it had been distributed to physician's offices that specialize in the treatment of GI disorders in addition to GI conferences and meetings," Shire spokesman Matt Cabrey said in an e-mail. The Lialda brochures had been distributed to GI specialists' offices since the drug was approved in 2007, he said.

The two drugs have slightly different indications, with Lialda approved for the induction of remission in patients with active mild-to-moderate ulcerative colitis and Pentasa approved for the treatment of the same condition as well as the induction of remission.

Shire had touted their different delivery systems, claiming that Lialda has a "hydrophilic component [that] forms a viscous gel designed to interact with intestinal fluids, causing the tablet to swell and form an outer viscous gel. [The] lipophilic component slows dissolution, [which is] designed to prolong dissolution of mesalamine throughout the colon by slowing the penetration of fluids into the tablet core."

Similarly, Shire claimed an advantage for Pentasa in that it "reliably delivers a continuous release of 4 grams of mesalamine throughout the small and large intestine," and that, "moisture-activated Pentasa delivers independent of pH, allowing mesalamine to begin releasing in the duodenum."

Neither of these claims stands up to scrutiny based on the clinical evidence, DDMAC said. "Lialda is not the only mesalamine drug formulation designed to delay the release of mesalamine. The cited reference ... was not designed to evaluate all of the claimed mechanistic descriptions, and does not provide substantial evidence to support the implication that Lialda's delivery system offers a therapeutic advantage to that of other mesalamine formulations."

For Pentasa, "we are not aware of substantial evidence or substantial clinical experience to support the implication that Pentasa's delivery system offers a clinical advantage over other products. Furthermore, we note that some of the claimed advantages, such as drug release in the small intestine, are irrelevant for Pentasa's indicated condition (ulcerative colitis), as the large intestine is the site of disease, and that Pentasa is not the only product that has some of the claimed attributes, such as release in the small intestine."

The Lialda brochure also was cited for a bar graph that showed two different Lialda doses to be numerically superior to Warner Chilcott's Asacol , another mesalamine drug, regarding the percentage of patients who achieve complete remission after eight weeks. This was unacceptable because there never has been a head-to-head trial of the two drugs, DDMAC said.

The citations hint at the difficulty Shire is having distinguishing Lialda and Pentasa from competing formulations of mesalamine and other 5-aminosalicylic acid drugs to treat colitis. For example, the company claimed for Pentasa that "not all 5-ASAs are designed to deliver the same," one of the group of delivery claims that DDMAC disapproved.

Overstated Efficacy And Superiority Claims

Another point in common between the Lialda and Pentasa letters is DDMAC's disapproval of efficacy claims that went too far. In the Lialda brochure, a key problem was that Shire "misleadingly impl[ied] that treatment with Lialda results in 'complete remission,' and thus absence of the disease, when such has not been demonstrated by substantial evidence or substantial clinical experience. The clinical trials used to support Lialda's approval ... do not provide support for claims of complete remission or total absence of the disease. Complete remission was not a primary endpoint in these clinical trials."

Similarly, Shire claimed that Lialda promotes mucosal healing, but this term was not a pre-specified primary or secondary efficacy endpoint in the clinical trial cited, and the company had to rely on a post-hoc analysis to make this case in the brochure.

"FDA hates 'retrospective' analysis of data primarily because, in the agency's view, it provides opportunities to 'slice the salami' in ways that the study was never intended to evaluate in the first instance," Arnie Friede, a former FDA and Pfizer attorney now with Arnold I. Friede & Associates, commented.

Another problematic efficacy claim for Pentasa had to do with the quality of patient's lives. The company cited a patient-reported outcome measure based on a survey that found patients had improved quality of life in sexual relationships, work, social activities, hobbies, indoor and outdoor activities, and sleep. However, the study cited "does not constitute substantial evidence to support such claims," DDMAC said.

"The instruments used to measure 'quality of life' in the study included patient responses to questions relating to seven general parameters ... a single-item question is not able to provide a complete understanding of a treatment's effect on the general concepts claimed in the piece ... because it cannot capture all of the domains of the general concept."

"Quality of life claims are among the most difficult to substantiate to FDA's satisfaction," Friede said.

Description Of Patient Population Is Concern

While many of the citations for both Lialda and Pentasa fit in with general themes FDA has been pursuing, the agency also cited the Lialda brochure simple for stating the size of the patient population. "This claim is misleading in the context of the overall piece because it implies that Lialda is appropriate therapy for all 700,000 patients who may have varying degrees of severity of ulcerative colitis," DDMAC said.

In another ominous sign for what may be a widespread promotional practice, DDMAC criticized Shire for making such statements as, "Pentasa is delivered to and throughout the small and large intestine," which could be taken as a "suggestion that Pentasa has a therapeutic effect in the small intestine," which would be misleading because the drug is not approved to treat disorders of the small intestine such as Crohn's disease.

Finally, while the Pentasa promotion had no safety-related issues, the Lialda brochure left out some important risk information, such as the fact that "patients with pyloric stenosis may have prolonged gastric retention of Lialda, which could delay mesalamine release in the colon [and] fails to reveal that symptoms of acute intolerance syndrome include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache and rash.

"Furthermore, the brochure fails to convey that caution should be taken in prescribing this medication to patients with conditions that predispose them to the development of myocarditis or pericarditis. Moreover, the brochure omits that reports of renal impairment, including minimal change nephropathy and acute or chronic interstitial nephritis, have been associated with mesalamine medications and pro-drugs of mesalamine, and that it is recommended that all patients have an evaluation of renal function prior to initiation of therapy and periodically while on treatment."

If the citations and attendant promotional shifts result in a decline in scripts, that could have a significant impact for Shire, since Lialda and Pentasa make up a large proportion of the company's sales. In the first quarter of 2010, sales of Lialda were $63.6 million, while Pentasa sales were $58.2 million, out of total revenues of $816 million.

In order to comply with DDMAC's requests, "our sales representatives are now using the PI on the medicines label when communicating information with physicians about Shire's GI medicines," Cabrey said.

-Martin Berman-Gorvine ([email protected])