FDA Warning Letter, Shire Development, Inc. (LIALDA® (mesalamine) Delayed Release Tablets)

Harris Rotman
Director, Global Regulatory Affairs
Shire Development, Inc.
725 Chesterbrook Boulevard
Wayne, PA 19087-5637

RE: NDA 022000
LIALDA^® (mesalamine) Delayed Release Tablets
MACMIS #18526

Dear Mr. Rotman:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has reviewed a professional Perspectives Version A 3^rd Wave (LIA-01038) brochure (brochure) for LIALDA^® (mesalamine) Delayed Release Tablets (Lialda) submitted by Shire Development, Inc. (Shire) under cover of Form FDA-2253. The brochure is false or misleading because it overstates the efficacy of Lialda, contains unsubstantiated superiority claims, omits risk information associated with the drug, broadens the indication of the drug, and contains unsubstantiated claims. Thus, the brochure misbrands Lialda in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(5)(i), (iii); (e)(6)(i), (ii) & (e)(7)(i).

Background

According to the INDICATIONS AND USAGE section of Lialda’s FDA-approved product labeling (PI)¹ (emphasis in original):

LIALDA tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. Safety and effectiveness of LIALDA beyond 8 weeks has not been established.

The PRECAUTIONS section of the PI states (in pertinent part; emphasis in original):

General: Patients with pyloric stenosis may have prolonged gastric retention of LIALDA, which could delay mesalamine release in the colon.
. . .

Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. . . . Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache and rash. If acute intolerance syndrome is suspected, prompt withdrawal is required.

Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with LIALDA and other mesalamine medications. Caution should be taken in prescribing this medication to patients with conditions predisposing to the development of myocarditis or pericarditis.

Renal: 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. For any patient with known renal dysfunction, caution should been exercised and LIALDA should be used only if the benefits outweigh the risks. It is recommended that all patients have an evaluation of renal function prior to initiation of therapy and periodically while on treatment. . . .

Overstatement of Efficacy

Promotional materials are misleading if they represent or suggest that a drug is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The brochure presents numerous claims and presentations that misleadingly overstate the efficacy of Lialda. For example, the brochure includes claims such as the following (bolded and italicized emphasis in original; underlined emphasis added):

	“Induce Complete Remission by resolving symptoms and healing the mucosa” (page 3)
	“For Complete Remission, lead with Lialda” (back cover)
	“Induce Complete Remission in patients with active, mild to moderate UC [ulcerative colitis]” (back cover)
	“Induce Complete Remission in patients with active UC (newly diagnosed and those with a history of UC)”^2,3 (reference omitted) (back cover)
	“**The path to complete remission**” (pages 4, 5, and back cover)

Page 2 of the brochure also includes the following claims and presentations (bolded emphasis in original; underlined emphasis added):

	“Help put your patients with active, mild to moderate UC on the path to Complete Remission with Lialda^® (mesalamine)”
	“Symptom Resolution” (reference omitted)

○ This claim is presented in conjunction with a graphic that includes the following claims:

● “No rectal bleeding
     No excessive stool frequency
     PGA* score ≤ 1
     *Physician’s Global Assessment.
     AND
     No mucosal friability
     Improved mucosal appearance
     = Complete Remission”

These and similar claims in the brochure misleadingly imply 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, published in the Kamm, et al. and Lichtenstein, et al. references cited in the brochure to support the above presentations, 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. Rather, according to the CLINICAL TRIALS section of the Lialda PI, “The primary efficacy end-point in both trials was to compare the percentage of patients in remission after 8 weeks of treatment for the LIALDA treatment groups vs placebo” (bolded emphasis in original; underlined emphasis added). Remission was defined as an improvement in the Ulcerative Colitis Disease Activity Index (UC-DAI) with specific scores required for some of the four subscore components (rectal bleeding, stool frequency, mucosal appearance on sigmoidoscopy, and physician global assessment). The clinical studies do not support attainment of complete remission/absence of disease; while patients who met the definition of remission in the clinical studies had scores of zero on two of the subscore components (stool frequency and rectal bleeding), the UC-DAI scoring system does not include all ulcerative colitis-related symptoms (e.g., abdominal pain), and these studies did not assess whether patients were completely free of symptoms of ulcerative colitis. Therefore, these claims misleadingly imply that Lialda is more efficacious than has been demonstrated.

In addition, the brochure includes claims such as the following (bolded emphasis in original; underlined emphasis added):

	“Mucosal Healing^┼with Improvement” (reference omitted) “^┼Mucosal healing was defined as endoscopic remission, which was a sigmoidoscopy score of ≤1 at week 8 as measured in a post hoc analysis.” (page 2)
	“Induce Complete Remission by resolving symptoms and healing the mucosa” (page 3)
	“Efficacy Resolve disruptive symptoms and achieve mucosal healing” (reference and footnotes omitted) (back cover)

These claims misleadingly imply that treatment with Lialda results in mucosal healing, when such has not been demonstrated by substantial evidence or substantial clinical experience. The brochure references a post hoc analysis of study data published by Kamm, et al. to support these claims. However, the term “mucosal healing” was not a pre-specified primary or secondary efficacy endpoint in the clinical study included in Kamm, et al. In addition, the definition of mucosal healing included in the above claims, “endoscopic remission, which was a sigmoidoscopy score of ≤1 at week 8,” was not defined in the study protocols submitted to the FDA and is not discussed in the PI or in Kamm, et al. In the absence of substantial evidence or substantial clinical experience to support the claims of mucosal healing, these presentations overstate the efficacy of Lialda.

Unsubstantiated Superiority Claims

Promotional materials are misleading if they contain a drug comparison that represents or suggests that a drug is safer or more effective than another drug, when this has not been demonstrated by substantial evidence or substantial clinical experience.

Page three of the brochure presents a bar graph titled, “Patients who achieved Complete Remission at week 8” (emphasis in original; reference and footnotes omitted). This graph compares Lialda 4.8 g/d QD, Lialda 2.4 g/d QD, Asacol 2.4 g/d TID, and placebo. The bar graph shows both Lialda doses as numerically superior to Asacol and placebo for the percentage of patients who achieve “Complete Remission at week 8”. The totality of this presentation misleadingly implies that Lialda is more effective than Asacol. FDA is not aware of any adequate and well-controlled, head-to-head clinical trials comparing these two products. The Kamm, et al. reference cited to support these claims did not include a pre-specified efficacy analysis for this drug comparison. The exploratory analysis included in the brochure was retrospective and post-hoc to the study’s original design, and did not show a statistically significant difference between the treatment effect of Lialda and Asacol. We note the brochure includes the statements, “Asacol 2.4 g/d was included in this study as a reference arm only” (emphasis in original) and “The study was not designed as a comparative head-to-head trial of Lialda versus Asacol” (reference omitted); however, these statements do not mitigate the misleading overall implication that Lialda is better than Asacol.

In addition, page five of the brochure presents a graphic representation of Lialda’s Multi Matrix System Technology (MMX) in conjunction with the following claims (bolded emphasis in original; underlined emphasis added; references omitted):

• “Lialda is the only mesalamine with MMX^® Technology
    . . .
    Hydrophilic component forms a viscous gel
    Designed to interact with intestinal fluids, causing the tablet to swell and
    form an outer viscous gel

    Lipophilic component slows dissolution
    Designed to prolong dissolution of mesalamine throughout the colon by
    slowing the penetration of fluids into the tablet core”

The totality of these claims and presentations suggests that, as a result of its delivery system, Lialda offers a therapeutic advantage over other available treatment options. However, this has not been demonstrated by substantial evidence or substantial clinical experience. Lialda is not the only mesalamine drug formulation designed to delay the release of mesalamine. The cited reference, Lichtenstein, et al., 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. Therefore, these claims and presentations are misleading.

Omission of Risk Information

Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials.

The brochure fails to include important risk information about the Precautions associated with Lialda. Specifically, although the brochure does present some information about material Precautions on page four, it fails to reveal that patients with pyloric stenosis may have prolonged gastric retention of Lialda, which could delay mesalamine release in the colon. The piece also 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. Because the brochure omits this important risk information, it misleadingly suggests that Lialda is safer than has been demonstrated by substantial evidence or substantial clinical experience.

Broadening of Indication

Promotional materials are misleading if they suggest that a drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. Page one of the brochure includes the following claim:

• “Nearly 700,000 patients are living with ulcerative colitis (UC)”⁴

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. However, Lialda is only indicated for “. . . the induction of remission in patients with active, mild to moderate ulcerative colitis. . .” (emphasis added). We acknowledge that the indication for Lialda is presented on page four of the brochure; however, this does not mitigate the misleading implication that Lialda is approved to treat a broader patient population than active, mild to moderate UC.

Unsubstantiated Claims

Page five of the brochure includes the following claim (bolded emphasis in original; underlined emphasis added):

• “Biopsies from the sigmoid and rectum suggest Lialda with MMX Technology delivered mesalamine throughout the colon”⁵

This claim is presented in conjunction with graphic images of the colon, showing the time-lapse delivery of Lialda throughout the colon. The totality of these claims and presentations misleadingly suggests that the delayed release technology has been shown to have a clinically relevant effect on the extent or exposure of the drug on the colon based on biopsy data. However, the biopsy data from the D’Haens, et al. reference cited to support this presentation does not confirm or deny the extent of the delivery of Lialda in the colon or the exposure of the entire colon to the drug product during the same period of time. Therefore, the claim that biopsy data supports the delivery of mesalamine throughout the colon is not supported by substantial evidence.

Conclusion and Requested Action

For the reasons discussed above, the brochure misbrands Lialda in violation of the Act, 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(5)(i), (iii); (e)(6)(i), (ii) & (e)(7)(i).

DDMAC requests that Shire immediately cease the dissemination of violative promotional materials for Lialda such as those described above. Please submit a written response to this letter on or before May 11, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Lialda that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to Macmis #18526 in addition to the NDA number. We remind you that only written communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Lialda comply with each applicable requirement of the Act and FDA implementing regulations.

Sincerely,

Kathleen Klemm, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications

___________________________________________________________

¹ The PI submitted with the promotional piece on Form FDA-2253 was dated June 2009. Although not relevant to the issues raised in this letter, we note that Lialda’s PI was updated on October 30, 2009.

² Kamm MA, Sandborn WJ, et al. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology. 2007;132:66-75.

³ Lichtenstein GR, Kamm MA, Boddu P, et al. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol. 2007;5:95-102.

⁴ Commercial and pipeline insight: Inflammatory bowel disease. Datamonitor. November 2006.

⁵ D’Haens G, Hommes D, Engels L, et al. Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study. Aliment Pharmacol Ther. 2006;24:1087-1097.