Released by FDA: 4/28/00.  Posted by FDA:  5/11/00

Michele M. Hardy 
Director, Advertising Policy 
Glaxo Wellcome Inc. 
Five Moore Drive 
Research Triangle Park, North Carolina 27709

RE:   LOTRONEX (alosetron hydrochloride) Tablets 
        NDA 21-107 
        MACMIS ID # 8772

Dear Ms. Hardy:

This letter concerns the dissemination of violative promotional materials by Glaxo Wellcome, Inc. (Glaxo) for Lotronex (alosetron hydrochloride) Tablets.  The materials consist of a Formulary Kit [Lot 186R0], which includes a Sales Brochure, a Slide Kit, and a Sell Sheet.  The Division of Drug Marketing, Advertising and Communication (DDMAC), has determined that the materials violate the Federal Food, Drug, and Cosmetic Act because they contain unsubstantiated Health- Related Quality of Life (HQRL), productivity and economic claims.  The violations we have identified and described below are not exhaustive, and our objections extend to all other Lotronex materials containing similar claims.

1. Unsubstantiated Health-Related Quality of Life (HRQL) Claims

The Lotronex Formulary Kit states that the condition of Irritable Bowel Syndrome (IBS) negatively affects the HRQL for IBS patients and suggests that treatment with Lotronex has a positive effect on the HQRL of IBS patients.  These representations are misleading because they are not based on substantial evidence, and overstate the effect of Lotronex on the HRQL of IBS patients.  Examples of misleading HRQL claims from the Lotronex Formulary Kit follow.

The representation that IBS “affects quality of life as much or more than diabetes and clinical depression”¹ and the implication that Lotronex would improve the quality of life of IBS patients, is unsubstantiated.  The Wells² article, referenced to support this representation, fails to evaluate the effects of Lotronex on HRQL.

The representation that IBS “impacts sleep, diet, work, leisure, travel, and sexual functioning,”³ and the implication that Lotronex treatment can improve these outcomes in IBS patients is misleading because it is unsupported by the reference cited.  This representation is based on an article describing a study by Whitehead et. al (1996),⁴ and on the results of the Landmark Survey⁵ sponsored by Glaxo.  The Whitehead study and the Landmark Survey, however, both fail to evaluate the effect of Lotronex in IBS patients.

2. Unsubstantiated Economic Impact Claims

The Lotronex Formulary Kit implies that Lotronex reduces or eliminates the economic burden of disease [IBS] by presenting information about the economic burden of IBS and presenting information about the efficacy and safety of Lotronex.  For example, the Sales Brochure (page 7) contains a section on the “Economic Impact” [of IBS]:

The economic costs of IBS are substantial. Talley and associates reported that, in 1992, patients with IBS in Olmstead County; Minnesota, incurred median direct medical charges (excluding outpatient medications) of $742, which was $313 more than control subjects.  Extrapolation of these data to the entire Caucasian population of the United States would result in an estimated $8 billion annually in direct medical costs (excluding outpatient medications).

It should be noted, however, that as staggering as this estimate is, it did not take into account a number of other direct costs associated with IBS, including drug - costs associated with IBS, including prescription drug expenditures, or indirect costs such as lost wages. Accordingly, it is likely an underestimate of the true economic cost of IBS in US patients.

The presentation of the economic burden of IBS, together with efficacy claims for Lotronex, suggests that Lotronex has a positive impact on reducing the economic burden of IBS.  This presentation, however, lacks adequate evidence and is misleading because the Talley study⁶, referenced by Glaxo in support, does not evaluate the impact of Lotronex on the economic burden of IBS.

3. Unsubstantiated Productivity Claims

The Lotronex Formulary Kit presents information on the impact of IBS on work absenteeism and implies that Lotronex has a positive impact on increasing the productivity of IBS patients and reducing the costs of absenteeism.  For example, page 6 of the Sales Brochure contains the following information:

In a survey-based study comprising responses from a random sample of over 5000 U. S. households, Drossman and coworkers documented that people with symptoms consistent with a diagnosis of IBS missed an average of 13.4 work days a year because of IBS symptoms.  This was in comparison with fewer than 5 absentee days for workers without symptoms of IBS.  A higher proportion of those with IBS symptoms also reported currently being too sick to go to work or school (11.3% vs. 4.2% of patients without symptoms).

In another postal survey of patients in the U.S., nearly one-third of patients reported missing at least 1 day of work in the previous 4 weeks because of IBS.  On average, patients lost nearly 2 days of work and cut back on their workdays 3 days a month because of their IBS. (Hahn et a!.)

A 1999 U.S. national survey of 1014 women with IBS found that on average, women with IBS reported being almost 2 times more likely than women without IBS to have missed workdays or schooldays in the past year as a result of illness.

This information is supported by two studies.^{7, 8} However, neither of these studies evaluated the impact of Lotronex on productivity.

5.  Overstated Efficacy Claims

Glaxo, in the Product Facts Section of the Formulary Guide, under the header “Multisymptom Relief,” claims that “[Lotronex] relieves symptoms identified by... women with IBS as most bothersome.. .abdominal pain, urgency, frequency, bloating, and mucus.”   This claim overstates the efficacy of Lotronex, since Lotronex has not been proven to affect the symptoms of bloating or mucus in IBS patients.

6.  Lack of Drug Interactions with Haloperidol

Glaxo’s claim that Lotronex does not interact with haloperidol [in IBS patients] is misleading, because it is not based on substantial evidence.  For example, the Formulary Slide Kit (Slide No. 33), claims that “Lotronex also had no effect on the metabolism of haloperidol, “and references a study by Gupta et. al. (1995).⁹  The Gupta study, however, is inadequate to support the haloperidol claim because it was not designed to measure the effect of Lotronex on haloperidol in IBS patients at the Lotronex dose approved for use in IBS patients.  The Gupta study measured the pharmacokinetics of haloperidol in 13 schizophrenic patients (not IBS patients) over a period of 56 days (not 12 weeks), at one-half the approved dose of Lotronex (1mg/daily rather than 1 mg/twice daily) as indicated for the treatment of IBS.

7.  Misrepresentation of CNS Adverse affects

The Lotronex Formulary Kit contains an Executive Summary Sheet that states that “LOTRONEX [patients] reported no significant difference versus placebo in CNS adverse events (dizziness, sleep or depressive disorders, visual disturbances) versus patients in the placebo group.”  This claim is misleading because it fails to disclose that the actual CNS adverse event rates experienced by Lotronex patients were higher than placebo.  For example, sleep disorders occurred in 3% of the Lotronex patients vs. 2% placebo; depression occurred in 2% of Lotronex patients vs. I % placebo.  Failure to provide this additional information relative to the adverse event profile claim suggests that the Lotronex is safer than has actually been demonstrated.

8.  Lack of Fair Balance

The presentation of the risk information within the Safety Section of the Sales Brochure in the Lotronex Formulary Kid. lacks fair balance.  This section uses highlighted large-font graphics to emphasize the low CNS adverse event frequencies of Lotronex and the favorable long-term safety information for Lotronex, but “buries” important risk information within long bodies of text. Important warnings, such as ‘totronex should be discontinued in patients experiencing rectal bleeding and a sudden worsening of abdominal pain,” and  “Lotronex should not be used in patients who are currently constipated or whose predominant bowel symptom is constipation,” are minimized and hidden within the text of the Safety Section.

Glaxo should immediately cease distribution of these and other similar promotional materials, for Lotronex that contain the same or similar claims or presentations.  Glaxo should submit a written response to DDMAC on or before May 15, 1999, describing its intent and plans to comply with the above.  In its letter to DDMAC, Glaxo should include a list of materials discontinued and the date on which these materials were discontinued.

If you have any questions or comments, please contact the undersigned by facsimile at (301) 594-6759, or at the Food and Drug Administration, Division of Drug Marketing, Advertising and Communications, HFD-42, Rm. 17-B-20, 5600 Fishers Lane, Rockville, MD 20857.  DDMAC reminds you that only written communications are considered official.  In all future correspondence regarding this particular matter, please refer to MACMIS ID # 8772.

Sincerely,

Patricia Kuker Staub, R.Ph., JD 
Regulatory Reviewer 
Division of Drug Marketing, 
   Advertising and Communications

______________________________________________________

¹  This claim is found on the “IBS Facts” Page of the Formulary Kit, and on page 6 of the Sales Brochure in the Formulary Kit.

2  Wells NEJ, Hahn BA, Whorwell PJ.  Clinical economics review: irritable bowel syndrome. Ailment Pharmacol Ther, 1997; 1:1019-1030. 

³  This claim appears both on the inside flap of the Lotronex Formulary Kit, and on page 5 of the Sales Brochure portion of the Formulary Kit. 

⁴  Whitehead WE, Burnett VK, Cook EW, Taub E. Impact of irritable bowel syndrome on quality of life. Dig Dis Sd, 1996; 41:2248-2253. 

⁵  Data on file (Irritable bowel syndrome in American women, a landmark survey, July 1999), Glaxo Wellcome Inc.

⁶  TaIley, NJ, Gabriel SE, Harmsen WS, Zinsmeister AR, Evans RW. Medical costs in community subjects with irritable bowel syndrome. Gastroenterology. 1995; 109:1736-1741. 

⁷  Drossman, DA.  Review article: an integrated approach to the irritable bowel syndrome. Aliment Pharmacol Ther. 1999;13 (Suppi 2):3-14. 

⁸  Hahn BA, Yan S, Strassels S.  Impact of irritable bowel syndrome on quality of life and resource use in the United States and United Kingdom. Digestion. l999;60:77-81. 

⁹  Gupta, Kanka, Metz, et al. The effect of alosetron (a new 5-HT3 receptor antagonist) on the pharmacokinetics of haloperidol in schizophrenic patients. [J. Clin Pharmacol 1995; 35:202-207.]