Released by FDA: 12/7/00.  Posted by FDA:  12/15/00

Kathleen J. Day 
Senior Director 
Global Regulatory Affairs, Labeling and Promotion 
Pharmacia & Upjohn 
7000 Portage Road 
Kalamazoo, MI 49001-0199

RE:   Detrol (tolterodine tartrate tablets) 
          NDA 0-771 
          MACMIS ID #9318

Dear Ms. Day:

This letter concerns several promotional pieces (flipchart #UX00828.00; journal advertisement #UJ01855.00; and sales aids UX02331.00, UX02332.00) for Detrol (tolterodine tartrate tablets) disseminated by Pharmacia &. Upjohn (P&U ).   As part of its monitoring program, the Division of Drug Marketing, Advertising and Communications (DDMAC) has reviewed these promotional materials and has concluded that they are false or misleading,. in violation of the Federal Food, Drug, and Cosmetic Act and its implementing regulations.  Our specific objections follow.

Broadened Indication

The approved product labeling (P1 ) for Detrol states that “Detrol tablets are indicated for the treatment of patients with an overactive bladder with symptoms or urinary frequency, urgency, or urge incontinence."  Detrol is not indicated for the treatment of stress incontinence.   However, in flipchart #UX00828.00, you include a large questionnaire titled “Could you have stress incontinence,” followed by the symptoms of stress incontinence.  This claim and presentation is misleading because it suggests that Detrol is useful in patients with stress incontinence when such has not been demonstrated by substantial evidence.

Unsubstantiated Patient Satisfaction Claims

In sales aid UX02331.00, you present patient satisfaction claims that are unsubstantiated.  For example. you present claims, based on survey results, such as “Patients taking Detrol tolterodine tartrate tablets reported improved sense of well being" and “Detrol had a positive impact on behavior."  Claims such as these. concerning the subjective impact of overactive bladder and its treatment need to be supported by substantial evidence, such as adequate and well-controlled trials using validated instruments to measure these outcomes, along with concurrent evaluations of efficacy and safety.  Your claims and representations are misleading because they are not supported by such evidence.  Rather, they are based solely on a market research survey of Detrol  “users."   In this case, you collected outcomes only from patients who remained on Detrol therapy, potentially biasing the results in favor of those who were “satisfied” with their treatment results.

Unsubstantiated Compliance Claims

In journal advertisement UJ01855.00 and sales aid UX02331.00, the claims “Favorable tolerability profile helps patients stay on therapy” and "Tolerability helps patients stay on therapy” are misleading because they lack substantial evidence.  There are several factors other than tolerability that influence patient compliance.  Therefore, in the absence of Detrol specific compliance data, your suggestions of improved patient compliance are misleading.

Misleading Efficacy Claims

Promotional materials are misleading if they suggest that a drug is more effective than has been demonstrated by substantial evidence.  Your sales aid (UX0223l .00) prominently presents a graphic that Detrol 2 mg bid demonstrated a 76% median change from baseline in urge incontinence in open-label trials after nine months of treatment.   The efficacy found in the open-label trial is inconsistent with the PI, in which three clinical studies demonstrated a median change from baseline in urge incontinence of 50-56%.

Minimizing Risk

In sales aid UX02331.00 you present the incidence of dry mouth to be 39.5% for Detrol compared to 15.9% for placebo treated patients, which is consistent with the PI. However, this statement is followed by a chart depicting the overall incidence of dry mouth and the severity (mild, moderate, and severe).  This chart depicts the overall incidence of dry mouth to be 30% with Detrol, which is misleading because it minimizes the risk of dry mouth and is inconsistent with the PI.

In sales aid UX02332.00 the tagline “A CNS safety profile that helps patients stay alert and active” is misleading because it minimizes the risk of somnolence in patients taking Detrol.  As you acknowledge, somnolence has been reported by 3% of patients taking Detrol compared to 1.7% of patients taking placebo.  Additionally, other adverse effects such as nervousness and dizziness are associated with Detrol therapy and may impact a patient’s ability to stay alert and active.

Misleading Graphic Representation of tolterodine concentration in respective tissues

In sales aids #UX02331.00 and UX02332.00, you include a graphic representation of the concentration of’ tolterodine in the bladder and other elimination organs compared to the central nervous system and skeletal muscle.  This graphic implies that 87°o of the tolterodine concentration is selective for the bladder and other elimination organs, while 13% of the tolterodine concentration is selective for the central nervous system and skeletal muscle.   However, the difference in tolterodine’s selectivity between the organs is unknown.   This graphic is also misleading because it suggests clinical significance when, in fact, no such clinical significance has been demonstrated.  The PI states that the drug shows selectivity for the urinary bladder over salivary glands in cuts and the clinical relevance of this finding has not been established.

Requested Action

P&U should immediately discontinue these and all other promotional materials for Detrol that contain the same or similar claims or presentations.  We request that P&U respond. in writing, with its intent to comply with the above.  We should receive your written response no later than December 21, 2000.   This response should list similarly violative materials with a description of the method for discontinuation and the discontinuation date.

If P&U has any questions or comments, please contact me by facsimile at (311) 594-6771, or at the Food and Drug Administration, Division of Drug Marketing. Advertising and Communications, HFD-42, Rm 17B-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 #9318 in addition to the NDA number.

Sincerely.

Barbara S. Chong, Pharm.D., BCPS
Regulatory Review Officer 
Division of Drug Marketing,
    Advertising and Communications