Released by FDA: 3/13/01.  Posted by FDA:  3/21/01

Karen Horgan-Peltier, BSN, ET 
Director, Promotional Compliance 
Bristol-Myers Squibb
P0 Box 4500 
Princeton, NJ 08543-4500

RE:   NDA#19-763 
         Ifex® (ifosfamide) Injection 
         MACMIS lD#9593

Dear Ms. Horgan-Peltier:

Through routine monitoring and surveillance, the Division of Drug Marketing, Advertising, and Communications (DDMAC) has become aware of promotional materials disseminated by Bristol-Myers Squibb (BMS) for Ifex (ifosfamide) Injection that are false, misleading, or otherwise in violation of the Federal Food, Drug, and Cosmetic Act (Act) and its implementing regulations.  Specifically, the following promotional materials promote unapproved uses and/or broaden the approved indication of Ifex:

• Journal Advertisement (lD# H5-KOO3RI) 
• Website www.bms.com  
• Website www.ifex.com 

Promotion of Unapproved Uses

Ifex is indicated for third line chemotherapy of germ cell testicular cancer in combination with certain other approved antineoplastic agents.  The product specific BMS website www.ifex.com contains the webpage (http://www.bms.com/donc/hprofx/data/fxl122.html) entitled “Continuous vs. Divided vs. Single Dose (1122)” that provides information for unapproved uses of Ifex.   For example, the following statements are made:

“..in humans, under the protection of mesna, the continuous infusion of ifosfamide over five days leads to an increase of a) the maximum tolerated dose (MTD) compared with single daily shod-term infusion and b) responses in some solid tumors, i.e. soft tissue sarcomas”

“Antman, cited a series of patients, with advanced sarcoma treated with 8 to 10 gm/m² of ifosfamide by bolus or continuous infusion. The response rate for the 64 patients receiving bolus administration was 23% compared with 12% for the 60 patients receiving a continuous infusion schedule (p=.09).   The authors found a statistically significant difference in response rates for soft tissue sarcomas between bolus infusion vs. continuous infusion with the higher response rate through the bolus arm.”

"Anderson, treated a series of 47 poor risk small-cell lung cancer patients with a regimen of ho/us ifosfamide at 1.5 g/m² with equidose mesna as a 30 minute infusion followed by 100 mg of oral etoposide daily for eight days.  The overall response rate was 60% (75% for limited stage and 48% for extensive stage of the disease), and the overall median survival was seven months.   Therapy was well tolerated."

Furthermore, the product specific BMS website www.ifex.com also contains an informational database which leads to a webpage (http://www.bms.com/cgi-bin/bmscom/litdb/onclgy/search.cgi) entitled “Search.”   This webpage includes a list of unapproved uses for Ifex.   Specifically, Ifex can be matched to one or all of seventy-two “Tumor or Disease Term[s],” via pull down menus.   From here electronic information about unapproved uses are presented.   For example, selecting Ifex and the Tumor or Disease Term “Small Intestine Carcinoma” results in the retrieval of two informational pieces about this unapproved use.   Thus, BMS is promoting Ifex for unapproved uses.

Unsubstantiated Claims

The claims “The patient undergoing outpatient treatment may experience daily activities nearer to a normal routine.  There may be less disruption of lifestyle when the patient returns to a home environment" are made in the journal advertisement.   These claims are misleading because they suggest that Ifex therapy minimizes disruption of a patient’s daily activities or lifestyle during third line treatment of germ cell testicular cancer using Ifex in combination with certain other approved antineoplastic agents.   These claims are not supported by substantial evidence because none of the seven articles and abstracts submitted by BMS to support these claims discuss the use of lfex and its affect on daily activities.   Thus, these articles and abstracts are inadequate to substantiate the claims made by BMS.

In addition, these claims combined with the pictorial representations of a very healthy-looking patient are misleading.   The patient is not representative of a patient population that has already undergone first and second line chemotherapy and is now receiving third line chemotherapy containing a drug with a boxed warning of severe CNS toxicity, including coma, a well as significant side effects such as moderate to severe myelosuppression (50%), alopecia (83%), nausea-vomiting (58%), and hematuria (46%).

Failure to Comply with CFR 314.81 (b)(3)(i)

Since the web-based promotional materials discussed here were not submitted on Form FDA 2253 at the time of initial dissemination, BMS has violated the post-marketing reporting requirements of the Act.

Requested Actions

BMS should immediately cease distribution of this and other similar promotional materials for Ifex® that contain the same or similar claims or presentations.   BMS should submit a written response to DDMAC on or before March 27, 2001, describing its intent and plans to comply with the above.   In its letter to DDMAC, BMS should include the date on which this and other similarly violative materials were discontinued.

BMS should direct its response to me by facsimile at (301) 594-6771 or by written communication at the Division of Drug Marketing, Advertising and Communications, HFD-42, Rm. 17B-20, 5300 Fishers Lane, Rockville, MD 20857.   In all future correspondence regarding this matter; please refer to MACMIS ID # 9593 in addition to the NDA number.   DDMAC reminds BMS that only written communications are considered official.

Sincerely,

Joseph A. Grillo, Pharm.D. 
Regulatory Review Officer 
Division of Drug Marketing, 
    Advertising, and Communications