Released by FDA: 5/10/01.  Posted by FDA:  5/22/01

Sam Boddapati, Ph.D. 
Senior Director, Regulatory Affairs 
Supergen, Inc. 
Two Annabel Lane, Suite 220 
San Ramon, CA 94583

RE:    NDA2O-122 
         Nipent® (pentostatin) for Injection 
         MACMIS 1D# 9696

Dear Dr. Boddapati:

Through routine monitoring and surveillance, the Division of Drug Marketing, Advertising, and Communications (DDMAC) has become aware of promotional materials disseminated by Supergen, Inc. (Supergen) for Nipent (pentostatin) for Injection that are false, misleading, or otherwise in violation of the Federal Food, Drug, and Cosmetic Act and its implementing regulations.   Specifically, the following promotional materials present misleading claims of long term safety and efficacy, promote unapproved uses, or lack fair balance:

• Reprint Carrier ID #80032(301) 
• Journal Advertisement ID# 800J2(200) 
• www.supergen.com website (5/8/01)

Misleading Safety and Efficacy Claims

Supergen’s reprint carrier and journal advertisement contain multiple claims relating to ten-year survival and an incidence of secondary malignancy equal to that of the general population that are referenced to a study by Flinn IW, et al. (Blood 2000; 96(9): 2981-6).   For example, the reprint carrier and journal advertisement include the following statements:

“67% ten-year relapse-free survival rate” (reprint carrier and journal advertisement)

“81% ten-year overall survival rate” (‘reprint carrier and journal advertisement)

‘The incidence of overall second malignancies and of solid tumors was not increased among patients treated with pentostatin in this study” (reprint carrier)

These claims that were derived from the Flinn study are not supported by substantial evidence.   First, the clinical data summarized in the Flinn study were from two studies where evaluation of survival was not a uniformly pre-defined endpoint.   Second, the total number of patients enrolled was inadequate to clearly establish clinical benefit from the survival results.   Lastly, use of a historical control and the small number of patients in the Flinn study are not adequate to compare incidences of secondary malignancy. Furthermore, the approved product labeling (PI) specifically states, “At a median follow-up duration of 46 months, there was no statistically significant difference in survival between hairy cell leukemia patients initially treated with Nipent and those initially treated with IFN.   However, no definite conclusions regarding survival can be made from these results because they are complicated by the fact that the majority of IFN patients crossed over to Nipent treatment.”   Therefore, the survival and safety claims in the reprint carrier and journal advertisement are misleading because they are not supported by substantial evidence and are inconsistent with the PI.

Promotion of Unapproved Uses

Website

The “Products-Focus on Oncology” (http://www.nipent.com/product/2_3.htm) webpage on the www.supergen.com website promotes Nipent for unapproved uses. As stated in the PI, Nipent is indicated as “single-agent treatment for both untreated and alpha-interferon- refractory hairy cell leukemia patients with active disease as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.”   However, the “Products-Focus on Oncology” webpage lists the uses for Nipent as “Leukemias and Lymphomas.”   Therefore, this statement broadens the approved indication to include all leukemias and promotes an unapproved use of Nipent for all lymphomas.

Furthermore, the presentation of Nipent information on the “Products - Pipeline” webpage (http://www.supergen.com/product/2_2.htm) also promotes Nipent for unapproved uses.   Specifically, the introductory paragraph states the products on the page “have not yet been cleared for marketing.”   However, in the Nipent pipeline chart, the first “indication” listed, hairy cell leukemia, is an approved indication for marketing.   The subsequent uses, i.e., “cutaneous & peripheral T-cell lymphoma,” “chronic lymph [sic] leukemia,” “non-Hodgkin’s lymphoma,” “graft-vs-host disease,” and “rheumatoid arthritis” listed under “Indication” are unapproved uses for Nipent. Presenting product information for approved and unapproved uses together in this manner is misleading because the presentation implies that the unapproved uses are approved.

Journal Advertisement

Supergen’s journal advertisement states that “Purine-nucleoside analogs should play a major role in the treatment of low-grade lymphoid malignancies.”   The phrase “low-grade lymphoid malignancies” broadens Nipent’s indication since Nipent is only indicated for "single-agent treatment for both untreated and alpha-interferon-refractory hairy cell leukemia patients with active disease as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease related symptoms.”   Therefore, the journal advertisement is misleading because it promotes unapproved uses for Nipent.

Lack of Fair Balance

Promotional materials lack fair balance when they fail to present risk information with a prominence and readability reasonably comparable with the presentation of information relating to effectiveness of the drug, taking into account all implementing factors such as typography, layout, contrast, headlines, paragraphing, white space, and any other techniques apt to achieve emphasis.   The reprint carrier and journal advertisement fail to include the boxed warning regarding the risk of fatal pulmonary toxicity when Nipent is used in combination with fludarabine phosphate.   Further, the risk information that is listed lacks prominence compared to the efficacy claims.   For example, the risk information is presented in text format with a very small font size whereas the efficacy claims are presented in large, colorful fonts.

In addition, the “Products-Focus on Oncology” (http://www.nipent.com/product/2_3.htm) and “Products-Product Platforms-Oncology” (http://www.5upergen.com/product/2_3_1.htm) webpages provide efficacy information but fail to include any risk information for Nipent.

Requested Actions

Supergen should immediately cease distribution of this and other similar promotional materials for Nipent that contain the same or similar claims or presentations.   Supergen should submit a written response to DDMAC on or before May 24, 2001, describing its intent and plans to comply with the above.   In its letter to DDMAC, Supergen should include the date on which this and other similarly violative materials were discontinued.

Supergen 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, 5600 Fishers Lane, Rockville, MD 20857.   In all future correspondence regarding this matter, please refer to MACMIS ID #9696 in addition to the NDA number.   DDMAC reminds Supergen that only written communications are considered official.

Sincerely,

 

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