Released by FDA: 8/17/01.  Posted by FDA:  9/14/01

Martha J. Carter
Vice President, Regulatory Affairs 
GelTex Pharmaceuticals, Inc.
153 Second Avenue 
Waltham, MA 02451

RE:   NDA# 20-926 
        NDA# 21-179 
        Renagel Capsules (sevelamer hydrochloride) 
        Renagel Tablets (sevelamer hydrochloride) 
        MACMIS ID # 10194

Dear Ms. Carter:

This letter concerns dissemination of promotional materials for Renagel Capsules and Tablets (sevelamer hydrochloride).  As part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a press release entitled "Genzyme Study Demonstrates Significant Impact of Renagel On Cardiac Calcification" submitted under cover of Form FDA 2253 by GelTex Pharmaceuticals, Inc_ (GelTex).  The press release promotes Renagel in violation of the Federal Food, Drug, and Cosmetic Act and its implementing regulations.  Specifically, we have the following objections:

Unsubstantiated Outcomes Claims

Several statements in the press release misleadingly state or imply outcomes of Renagel therapy that have not been demonstrated by substantial evidence.  For example, the press release includes conclusory statements relating to preliminary, interim data derived from an ongoing study of cardiac calcification:

The title of the press release - "Genzyme Study Demonstrates Significant Impact of Renagel On Cardiac Calcification"

"In a powerful way, the `Treat to Goal' study has begun to clarify and confirm the vital clinical role Renagel can play in allowing patients to avoid the progression of cardiovascular calcification." (emphasis added)

These statements imply that Renagel is effective in reducing the risk of cardiac calcification when, in fact, substantial evidence of that effect has not been established. Until the "Treat to Goal" study is completed, conclusions regarding treatment outcomes, based on interim data, are misleading because the final results may not support these claims.

In addition, the press release misleadingly implies that treatment with Renagel will decrease morbidity or mortality.  For example:

"Patients on dialysis are at high risk for elevated phosphorus levels, which can lead to cardiac complications, bone disease, and increased mortality rates.  Nearly all patients on dialysis take a phosphate binder to control the level of phosphorus in their blood. Before the introduction of Renagel, the majority of patients were treated with calcium-based binders.  Independent studies have associated excessive calcium intake with increased morbidity in dialysis patients.  Renagel is the only calcium-free, aluminum free phosphate binder on the market."

The approved product labeling (PI) for Renagel does not report an effect on either cardiac calcification or overall morbidity and mortality because the trials that formed the basis for Renagel's approval did not measure these outcomes.  Therefore, the press release misleadingly overstates the benefits of Renagel therapy because substantial evidence of the impact of Renagel treatment on these outcomes has not been established.

Unsubstantiated Superiority Claims

In addition, the press release contains unsubstantiated claims regarding the superiority of Renagel over unspecified calcium-based phosphate binders.  These claims are also misleading conclusions based on preliminary, interim results of an ongoing study.  The unsubstantiated superiority claims include:

"The findings from this trial reveal a clear difference between the two groups in the progression of cardiovascular disease"

"Despite this similar degree of phosphorus control, the study's investigators found a clear, highly significant difference between the two patient groups in the progression of cardiac calcification."

Until the study is completed, conclusions regarding the superiority of Renagel over other therapies in the progression of either cardiac calcification or general cardiovascular disease are misleading because the final results may not support these claims. Furthermore, other factors may be responsible for the disparity in results.  These factors may not be evident until the final analysis of the completed study.

The PI for Renagel includes the statements that "the risk of developing hypercalcemia is less with Renagel Capsules compared to calcium acetate" and that "Renagel decreases the incidence of hypercalcemic episodes relative to patients on calcium acetate treatment."  The PI does not extrapolate these findings to conclude that Renagel has a superior effect on the relative risk of either cardiac calcification or the broader risk of cardiovascular disease progression.  Therefore, presentation of these conclusions misleadingly overstates the comparative safety of Renagel therapy.

Broadening of Approved Indication

The claim that "Renagel offers long-term phosphorus control in patients with end-stage renal disease on hemodialysis, without adding excess calcium or aluminum" (emphasis added) is misleading because it implies a higher degree of efficacy than has been demonstrated for Renagel.  According to the PI, Renagel is only approved for reduction of serum phosphorus in patients with end-stage renal disease on hemodialysis. Therefore, this claim misleadingly broadens the approved indication of Renagel because patients may experience a reduction in serum phosphorus levels while still remaining hyperphosphatemic.

In addition, references throughout the press release to "dialysis" patients are misleading because they imply that Renagel is useful in a broader population than has been demonstrated by substantial evidence.  Dialysis procedures include both hemodialysis and peritoneal dialysis.  Renagel is approved for use in hemodialysis patients only.  It is not approved for use in peritoneal dialysis patients.

DDMAC requests that GelTex immediately discontinue the dissemination, including posting on the internet, of this violative press release.  All other promotional materials that contain the same or similar violative claims or representations should be discontinued.  DDMAC requests that GelTex submit a written response to this letter no later than August 31, 2001, including your plan to comply with DDMAC's request. Your written response should include a list of all materials that you have discontinued and the date that they were discontinued.

If you have any questions or comments, please contact me by facsimile at (301) 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 #10194 in addition to the NDA number.

Sincerely,

 

Margaret M. Kober, R. Ph. 
Regulatory Review Officer 
Division of Drug Marketing, 
     Advertising, and Communications