Released by FDA: 10/20/00.  Posted by FDA:  10/31/00

Sharon W. Shapowal. R.Ph. 
Director, Avandia 
N.A. Regulatory Affairs 
SmithKline Beecham Pharmaceuticals 
One Franklin Plaza 
PO BOX 7929
Philadelphia, PA 19101

RE:   Avandia® (rosiglitazone nialeate) Tablets 
        NDA  21-071 
        MACMIS ID#9308

Dear Ms. Shapowal:

This letter concerns several promotional materials (sales aids AV4062, AV4759, and AV5508, journal advertisement AV374l; customized menus AV3747F-l and AV3747E- 2) for Avandia tablets (rosiglitazone maleate) disseminated by SmithKline Beecham Pharmaceuticals (SB).  As part of its monitoring program, the Division of Drug Marketing, Advertising and Communications (DDMAC) has reviewed these materials and has concluded that they are false or misleading, in violation of the Federal Food, Drug and Cosmetic Act and its implementing regulations.  A description of our objections follows.  The violations discussed in this letter do not necessarily constitute an exhaustive list.

Minimizing Hepatic Risk

The hepatic precautions in the approved product labeling (P1) include the following:

1. Although available clinical data show no evidence of Avandia induced hepatotoxicity or alanine aminotransferase (ALT) elevations, rosiglitazone is structurally related to troglilazone. which has been associated with idiosyncratic hepatotoxicitv and rare cases of liver failur, liver transplants. and death. 
2. Pending the availability of the results of additional large, long-term controlled clinical trials and postmarketing safety data following wide clinical use of Avandia to more fully define its hepatic safety profile,  it is recommended that patients treated with Avandia undergo periodic monitoring of liver enzymes. 
3. Liver enzymes should be checked prior to the initiation of therapy with Avandia in all patients. 
4. Therapy with Avandia should not be initiated in patients with increased baseline liver enzyme levels [ALT >2.5X upper limit of normal (ULN)] 
5. In patients with normal baseline liver enzymes, following initiation of therapy with Avandia, it is recommended that liver enzymes be monitored every two months for the first twelve months, and periodically thereafter. 
6. Patients with mildly elevated liver enzymes (ALT levels one to 2.5X ULN) at baseline or during therapy with Avandia should be evaluated to determine the cause of the liver enzyme elevation.  Initiation of. or continuation of, therapy with Avandia should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. 
7. If at any time ALT levels increase to >3X ULN in patients on therapy with Avandia, liver enzyme levels should he checked as soon as possible. 
8. If ALT levels remain >3X ULN, therapy with Avandia should be discontinued.

In sales aid AV4759, you misleadingly claim that Avandia is “Appropriate for many patients with type 2 diabetes including: obese, elderly, and renally or hepatically impaired”   According to the approved P1, “Therapy with Avandia should not he initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT> 2.5X ULN) at baseline.”  Therefore, your claim that Avandia is “appropriate” for hepatically impaired patients is misleading.  Your presentation of qualifying information in a footnote fails to correct this misleading statement.  Moreover, journal advertisement AV3741 includes bullets on the effectiveness of Avandia but fails to mention any of the hepatic precautions.   DDMAC is seriously concerned that SB has minimized the precautions concerning hepatic effects in its materials.

Misleading Efficacy Claims

Promotional materials are misleading if they suggest that a drug is more effective than has been demonstrated by substantial evidence.  Your promotional materials AV3741, AV406. and AV4759 prominently present efficacy claims based on an ad hoc analysis in patients with baseline hemoglobin A1c (HbA 1c) > 9%.  For example, you present claims that Avandia decreased HbA1c by 2.3% (Avandia 4 mg QD)) and 1.7% (Avandia 4 mg BID) in drug-naïve patients and previously-treated patients, respectively.  The claim involving drug-naive patients that supposedly demonstrated the 2.3% decrease in HbA1c is based on a study that involved a total of 14 patients.  In contrast, the P1 (study 13) indicates that the same Avandia dose (4 mg QD) in 1 80 patients with a mean baseline HbA1c of 8.9% decreased HbA1c by 0.8%.  Therefore, your presentations that Avandia 4 mg QD decreases HbA1c by 2.3% are misleading because they suggest that Avandia is more effective than has been demonstrated by substantial evidence.

Fair Balance

The promotional materials (AV3741, AV4759, and AV5508) are misleading because they fail to present risk information with a prominence and readability reasonably comparable with the presentation of information relating to effectiveness of the drug. Factors impacting prominence and readability include typography, layout. contrast, headlines, paragraphing. white space, and other techniques apt to achieve emphasis. For example, in journal advertisement AV3741, the efficacy data is presented in a large font with bullets while the risk information is presented as a footnote at the bottom.

The “Perfect 10:  I can customized menus” (AV3747E-l and AV3747E-2) lack fair balance because the materials present the product’s indication without disclosing risks associated with Avandia.  For example. you have exclusively presented the product logo in conjunction with the statement “Help use the natural insulin in you” without any mention of the risk information.

Requested Action

SB should immediately discontinue these and all other promotional materials for Avandia that contain the same or similar claims or presentations.  We request that SB respond, in writing, with its intent to comply with the above.  DDMAC should receive your written response no later than November 3. 2000.  This response should list similarly violative materials with a description of’ the method for discontinuation and the discontinuation date.

If SB has 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, IIFD-4, Rim 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 #9308 in addition to the NDA number.

Sincerely,

 

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