Margaret J. Jack
Director, DRA
Hoffmann-La Roche Inc., Bldg 1/2
340 Kingsland Street Nutley, NJ 07110
 

RE:   NDA #21-455, 21-858 BONIVA (ibandronate sodium) Tablets
        BLA #103964 PEGASYS (peginterferon alfa-2a) for Injection
        NDA #20-896 XELODA (capecitabine) Tablets
        MACMIS ID #17318

Dear Ms. Jack:

As part of its monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has reviewed Hoffmann-La Roche Inc.’s (Hoffmann-La Roche) sponsored links on internet search engines (e.g., Google.com) for the following products: BONIVA (ibandronate sodium) Tablets (Boniva), PEGASYS (peginterferon alfa-2a) for Injection (Pegasys), and XELODA (capecitabine) Tablets (Xeloda).  The sponsored links are misleading because they make representations and/or suggestions about the efficacy of Boniva, Pegasys, and Xeloda, but fail to communicate any risk information associated with the use of these drugs.  In addition, the sponsored links for Pegasys and Xeloda inadequately communicate the drugs’ indications and also fail to use the required established name.  Thus, the sponsored links misbrand the drugs in violation of the Federal Food, Drug, and Cosmetic Act (the Act) and FDA implementing regulations.  See 21 U.S.C. 352(a) & (n), 321(n); 21 CFR 201.10(g)(1), 202.1(b)(1), (e)(3)(i), (ii) & (e)(6)(i). 

Background

Boniva
According to its FDA-approved product labeling (PI), Boniva is indicated for the treatment and prevention of osteoporosis in postmenopausal women.  Boniva increases bone mineral density (BMD) and reduces the incidence of vertebral fractures. 

Boniva is associated with a number of risks, as reflected in the Contraindications, Warnings, Precautions, and Adverse Reactions sections of its PI. 

Pegasys
According to its FDA-approved PI, Pegasys is indicated, among other things, alone or in combination with Copegus (ribavirin) for the treatment of adults with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. 

Pegasys is associated with a number of risks, as reflected in the Boxed Warning, Contraindications, Warnings, Precautions, and Adverse Reactions sections of its PI. 

Xeloda
According to its FDA-approved PI, Xeloda is indicated, among other things, as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred.  Xeloda was non-inferior to 5-flourouracil and leucovorin (5-FU/LV) for disease-free survival and while neither Xeloda nor combination therapy increases overall survival, combination therapy has been shown to improve disease-free survival compared to 5-FU/LV. 

Xeloda is also indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.  Combination chemotherapy demonstrated a survival benefit compared to 5-FU/LV alone, however, a survival benefit over 5-FU/LV has not been demonstrated with Xeloda monotherapy

Xeloda is associated with a number of risks, as reflected in the Boxed Warning, Contraindications, Warnings, Precautions, and Adverse Reactions sections of its PI. 

Omission of Risk Information

Promotional materials, other than reminder pieces, which include the name of the drug product but do not include indications or other representations or suggestions relative to the drug product (see 21 CFR 200.200, 201.100(f), 202.1(e)(2)(i)), are required to disclose risk and other information about the drug.  Such materials are misleading if they fail to reveal facts that are material in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials.  The sponsored links present the following claims:

•  Free Trial Offer
www.Boniva.com BONIVA® (ibandronate sodium).  Learn About Postmenopausal Osteoporosis. 

•  PEGASYS® Official Site
www.PEGASYS.com Learn About PEGASYS & Hepatitis C Register For The E-Mail Newsletter. 

•  XELODA® Information
www.xeloda.com Learn About An Oral Chemotherapy Treatment For Colon Cancer. 

These sponsored links make representations and/or suggestions about the efficacy of Boniva, Pegasys, and Xeloda, respectively, but fail to communicate any risk information.  This omission of risk information is particularly concerning as two of the products, Pegasys and Xeloda, have Boxed Warnings.  For promotional materials to be truthful and non- misleading, they must contain risk information in each part as necessary to qualify any claims made about the drug. 

By omitting the most serious and frequently occurring risks associated with the drugs promoted in the links above, the sponsored links misleadingly suggest that Boniva, Pegasys and Xeloda are safer than has been demonstrated.  We note that these sponsored links contain a link to the products’ websites.  However, this is insufficient to mitigate the misleading omission of risk information from these promotional materials. 

Inadequate Communication of Indication

The sponsored links for Pegasys and Xeloda provide very brief statements about what the drugs are for; however, these statements are incomplete and misleading, suggesting that the drugs are useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. 

Specifically, the sponsored link for Pegasys misleadingly broadens the indication for Pegasys by implying that all patients with hepatitis C are candidates for Pegasys therapy (“Learn About PEGASYS & Hepatitis C...”), when this is not the case.  Rather, Pegasys is only indicated (alone or in combination) for the treatment of chronic hepatitis C virus infection in adults who have compensated liver disease and who have not been treated with interferon alpha previously. 

Similarly, the sponsored link for Xeloda misleadingly broadens the indication for Xeloda by implying that the drug is approved to treat any type of colon cancer (“Learn About An Oral Chemotherapy Treatment For Colon Cancer”), when this is not the case.  Rather, Xeloda’s indication is limited to adjuvant treatment in patients with Duke’s C colon cancer and as first-line treatment for metastatic colorectal carcinoma.  Furthermore, the sponsored link fails to communicate any of the limitations to either of these indications or the drug’s limited proven survival benefits. 

Failure to Use Required Established Name

The sponsored links for Pegasys and Xeloda fail to present the full established name of the drugs being promoted, despite the requirement to do so.  See 21 CFR 201.10(g)(1) & 202.1(b)(1). 

Conclusions and Requested Action

For the reasons discussed above, the sponsored links misbrand Boniva, Pegasys and Xeloda, in violation of the Act and FDA regulations.  See 21 U.S.C. 352(a) & (n), 321(n); 21 CFR 201.10(g)(1), 202.1(b)(1), (e)(3)(i), (ii) & (e)(6)(i). 

DDMAC requests that Hoffmann-La Roche immediately cease the dissemination of violative promotional materials for Boniva, Pegasys and Xeloda, such as those described above.  Please submit a written response to this letter on or before April 9, 2009, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) in use for these drugs as of the date of this letter, identifying which of these materials contain violations such as those described above, and explaining your plan for discontinuing use of such materials.  Finally, we encourage you to review your promotional materials for the other prescription drug products that Hoffmann-La Roche promotes in the United States and to discontinue or revise any materials with the same or similar violations, and request that your response address this issue as well. 

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD, facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS # 17318 in addition to the NDA numbers.  We remind you that only written communications are considered official. 

The violations discussed in this letter do not necessarily constitute an exhaustive list.  It is your responsibility to ensure that your promotional materials for Boniva, Pegasys, and Xeloda comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

Michael Sauers
Regulatory Review Officer
Division of Drug Marketing,
Advertising and Communications