Violative Advertising and Promotional Labeling Letter

Interferon beta-1a, Avonex (Biogen, Inc)

October 24, 2002

Nadine D. Cohen, Ph. D.
Biogen, Inc.
14 Cambridge Center
Cambridge, MA 02142

Dear Dr. Cohen:

Through routine monitoring and surveillance, the Advertising and Promotional Labeling Branch (APLB) in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) has identified promotional materials for your product, Avonex (Interferon beta-1a), that violate the Federal Food, Drug, and Cosmetic Act and its implementing regulations. APLB has reviewed a physician brochure (1-8244-01), patient brochure (1-3042-06), physician advertisement reprint (1-8320-01), MRI Evidence Flipchart (1-8279-01), long-term visual aid (1-8305-02), and patient advertisement (1-3230-01) and has concluded that these materials contain misleading claims about Avonex. Copies of all referenced materials are enclosed.

Examples of the violative statements and the requested corrective action include the following:

1. The headline, “AVONEX delivers the highest rate of satisfaction--95% among patients,” followed by the bar graph representing patient satisfaction, which are prominently presented in the physician and patient brochures and MRI Evidence Flipchart (Tabs A, B and D, respectively), are misleading because they misrepresent the results of the survey. The headline “Strong with Patients” (Tab A) and the results presented are also misleading because they do not identify the number of patients surveyed, thus presenting the information in a way that implies that the study represents a larger experience with the drug than actually occurred. The survey evaluated 75 patients in each of three MS therapies, Avonex, Betaseron and Copaxone. The 95% value stated in the headline only represents the total number of patients (n=75) who responded to the question, “ All things considered, how satisfied are you with Avonex?” However, in the Avonex patient group only 60% of the 75 patients were very satisfied while 35% were only somewhat satisfied. The omission of these details is misleading to the reader. You should immediately cease any further dissemination of all advertising and promotional materials that contain these claims and similar presentations.

2. “Cognitive dysfunction is significantly correlated with brain atrophy.” This claim was identified in the Physician Brochure (Tab A). FDA thanks you for your fax responding to our request for the references cited with this claim; however, the references did not clarify our concerns. Your clinical trials did not assess the correlation of cognitive dysfunction with brain atrophy. If Biogen has data consisting of substantial evidence to support this claim, please submit the data, within 10 days of the date of this letter, to CBER for review. In the absence of such data, you should immediately discontinue any further use of this phrase, in all advertising and promotional materials.

3. The visual aid (Tab F) states, “The most common side effects…tend to diminish with continued use over time,” and includes a graphic depicting side effects during the first 6 months and last 6 months of treatment. Your clinical trials did support the non-specific claim, “…tend to diminish with continued use over time,” but did not support claims regarding the specific duration of adverse events. If Biogen has data consisting of substantial evidence to support claims of the specific duration of adverse events, please submit the data, within 10 days of the date of this letter, to CBER for review. In the absence of such data, you should immediately cease any further dissemination of all advertising and promotional materials that contain claims of the specific duration of adverse events.

4. The title of the visual aid (Tab F), “Prescribe Therapy That Is Strong Over The Long Term” is qualified by the phrase “as proven in the 2 year phase III trial.” This qualifying statement lacks prominence and readability reasonably comparable to the headline. In addition, the subsequent pages indicate, “2 years, 4 years, and 5 years,” in text more prominent than any other in the brochure, which, combined with the headline, “Avonex is Strong to Treat for Years…,” implies efficacy beyond that approved in your labeling. If Biogen has data consisting of substantial evidence to support this claim, please submit it to CBER within 10 days of the date of this letter. In the absence of such data, you should immediately cease any further dissemination of all advertising and promotional materials containing this efficacy claim. In addition, you should revise your materials to ensure proper prominence and proper reference of approved efficacy and safety data.

5. The visual aid (Tab F) contains data on the “4-year dose-comparison study results,” that references a poster presented at a public meeting in April 2002. This is an inappropriate reference for efficacy or safety data. If Biogen has data consisting of substantial evidence to support this claim, please submit the data, within 10 days of the date of this letter, to CBER for review, otherwise please immediately cease any further dissemination of all advertising and promotional materials containing these data.

In addition to the misleading statements noted above, FDA has concerns regarding the following:

• The comparative chart for Avonex, Betaseron and Copaxone which appears in the patient brochure (Tab B) is potentially misleading because it fails to reveal material facts about the representation of the comparisons between Avonex, Betaseron and Copaxone. The chart includes selective categories such as active ingredient information, indication, number of injections per week, storage requirements and how the products are supplied and references the respective prescribing information as the source for this information. FDA recommends that an appropriate qualifying statement be added stating, “No conclusions regarding comparative safety or efficacy between products can be drawn from comparisons of this prescribing information.” This qualifying statement should appear with the same prominence and readability as the rest of the information on the page.

• Biogen disseminated several promotional pieces between March and May 2002, but did not submit them to CBER until August 2, 2002. The patient advertisement (Tab E) was initially distributed on March 1, 2002, but not submitted to CBER until July 3, 2002. In addition, the labeling referenced in Tabs A, B, and C are each dated January 2002, but were not submitted to APLB until March 20, 2002. APLB is concerned with these gaps in time between dissemination and submission to the agency and requests that Biogen comply with 21 CFR 314.81(b)(3)(i) which states that the applicant shall submit labeling devised for promotion of the drug product at the time of initial dissemination of the labeling. Please identify the initial dissemination date of each applicable item in the enclosures to clarify this point and immediately revise your practices, if necessary, to ensure submission to FDA at the time of initial dissemination of the labeling.

This letter is not intended to be an all-inclusive list of deficiencies associated with your promotion of the above product. It is your responsibility to ensure that all materials distributed within the United States are in conformance with each requirement of the Act and applicable regulations.

You should respond within ten (10) days of the date of this letter. Your response should include a statement of your intent to comply with each of the above, a list of all promotional materials with the same or similar issues, and your methods for discontinuing these promotional materials, as applicable.

Your response should be directed to Mr. Glenn N. Byrd, Chief, APLB, at the address listed below. Should you have any questions or concerns involving this matter, please contact Ms. Maryann Gallagher, Regulatory Review Officer at 301-827-3028.

Sincerely,

----- signature -----

Mary A. Malarkey
Director
Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

Enclosures

Last Updated: 10/29/2002

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