http://www.fda.gov/cber/adpromo/ifnbbio050902.htm

May 9, 2002
Last Updated: 5/23/2002

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 Office of Compliance and Biologics Quality has identified promotional materials for your product, Avonex (Interferon beta-1a), that violate the Federal Food, Drug, and Cosmetic Act (Act) and its implementing regulations. APLB has reviewed numerous promotional pieces including homemade sales materials, a DTC letter, professional print material and information on the internet site www.avonex.com and find that they are false and/or misleading. Copies of all referenced materials are enclosed.

The homemade material has been distributed to physician offices in the Detroit, Michigan; St. Louis and Springfield, Missouri; Dallas, Texas; Tulsa and Oklahoma City, Oklahoma; and Little Rock, Arkansas areas.

Examples of the violative statements include the following:

1. Biogen is promoting Avonex as more effective than Rebif in the “long term” and claiming Rebif as only offering a “short-term advantage.” Such statements are false, misleading, and/or lacking in fair balance. Both the Avonex placebo controlled study and the Rebif placebo controlled study were 2-year studies. The comparative study was a 6-month study (24 weeks was determined to be sufficient to generate results demonstrating Rebif to be clinically superior to Avonex). The results for the second 24-week study period support the data and effects observed in the first 24-week period. Examples of these statements include the following:
1. “Avonex is strong to treat for years.” (Dear Patient letter) This claim is directly contrary to the approved labeling, which states that safety and efficacy have not been established beyond two years. Biogen’s statement is misleading in that it implies a timeframe that can easily be interpreted by patients as longer than two years.
2. “The data showed that in weeks 25-48, Avonex actually out performed Rebif.” (Home made material: Dear Doctor letter) This is a false statement. The results of the second 24-week study period supported the data and effects observed in the first 24-week period. For the subset of patients who were exacerbation-free at 24 weeks, the proportion that remained exacerbation-free through 48 weeks was essentially the same in both treatment groups (82% Rebif vs. 83% Avonex). The difference is not statistically significant.
3. “…the second 24 weeks of the same study showed that the risk of relapse was equivalent or if anything, slightly less in the people treated with AVONEX compared to people treated with Rebif.” (Frequently Asked Questions (FAQ) on the website) and “You have probably heard about the 24-week Evidence Study upon which the decision was based…Serono released the results of the second 24 weeks of the study …which demonstrates a very different picture.” (Home made sales material)

   It is true that for the subset of patients who were exacerbation-free at 24 weeks, the proportion that remained exacerbation-free through 48 weeks were essentially the same in both treatment groups (82% Rebif vs. 83% Avonex). However, the second 24-week period comparative data did not demonstrate that patients on Avonex had the same or slightly less risk of relapse compared to patients on Rebif because the study was not designed to draw independent conclusions regarding that time period. The comparative study did show that through the 48-week timepoint, 62% and 52% of Rebif- and Avonex-treated subjects were exacerbation free, respectively (a statistically significant difference in favor of Rebif).

4. “The 24-week Serono study demonstrated a short-term advantage for people treated with Rebif in relapses only…the Serono study does not indicate that Rebif works better than AVONEX in the long term.” (Dear Patient Letter and Frequently Asked Questions (FAQ) on the website) The bold text and the use of “short-term” and “long-term” are misleading. Terminology such as short- and long-term mean different things to different people and have no objective basis. Both the Avonex placebo controlled study and the Rebif placebo controlled study were 2-year studies. The comparative study was a 6-month study (24-weeks) which, FDA determined, demonstrated that Rebif is clinically superior to Avonex. FDA determined that the effectiveness results observed during the trial would persist.
2. “Serono’s phase III study for Rebif demonstrated only a 30% effect on accumulation of disability… over 2 years.” (Dear Patient letter) This is true but misleading because it does not state that the 2-year data for Avonex demonstrated a similar effect (well within the confidence intervals from the two separate studies) on accumulation of disability and that both rates were in comparison to placebo.
3. Many of Biogen’s side effect statements describe the percentages taken from each of the products’ labeling, which compared the product to a placebo, instead of using the values from the “Evidence” trial, which compared Rebif to Avonex. In addition, Biogen continues to present information on side effects that omit data on headache and pain. Previously FDA specifically requested that Biogen include such data (see February 19, 1999, and April 12, 1999, FDA letters). An example of a statement that is misleading and/or lacking in fair balance is as follows:

“The side effects in the U.S. package inserts indicate injection site reactions occurred in 92% versus 4%, elevated LFTs in 27% versus 8%, and leukopenia in 36% versus 1% of patients on Rebif and Avonex…” (Dear Doctor and Dear Colleague letter) and “Also important, there are large differences in the safety profiles of these two drugs. Rebif shows 27% incidence of liver enzymes elevations (Avonex 8%)…Rebif package insert notes 92% injection site reactions (Avonex, 4%) and 3-5% injection site necrosis (Avonex, 0%). (Home made material)

The statements in these materials are misleading and lacking in fair balance because they do not state that each of the values are from separate trials comparing each product to placebo and do not provide direct comparative data. In the direct comparative trial of Rebif to Avonex, the adverse reactions were generally similar between the two treatment groups. Exceptions included injection site disorders (80% Rebif vs. 24% Avonex), hepatic function disorders (14% Rebif vs. 7% Avonex), and leukopenia (3% Rebif vs. <1% Avonex).

4. In a Dear Patient letter you stated, “…24% of people treated with Rebif developed neutralizing antibodies, antibodies your body produces that reduce the long-term effectiveness of therapy.” There is no evidence to support this statement. You also failed to mention that 19% of Avonex subjects develop neutralizing antibodies. The paragraph continues to point out the adverse events associated with Rebif but omits the Avonex adverse event values. These statements are misleading and lacking in fair balance.

   In recognition of the uncertainty regarding the impact of antibody formation on the efficacy of interferons, a recent “Report of the Therapeutics and Technology Assessment Subcommittee” of the Academy of Neurology and the MS Council for Clinical Practice Guidelines concluded that the biological effect of neutralizing antibodies is uncertain, although it is possible that antibodies will have some effect on reducing effectiveness. However, neither the exacerbation data nor the MRI outcomes at one year suggest that the advantages of Rebif observed at 6 months were reversing.

To address these objections, APLB recommends that Biogen do the following:

1. Immediately discontinue the distribution and use of the above-mentioned promotional materials and all other promotional materials containing the same or related claims or presentations.
2. Immediately stop using subjective terminology such as “short-term” and “long-term” and replace these terms with objective data defining the exact timeframe of comparison.
3. Include data on headache and pain in all future material when reporting either side effects or “common side effects” as requested in FDA letters dated February 19, 1999, and April 12, 1999.

Biogen should respond to this letter in writing within ten days of receipt. Your response should include a statement of your intent to comply with each of the above, a list of all promotional materials that were discontinued, and the discontinuation date.

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 301-827-6060.

Sincerely,

----- signature -----

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

Enclosure