June 24, 2004
Ms. Nedra Waelti
Berna Biotech Ltd.
Re: BLA STN #103936
Vivotif [Typhoid Vaccine Live Oral Ty21a]
Dear Ms. Waelti:
The Advertising and Promotional Labeling Branch (APLB) in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) has reviewed a flyer for Vivotif [Typhoid Vaccine Live Oral Ty21a] (copy enclosed). This flyer violates section 502(a) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 352(a)) because it contains false or misleading comparative claims in violation of 21 CFR 201.6(a), Cf. 21 CFR 202.1(e)(6)(ii). The flyer could, therefore, mislead patients and/or health care practitioners to believe that Vivotif is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The flyer also violates section 502(a) because it misidentifies Vivotif by using an incorrect proprietary name.
Vivotif is a live attenuated vaccine that contains the attenuated strain Salmonella typhi Ty21a in an enteric-coated capsule for oral administration. According to the FDA-approved professional labeling (PI), Vivotif is indicated for immunization of adults and children greater than 6 years of age against disease caused by Salmonella typhi. The PI states that one capsule is to be swallowed approximately 1 hour before a meal with a cold or luke-warm drink on alternate days, e.g., days 1, 3, 5 and 7. Immunization (ingestion of all four doses of Vivotif) should be completed at least 1 week prior to potential exposure to S. typhi.
Concerning reimmunization, the PI states that the optimum booster schedule has not been determined. "Efficacy has been shown to persist for at least 5 years." It is recommended that a re-immunization be given "every 5 years" under conditions of repeated or continued exposure to typhoid fever.
Unsubstantiated Comparative Efficacy Claims
Your flyer entitled "Between the Oral Typhoid Fever Vaccine (VIVOTIF BERNA) and the Injectable Vaccine* The Differences Are Noteworthy" contains several comparisons between Vivotif and Typhim Vi, an injectable typhoid vaccine manufactured by Aventis Pasteur, Inc. Specifically, your flyer contains the following comparative claims:
1. "A Difference in How Immunity is Achieved." To the right of this in smaller print, another statement claims that "[o]ral administration is considered to be particularly advantageous in providing optimal protection against enteric diseases. Experts consider this to be the best route to stimulate intestinal immunity." There is an accompanying footnote that cites the reference text, Levine and Tacket, Ch. 26, Vibrio cholerae and Cholera: Molecular to Global Perspectives, (Wachsmuth, Blake, and Olsvik, eds., American Society for Microbiology 1994).
CBER is unaware of substantial evidence or substantial clinical experience demonstrating that Vivotif, because of its oral route of administration, is "particularly advantageous in providing optimal protection" against typhoid when compared to Typhim Vi. The cited reference text does not provide substantial evidence or substantial clinical experience to support your claim, because it only focuses on oral cholera vaccines. The text provides no data concerning a comparison of oral and injectable typhoid vaccines. Therefore, in the absence of data consisting of substantial evidence or substantial clinical experience, Vivotif is misbranded because the flyer makes a false or misleading representation concerning Vivotif with respect to another drug, 21 CFR 201.6(a).
2. "A Difference in the Length of Protection." To the right of this statement, a bar graph and another statement, in smaller print, declare that immunity from the oral vaccine extends "3 years longer than the protection from the injectable vaccine."
Based on an accompanying footnote to the Physician's Desk Reference, 56th edition, 2002, this claim seems to be based on the following information in the PDR concerning Vivotif and Typhim, respectively. For Vivotif, although the optimum booster schedule has not been determined, "[e]fficacy has been shown to persist for at least 5 years." For Typhim, an optimal reimmunization schedule has not been established, and reimmunization is recommended every two years under conditions of continued or repeated exposure to S. typhi.
The information in your flyer concerning "the length of protection" goes beyond a mere recitation of differences concerning immunization frequency contained in the labeling of both products. Instead, your statements and graph imply that Vivotif may provide equal or greater protection against typhoid in years three to five, after immunization with Vivotif, than reimmunizations with Typhim Vi would confer. CBER is unaware of any direct comparative clinical trial data for Vivotif and Typhim Vi, to support your claim of the superior effectiveness of Vivotif, in years three to five, compared to reimmunization with Typhim Vi. To the extent that you may have data suggesting otherwise, we invite you to submit it. In the absence of substantial evidence or substantial clinical experience, Vivotif is misbranded because the flyer makes a false or misleading representation concerning Vivotif with respect to another drug, 21 CFR 201.6(a).
False or Misleading Labeling
The referenced flyer contains an incorrect proprietary name for Vivotif and was accompanied by an outdated version of the PI. FDA approved revised labeling for Vivotif on April 15, 2003, reflecting a change in the product's proprietary name. However, your flyer was disseminated in September 2003 without the updated proprietary name, five months after the revised labeling was approved. In a January 6, 2004, telephone call between Ms. Michele Moskowitz of Berna Products Corp., a distributor for Berna Biotech Ltd., and Ms. Maryann Gallagher, APLB, Ms. Moskowitz confirmed that Berna Products Corp., disseminated the flyer knowing that it contained the incorrect proprietary name and also disseminated an accompanying outdated version of the PI.
Conclusion and Requested Actions
The referenced flyer misbrands Vivotif within the meaning of section 502(a) of the Act (21 U.S.C. § 352(a)) because it presents false or misleading representations with respect to another drug in violation of 21 C.F.R. § 201.6(a), cf. 21 CFR. § 202.1(e)(6)(ii). The flyer's representations concerning the effectiveness of Vivotif have not been demonstrated by substantial evidence or substantial clinical experience. In addition, the flyer violates section 502(a) in that it misidentifies Vivotif by using an incorrect proprietary name.
We request that Berna Biotech immediately cease disseminating promotional materials for Vivotif that contain claims the same as, or similar to, those described above. We request that all of your advertising and promotional labeling for Vivotif contain the correct proprietary name of the product, and that any PI that you disseminate be the most current approved version. In addition we recommend that in promotional materials you cite the current FDA approved PI rather than the PDR. Please submit a written response to this letter within 10 business days of the date of this letter, describing your intent to comply with this request, listing all promotional materials for Vivotif that contain claims the same as or similar to those described above, and explaining your plan for discontinuing use of such materials.
Please direct your response to Mr. Glenn N. Byrd, Chief, APLB, at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448, facsimile 301-827-3528. In all future correspondence regarding this matter, please refer to the BLA/STN number. We remind you that only written communications are considered official responses.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Vivotif comply with each applicable requirement of the Act and FDA implementing regulations.
If you choose to revise your promotional materials, APLB is willing to assist you in assuring that your revised materials comply with applicable provisions of the Act by reviewing your revisions before you use them in promotion.
----- signature -----
Mary A. Malarkey, Director
Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
cc: Andres Murai, Jr.