December 18, 2003
Ms. Janet Ernst Gerner
Director, Marketing Communications
Merck & Co., Inc.
770 Sumneytown Pike
P.O. Box 4
West Point, PA 19486-0004
Re: BLA STN #103623
Comvax [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and
Hepatitis B (Recombinant) Vaccine]
Dear Ms. Ernst Gerner:
Through routine monitoring and surveillance, the Advertising and Promotional Labeling Branch (APLB) of the Center for Biologics Evaluation and Research (CBER) in the Food and Drug Administration (FDA) has identified a Dose Spacing Slide Rule (20302533-01-CMV) (the Slide Rule) for your product, Comvax [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine], that is false or misleading under the Federal Food, Drug, and Cosmetic Act (Act) and FDA implementing regulations. 21 U.S.C. § 352(a); 21 C.F.R. § 201.6(a). Specifically, APLB has determined that the Slide Rule contains a false or misleading representation with respect to Pediarix [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined], which is manufactured by GlaxoSmithKline, and its "compliance" with certain immunization recommendations issued by the Centers for Disease Control and Prevention (CDC) and approved by the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP). The Slide Rule thus discourages health care providers from using Pediarix pursuant to its FDA-approved labeling.
According to the approved labeling (PI), Comvax is indicated for "vaccination against invasive disease caused by Haemophilus influenzae type b and against infection caused by all known subtypes of hepatitis B virus in infants 6 weeks to 15 months of age born of HBsAg negative mothers." The recommended dosing schedule for such infants, according to the PI, is three doses, "ideally at 2, 4, and 12-15 months of age." The PI further states: "If the recommended schedule cannot be followed, the interval between the first two doses should be at least six weeks and the interval between the second and third dose should be as close as possible to eight to eleven months."
According to its PI, Pediarix is indicated for "active immunization against diphtheria, tetanus, pertussis (whooping cough), all known subtypes of hepatitis B virus, and poliomyelitis caused by poliovirus Types 1, 2, and 3 as a three-dose primary series in infants born of HBsAg-negative mothers, beginning as early as 6 weeks of age." According to the PI, the primary immunization series for Pediarix is three doses at "6- to 8-week intervals (preferably 8 weeks)." The PI states, further: "The customary age for the first dose is 2 months of age, but it may be given starting at 6 weeks of age." Finally, according to the PI, a "delay between doses should not interfere with the final immunity achieved with Pediarix. There is no need to start the series over again, regardless of the time elapsed between doses."
The Recommended Childhood and Adolescent Immunization Schedule -- United States, 2003, which was published by the CDC and approved by the AAP, the AAFP, and the ACIP, recommends that, with respect to hepatitis B vaccine, "the second dose should be given at least 4 weeks after the first dose," and the "third dose should be given at least 16 weeks after the first dose and at least 8 weeks after the second dose." The CDC also publishes a "catch-up schedule" for children who have delayed immunizations. This schedule provides minimum intervals between doses for a number of childhood vaccines. For hepatitis B vaccine, the minimum interval between doses one and two is four weeks, and the minimum interval between doses two and three is eight weeks, with a minimum of sixteen weeks between doses one and three.
False or Misleading Representation
The Slide Rule consists of two pull-out tables that compare the dosing schedules of Comvax and Pediarix for "[c]ompliance with AAP/ACIP minimum hepatitis B dose-spacing." One table compares Comvax to Pediarix for compliance with "AAP/ACIP minimum hepatitis B dose spacing between Doses 1 and 3 (16 weeks)" when the two-month visit (i.e., the first dose) is delayed by one to four weeks. The second table compares Comvax to Pediarix for compliance with "AAP/ACIP minimum hepatitis B dose spacing between Doses 2 and 3 (8 weeks)" when the four-month visit (i.e., the second dose) is delayed by one to four weeks. According to the Slide Rule, when the two-month visit is late by one week, Comvax complies with the AAP/ACIP recommendations for minimum hepatitis B dose spacing, while Pediarix does not. The Slide Rule claims that Comvax complies with the recommendations and that Pediarix does not when the two-month visit is late by two, three, and four weeks, and when the four-month visit is late by one, two, three, and four weeks. The Slide Rule thus represents that, in each of the eight dosing scenarios, Comvax is in "compliance" with AAP/ACIP recommendations for minimum hepatitis B dose spacing and Pediarix is not.
This representation is false or misleading. First, Pediarix will not always be non-compliant with AAP/ACIP recommendations when doses are delayed as described in the Slide Rule. For example, if, under the "2-month visit" table, the first dose of Pediarix is late by one week (i.e., given at two months plus one week), the second dose is given at seventeen weeks, and the third dose is given at 25 weeks, Pediarix would, in fact, be compliant with AAP/ACIP recommendations because there would be an interval of sixteen weeks between the first and third doses1. Similarly, if, under the "4-month visit" table, the second dose is delayed by four weeks, and the third dose is given at 28 weeks, the schedule would comply with AAP/ACIP recommendations because there would be an interval of at least four weeks between the first and second doses, at least eight weeks between the second and third doses, and at least sixteen weeks between the first and third doses. A health care provider could make similar adjustments for every delayed dosing scenario described in the Slide Rule.
The disclaimer, appearing in small print in one part of the Slide Rule and conveying that Pediarix fails to comply with AAP/ACIP recommendations if the third dose is given "on time at 6 months of age," is insufficiently prominent to correct the false or misleading representation that Pediarix does not comply with the recommendations in the scenarios described in the Slide Rule. Moreover, the disclaimer itself is false or misleading, in that it implies that the third dose of Pediarix must be given at 24 weeks (6 months), when according to the PI for Pediarix, the primary immunization series is three doses at, "6- to 8-week intervals (preferably 8 weeks)," and a late dose is unlikely to affect final immunity.
Conclusion and Requested Action
The Slide Rule misbrands Comvax within the meaning of 21 U.S.C. § 352(a) because it falsely or misleadingly represents that Pediarix, in certain dosing scenarios, is not in "compliance" with AAP/ACIP recommendations. 21 C.F.R. § 201.6.
You should immediately cease the dissemination of all promotional materials containing representations that are the same as, or similar to, those described above. If you choose to disseminate revised promotional materials, APLB is willing to assist you to ensure that your revised materials are in compliance with applicable provisions of the Act and FDA regulations. APLB requests that you respond within ten business 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 similarly violative materials, a description of the method for discontinuation, and the discontinuation date.
Your response should be directed to Mr. Glenn N. Byrd, Chief, APLB, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality Division of Case Management, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448 (facsimile (301) 827-3528). If you have any questions or concerns involving this matter, please contact Dr. Yongkai Weng, Consumer Safety Officer, at 301-827-3028.
This letter is not intended to be an all-inclusive list of deficiencies associated with advertising and promotional labeling for your product. It is your responsibility to ensure that advertising and promotional labeling distributed by you or on your behalf within the United States for the product complies with each applicable requirement of the Act and of FDA regulations.
----- signature -----
Mary A. Malarkey
Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research