November 21, 2007
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Gary Chikami, MD
Associate Vice President
Regulatory Affairs North America
and Authorized Official
sanofi pasteur Inc.
Swiftwater, PA 18370
BLA STN #103935
ActHIB® [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)]
Dear Dr. Chikami:
The Advertising and Promotional Labeling Branch (APLB) in the Food and Drug Administration’s Center for Biologics Evaluation and Research has reviewed a professional journal advertisement (MKT 12447) (enclosed) for ActHIB [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] submitted by your firm under cover of Form FDA 2253. This piece makes unsubstantiated superiority claims for ActHIB. Thus, it misbrands the drug in violation of the Federal Food, and Drug, and Cosmetic Act (Act), 21 U.S.C. § 352(n), and FDA's implementing regulation, 21 CFR 202.1 (e)(6)(i).
ActHIB is a lyophilized powder that can be reconstituted with a saline diluent (0.4 % Sodium Chloride), or Sanofi Pasteur Inc. Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP; Tripedia®), and used according to the Indications and Usage section of the FDA-approved professional labeling (PI; version dated December 2005):
- ActHIB vaccine is indicated for the active immunization of infants and children 2 through 18 months of age for the prevention of invasive disease caused by H influenzae type b and/or diphtheria, tetanus and pertussis.
- TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, is indicated for the active immunization of children 15 to 18 months of age for the prevention of invasive disease caused by H influenzae type b and diphtheria, tetanus and pertussis.
The number of ActHIB doses indicated for previously unvaccinated infants depends on the age at which immunization begins, and is described in the PI.
The clinical pharmacology section of the PI states (in pertinent part) that a 3-dose primary series of ActHIB administered to previously unvaccinated infants induced a protective anti-PRP antibody response measured one month post-dose 3 (i.e., at 7 months old) and were considered protective when a 3-dose ActHIB primary vaccination series was administered to previously unvaccinated infants. Infants, after a 2-dose primary series of PRP-OMP [Merck and Co, Inc; PedvaxHIB®], were considered protected at an earlier age (i.e. before 6 months of age). Factors other than the peak PRP antibody level are important to consider in the evaluation of Hib conjugate vaccine effectiveness, such as the immune response observed after the initial Hib conjugate dose and the pattern of antibody response after each dose.
Misleading Superiority Claims
Promotional materials are false or misleading if they contain a drug comparison that represents or suggests that a drug is safer or more effective than another drug in some particular when such has not been demonstrated by substantial evidence or substantial clinical experience.
The professional journal advertisement is misleading because it states that ActHIB is superior to PedvaxHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] and HibTITER [Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate)], when this has not been demonstrated by substantial evidence or substantial clinical experience. Specifically, the professional journal ad includes the following claims:
- “The most vulnerable need the most reliable”
- “Protect your patients with ActHIB vaccine-the only Hib conjugate vaccine proven in 3 head-to-head clinical trials to provide superior seroprotection.2-4”
- “Proven superior to PedvaxHIB® (Haemophilus b Conjugate Vaccine [Meningococcal Protein Conjugate]) 2-4”
- Provides higher post-vaccination antibody titers compared with HibTITER® (Haemophilus b Conjugate Vaccine [Diphtheria CRM197 Protein Conjugate])2-4”
None of the three referenced clinical studies was prospectively designed to assess the superiority of ActHIB over PedvaxHIB or HibTITER. The first study, Decker et al. (1992), was a double-blind, randomized trial that compared the immunogenicity and reactogenicity of four conjugate Haemophilus influenzae type b vaccines (ActHIB, HibTITER, PedvaxHIB, and ProHIBIT) given at 2, 4, and 6 months of age. The second study, Greenberg et al. (1995), was a randomized trial to evaluate antibody responses to several different sequences of heterogeneous Hib conjugate vaccines (ActHIB, HibTITER, and PedvaxHIB) compared to conventional schedules of single Hib vaccines given at 2, 4, and 6 months of age. The third study, Granoff et al. (1992), was a multicenter, randomized trial in infants 2, 4 and 6 months of age to compare the immunogenicity of three Hib conjugate vaccines (ActHIB, HibTITER, and PedvaxHIB). These studies compared the anti-PRP antibody response to the vaccines after the primary immunization series, without considering the antibody kinetics after each dose, which may not be predictive of the overall efficacy of the individual Hib conjugate vaccines. Further, these studies were not intended to evaluate the superiority of ActHIB.
In fact, FDA is not aware of any comparative clinical trials which demonstrate superior protection of ActHIB, either by substantial evidence or substantial clinical experience, compared to PedvaxHIB or HibTITER. If you have such evidence, please submit them for review.
Conclusion and Requested Action
For reasons discussed above, your professional journal advertisement misbrands ActHIB in violation of section 502(n) of the Act (21 U.S.C. § 352(n)), and FDA's implementing regulation, 21 CFR 202.1(e)(6)(i).
We request that sanofi pasteur immediately cease the dissemination of the violative promotional material for ActHIB as described above. Please submit a written response to this letter within ten (10) business days of the date of this letter, stating whether you intend to comply with this request, listing all violative promotional materials for ActHIB and explaining your plan for discontinuing use of such materials. Please direct your response to Ms. Ele Ibarra-Pratt, RN, MPH, Branch Chief at the Food and Drug Administration, 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, Maryland 20852-1448. 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 ActHIB 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.
/Robert A. Sausville/
Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research