July 1997
BETHESDA, Md. — Members of the Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee unanimously agreed that Pasteur Mérieux Connaught's combination vaccine against diphtheria-tetanus-pertussis (DTP) and Haemophilus influenzae type b (Hib) diseases produced sufficient immune responses, and the rates of local and systemic reactions were acceptable when compared with the separate vaccines.
The advisory committee recently reviewed the TriHIBit vaccine and agreed that the data showed adequate safety, efficacy and immunogenicity for use in the primary immunization series. However, the committee also agreed post-marketing data should be reviewed to confirm the rate of local and systemic reaction.
"For those rare events ... we would need postmarketing to be able to nail down whether those more rare events are in fact meaningfully increasing," said Thomas Fleming, professor and chairman of the department of biostatistics, University of Washington, Seattle.
Most of the committee agreed that the combined product did not elicit as high an immune response to the Haemophilus polysaccharide as when the two vaccines were given separately. They were, however, uncertain of the clinical importance of this difference.
The vaccine is a combination of the company's Hib conjugate vaccine (ActHIB) reconstituted with its diphtheria and tetanus toxoids and acellular pertussis vaccine (Tripedia).
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FDA investigator Carl Frasch, PhD, said the antibody response with the combination vaccine compared with the separate vaccines was not significantly different for all vaccine antigens except the Hib conjugate, and that difference was not considered clinically important.
"The key question is: if we can achieve 100% with separate administration, and we would tolerate slightly less than that with combined, how much would we tolerate before we would judge that to be clinically meaningful?" added Robert Daum, MD, professor of pediatrics, University of Chicago.
Emmanuel Vidor, MD, Pasteur Mérieux Connaught director of clinical research, presented data from five studies showing safety and reactogenicity, efficacy and immunogenicity, as well as comparative studies using TriHIBit for the primary series. Pasteur Mérieux also presented data from studies using the DTaP-Hib vaccine as a primary series followed by a booster dose at 15 to 18 months.
Safety was demonstrated on over 4,300 infants using TriHIBit compared with ActHib and Tripedia given separately. "The safety profile is similar to that of the separate vaccines, said Jim Williams, MD, Pasteur Mérieux director of regulatory affairs. In addition, no clinically relevant variations for reaction rates were observed when TriHIBit was given as fourth dose to children primed with TriHIBit.
Despite the committee's majority vote of insufficient evidence, Williams said immunogenicity studies show three doses of TriHIBit produced an acceptable immune response to Haemophilus polysaccharide and is consistent with historical data. The combination vaccine elicits an immune response to pertussis toxin and filamentous hemagglutinin, which is comparable to the separate vaccines, Williams said.
The most common adverse events associated with the vaccine included low-grade fever and persistent crying; two vaccine-associated seizures were observed.
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