Lederle-Praxis' Acel-Imune acellular pertussis vaccine was recommended for approval as a booster to whole-cell vaccination by FDA's Vaccines & Related Biological Products Advisory Committee Jan. 29. The product license application for the combination diphtheria, tetanus, and pertussis vaccine for use as a fourth and fifth dose in children 18 months and older was submitted beginning in June 1990. Lederle-Praxis licensed the acellular pertussis vaccine from Takeda, which has marketed the product in Japan since 1981. Lederle-Praxis presented data from U.S. and Japanese clinical studies. Lederle-Praxis Clinical Research Director Jill Hackell, MD, told the committee that the acellular pertussis vaccine has been used in over 2,500 children in the U.S., representing more than 6,500 doses. Hackell presented the results of several clinical trials undertaken to demonstrate that the vaccine produces an antibody response comparable to that of the whole-cell vaccine. Hackell also presented safety studies showing "substantially" fewer side effects from the acellular pertussis vaccine. Pain and tenderness at the injection sight, erythema, fever, drowsiness, fretfulness and vomiting were all reduced 50%, she said. Incidences of contraindicating reactions such as seizure and extreme fevers were equally reduced. FDA's key concern about the Lederle-Praxis data related to the equivalency between the Lederle-Praxis vaccine and the Takeda product. FDA's questions were expressed by Drusilla Burns, PhD, of the Center for Biologics Evaluation and Research Pertussis Lab. Burns said FDA's concerns focused on the "bridging data" submitted by Lederle-Praxis. In order to demonstrate that the Lederle-Praxis vaccine has the same biological effect as Takeda's, Lederle analyzed a non-random sampling of sera from a Japanese study in the same lab that it used to analyze blood samples from American trials. Burns asked whether possible bias and methodological differences may have compromised those results. Committee member Catherine Wilfert, MD, Duke University Medical Center, summarized the committee's response to these concerns: "It would seem to me that the measurements we know how to make are equivalent, and that demonstration that antibody responses in children are equivalent for those antigens that we know how to measure is the best that we can do." The committee did not recommend that the vaccine "replace" the whole-cell pertussis vaccine for the fourth and fifth dose. CBER Acting Director Gerald Quinnan, MD, clarified the question put to the committee: "Perhaps the issue of whether or not this vaccine should 'replace' the existing vaccine is not the correct question, but there is a question [that is] very relevant." The question is whether the data is "limited in some way" that should be brought "to the attention of physicians so that they can make the correct judgment of whether or not one vaccine or another should be used in a given circumstance," Quinnan said. Committee Chairman Floyd Denny, MD, University of North Carolina, responded: "I had taken it as a given that the package insert would be very explicit in its directions for the use of this vaccine if it is released by FDA." FDA consultant David Karzon, Vanderbilt University School of Medicine, added that "it should be made very clear that this recommendation is limited to a fourth and fifth dose and that the data is not available to support its use for a primary series of doses." Chairman Denny closed the meeting with a cautionary note: "We all ought to be aware that the new acellular vaccines are not totally innocuous vaccines. There are reactions to these; and we are not going to remove, in my opinion, all the problems that now exist with the whole-cell vaccine by offering the public an acellular vaccine." In the open public hearing preceding the Lederle-Praxis discussion, Connaught Labs presented data for its acellular pertussis vaccine, JNIH-6. Connaught presented results from U.S. clinical trials at three centers, as well as data from a 1988 Swedish study. The Swedish trial originally showed slightly lower efficacy results than that of whole-cell vaccines ("The Pink Sheet" April 25, 1988, p. 11). The company, however, told the committee that the data had been reanalyzed to show 79% efficacy with JNIH-6, rather than 69% as originally believed. Connaught filed a PLA for the vaccine in 1989.
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