Combination vaccines make life easier for our patients. But until the payment and regulatory issues are resolved, the same is not true for us.
In January, the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee endorsed the overall safety and efficacy of Sanofi Pasteur's Pentacel, a combination vaccine containing diphtheria, tetanus toxoid, and acellular pertussis (DTaP), inactivated polio (IPV), and Haemophilus influenzae type b (Hib). If approved, that vaccine will compete with GlaxoSmithKline's Pediarix, which contains DTaP, IPV, and hepatitis B antigens.
Infants given a dose of hepatitis B (HB) vaccine at birth and then Pentacel at 2, 4, and 6 months of age would not be receiving an extra dose of HB vaccine, as they would with Pediarix. Some see this as an advantage to Pentacel, but my colleagues and I showed that the extra HB dose was not a problem in terms of reactogenicity or immunogenicity, even though it resulted in considerably higher anti-HB levels (Pediatr. Infect. Dis. J. 2002;21:854–9).
Pediarix is now widely used in the public sector through the Vaccines for Children Program. In that setting, it has resulted in improved immunization rates and reduced errors. But the private sector has been slower to adopt Pediarix, and I predict that the same will be true of Pentacel for the same reason: The current lack of appropriate administration fees continues to present a huge barrier to the use of all combination vaccines.
Of course, we all want to minimize pain for our patients by reducing the total number of injections we give them at any one visit. However, because most insurers will only pay one administration fee per injection—no matter how many antigens it contains—the loss of income incurred by switching from separate vaccines to combinations is an unacceptable burden for many practitioners.
Here in Rochester, N.Y., for example, physicians charge a $12 administration fee to cover the informed consent process, record keeping, storage, and wastage for each vaccine. The use of either Pediarix or Pentacel (if licensed), results in a loss of $24 per visit per child.
In my mind, it's absolutely wrong to view vaccine “administration” as simply putting a needle into a child's leg. The American Academy of Pediatrics and the vaccine manufacturers have been working to change this system. We can only hope that the anticipated licensure of Pentacel—which has the advantage of fitting better into the current immunization schedule—will add momentum to those efforts. With even more combination vaccines in the pipeline, the issue of loss of income will need to be resolved.
Another complex problem regarding combination vaccines, this one regulatory, now faces the FDA as it decides whether to follow the advisory panel's advice on licensing Pentacel. At the January hearing, the panel debated a great deal about the importance of a slight diminution in immunogenicity to the vaccine's Hib component in some of Sanofi Pasteur's studies (PEDIATRIC NEWS, “FDA Panel Backs Five-in-One Combination Vaccine,” February 2007, p. 18).
Since 1997, the FDA has required that all components of a vaccine be noninferior to those of the separately administered antigens. The regulation has been widely interpreted to mean that a combination vaccine containing a Hib component must elicit an antibody response of at least 90% of the response to the separate Hib antigen; Pentacel technically did not meet all the criteria with regard to absolute antibody levels.
In contrast, European and Canadian licensing boards have decided that immunologic memory is more important than absolute antibody levels. Thus, a combination vaccine containing Hib conjugate has been licensed in many European countries because it establishes immunologic memory, even though the antibody response is more than 10% lower. Pentacel itself has been licensed in Canada since 1997 and used exclusively there since 1998, with more than 12 million doses distributed. It also is used in several European countries.
In Canada and in Germany, rates of Hib disease have remained very low or nondetectable since Hib-containing combination vaccines were introduced. Seems to me the Europeans got it right.
To resolve this discrepancy in regulatory policy, I think that the FDA needs to look at one more piece of the clinical trial data that it is not currently considering: Among vaccine recipients who don't meet the absolute noninferior antibody level, what is the proportion of nonresponders, compared with the proportion whose titers are just beneath the threshold? I'm not worried about the child whose level is at 89%. Thanks to immunologic memory, that child will be protected.
Rather, the important question is whether there is a large proportion with little or no anti-Hib antibody following immunization. Having participated in many of these trials, I can tell you the answer is no. The manufacturers have those data. The FDA needs to start considering them, in order to bring to the market more combination vaccines that could improve the health and well-being of our patients.