Evaluating the Immune Response to Combination Vaccines
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Division of Biostatistics, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research
,
Food and Drug Administration, Rockville, Maryland
1
Division of Vaccines and Related Products Applications, Office of Vaccines Research and Review
Assessment of the immune responses to combination vaccines in the United States has generally been based on randomized, controlled comparative trials, with such studies designed to rule out predefined differences. In designing clinical studies of the immune response to combination products, attention should be directed toward selecting the appropriate immunologic end points and control groups. Acceptable differences in immune responses between combination and control groups should be predefined, and an adequate statistical plan should be developed. In many cases, it may be necessary to evaluate simultaneous administration of other recommended vaccines, assess schedule changes for 1 or more components of a combination, and bridge immunologic data obtained from international studies to the population of the United States. We discuss the use of immunogenicity studies to support the licensure of combination vaccines when field efficacy studies are either not possible or not required and highlight some recent experiences with combination vaccines containing Haemophilus influenzae type b polysaccharide conjugates.
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REGULATORY APPROACH
FOR EVALUATING IMMUNE RESPONSE
Regulations and guidance documents. In licensing
combination vaccines, the US Food and Drug
Administration (FDA) is directed by the Code of Federal
Regulations (CFR). A new license is required when
alreadylicensed products are combined or when unlicensed
components are added to a licensed vaccine [4]. Thus, already-licensed
vaccines may not be mixed extemporaneously before
administration unless a license has been obtained for the new
combination. In addition, regulations state that safe and effective
active components may be combined if each component makes
a contribution to the claimed effects and combining does not
decrease the purity, potency, safety, or effectiveness of the
individual components (emphasis added) [5]. In applying the latter
regulation, the FDA has relied on the concept that clinical
studies of combination vaccines should be designed to rule out
clinically significant differences, as described in the 1997
guidance document [1]. Characterizing the acceptable predefined
difference is critical to the optimal design of clinical studies of
combination vaccinations and will be discussed further below
in the section about determining acceptable differences in
immune response.
Determination of effectiveness: clinical efficacy versus
immunogenicity. As defined in the CFR, the effectiveness of
biological products is defined as the clinically significant
prevention of disease in a significant proportion of the target
population, with proof of effectiveness consisting of controlled
investigations [6]. Large-scale field trials demonstrating disease
prevention may be needed if the combination contains a novel
component without a generally accepted serologic correlate of
immunity, or if it is the first of its kind in a target population.
However, direct evidence of field efficacy may not be necessary
for some combinations. Once a vaccine for a particular
indication is licensed in the United States, placebo-controlled
clinical end point efficacy trials may no longer be possible because
of ethical considerations as well as the consequent reduction
in clinical disease incidence. Active-controlled field efficacy
studies comparing an investigational product to a licensed
vaccine with the same indication are ordinarily acceptable to the
FDA, but this approach may be impractical because of the large
sample size involved. Demonstration of clinical efficacy may
not be necessary if an accepted immune correlate of protection
exists [6].
In addition, demonstration of field efficacy may not be
necessary when adding new serotypes to an already-licensed
multivalent productfor example, meningococcal vaccine. For rare
serotypes in which clinical end point efficacy trials are not
feasible, it may be possible to infer efficacy from immune
response data, particularly if immune correlates of protection
have been identified for serotypes in which field efficacy was
demonstrated. Evaluation of functional immune responses
(e.g., opsonophagocytic antibody) may help to strengthen the
use of immune responses in these cases. If the new combination
vaccine includes an antigen for which an immune correlate of
protection has not been identified (e.g., pertussis), the approach
has been to demonstrate noninferiority of the immune response
S300 CID 2001:33 (Suppl 4) Ball et al.
to that elicited by separate administration of the licensed
vaccine (DTaP) containing that specific antigen. This approach is
discussed in more detail below in the section about statistical
considerations.
General considerations in the des (...truncated)