BETHESDA, Md. Members of the FDA's
Vaccines and Related Biological Products Committee narrowly voted 6 to 5
against recommending approval of a combination vaccine that would protect
against five diseases.
Committee members generally felt the diphtheria, tetanus and
acellular pertussis, hepatitis B and inactivated polio vaccine
(InfanrixDTaP-HepB-IPV, GlaxoSmithKline) was efficacious and would be a
valuable addition to the vaccine arsenal.
However, they had some questions about efficacy against pertussis
and concerns about the largely homogenous study population. Additionally, they
expressed concern about an increased incidence of fever >38° C in
infants receiving the combination vaccine.
The manufacturer presented data from three trials. Much of the
data came from Germany, where children received the vaccine on a 3-, 4-,
5-month schedule, instead of the 2-, 4-, 6-month schedule used in the United
States. Study 011 was a large-scale safety trial comparing DTaP-HepB-IPV with
separately administered vaccines. The trial enrolled 4,696 German children into
the combination arm and 776 children into the control arm.
Study 015 was conducted in the United States and compared
immunogenicity and safety of the combination vaccine with separately
administered components. Two hundred children were enrolled in the combination
arm, and 100 children were enrolled in the control arm.
Study 044 compared lot consistency between the first and second
series and enrolled 484 U.S. children.
Additional studies included study 027, which looked at lot
consistency, safety and immunogenicity of DTaP-HepB-IPV when given with
Haemophilus influenzae type b (Hib) vaccine. The study enrolled 1,443
U.S. children. Study 003 (DTaP-HepB-IPV-Hib) compared safety after the birth
dose of HepB vaccine and enrolled 550 U.S. children.
Although committee members felt the combination vaccine was
generally efficacious, they expressed several concerns.
"There are a lot of 'what ifs' in my mind," said Pamela S. Diaz,
MD, medical director of communicable diseases, Chicago Department of Health.
"The data as they stand are reasonable in my mind, and yet the 'what ifs,' the
issues regarding lot-to-lot consistencies, the lack of any knowledge of how
this vaccine will behave in combination with pneumococcal 7-valent conjugate
vaccine (Prevnar, Wyeth Lederle) in particular, makes me a little
The small sample size of study 015 was a concern for many
committee members as well. "Basically I think this is probably an excellent
vaccine, that its immunogenicity is fine," said Diane E. Griffin, MD, PhD,
professor and chair, molecular microbiology and immunology at Johns Hopkins
University School of Hygiene and Public Health in Baltimore and professor of
medicine at Johns Hopkins University School of Medicine. However, "I would be
wildly more comfortable with much more data on this particular vaccine using
this schedule (2, 4, 6 months) in U.S. children. I think more data will show
that everything is fine."
Data from the 027 trial reassured many committee members.
However, they felt that combining the vaccine with Hib vaccine changed the
"The data from what I can read are probably adequate to support
efficacy," said David S. Stephens, MD, professor of medicine, microbiology and
immunology and director of the infectious diseases division at Emory University
School of Medicine in Atlanta. However, "I think we're being asked to make
certain assumptions regarding the efficacy of this vaccine. I'm encouraged more
by the 027 data than I am by the 015 data." Additionally, "I am somewhat
concerned by the issue of efficacy of this vaccine in all ethnic groups."
The study population in study 011 was 96.3% white, 0.5% black,
2.2% Asian and 1% other ethnicities. The 015 study population was 46% white,
12.3% black, 1% Asian and 40.7% other ethnicities. In the 044 study, the
population was 87% white, 2.5% black, 0.6% Asian and 9.9% other
Committee members also expressed concerns about safety,
especially regarding fever.
"We see fever that has increased at the lower range and also at
the intermediate range, to the point where fever of >101.5° F is
increased by about 5%," said Steve Kohl, MD, clinical professor at the Oregon
Health Sciences University in Portland and professor emeritus at the University
of California at San Francisco. "If this is a vaccine that is going to be
widely used, which I anticipate it will be, we're talking about 4 million kids
a year roughly. That's about 200,000 extra kids a year who are going to have a
"I think the big consideration is what the tradeoff is," Griffin
said. "You might be willing to have some percentage more children have fever
for [the convenience of] being able to use only one shot. The real issue is
what are the consequences of that, and we don't really know. I think the data
adequately say that we have a problem with more reactogenicity. What they
aren't adequate to say is in our medical system what the consequences are as
far as extra hospitalizations for these kids."
"It's one thing if it's a fever of 101° F, which is treated
with an antipyretic at home," said Michael A. Gerber, MD, professor of
pediatrics at the University of Cincinnati and a member of the Infectious
Diseases in Children editorial board. "It's another thing if it's going
to result in getting antibiotics, hospitalization or a physician visit. That's
the information I think we'll need."
Seizures were also a concern among some of the committee members.
Seven seizures (2 febrile, 5 afebrile) occurred among combination vaccine
recipients in studies 011 and 015. No seizures occurred among controls in these