Committee votes against recommending approval of Infanrix combination vaccine

April 2001

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.

Efficacy concerns

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 uncomfortable."

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 equation somewhat.

"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 ethnicities.

Safety concerns

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 significant fever."

"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 studies.