SILVER SPRING, MD. – Despite evidence of effectiveness and enthusiasm about its potential, more safety data in thousands of people are needed before a two-dose hepatitis B vaccine can be approved for use in adults, according to the majority of a Food and Drug Administration advisory panel.
At a meeting on Nov. 15, the FDA’s Vaccines and Related Biological Products Advisory Committee voted 13 to 1 that the immunogenicity data on the Heplisav vaccine were adequate to support its effectiveness in preventing hepatitis B infection in adults aged 18-70 years. The proposed indication for the vaccine, which combines hepatitis B surface antigen (HBsAg) with a novel adjuvant to enhance the immune response, is for the active immunization against all known subtypes of the hepatitis B virus in adults aged 18-70 years.
But the panel voted 8 to 5, with one abstention, that the available data were not adequate to support the safety of the vaccine, citing the need for more data because the adjuvant, a Toll-like receptor 9 agonist, is not included in any available vaccine. Almost 4,000 people received the vaccine in two phase III studies. The manufacturer, Dynavax Technologies, also has proposed a postmarketing safety study that will enroll up to 30,000 recipients of the vaccine in a managed care organization. Panelists voting no on the safety question said that more data from a more ethnically diverse population than those enrolled in the studies would be needed in as many as 10,000 patients before approval.
While a hepatitis B vaccine that is more immunogenic in populations that do not respond as well to the hepatitis B vaccines would be beneficial, "I don’t think the safety data is sufficiently large to support a recommendation for use in the general adult population given that this vaccine contains a new adjuvant," said one of the panelists, Dr. Melinda Wharton, deputy director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention.
The two Heplisav doses are administered intramuscularly 1 month apart, compared with the 0, 1, and 6 month schedule for the two currently approved hepatitis B vaccines, Engerix-B and Recombivax HB.
The two phase III noninferiority studies of healthy adults aged 18-70 years compared immune response to vaccination with Heplisav (administered at 0 and 1 months, with a saline placebo administered at 6 months) in 3,778 adults, and with Engerix-B (administered at 0, 1, and 6 months) in 1,089 people. The primary immunogenicity end point was the seroprotection rate (SPR) – an anti-HBsAg level of 10 mIU/mL or greater, recognized as conferring protection against hepatitis B virus infection. In both studies, the SPR results for Heplisav met the noninferiority criteria for the studies.
In the two studies, the SPRs were higher among those who received Heplisav: 95% and 90% at 3 months (8 weeks after the last active dose), compared with 81.1% (4 weeks after the last dose) and 70.5% (8 weeks after the last dose), respectively, of those who received Engerix-B.
The most common adverse event associated with the vaccine was injection-site reaction in both groups. Rates of severe adverse events were lower among those who received Heplisav, and rates of autoimmune events and autoantibody conversions were similar in the two groups, according to Dynavax.
However, thyroid-related adverse events, which could be representative of autoimmune events, were reported in a higher proportion of people who received Heplisav. Cases of serious events, although rare, included one of Wegener’s granulomatosis and one of Guillain-Barré syndrome. Autoimmune diseases are relatively rare in the general population, and a large sample size of patients was necessary to accurately evaluate the associated risk, according to the FDA reviewer.
An increased risk of autoimmune reactions is a theoretical risk with adjuvants.
The FDA’s deadline for making a decision on the approval is Feb. 24, 2013, according to Dynavax. If approved, the company plans to market the vaccine as Heplisav. The vaccine also is under review in Europe.
The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver for conflict of interest, but none were granted at this meeting.