Members of the Vaccines and Related Biological Products Advisory Committee did not find the promise for a 30,000-patient post-market safety study sufficient to assuage their concerns about the risks of approving Dynavax Technologies Corp.’s hepatitis B vaccine Heplisav (rHBsAg-1018 ISS) for the general adult population.

The panel voted 8 to 5 with one abstention that available data do not support the safety of the vaccine in those 18 to 70 years of age; it accepted by 13 to 1 that immunogenicity data submitted with the BLA for Heplisav support the product’s efficacy. FDA did not ask for a vote on whether the vaccine’s benefits outweigh its risks.

Heplisav has been tainted by the possibility of causing an autoimmune response since a case of Wegener’s granulomatosis prompted FDA to temporarily put a clinical hold on the vaccine’s development Also see "Merck Returns Heplisav To Dynavax After FDA Rules Vaccine Too Risky For Healthy Adults" - Pink Sheet, 19 December, 2008..

With this safety issue in mind, committee members objected to the size of Heplisav’s safety database, particularly since the vaccine contains a novel adjuvant, 1018 ISS. “I would like to see a larger database … somewhere on the order of 10,000,” Edgar Marcuse, Seattle Children’s Hospital, said.

But a larger dataset may not be the solution. Bruce Gellin, HHS, noted the difficulty of looking for events with rare occurrences. “We have to be realistic that if you double or triple the number in the trial, you’re still looking for rare things to happen … they’re unlikely to light up in a study population of 8, 10, 15,000” when they occur at a rate of 1 in a million, he said.

The current safety population for the vaccine consists of 5,845 patients from Phase III and supporting trials. A total of 4,425 were administered Heplisav and 1,420 received GlaxoSmithKline PLC’s Engenerix-B, which was used as the comparator in pivotal trials for Heplisav. Follow-up for adverse events was 28 weeks in the two pivotal trials; for serious adverse events it was 28 weeks in one of the two pivotal trials and 52 weeks in the other.

Discussions With Managed Care On Cohort Study

Dynavax reported during the meeting that it has been in discussions with Northern California Kaiser Permanete to use the managed care system’s database to conduct a post-approval cohort study with patients who receive Heplisav compared to those vaccinated with Engenerix-B.

Prior to the meeting, Dynavax had said it would conduct an open-label, prospective, observational study to assess the incidence of medically significant adverse events, including autoimmune disease, in 5,000 individuals vaccinated with Heplisav, compared to 5,000 people vaccinated with Engenerix-B Also see "Dynavax Hepatitis B Vaccine Could Get Comparative Post-Market Autoimmunity Assessment" - Pink Sheet, 14 November, 2012..

The sponsor’s current thinking is that patients administered Heplisav and Engenerix-B would be enrolled at a ratio of one to three and their records monitored for ICD-9 billing codes to search for disequilibrium in event rates between the two groups, Dynavax Chief Medical Officer J. Tyler Martin said. The Heplisav cohort would also be examined for event rates by time interval.

Enrollment over a three-year period would total 30,000, a number thought large enough to detect events that occur at a rate of one in 10,000, Martin said. The sponsor has not discussed the follow-up period with FDA, but “it seems the minimum follow needs to be one year,” he said. An initial analysis of the data would occur when records for 5,000 patients are accrued.

Melinda Wharton, Centers for Disease Control and Prevention, said she would be more comfortable with a post-market safety study if the drug was approved for high-risk patients who would derive greater benefit from the vaccine.

FDA has until Feb. 24, 2013 to take action on the application.

FDA Panel Considers Dynavax’s Heplisav Safety Database Insufficient

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