6:06 PM
 | 
Aug 04, 2017
 |  BioCentury  |  Regulation

Final stretch

Why design of a postmarketing CV study has delayed Dynavax’s Heplisav-B, again

Following a long and bumpy regulatory road, it appears Heplisav-B from Dynavax Technologies Corp. is finally in the home stretch. But how the company and FDA handle the final hurdle -- the design of a postmarketing CV safety study -- may determine whether bigger challenges lie ahead.

What makes the problem interesting is that the patients in whom Heplisav-B is most effective are also those most at risk of myocardial infarction.

That could make it difficult for Dynavax to enroll enough high-risk patients in the observational study it has proposed to assess the actual risk represented by an imbalance in MIs, which occurred at low rates in a Phase III trial.

Panel members at a July 28 meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted 12 to one, with three abstentions, that the available data support Heplisav-B’s safety. They were not asked to make a recommendation on approval.

One member suggested that the FDA label include a warning or alert for patients with increased CV risk factors.

And although they thought the MI finding was likely due to chance, all members agreed on the need for a stringent postmarketing study to further assess the risk of MI. They questioned whether Dynavax’s proposed postmarketing study could quickly and definitively answer questions about the product’s CV safety.

On Aug. 3, according to the company, issues related to designing such a study prompted FDA to request more information.

Specifically, Dynavax said the agency asked for details about the timeline for the study’s protocol submission, completion and final report submission; timeliness of accruing patients; time points for data review; measures to control potential biases between study arms; and an updated statistical analysis plan.

The agency’s request delays the PDUFA date by three months to Nov. 10.

Looking for trouble

Heplisav-B has been the subject of two complete response letters. Ironically, the study Dynavax performed to address the concern outlined in the first CRL is what revealed the MI signal that led to the second.

The first CRL was concerned with the risk that rare autoimmune adverse events might be caused by agonizing toll-like receptor...

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