he Food and Drug Administration recently had a very important question about a new hepatitis vaccine and wanted advice.
Hepatitis B is a serious disease that can damage the liver. A company called Dynavax has developed a new vaccine that stimulates the body to produce antibodies against the hepatitis B virus more vigorously than existing vaccines do, and with just two doses instead of the usual three. The vaccine works through a unique adjuvant — a substance that improves the body’s immune response to the virus. The advantages of the Dynavax vaccine were demonstrated in a randomized trial of more than 8,000 patients: About 5,600 received the new vaccine and about 2,800 received the existing standard hepatitis B vaccine.
During the trial, though, 14 people in the Dynavax group had heart attacks compared to just one in the conventional vaccine group. Since the Dynavax group was twice as large, the heart attack risk was seven times higher with the new vaccine.
The FDA wanted to know if the new vaccine should be approved for use in millions of people.
To help make a decision, it convened a public advisory committee meeting on July 28. The members of the committee consisted primarily of experts in infectious diseases and immunology. I was the only cardiologist on the committee.
If the 7-1 imbalance was due to the play of chance, then the issue of myocardial infarction risk was spurious, and the vaccine should be approved. But if the 7-1 imbalance reflected a real increase in cardiovascular risk, then approving the Dynavax vaccine would be problematic.
The advisory committee needed to consider whether it was biologically plausible for the new vaccine to cause heart attacks.
The new adjuvant in the vaccine caused an inflammatory response of uncertain duration. We know that inflammation causes atherosclerotic plaques in coronary arteries to rupture — the event that triggers most heart attacks. So a causal link between the vaccine and heart attacks wasn’t out of the question.
Most importantly, we needed to decide if the imbalance in heart attacks between the two groups could have been due to the play of chance. That was a great question, but one that was impossible to answer. Many might think that calculating a p-value would help, but it wouldn’t. P-values have a place in clinical trials, but not when the number of events is so small and the number of comparisons so great. So no one asked for or showed any p-values during the meeting. Everyone agreed that statistics could not resolve the uncertainty.
To know if the 7 -1 heart attack imbalance represented a real risk, we’d need comparative data in 50,000 people. The fastest way of obtaining that evidence would be through a post-marketing trial. But a post-marketing trial would be possible only if the vaccine was approved for public use.
The FDA asked the committee if there was reasonable evidence that the vaccine was safe. Twelve committee members voted in favor of the safety of the new vaccine, one voted against it, and three abstained. I was one of those who abstained. The vote is nonbinding. The FDA had originally said it would decide on the new vaccine by Aug. 10, but late yesterday asked Dynavax for more information about the company’s post-marketing study. An FDA decision about the vaccine is now expected in November.
Why did I abstain? Based on the available data, it was impossible for anyone to know if the increase in heart attack risk in the Dynavax group was real or spurious. So although the questions were fascinating and the discussions terrific, my vote wasn’t that complicated.
There is a simple rule in life: if you don’t know, you should say you don’t know.
Milton Packer, M.D., is the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center at Dallas. A version of this article originally appeared as part of his “Revolution and Revelation” column on MedPageToday.
This article was updated to reflect the FDA’s request for more information about the Dynavax vaccine.