A panel of independent expert advisors to the Food and Drug Administration on Thursday voted largely in favor of the agency approving Pfizer’s vaccine to protect children against the RSV respiratory virus — respiratory syncytial virus (sin-SISH-uhl) — which can be fatal to infants.
The vaccine, tentatively called Abresfu, is given to pregnant women between 24 and 36 weeks of gestation, which allows protective antibodies to develop and then cross the placenta to protect the fetus.
In a phase III trial involving nearly 7,400 pregnant women in 18 countries, the vaccine was approximately 82 percent effective in preventing severe RSV disease in the first 90 days of a child’s life. It was 69 percent effective after 180 days. With regard to protection against non-severe respiratory illness from respiratory syncytial virus, trial results did not meet statistical criteria for finding efficacy at 90 days, but data from 180 days indicate efficacy of about 51 percent.
In the first two votes at today’s meeting, FDA advisors voted unanimously, 14 to 0, that the efficacy data looked good and suggested that the vaccine would protect children against respiratory syncytial virus.
But the safety statements, which were the focus of the second vote, gave some members pause. While the vaccine appeared largely safe for pregnant women and infants compared to a placebo, data from the Phase II trial and the Phase III trial included a muted sign that vaccination could increase the risk of premature birth. In the phase 3 trial, there were 201 babies born prematurely (before 37 weeks) in the vaccination group, while there were only 169 premature babies in the placebo group. Of these premature births, 21 in the vaccination group had premature births (before 34 weeks), while there were only 12 premature births in the placebo group.
The differences were generally not statistically significant, and the rates of preterm birth were lower than normally observed in the general population. But, as several FDA advisors have noted, the Phase 3 trial was not set up to address this indication, despite seeing it in a previous Phase 2 trial. There was also an imbalance in where the signal was seen; Pfizer representatives confirmed that there was no difference in premature births among trial participants in high-income countries, including the United States.
Fears, but mostly excitement
On its own, this muted data may not be enough to raise concerns. But it alarmed some advisers, who noted that GSK, another pharmaceutical giant, had developed its own RSV vaccine and encountered the same signal. GlaxoSmithKline had a vaccine of the same design and dose similarly administered to pregnant women at the same gestational age of 24 to 36 weeks. In its Phase III trial, GSK experienced a statistically significant increase in preterm births. The company dropped the trial because of this.
It matters when a drug company abandons a trial, Dr. Paul Offit, a professor of pediatrics at the Children’s Hospital of Philadelphia, noted in the discussion section of the meeting. “These decisions are never taken lightly,” Offit said.
When the vote came in on whether the vaccine’s safety data was sufficient, it was a 10 to 4 breakdown, with Offit among the four who voted “no.” After the vote, he reiterated that the data provided by Pfizer did not ease his concerns about GSK’s results. “If you are in any way risking preterm labor with this vaccine, I think there is going to be a heavy price to pay,” he warned.
But most panelists were less alarmed by the uncertainty about the preterm birth signal, and some expected it would reveal a statistical anomaly, which is missed when the vaccine is given to larger numbers. Some members also noted that trial data on birth weights and similar rates of developmental delay were reassuring that the vaccine was safe. Pfizer has set up a post-market monitoring system to try to track such results.
In general, many advisors were excited about the vaccine’s potential. The efficacy is “very exciting,” said Amanda Cohn, director of the Division of Birth Defects and Infant Disorders at the Centers for Disease Control and Prevention, after voting “yes” to both efficacy and safety questions. This is a really important tool for prevention. [I’m] Very excited.”
In the United States, RSV is among the leading causes of hospitalization for children under 5 years of age. In a typical RSV season, the virus sends between 58,000 and 80,000 children under 5 to the hospital, and between 100 and 300 die from the infection, the CDC estimates.
The Food and Drug Administration will now decide whether to approve the vaccine. If that happens, the CDC will approve recommendations for its use in the United States.
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