FDA approves Pfizer’s maternal RSV vaccine despite trial safety signals of increased premature birth

A recent article published in The British Medical Journal (“The BMJ”) details the debate that has broken out over whether Pfizer should have told pregnant women participating in its trial of maternal respiratory syncytial virus (“RSV”) vaccination that a trial of GSK’s similar vaccine was halted over a safety signal around pre-term birth.

Pfizer’s maternal RSV vaccine is called Abrysvo.

Not only had GSK’s RSV vaccine trials shown a risk of babies being born prematurely but Pfizer was actively studying the risk as an “adverse event of special interest” in its trials.

The BMJ article described its investigation into the safety signal of increased pre-term and neonatal deaths and whether pregnant women who participated in Pfizer’s trial were adequately informed of the risk to their babies. 

Recombinant RSV F protein vaccines are being developed by GlaxoSmithKline (“GSK”) and Pfizer to inoculate women during pregnancy. After safety concerns were raised: a potential increase in the risk for preterm births and neonatal deaths, GSK ceased its Phase 3 vaccine study on 28 February 2022.

GSK told The BMJ that the increase in preterm births was observed primarily in low and middle-income countries, driven particularly by South Africa. and not consistently after a peak in late 2021 and it was still investigating the cause of the pre-term births but was no longer developing its vaccine.

Pfizer was studying pre-term births as an adverse event of special interest in its own phase 3 trial, and a numerical (not statistically significant) increase in pre-term births has recently emerged in the data, although there are not enough data to understand if there is truly an increased risk or what the cause is.

Although 4 out of 14 members voted that the data presented by Pfizer were not adequate to support safety, the US Food and Drug Administration’s vaccines and related biological products advisory committee advised that Pfizer’s maternal RSV candidate was safe.

Committee member Paul Offit, professor of paediatrics at the Children’s Hospital of Philadelphia, said in a meeting that Pfizer’s and GSK’s vaccines were “almost identical” and so was concerned by GSK’s results.

Hana El Sahly, professor of molecular virology and microbiology at Baylor College of Medicine and committee chairwoman, said that the signal of increased preterm births connected to the Pfizer vaccine was “significant in the phase 2, in the phase 3, and in a very similar product,” adding that failing to design the Pfizer phase 3 study to deliver clarity was a “big missed opportunity.”

The FDA approved Pfizer’s Abrysvo vaccine with conditions, including only giving it to women who are 32-36 weeks pregnant to avoid the risk of pre-term birth. The FDA is requiring Pfizer to conduct post-marketing studies to “assess the signal of serious risk of pre-term birth.”

The European Commission approved Abyrsvo in August 2023.  The European Medicines Agency’s Committee for Medicinal Products for Human Use, recommends the vaccine for both older adults and maternal immunisation.

Abrysvo is not yet authorised in the UK, and the details of authorisation are not yet clear.

Did Pfizer Afford Pregnant Women in its Trial Informed Consent?

After GSK’s trial was halted, opinion was split among clinical trial ethicists and some vaccine researchers over whether Pfizer should have informed all women participating in its trial about the potential risk or updated its consent forms. Some think that only women who had not yet been vaccinated needed to be informed, whereas others think that because there is currently neither convincing evidence nor an explanation for the increased preterm risk, informing expectant mothers would have only caused unnecessary anxiety.

Charles Weijer, bioethics professor at Western University in London, Canada, told The BMJ that informing pregnant women in Pfizer’s trial about GSK’s results would have allowed women who had not yet received the injection to consider whether they still wanted to get it and women who had already received it to seek additional medical advice and follow-up. “Any failure to provide new and potentially important safety information data to trial participants is ethically problematic,” Weijer said.

The independent Data and Safety Monitoring Board (“DSMB”), which reviews and evaluates study data to protect participants’ safety and monitor the study’s progress, should normally have considered GSK’s results and decided if they merited attention, said Stephen Evans, emeritus professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine. They should not base their decision simply on whether a particular result is “statistically significant.” These are difficult decisions and it is why DSMBs are independent of the company, he told The BMJ.

The DSMB for the Pfizer trial didn’t answer The BMJ’s questions about whether it had considered the GSK results, and two trial investigators told The BMJ that they hadn’t received any communication from the DSMB regarding the results. Pfizer has also been criticised for a passage in some of its trial consent forms, seen by The BMJ, saying that its vaccine candidate was risk-free for the baby; a research ethics expert described this assurance as “misleading” and “irresponsible.”

Pfizer also did not respond to The BMJ’s questions on the issue of informed consent. So, The BMJ contacted governmental health authorities in all 18 countries where Pfizer had trial sites, as well as more than 80 trial investigators, and none answered saying that it had. Some confirmed that Pfizer continued to enrol and vaccinate women for months after the news of the potential risk of preterm birth in GSK’s vaccine trial was made public.

Clinical trial ethicists and some other experts think that Pfizer should have made pregnant women in its trial aware of the potential preterm risk; some trial investigators and health authorities disagree. “Once the results of the GSK trial on premature births became public, RSV vaccine studies in pregnant women should be updated to include this possible preterm risk,” said Klaus Überla, director of the Institute of Clinical and Molecular Virology of the University Hospital Erlangen and a member of the German RSV working group of the standing committee on vaccination.

“The renewal of informed consent is a must,” added Rose Bernabe, professor of research ethics and research integrity at the University of Oslo, pointing to the guidelines from the Council for International Organisations of Medical Sciences.

A trial investigator from South Africa, speaking on the condition of anonymity, said that participants should have been informed. But other trial investigators disagree.

Beate Kampmann, director of the Centre for Global Health at Charite University Hospital Berlin, one of the lead authors of Pfizer’s phase 3 trial publication, and who was responsible for a trial site in the Gambia, told The BMJ that GSK’s results weren’t relevant to her trial participants “as most participants were already in follow-up” and the Pfizer vaccine was not the same as the GSK product.

As the risk was uncertain and the cause of the increase in preterm births still not understood, amending the consent forms was not warranted, said Joop van Gerven, chair of the Dutch Central Committee on Research Involving Human Subjects (“CCMO”), a national ethics body responsible for the trial. The Spanish health ministry shared this view.

Pfizer’s Misleading Consent Forms

Pfizer did not disclose in patient consent forms for its phase 3 trial that it was studying preterm birth as an “adverse event of special interest,” documents from the US, Canada, the Netherlands, Finland, and New Zealand, obtained by The BMJ show. In addition, some Pfizer trial consent forms seen by The BMJ contain contradictory statements, warning of possible “life-threatening” effects of the vaccine on the baby while also carrying a passage saying that only the expectant mother is at risk from adverse effects.

“Knowing what we know now, the statement in question is irresponsible and, given the benefit of hindsight, is actually factually incorrect,” said Bernabe of the University of Oslo. “The statement gives the false sense of security that the foetus or neonate will not be exposed to any risk or inconvenience. Considering the gravity of the risk that this irresponsible statement veils, this misleading statement should be a ground for questioning the validity of the consent process.”

You can read the full article ‘Concerns over informed consent for pregnant women in Pfizer’s RSV vaccine trial’ published on 15 November 2023 by The BMJ HERE.