An investigation by The BMJ has reported on a debate taking place among medical ethicists over whether pharmaceutical giant Pfizer should have told pregnant women taking part in a trial of its maternal respiratory syncytial virus (RSV) vaccine that a trial of a similar GSK vaccine in pregnant women was stopped over a safety signal concerning an increased risk of preterm birth.
Both the GSK and Pfizer vaccines used the same recombinant RSV F protein technology to inoculate pregnant women with the aim of protecting their babies against RSV. The BMJ analysis, by freelance journalist Hristio Boytchev, said that there were "not enough data to understand if there is truly an increased risk or what the cause is".
Clinical trial ethicists and vaccine researchers were divided on whether Pfizer should have informed all participating women about the potential risk.
Pfizer's vaccine candidate, Abrysvo, has been approved for use in the European Union. However, the Medicines and Healthcare products Regulatory Agency (MHRA) has not yet authorised it in the UK. In July, GSK's vaccine, Arexvy, became the first RSV vaccine to be authorised in the UK, but it was restricted to use in people aged 60 years and over.
According to The BMJ's investigative feature, in the GSK trial, 6.81% (95% CI, 5.99-7.69%) of births were preterm in the vaccine arm, compared with 4.95% (CI 3.97-6.07%) in the saline placebo arm. For neonatal deaths, the respective percentages were vaccine 0.37% (0.20-0.64%) versus placebo 0.17% (0.04-0.50%).
No clear explanation was found for the increase in preterm births, but the phase 3 trial was halted in February 2022. GSK told The BMJ that the cause was still being investigated, but it was no longer developing its vaccine.
Pfizer was assessing preterm births as an "adverse event of special interest" in its own phase 3 trial, after an imbalance in preterm births emerged in the data: a 5.7% (CI, 4.9-6.5%) premature birth rate in the vaccine arm versus 4.7% (CI, 4.1-5.5%) in the inactivated influenza vaccine placebo arm.
JCVI Reassured
The UK's Joint Committee on Vaccination and Immunisation (JCVI) said in September that either passive immunisation of neonates with monoclonal antibody or maternal active immunisation would be suitable for a universal programme to protect neonates and infants from RSV, and it did not have a preference between the two options.
Its scrutiny of the Pfizer data showed that the excess of preterm birth was confined to upper middle-income countries, South Africa, and Brazil. The Committee was "relatively reassured" that there was not an obvious signal of preterm births in high-income countries, and the safety data "does not raise significant concerns on its potential use in an RSV programme".
However, Pfizer's failure to inform pregnant women in its trial about the GSK results was described as "ethically problematic" by Charles Weijer, bioethics professor at Western University in London, Canada. He told The BMJ that informing women would have allowed those in the trial who had not yet received the vaccine to "consider whether they still wanted to get it", while women who had already received it might have sought additional medical advice and follow-up.
Stephen Evans, emeritus professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, told the journal that the independent Data and Safety Monitoring Board (DSMB) "should have regularly assessed the benefit-harm balance" on the Pfizer product, both on the data in its own trial and on whether the GSK results affected that balance.
However, the Board, responsible for evaluating study data to protect participants' safety, did not answer The BMJ's questions about whether it had considered GSK's results.
Questions Over Consent Forms
Pfizer also did not respond to the journal's questions about informed consent for the trial, some consent forms for which stated that the vaccine candidate was risk-free for the baby. Rose Bernabe, professor of research ethics and research integrity at the University of Oslo, said that "given the benefit of hindsight", such a statement was "irresponsible", "factually incorrect”, and could give a "false sense of security". "Considering the gravity of the risk", the "misleading" statement "should be a ground for questioning the validity of the consent process", she added.
In contrast, Joop van Gerven, chair of the Dutch Central Committee on Research Involving Human Subjects, the national ethics body responsible for the trial, told The BMJ that changing the consent forms "would have caused too much uncertainty" for women who had already received the vaccine.
The BMJ also reported that Paul Offit, professor of paediatrics at the Children's Hospital of Philadelphia and a member of the U.S. Food and Drug Administration (FDA)'s vaccines and related biological products advisory committee, said that he was "concerned" by GSK's results, and that the Pfizer and GSK vaccines were "almost identical".
The FDA panel voted unanimously that Pfizer's maternal RSV candidate was effective in protecting infants from severe RSV infection during their first 6 months. However, the panel was split on the question of safety, with four of its 14 members voting that Pfizer's data were "not adequate to support safety" on preterm births. The FDA approved it with a warning that to avoid the potential risk of preterm birth, it should be administered to pregnant women only between 32 and 36 weeks gestation.
U.S. prescribing information for the vaccine Abrysvo now states that "available data are insufficient to establish or exclude a causal relationship between preterm birth and Abrysvo". The FDA is also requiring Pfizer to conduct postmarketing studies to "assess the signal of serious risk of preterm birth".
However, neither the JCVI nor the European Medicines Agency considers it necessary to give a warning about the possible risk of preterm birth, or to restrict use of the vaccine to the later weeks of pregnancy, according to the report.
