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When Pfizer conducted a large clinical trial to test a new respiratory syncytial virus (RSV) vaccine for pregnant women — aimed at protecting their babies — the pharmaceutical giant failed to inform trial participants that GlaxoSmithKline Biologicals (GSK) had halted its trial for a similar vaccine due to a concerning safety signal showing a potential risk of preterm birth.
Even though Pfizer knew about the GSK trial and safety signal, it continued enrolling thousands of unsuspecting pregnant women without disclosing the preterm birth risk in its consent forms, according to an investigation by The BMJ.
To many healthcare advocates and experts, Pfizer’s omission represents an egregious violation of informed consent and a disregard for the autonomy of pregnant women participating in clinical research.
“Any failure to provide new and potentially important safety information data to trial participants is ethically problematic,” Dr. Charles Weijer, bioethics professor at Western University in London, Ontario, Canada, told The BMJ.
Children’s Health Defense CEO Mary Holland told The Defender:
“I am horrified that it’s even a question whether Pfizer should have told pregnant women that a previous clinical trial was halted because the RSV vaccine caused preterm birth. Of course it should have told them.
“The standard must be, ‘What would a reasonable pregnant woman want to know about this product?’ And any reasonable pregnant woman would want to know if it causes preterm birth. This cavalier attitude towards the truth and human life is alarming.”
After the safety signals emerged in GSK’s study, the U.S. Food and Drug Administration (FDA) took no action to halt enrollment or to pause or restrict Pfizer’s ongoing maternal RSV vaccine trial.
‘Statistically significant’ shouldn’t form sole basis of Pfizer’s decision
Months after GSK’s revelation of the concerning safety signal, Pfizer also began detecting a numerical imbalance in preterm births in its own trial data but said the data were not statistically significant.
According to The BMJ, Pfizer was tracking preterm births as an “adverse event of special interest” in its trial. But the company did not disclose this on consent forms given to thousands of pregnant trial participants across 18 countries.
“Once the results of the GSK trial on premature births became public, RSV vaccine studies in pregnant women should have been updated to include this possible preterm risk,” said Klaus Überla, Ph.D., chair of Clinical and Molecular Virology at the University Hospital Erlangen, in The BMJ report.
However, regulators took little action to encourage disclosure. The FDA ultimately limited approval of Pfizer’s vaccine to late pregnancy — specifically, for administration between 32-36 weeks only — due to preterm concerns. But the agency did nothing to restrict trial enrollment or require risk disclosure after the GSK findings emerged.
Some defend Pfizer’s lack of disclosure to trial participants by arguing the preterm risk was inconclusive. Dr. Joop van Gerven, an ethics chair in the Netherlands, told The BMJ that informing women “would have caused too much uncertainty.”
However, others challenged this notion. “The renewal of informed consent is a must,” Rose Bernabe, Ph.D., told The BMJ.
Bernabe, a professor of medical research ethics at the University of South-Eastern Norway, referenced guidelines from the Council for International Organizations of Medical Sciences, which state: “Researchers must renew the informed consent … if new information becomes available that could affect the willingness of participants to continue.”
“For Pfizer, the DSMB [Data Safety and Monitoring Board] should have regularly assessed the benefit-harm balance, both on the data in the trial and whether the GSK results affected that balance. 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.”
Justine Tanguay, CHD lawyer and director of campaign research for Reform Pharma, told The Defender:
“It’s no surprise that regulatory agencies such as the FDA are prioritizing Big Pharma’s profit over the health interests of its pregnant trial participants when you pull back the curtain and expose the revolving door between government’s top federal employees and key executives for Big Pharma — the industry that FDA is supposed to be regulating.
“In fact, the revolving door has become so commonplace that it is hard to decipher the tangled mess between the private sector and governmental agencies.
“For instance, a former deputy director at the FDA who ran the Office of Vaccines Research and Review and pushed for the licensure of COVID-19 vaccines now works for Moderna as the head of the Infectious Diseases Early Clinical Development and Translational Medicine Program.
“For the sake of public health, such egregious conflict of interests must end.”
‘I think it needs to be addressed’
According to The BMJ investigation, in February 2022, GSK reported that a safety signal had emerged in its maternal RSV vaccine trial, indicating a concerning imbalance in preterm births between the vaccine and placebo groups.
Specifically, GSK observed that 6.81% of births in the vaccine arm were preterm, compared to just 4.95% of births in the placebo arm. Additionally, neonatal deaths were 0.37% in the vaccine group versus 0.17% in the placebo group.
This unexpected safety signal prompted GSK to immediately halt its Phase 3 trial and discontinue the development of its vaccine.
However, Pfizer’s trial of a similar maternal RSV vaccine continued enrolling participants.
Both companies were developing versions of an RSV F protein vaccine that works by targeting the RSV fusion protein to generate antibodies that can neutralize the virus. The F protein is essential for viral entry and its structure is highly consistent across different strains of RSV.
In Pfizer’s Phase 3 data, 5.7% of births in the vaccine arm were preterm compared to just 4.7% in placebo. Ten stillbirths occurred in the vaccine group versus eight in the placebo group. Neonatal deaths in the placebo group (.3%) exceeded those in the vaccine group (.1%). One vaccine recipient died from postpartum hemorrhage and hypovolemic shock.
Pfizer reported the increase in preterm births was most pronounced in trial participants from upper-middle-income countries, notably South Africa, according to the May 18 meeting of the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC).
While Pfizer claimed these numbers were not statistically significant, experts noted this numerical increase in preterm births mirrored the safety signal in the halted GSK trial, raising further questions about the risks of maternal RSV vaccination.
VRBPAC Chairwoman Hana El Sahly, during the May meeting, characterized the signal of increased preterm births during Pfizer’s Phase 2 and 3 trials as “significant” and said it was “probably” reason enough to pause the trial. She said that “failing to design the Pfizer Phase 3 study to deliver that clarity … is a big missed opportunity.”
Four of the 14 VRBPAC members were sufficiently concerned that they voted against finding the drug safe for pregnant women. Notably, one of the dissenting votes came from Dr. Paul Offit, a pediatrician at Children’s Hospital of Philadelphia, who said, “If GSK truly abandons a program on a similar, almost identical vaccine, that is going to hang over [Pfizer’s] program. I think it needs to be addressed.”
Vaccine efficacy inconclusive, limited, with ‘no direct benefit to the mothers’
Peter McCullough, M.D., MPH, in an April 21 Substack post, raised a different point about the viability of the Pfizer vaccine, arguing Pfizer’s study design relied on an outcome that occurred too rarely to reliably measure efficacy.
Basing results on fewer than 2% of babies getting sick left the findings “a statistical blur,” he said — meaning the findings on whether the vaccine provided meaningful protection were inconclusive.
“Pfizer has aggressively advanced RCTs [randomized control trials] into the pregnant population with no assurances on long-term outcomes,” McCullough added, and with “no direct benefit to the mothers.”
In the May VRBPAC meeting, it was further noted that while the incidence of RSV for babies was lower in the vaccine group up to 6 months of age, during the 181- to 360-day period after birth, babies in both groups contracted RSV at similar rates.
After the Centers for Disease Control and Prevention (CDC) recommended the vaccine for pregnant women in September, McCullough told The Defender, “Vaccination of the mother for passive immunization of the infant is an unnecessary and risky strategy that will undoubtedly lead to fetal loss or premature deliveries when deployed on a large scale.”
This controversy comes at a time when the CDC is reporting the largest rise in infant mortality in 20 years, and amidst concerns that doctors are being paid to push vaccines on pregnant women.
Warnings fell on deaf ears
The recent BMJ investigation was not its first warning about the RSV trials. On May 10, following Pfizer’s publication of its Phase 3 trials data, The BMJ warned that Pfizer’s safety signals were similar enough to GSK’s to warrant further analysis.
Überla told The BMJ, “My interpretation of all these data is that there may be a safety signal for preterm births that should be followed up.”
A scientist at the National Institutes of Health who wished to remain anonymous told The BMJ the Pfizer data should be analyzed using more sensitive measures such as average birth weight and subgroup analyses to determine the validity of the safety signal.
On May 23, The BMJ reported on the safety concerns noted by several VRBPAC members at their May meeting.
Before the FDA discussed the Pfizer RSV vaccine in May, “Peter Selley” from the U.K. posted a public comment to its website that said:
“It is remarkable that the FDA:
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- Do not have an obstetrician or midwife on this VRBPAC committee.
- Allowed these trials when, it seems, there were no safety trials of this vaccine in pregnant non-human primates.
- Allowed these large trials in pregnant women when pregnant women had been specifically excluded from smaller Phase 1 safety trials.
- Allowed Pfizer’s phase 2 trial that involved 3-5 venous blood draws from healthy babies who would derive no benefit.
- When notified in February 2022 by GSK of a safety signal of excess preterm births and neonatal deaths in a trial of a similar RSV vaccine, the FDA did not insist that participants in Pfizer’s Phase 3 trial should be informed of the finding.
- Authorized an Institutional Review Board – Advarra – that approved the Phase 3 trial in pregnant women. Advarra’s informed consent form for the ongoing trial contains the advice: “The risks associated with the study vaccine (RSVpreF or placebo) may be experienced by you, but not your baby, since your baby will not receive the study vaccine or placebo directly.” (According to the trial protocol, this wording was also approved by Pfizer.)
- Allowed the Phase 3 trial to stop early, although this may have prevented participants from experiencing adverse reactions.”
Selley appended a document detailing further safety considerations in the Pfizer trials, where he also cited Dr. Eric Simões, lead author of the Phase 2 study, who wrote in a different study, “The role of breast-feeding in preventing RSV disease and hospitalization for RSV is undisputed.”
