Pfizer's COVID-19 Vaccine Brings Gaps In Efficacy And Safety Data To US FDA Panel
Executive Summary
Agency details a host of unknowns regarding the benefits and risks of the first COVID-19 vaccine to reach the advisory committee stage, including uncertainties about duration of protection, effectiveness against transmission and vaccine-enhanced disease.
The US Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee on 10 December will be tasked with reviewing the available efficacy and safety data on Pfizer Inc./BioNTech SE’s COVID-19 vaccine.
However, given the unprecedented speed with which BNT162b2 was developed amid a pandemic that has killed more than 280,000 US residents, the panel’s attention also is likely to focus on what is not yet known about how the vaccine performs or what risks it entails.
The FDA dedicated a section of its advisory committee briefing document to listing the unknown benefits and risks, and the data gaps, that should be considered in the context of a benefit/risk assessment on Pfizer’s request for emergency use authorization of the mRNA vaccine. It’s clear there is no shortage of unknowns about BNT162b2, with the UK’s allergy warning chief among them. (Also see "US FDA’s Marks Criticizes UK For ‘Rushing’ Adverse Event Announcement On COVID Vaccine" - Pink Sheet, 9 Dec, 2020.)
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How concerning these unknowns are, and how best to fill in the data gaps through clinical trials and post-authorization observational studies, are likely to be discussed by the 22 members of the VRBPAC. (See sidebar.)
[Editor’s note: We’re devoting team coverage to Thursday’s US COVID-19 advisory committee. For up-to-the-minute bulletins that day, follow @SarahKarlin on Twitter. Look for all our in-depth coverage at the Pink Sheet and in our daily email alerts.]
Efficacy Unknowns
Among the efficacy data gaps highlighted by the agency is the duration of protection provided by the vaccine.
The Pfizer vaccine is given in two doses, 21 days apart. Although there did not appear to be evidence of waning protection in the two months after the second dose, given the limited length of follow-up to date it is not yet possible to assess sustained efficacy over a longer period of time, the agency said.
Data also are not available on the vaccine effectiveness in certain populations, including immunocompromised individuals, pediatric populations and those previously infected with SARS-CoV-2.
Pfizer’s Phase III trial started enrolling individuals with HIV, hepatitis B and C, as well as adolescents ages 12-15 years, after the initial enrollment of 30,000 subjects.
Only 120 people with HIV had been enrolled as of 9 October, and the FDA said the number of immunocompromised individuals is too small to evaluate efficacy outcomes.
Similarly, the representation of pediatric participants was too limited to adequately evaluate efficacy in those under age 16 years.
Pfizer is seeking an EUA for use in individuals ages 16 years and older. Although the overall efficacy analysis of the Phase III trial included 16- and 17-year-olds, there was only one confirmed case of COVID-19 reported in this age group. “However, it is biologically reasonable to extrapolate that effectiveness in ages 16 and 17 years would be similar to effectiveness in younger adults,” the agency said.
Only 3% of study participants had evidence of prior infection at study enrollment, and there were few COVID-19 cases occurring in these participants over the course of the entire study. However, the placebo group attack rate was the same for those without evidence of prior infection and those with evidence of prior infection. “While limited, these data do suggest that previously infected individuals can be at risk of COVID-19 (i.e., reinfection) and could benefit from vaccination,” the agency said.
It is unclear how changes in pandemic characteristics – such as attack rates and viral mutations – could affect vaccine effectiveness, the agency said.
Additional evaluations will be needed to assess vaccine effectiveness in preventing asymptomatic infections as measured by detection of the virus or antibodies against non-vaccine antigens. Those data will need to come from additional clinical trials and from the vaccine’s use post-authorization.
Similarly, additional data are needed to assess the vaccine effectiveness in preventing virus shedding and transmission, particularly in individuals with asymptomatic infection, the FDA said.
During an October meeting on general issues related COVID-19 vaccine development, some VRBPAC members objected to the use of virologically confirmed and symptomatic SARS-CoV-2 infection as the primary endpoint in Phase III trials, as was used in Pfizer’s study.
“At present it is not possible to assess whether the vaccine will have an impact on specific long-term sequelae of COVID-19 disease in individuals who are infected despite vaccination.” – FDA
Reduction in the risk of mild disease is not a meaningful outcome if it results in asymptomatic disease that is still transmissible, some panelists said, instead favoring an endpoint based on cases of severe disease. (Also see "COVID-19 Vaccines: Advisory Committee Picks Apart US FDA Guidance On Efficacy Endpoints" - Pink Sheet, 22 Oct, 2020.)
It also is unknown if the vaccine prevents long-term effects caused by COVID-19 disease and mortality.
“COVID-19 disease may have long-term effects on certain organs, and at present it is not possible to assess whether the vaccine will have an impact on specific long-term sequelae of COVID-19 disease in individuals who are infected despite vaccination,” the agency said.
“Demonstrated high efficacy against symptomatic COVID-19 should translate to overall prevention of COVID-19-related sequelae in vaccinated populations, though it is possible that asymptomatic infections may not be prevented as effectively as symptomatic infections and may be associated with sequelae that are either late-onset or undetected at the time of infection (e.g., myocarditis).”
On the mortality question, the agency said a larger number of individuals at high risk for COVID-19 and higher attack rates would be needed to confirm the vaccine’s efficacy in this regard. “Benefits in preventing death should be evaluated in large observational studies following authorization,” the agency said.
Safety Unknowns
The agency lists three categories of data gaps with regard to risks.
Data are insufficient to make safety conclusions about:
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Use in children under 16 years,
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Pregnant and lactating women, and
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Immunocompromised individuals.
Pregnancy was an exclusion criteria in the study, and female subjects of childbearing potential were screened for pregnancy prior to each vaccination.
Nevertheless, 23 pregnancies were reported through the data cut-off date of 14 November, with 12 in the vaccine group and 11 in the placebo arm. “Unsolicited AEs related to pregnancy include spontaneous abortion and retained products of conception, both in the placebo group,” the FDA said. “Pregnancy outcomes are otherwise unknown at this time.”
Pfizer will submit plans for a clinical study to assess safety and immunogenicity in pregnant women and has proposed active surveillance studies designed to monitor vaccination during pregnancy.
Despite the relative dearth of efficacy and safety data in pregnant and lactating women, FDA labeling for the Pfizer vaccine is not expected to include a recommendation against use in this subpopulation. (Also see "US Label For COVID-19 Vaccine Will Not Recommend Against Use In Pregnancy" - Pink Sheet, 7 Dec, 2020.)
The FDA said that Pfizer will submit plans for a clinical study to assess safety and immunogenicity in pregnant women and has proposed active surveillance studies designed to monitor vaccination during pregnancy within populations expected to receive the vaccine under EUA. Those initial priority populations are expected to include health care workers. (Also see "Health Care Personnel, Long-Term Care Residents Should Get COVID-19 Vaccine First, ACIP Votes" - Pink Sheet, 1 Dec, 2020.)
Adverse reactions that are very uncommon or that require longer follow-up for detection also will require more data through active and passive safety surveillance during the post-authorization period, the FDA said. These signal detection efforts should include reports of appendicitis and Bell’s palsy, as there were unfavorable imbalances in both conditions in the Phase III trial. (Also see "Pfizer’s COVID Vaccine Raises No Safety Red Flags, But Managing Reactogenicity May Be Practical Challenge" - Pink Sheet, 8 Dec, 2020.)
The occurrence of two anaphylactoid reactions on the first day of the vaccine’s rollout in the UK also could inform active and passive surveillance targets under an EUA. (See sidebar.)
The FDA also points to gaps in the data on vaccine-enhanced disease.
The Phase III data do not indicate a risk and, in fact, suggest effectiveness against severe disease. Nevertheless, “risk of vaccine-enhanced disease over time, potentially associated with waning immunity, remains unknown and needs to be evaluated further in ongoing trials and in observational studies after authorization,” the agency said.
Missed Or Delayed Second Dose
Another unknown is the impact of missed or delayed second doses on the vaccine’s efficacy, although the FDA does not specifically list this issue as a data gap.
The 21-day, two-dose regimen and the vaccine’s ultra-cold storage requirements are expected to pose logistical challenges that could complicate compliance, as could the vaccine’s reactogenicity side effects.
In the Phase III study, more than 94% of participants in the vaccine and placebo arms completed both doses of vaccination. The primary efficacy analysis showed the vaccine had a 95% efficacy rate seven days after the second dose. Vaccine efficacy of the first dose, based on the number of confirmed COVID-19 cases occurring before the second dose, was 52.4%. However, the FDA said these data do not allow for firm conclusions on the efficacy of administering just one dose. (Also see "Last Minute Allocation Shake Up? Pfizer’s One-Dose Data Could Change COVID-19 Vaccine Rollout" - Pink Sheet, 8 Dec, 2020.)