Burk Declaration
- Date
- 2021-12-17
Summary
Document 40-9 in Case 2:21-cv-00702-CLM in the U.S. District Court, N.D. of Alabama, filed December 17, 2021 and labeled Burk Declaration Exhibit 9. It reproduces an FDA review memorandum from CBER dated August 12, 2021, from David Cho, PhD, through Peter Marks, MD, PhD, on Pfizer's request to amend EUA 27034. The memorandum assesses a third dose (0.3 ml) of the Pfizer-BioNTech COVID-19 Vaccine for certain immunocompromised individuals age 12 years or older, including solid organ transplant recipients. It reviews published studies, including a single arm study in 101 individuals and a randomized study of a Moderna vaccine in 120 individuals. It recommends amending the authorization to include the third dose, while stating that recipients should continue barrier measures.
Summary drafted by a model from the document's text below and checked by script against that text before publication. It is a navigation aid, not a reading of what the document proves. Where AI is used
Full text
Case 2:21-cv-00702-CLM Document 40-9 Filed 12/17/21 Page 1 of 4 FILED
2021 Dec-17 PM 01:27
U.S. DISTRICT COURT
N.D. OF ALABAMA
Burk Declaration
Exhibit 9
Case 2:21-cv-00702-CLM Document 40-9 Filed 12/17/21 Page 2 of 4
Review Memorandum
Date: August 12, 2021
To: The File
From: David Cho, PhD (CBER/OD)
Through: Peter Marks, MD, PhD (CBER/OD)
Applicant name: Pfizer-BioNTech
Application Number: EUA 27034
Product: Pfizer-BioNTech COVID-19 Vaccine
Subject: CBER Assessment of third dose of Pfizer-BioNTech COVID-19
Vaccine (0.3 ml) administered at least 28 days following the first
two doses of this vaccine to individuals who have undergone solid
organ transplantation, or who are diagnosed with conditions that
are considered to have an equivalent level of immunocompromise
This memorandum provides a summary, review, and recommendation on the submission by Pfizer to
amend the emergency use authorization (EUA) of their COVID-19 vaccine to authorize administration of a
third dose of the vaccine to certain immunocompromised individuals age 12 years or older who have
received two doses of the Pfizer-BioNTech COVID-19 vaccine and who have undergone solid organ
transplantation, or who are diagnosed with conditions that are considered to have an equivalent level of
immunocompromise.
Executive Summary
Pfizer has provided a proposed Amendment to EUA 27034 to amend the emergency use authorization
(EUA) to include a third dose of the Pfizer-BioNTech COVID-19 vaccine for certain immunocompromised
individuals. Reference is made to the EUA for Pfizer-BioNTech COVID-19 Vaccine issued on December
11, 2020, which describes the safety and effectiveness of this vaccine based on a large placebo-controlled
randomized trial. Pfizer’s currently authorized indication is for active immunization to prevent coronavirus
disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in
individuals age 12 years and older. The proposed additional indication for this submission is: Individuals at
least 12 years of age who have received two doses of the Pfizer-BioNTech COVID-19 vaccine and who
have undergone solid organ transplantation, or who are diagnosed with conditions that are considered to
have an equivalent level of immunocompromise, may receive a third dose of the Pfizer-BioNTech COVID-
Case 2:21-cv-00702-CLM Document 40-9 Filed 12/17/21 Page 3 of 4
19 vaccine (0.3 ml) administered at least 28 days following the second dose of the two dose regimen of this
vaccine.
Review
The data presented in the request for an EUA amendment are based on published literature [Kamar
N, Abravanel F, Marion O, et al. (2021), Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ
Transplant Recipients. NEJM. DOI: 10.1056/NEJMc2108861] reporting that the standard two dose regimen
of vaccination with mRNA-based COVID-19 vaccines may produce suboptimal immunogenicity in solid
organ transplant recipients. Investigators stipulate that the use of a third vaccine dose in these individuals
may improve the immune response in these individuals, and by extension those who are considered to have
an equivalent level of immunocompromise, without a significant change in the safety profile. The paper
describes a single arm study conducted in 101 individuals who had undergone various solid organ
transplant procedures (heart, kidney, liver, lung, pancreas) a median of 97+8 months previously. A third
dose of Pfizer-BioNTech COVID-19 vaccine was administered to 99 of these individuals approximately
2 months after they received a second dose. Levels of total SARS-CoV-2 binding antibodies meeting the
pre-identified criteria for success occurred four weeks after the third dose of the Pfizer-BioNTech COVID-
19 vaccine in 26/59 (44.0%) of those who were initially considered to be seronegative; 67/99 (68%) of the
entire group receiving a third vaccination had an increase in antibody titers that the investigators considered
significant. In those who received a third vaccine dose, the adverse event profile was similar to that after
the second dose, and no grade 3 or grade 4 events were reported.
CBER also reviewed a supportive and confirmatory paper, exclusively using a similar mRNA COVID
vaccine (Moderna COVID-19 vaccine) written by Hall et al. (Hall VG, Ferreira VH, Ku T, et al. (2021). A
Randomized Trial of Third Dose mRNA-1273 Vaccine in Transplant Recipients. NEJM DOI:
10.1056/NEJMc2111462) describes a double-blind, randomized-controlled study conducted in 120
individuals who had undergone various solid organ transplant procedures (heart, kidney, kidney-pancreas,
liver, lung, pancreas) a median of 3.57 years previously (range 1.99-6.75 years). A third dose of the
Moderna COVID-19 vaccine was administered to 60 individuals approximately 2 months after they had
received a second dose of the same vaccine (i.e., doses at 0, 1 and 3 months); saline placebo was given to
60 individuals for comparison. The primary outcome was anti-RBD antibody at 4 months greater than 100
U/mL. This titer was selected based on NHP challenge studies as well as a large clinical cohort study to
indicate this antibody titer was possibly protective. Secondary outcomes were based on a virus
neutralization assay as well as polyfunctional T cell responses. Baseline characteristics were comparable
between the two study arms as were pre-intervention anti-RBD titer and neutralizing antibodies. Levels of
SARS-CoV-2 antibodies indicative of a significant response occurred four weeks after the third dose in
33/60 (55.0%) of the Moderna COVID-19 vaccinated group and 10/57 (17.5%) of the placebo individuals.
In the 60 individuals who received a third vaccine dose, the adverse event profile was similar to that after
the second dose and no grade 3 or grade 4 events were reported.
Additional literature reviewed included background information on COVID-19 vaccine regimens in solid
organ transplant and hemodialysis patients demonstrating a notable suboptimal response to vaccination in
the solid organ transplant population (Carr et al, Review of Early Immune Response to SARS-CoV-2
Vaccination Among Patients With CKD, Kidney Int Rep; 2021, doi:10.1016/j.ekir.2021.06.027); and a study
of multiple vaccines in solid organ transplant recipients that did not study a sufficient number of
Case 2:21-cv-00702-CLM Document 40-9 Filed 12/17/21 Page 4 of 4
individuals with a given vaccine regimen to interpret effectiveness (Werbel et al. Safety and
Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case
Series. Ann Int Med; 2021, doi:10.7326/L21-0282)
Recommendation
FDA has been continuously reviewing the literature for information on the safety and efficacy of vaccines
to prevent COVID-19 in the immunocompromised. The data from the primary paper (Kamal et al.) show
that administration of a third dose of the Pfizer-BioNTech COVID-19 vaccine appears to be only
moderately effective in increasing total antibody titers in the individuals studied. It is also unclear whether
the antibodies generated from the third dose are protective. Since the third dose of vaccine can lead to a
false sense of protection, individuals who receive the third dose should continue barrier measures and the
close contacts of immunocompromised persons should be vaccinated as appropriate for their health status.
There were no serious adverse events mentioned by the authors in this report. Despite the moderate
enhancement in antibody titers, the totality of data (including the supportive paper by Hall et al and
demonstrated efficacy of the product in the elderly and persons with co-morbidities) supports the
conclusion that a third dose of the Pfizer-BioNTech COVID-19 vaccine may be effective in this population,
and that the known and potential benefit of a third dose of Pfizer-BioNTech COVID-19 vaccine dose
outweigh the known and potential risks of the vaccine for immunocompromised individuals at least 12
years of age who have received two doses of the Pfizer-BioNTech COVID-19 vaccine and who have
undergone solid organ transplantation, or who are diagnosed with conditions that are considered to have an
equivalent level of immunocompromise. We conclude that administration to individuals 12 years of age
and older is justified, as it was determined in prior studies of the Pfizer-BioNTech COVID-19 vaccine in
the 12-15 year age range that the immune response and safety profile was similar to that in individuals 16
years of age and older.
Regarding “the equivalent level of immunocompromise” statement, FDA recognizes that there are a myriad
of different immunocompromising conditions. Solid organ transplant patients are immunosuppressed
because they are taking a variety of immunosuppressive medications such as cyclosporin, tacrolimus,
sirolimus, mycophenolate, azathioprine, and anti-thymocyte globulin. These immunosuppressive
medications are used in a variety of other conditions to address immune dysregulation. The effects of these
drugs in these other conditions are very similar to the effects in those who have undergone solid organ
transplantation: that is there is interference with the cellular and humoral immune response. Thus,
individuals receiving these medications whether in the setting for solid organ transplant or for the treatment
of immune dysregulation likely both have a similarly attenuated response to the administration of vaccines
to prevent COVID-19. Conversely, it is reasonable to extrapolate that the administration of an additional
dose of a COVID-19 vaccine to these individuals with immune dysregulation may produce similar
responses to those seen in solid organ transplant. It is also reasonable to make the extrapolation that
individuals with inherited or acquired conditions that produce reduction in the cellular or humoral immune
response similar to that seen in solid organ transplant may produce similar immune responses to a third
dose of a COVID-19 vaccine. We therefore believe it is appropriate to amend the authorization to include a
third dose of the vaccine for individuals at least 12 years of age who are diagnosed with conditions that are
considered to have an equivalent level of immunocompromise.
File and source
- File
- gov.uscourts.alnd.177186.40.9.pdf
- Size
- 297,320 bytes
- SHA-256
- 893c7d4f42dc17dd51a4f98144dc8a4f22430839a7d3f7f77710243b762747d9
- Original
- archive.org