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From: Smith, Michael (CBER)
Sent: Monday, August 2, 2021 4:40 PM
To: Harkins Tull, Elisa <[email protected]>; Aghajani Memar, Neda
<[email protected]>; Devlin, Carmel M <[email protected]>
Cc: Naik, Ramachandra <[email protected]>; Gottschalk, Laura
<[email protected]>
Subject: STN 125742.0: Questions regarding the Validation Report VR -MVR -10077
Elisa,
The review team has the below set of questions for Pfizer regarding the Validation Report (VR -MVR -10077) entitled “Validation Report for a
” that was submitted in STN 125742.0.19 on July 28, 2021.
1. In your C4591001 clinical protocol amendment 17 (submitted to IND 19736
in amendment 414 on July 20, 2021), you stated that
assay or S1 -binding IgG assay will be used for the exploratory
immunogenicity endpoint. Please clarify which immunoassay has been
used for the assessment of binding antibodies for your Phase 2 and 3 studies. If both assays are used, please provide the validation study report
for the S1 IgG dLIA assay. In addition, please provide the SOP of the
assay (VR -TM-10309), including a description of critical
materials (e.g., reference standard, quality control sample (QCS),
antigen, , etc.), assay validity criteria,
sample validity criteria, and interpretation of results. Please also provide
the test method VR -TM-10309, and the validation protocol VR -MVP -10077.
2. We note that assay cr oss-reactivity was not assessed in your validation
studies. Please provide data for specificity analysis, including inhibition
experiments comparing the effects of heterologous antigens (e.g., antigen
from other coronaviruses) and homologous antigens (e. g., antigens at
different concentrations) when spiked into the panel of samples. Alternatively, you can evaluate the assay cross -reactivity using a
set of antibodies or serum samples with known reactivity to distinct strains of human seasonal coronaviruse s.
3. We note that assay robustness was not assessed in your validation studies.
Please consider evaluating the assay robustness for any variables that may
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potentially affect assay results, for example, stability of the antigen -coated
beads, assay incubation time and temperature, etc.
4. Please provide information on the source, preparation instructions, and
titer assignment for the reference standard and quality control samples
that contains in the validation study. A
negative QCS below or at the lower limit of quantitation (LLOQ) level should
be included in routine testing for the assay. Please explain how
you determine the cut -off values for specific levels in the seronegative
samples.
5. Please note that your assa y needs to be validated using incurred samples
from the vaccine trials for precision and accuracy via linearity including verification of the LLOQ, ULOQ, and the assay range. The assay
should be fully validated prior to testing the Phase 3 clinical samples.
6. Performance of your assay would be strengthened by inclusion of the WHO
SARS -CoV-2 International Antibody Standard. You might inquire from the
National Institute of Biological Standards and Control (NIBSC) about the
availability of this rea gent. We recommend assessing the performance of
your assay using the International Antibody Standard and convert your results to International Units.
7. You set the LLOQ to be , which was obtained by
Such LLOQ could serve as a theoretical LLOQ, but data are needed
to support adequate assay performance at such LLOQ. We note that the
precision near the lower assay limit on well concentration level was
evaluated mostly with data at the
(green stars and light green diamonds
in Figure 2 on Page 17 of the report). We also note that the lowest incurred
sample included in the precision evaluation has concentration of
(Table 12 on Pages 36- 37 of the report), which is far above the theoretical
LLOQ (i.e., ). Please explain how the current data support
adequate precision at the proposed LLOQ of or provide
additional data.
8. We note that, in Table 10 on Page 34 of the report, the
do not include the for
some samples. Taking Sample as an example, the
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which do es not include the
Please verify the numbers in this table and make
corrections, if needed.
9. You stated in Section 5.2.7.2 of the r eport that the mean, standard
deviation, and
However, as shown in Table 8
on Page 21 of the report,
10.Please s ubmit the data sets used for the linearity and precision
analyses in an analyzable format (e.g., spreadsheet).
11.The x -axis in Figure 4 on page 35 of the report is blurry. Please resubmit
the figure in higher quality so that it is readable.
Regards,
Mike
- Please confirm receipt of this e -mail and let us know if you have any
questions.
Mike Smith, Ph.D.
Captain, USPHS
Senior Regulatory Review Officer
Food and Drug Administration
Center for Biologics Evaluation & Research
Office of Vaccines Research & Review
Division of Vaccines and Related Products Applications
Tel: 301- 796-2640
[email protected]
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FDA-CBER-2021-5683-1024725
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FDA-CBER-2021-5683-1024726