Pfizer Docs Part 7: Postmarketing Experience
Everyone keeps getting very excited about the numbers in this report because they think it's about the clinical study. It's not.
We weren’t going to review this document until much later, but we’re covering it now because it’s getting misrepresented all over social media. Lots of people seem to think this is a report of adverse events and deaths among the 44,000 participants in the clinical trial - which is wrong.
The file is 5.3.6-postmarketing-experience.pdf, and the title of the document in this file is:
5.3.6 CUMULATIVE ANALYSIS OF POST-AUTHORIZATION ADVERSE EVENT REPORTS OF PF-07302048 (BNT162B2) RECEIVED THROUGH 28-FEB-2021
This report is part of module 5 and was compiled by Pfizer at the request of the FDA. Pfizer tells us what’s in this report:
This document provides an integrated analysis of the cumulative post-authorization safety data, including U.S. and foreign post-authorization adverse event reports received through 28 February 2021. (Postmarketing Experience, page 5)
The report is a summary of adverse events (AE) reports they received following EUA authorization of their vaccine, and at the request of the FDA it’s being submitted with the Biologics License Application (BLA).
What is the source of the adverse event reports?
The adverse event reports come from multiple sources.
Pfizer’s safety database contains cases of AEs reported spontaneously to Pfizer, cases reported by the health authorities, cases published in the medical literature, cases from Pfizer-sponsored marketing programs, non-interventional studies, and cases of serious AEs reported from clinical studies regardless of causality assessment. (Postmarketing Experience, page 5)
So these include:
Cases reported directly to Pfizer
Cases reported by health authorities
Cases reported in medical literature
Cases from Pfizer’s own programs and studies
The report contains adverse event reports from the administration of the vaccine under EUA (which is the overwhelming majority of the reports) as well as the adverse event reports from Pfizer’s studies.
Are these all issues caused by the vaccine? Not necessarily.
An accumulation of adverse event reports (AERs) does not necessarily indicate that a particular AE was caused by the drug; rather, the event may be due to an underlying disease or some other factor(s) such as past medical history or concomitant medication. (Postmarketing Experience, page 6)
How is the data organized?
The FDA identified specific things they wanted to see in the report.
“Please include a cumulative analysis of the Important Identified Risks, Important Potential Risks, and areas of Important Missing Information identified in your Pharmacovigilance Plan, as well as adverse events of special interest and vaccine administration errors (whether or not associated with an adverse event). Please also include distribution data and an analysis of the most common adverse events. In addition, please submit your updated Pharmacovigilance Plan with your BLA submission.” (Postmarketing Experience, page 5)
And the report contains those exact things:
Items from the Pharmacovigilance Plan (pages 9-15)
Summary of Adverse Events of Special Interest (pages 16-25)
Summary of vaccine administration errors (pages 26-28)
Pfizer also included a general overview of cases:
Cases by System Organ Class and Preferred Term (pages 6-9)
There are four sets of tables in this report, corresponding to these four categories.
Update: Removal of redactions
The FDA included this document in the second document dump, this time without the redactions. For details, look at the explanation in Part 8:
How many AE reports did Pfizer receive?
Apparently quite a lot compared to their normal workload. Pfizer already sells vaccines, but their new product has resulted in so many reports that they need to prioritize the serious cases.
Due to the large numbers of spontaneous adverse event reports received for the product, the MAH has prioritised the processing of serious cases, in order to meet expedited regulatory reporting timelines and ensure these reports are available for signal detection and evaluation activity. (Postmarketing Experience, page 6)
They have also brought on additional staff to deal with the workload, although the number of staff is redacted (the redacted information is replaced with “(b) (4)”).
Pfizer has also taken a multiple actions to help alleviate the large increase of adverse event reports. This includes significant technology enhancements, and process and workflow solutions, as well as increasing the number of data entry and case (b) (4) processing colleagues. To date, Pfizer has onboarded approximately additional full-time employees (FTEs). More are joining each month with an expected total of more than (b) (4) additional resources by the end of June 2021. (Postmarketing Experience, page 6)
Length of time and number of case reports
The report covers vaccinations for the first three months after they received Emergency Use Authorization (EUA). We don’t know how many people were vaccinated because the number of doses is also redacted.
It is estimated that approximately (b) (4) doses of BNT162b2 were shipped worldwide from the receipt of the first temporary authorisation for emergency supply on 01 December 2020 through 28 February 2021. (Postmarketing Experience, page 6)
They received the first EUA on 01 December 2020 (useful, because now we don’t have to look it up). Keep in mind this first three months occurs during the clinical trial, for which Pfizer submitted data up to six months after vaccination.
[In the last post (Part 6) we looked at the Case Report Forms for a participant in the clinical trial. That person received the first vaccine dose on 1 August 2020, the second dose on 22 August 2020, and the six month follow up was on 9 March 2021.]
During the three months being reviewed, Pfizer found just over 42,000 case reports from 63 countries.
Cumulatively, through 28 February 2021, there was a total of 42,086 case reports (25,379 medically confirmed and 16,707 non-medically confirmed) containing 158,893 events. Most cases (34,762) were received from United States (13,739), United Kingdom (13,404) Italy (2,578), Germany (1913), France (1506), Portugal (866) and Spain (756); the remaining 7,324 were distributed among 56 other countries. (Postmarketing Experience, page 6)
Now that we have the background let’s go through the four sections.
General Overview
(section 3.1.1, pages 6-9)
This one contains the table that people are excited about:
There were 1,223 reported deaths within the first three months after receiving Emergency Use Authorization. Is this good or bad? We don’t know because we don’t know how many people were vaccinated.
Remember this report isn’t just the data from the clinical study - it’s a summary of all reports Pfizer could find of adverse events during the first three months of vaccinations with the EUA authorized vaccine.
Per Pfizer’s Clinical Overview there were 15 deaths in their vaccine group and 14 in the placebo group - so 29 total in the clinical study (STN-125742_0_0-Section-2.5-Clinical-Overview.pdf, page 272).
The table is followed by this bar chart:
The data is grouped by something called “System Organ Classes.” These classes come from the MedDRA (Medical Dictionary for Regulatory Activities), and it provides a hierarchy for classifying events. Note the bar chart contains 27 items, which corresponds to the 27 System Organ Classes in the MedDRA.
The MedDRA is published by an organization called ICH, and they have published a guideline document (MedDRA Coding Basics1) that helps us with an outline of the MedDRA structure.
SOC (System Organ Class) - 27 total classes
HLGT (High Level Group Term) - 337 terms
HLT (High Level Term) - 1,738 terms
PT (Preferred Term) - 24,313 terms
LLT (Lowest Level Term) - 81,885 terms
The point of this system is to use standardized terms for illnesses. The LLTs are the actual events listed on adverse event reports, which are translated to PTs, each of which represents a single specific medical concept. This process is useful if people reporting the events use different terms for the same illness.
Table 2, starting on page 8, shows totals for events reported in at least 2% of cases, and is organized by MedDRA SOC (System Organ Class) and PT (Preferred Term).
A note on something called ICH
The MedDRA was developed by an organization called The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)2.
Here is their lofty mission statement:
ICH's mission is to achieve greater harmonisation worldwide to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.
ICH is also the source of the Common Technical Document (CTD) format that Pfizer used as the format for the BLA, and which is discussed in more detail in a previous Substack post3.
ICH has published many different guidelines, including guidelines on pharmacovigilance planning. A lot what we are reviewing is influenced by their guidelines.
Pharmacovigilance Plan
(section 3.1.2, pages 9-15)
The next section is data based on Pfizer’s pharmacovigilance plan. It’s a review of the data looking for items that had previously been identified as potential risks. The WHO provides us with a definition of pharmacovigilance.4
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine/vaccine related problem.
Pfizer identified specific risks, in advance, of their vaccine. These tables summarize their analysis of the evidence for each of these risks. For example, for Vaccine-Associated Enhanced Disease (VAED) here was their conclusion:
Conclusion: VAED may present as severe or unusual clinical manifestations of COVID-19. Overall, there were 37 subjects with suspected COVID-19 and 101 subjects with confirmed COVID-19 following one or both doses of the vaccine; 75 of the 101 cases were severe, resulting in hospitalisation, disability, life-threatening consequences or death. None of the 75 cases could be definitively considered as VAED/VAERD. (Postmarketing Experience, page 11)
“101 subjects with confirmed COVID-19 following one or both doses of the vaccine” - this means they were aware of the existence of breakthrough infections (people who were vaccinated but still got COVID-19) by the end of February 2021. This is within the first three months of distribution of the EUA vaccine.
Adverse Events of Special Interest (AESIs)
(section 3.1.3., pages 16-25)
Some people are also excited about the nine page list of what people are describing as “side effects” listed at the end of this document. It’s not actually a list of all known side effects of the vaccine, it’s the list of AESIs.
What are AESIs? The World Health Organization give us a definition in their Safety Surveillance Manual for COVID-19 vaccines5.
The US FDA defines an adverse event of special interest (serious or non-serious) as one of scientific and medical concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor can be appropriate. Such an event might warrant further investigation in order to characterize and understand it. Depending on the nature of the event, rapid communication by the trial sponsor to other parties (e.g., regulators) might also be warranted.
Law Insider6 gives us a simpler, more direct explanation:
Adverse Event of Special Interest (AESI) means an AE that requires reporting even if does not meet the standard criteria for seriousness, or it occurs outside the standard AE reporting timeframes for the trial;
Where did Pfizer get their AESI list? They compiled it from several published and unpublished lists and guidelines, about COVID-19 and vaccines in general.
The company’s AESI list takes into consideration the lists of AESIs from the following expert groups and regulatory authorities: Brighton Collaboration (SPEAC), ACCESS protocol, US CDC (preliminary list of AESI for VAERS surveillance), MHRA (unpublished guideline).
The AESI terms are incorporated into a TME list and include events of interest due to their association with severe COVID-19 and events of interest for vaccines in general. (Postmarketing Experience, page 16)
So this is a list of things they are looking for in their various sources of data, because these are things that have been associated with vaccines before.
Here is the start of that impressively dense list of items:
It also includes things like “deja vu.” I’m not kidding about that, it’s on page 32. The report lists several categories of AESIs and their analysis of cases related to those AESIs. For all but one category their conclusions are the same:
Conclusion: This cumulative case review does not raise new safety
issues. Surveillance will continue.
That one other category is Facial Paralysis.
Overall Conclusion: This cumulative case review does not raise new
safety issues. Surveillance will continue. Causality assessment will be
further evaluated following availability of additional unblinded data
from the clinical study C4591001, which will be unblinded for final
analysis approximately mid-April 2021. Additionally, non-
interventional post-authorisation safety studies, C4591011 and
C4591012 are expected to capture data on a sufficiently large
vaccinated population to detect an increased risk of Bell’s palsy in
vaccinated individuals. The timeline for conducting these analyses will
be established based on the size of the vaccinated population captured
in the study data sources by the first interim reports (due 30 June 2021). Study C4591021, pending protocol endorsement by EMA, is
also intended to inform this risk. (Postmarketing Experience, page 19)
Apparently the one thing they’re worried about is an increase in Bell’s palsy.
This is something we should keep in mind when more Case Report Forms (CRFs) are available from the clinical study. Since we know how to search for terms in the participant records we can look for ourselves and see how many cases there were (assuming all participant records actually get released, remember we only have 52 of the 44,000 right now).
Medication Errors
(section 3.1.4, pages 26-28)
There are only a small number of medication errors (MEs) listed.
1371 cases reported only MEs without any associated clinical adverse event.
In 685 cases, there were co-reported AEs.
(Postmarketing Experience, page 27)
Examples include things like Poor quality product administered, Product temperature excursion issue (it was stored incorrectly), Inappropriate schedule of product administration, and Product preparation error.
So what can we learn from this report?
Almost nothing. Without context, we have no idea if the reported events are occurring at an elevated rate, or if this is the number of these events we would see without vaccination at all.
Is 1,223 deaths, temporally associated with vaccination, over a three month period significant? If they only vaccinated 22,000 people this would be huge - not that many people could possibly die from other causes in just three months. But if they vaccinated 22 million it would be insignificant - there are thousands of all-cause deaths per day in the U.S. alone.
To make use of this data we will need to learn:
How many people were vaccinated in those 63 countries
The normal rate of occurrence for each of the issues reported
Maybe some of this data will come out in future document dumps, so we’ll keep our eyes open for it. Otherwise some enterprising researcher will need to find alternate sources for the number of vaccinations, and find the normal rates of these events for comparison.
A few useful things we extracted today
Pfizer began shipping the vaccine under EUA on 1 December 2020.
The FDA redacted the number of vaccine doses administered under EUA in the first three months.
Pfizer had to increase the size of the the staff that reviews case reports due to the large number of those reports.
Pfizer was aware of the existence of breakthrough infections by the end of February 2021.
Pfizer is monitoring adverse event reports for evidence of an increase in Bell’s palsy.
There may be more - don’t assume I found everything of interest. These are just things I thought were noteworthy.
Why do we have an FDA?
The FDA really screwed us here, by removing the one piece of information (the total number of doses) that we need to put the number of adverse events and deaths in context.
This is part of the report exemplifies that issue:
Review of the available data for this cumulative PM experience, confirms a favorable benefit: risk balance for BNT162b2. (Postmarketing Experience, page 29)
How did they calculate the benefit/risk balance? We have no idea because there are no such calculations in this report, and no reference to where we can find those calculations in another document.
The FDA doesn’t do this analysis - Pfizer does. The FDA essentially told them “go look into all available sources of adverse event reports, compile them into a big list, review that list, and tell us if your vaccine is causing more harm than good.”
What answer were you expecting to get?
To continue with the series, click here:
You can also start this series from the beginning by going here:
MedDRA coding basics:
https://admin.new.meddra.org/sites/default/files/page/documents_insert/000411_meddra_coding_basics_webinar_0.pdf
Archived copy:
https://web.archive.org/web/20220326173056/https://admin.new.meddra.org/sites/default/files/page/documents_insert/000411_meddra_coding_basics_webinar_0.pdf
https://www.ich.org/
WHO on pharamacovigilance:
https://www.who.int/teams/regulation-prequalification/regulation-and-safety/pharmacovigilance
Archived copy:
https://web.archive.org/web/20220324114457/https://www.who.int/teams/regulation-prequalification/regulation-and-safety/pharmacovigilance
WHO manual on vaccine safety surveillance:
https://www.who.int/vaccine_safety/committee/Module_AESI.pdf
Archived copy:
https://web.archive.org/web/20220321164427/https://www.who.int/vaccine_safety/committee/Module_AESI.pdf
Definition of AESI from law insider:
https://www.lawinsider.com/dictionary/adverse-event-of-special-interest-aesi
Archived copy:
https://web.archive.org/save/https://www.lawinsider.com/dictionary/adverse-event-of-special-interest-aesi