Only 170 out of 44,000 enrolled subjects in the Pfizer trial changed the world.
Were they as kosher as they were meant to be?
Pfizer’s EUA Granted Based on Fewer Than 0.4% of Clinical Trial Participants. FDA Ignored Disqualifying Protocol Deviations to Grant EUA
https://dailyclout.io/report-41-the-170-clinical-trial-participants-who-changed-the-world-pfizer-ignored-protocol-deviations-to-obtain-emergency-use-authorization-for-its-covid-19-mrna-vaccine/
Clinical trials are usually heavily monitored, and the protocol (i.e., instructions) for a trial must be followed to the letter so its trial participants can rely on its conclusions.
Protocol deviations – not following the instructions – lead to subjects being excluded from a trial and not being included for analysis.
When you consider that only 170 patients out of the 44,000 enrolled subjects provided the basis for Pfizers EUA, any analysis which finds irregularities among this select 0.4% is serious cause for concern. That is one of the main highlights of the paper by my colleague Dr Jeyanthi Kunadhasan, et al.
The report goes into some detail, diving into the clinical trial design, how it was changed along the way, and the Statistical Analyses Plan (which needs to be locked before any planned analysis of the data).
“Why give this long explanation into the many iterations of the protocol and have so much discussion about the ‘predefined window’?”
“These eight positive vaccinated and 162 positive placebo subjects are the ‘170 that changed the world’. Were they as kosher as they were meant to be? Remember, patients that are part of the evaluable population needed to have zero protocol deviations.”
After painstakingly establishing a dosing interval of 21 days ( range 19 to 23 days) why did they suddenly double the duration for this paper?
The predefined window they used was (19 to 42 days after Dose 1).
Such a practice would normally constitute a protocol violation, unless a formal protocol amendment had been filed.
What did the analysis of the 170 subjects show?
We found five subjects whose dosing interval between Dose 1 and Dose 2 fell outside the 19- to 23-day window.
“Whilst we understand the temptation of clinical trial specialists to include these subjects in the Final Analysis of Efficacy, this is not how clinical trials are conducted. An important part of any clinical trial is the removal of subjects who did not follow the trial protocol from analysis. If a deviation in the protocol is to be included, an appropriate amendment must be filed”.
Why, then, is the extension of the dosing interval to 42 days so important?
The undocumented change in the protocol (i.e., without an amendment) enabled Pfizer to include an additional 1,410 subjects in the analysis, because – by adding 19 days – Pfizer was able to recover 1,410 patients who were otherwise ineligible for the efficacy analysis. Those 1,410 enabled the inclusion of the four placebo patients and one BNT162b2 patient in the 170 population.
The 170 patients came only from 66 of the 153 sites, even though all patients enrolled in the trial should have been eligible to be included in the Final Efficacy Analysis. As a team, we intend to audit the sites that enrolled patients in this trial
Say what? How statistically likely is it that all the 170 patients used in the final analysis submitted to justify the EUA came from only 63 of the 153 sites?
“We also noted interesting coincidences of these 170 in a trial of nearly 44,000 enrolled subjects and an evaluable group of around 37,000, where every patient had equal chances of reaching the evaluable analysis. There were six paired instances of sequential numbers.”
Cue the theme from the “Twilight Zone”
However, going back to the ‘predefined window’ issue, when did the doubling of a dosing interval of a novel drug seemingly become an acceptable practice?
This plan, as described before in the Clinical Protocol, described a study design of a two-dose schedule separated by 21 days.
Among the 170 they found enough subjects to raise questions about the validity of the whole trial including a patient who requested withdrawal from the trial, another that was found on a list of patients withdrawn from the trial and was nonetheless included in the data analysis used. Others had protocol deviations like having received blood or plasma products within 60 days of enrolment or a Dosing Administration Error.
Conclusions
We are now in an intriguing situation where the endpoint for immunogenicity data for Phase 1, has a visit window of 19 to 23 days; but for Phase 2, for the same immunogenicity data of the same drug, the window was 19 to 42 days. They had not met the threshold for final interim analysis within the 19- to 23-day window but managed to meet it by changing the threshold.
This highlights questions of when the data lock happened, and if the “predefined window” is in fact a post-hoc defined window. Questions arise as to why ambiguity was allowed with regards to the words “predefined window” throughout the trial, in which a number was not defined in all the analysis sets.
We identified that seven patients – five outside of the dosing window and two with major protocol deviations – were part of the final efficacy analysis; therefore, the basis on which the EUA was granted must be revisited, as this brings the evaluable population down to 163, which is below the final threshold for interim analysis. So many norms in society have fallen during the pandemic. If the scientific community is to move forward with integrity, it cannot allow practices like this to stand.
As a team of volunteers, we continue our audit of all the sites with publicly available information.
An extraordinary amount of taxpayer money was used for the Pfizer trial whose Primary Investigators (PIs) may have not followed the trial protocol correctly. In normal circumstances, clinical trials are funded by the company running the trial from their research budget. What we have found in these documents calls into question the validity of the clinical trial results, as well as the potential misuse of billions of United States taxpayer dollars.