Few people realise that the Emergency Use Authorisation (EUA)of the Pfizer-BioNTech Covid-19 Vaccine/BNT 162b2 was granted on the efficacy data of 170 patients. The 162 who received a placebo and 8 patients who were vaccinated formed the basis of the 95 per cent efficacy claims.

There has not been much discussion of these patients. Where did they come from? Can we get an approximate timeline as when these patients would have been collected?

The endpoint of the Pfizer-BioNTech trial(1) was getting a Covid infection at least 7 days after dose 2, and vaccine efficacy was measured by calculating the risk of disease among vaccinated and unvaccinated persons and determining the percentage reduction in risk of disease among vaccinated persons relative to unvaccinated persons.(2)

The 170 patients were found, buried deep amongst the hundreds of thousands of pages, made available only via court order.

In a paper(3) published on dailyclout.io, my co-authors and I go into the detail of how they were found. We also cross-referenced our list with publicly available demographic data yielding a perfect match. As such, we are confident that our list of the 170 patients, publicly available in our article as an excel spreadsheet, are in fact the 170 that were the basis of the ‘effective’ claim in the ‘safe and effective’ mantra.

According to the trial protocol, a major protocol deviation in the evaluable efficacy population would exclude a participant from the final analysis. This makes sense, if you are going to declare a drug effective, you would want to do it based on a population that had gone through your trial protocol properly and had none of the disqualifying events that had been laid out in your protocol.

What did we find in the 170 patient population?

One of the 170 didn’t receive the correct dose of the investigational product, another received a blood product within 60 days which is a major protocol deviation. Two others were withdrawn from the trial prior to the date of issuance of the EUA but were still included in the 170. (One of them disagreed with how they were medically managed in the trial.)

We also noted how the dosing interval (that was stated in the protocol to be 21 days, with an allowance of 19-23 days between dose 1 and 2) was curiously widened to 19-42 days. We show in our paper(4), how at least 1,410 patients who would have otherwise been considered protocol deviations for failure to administer the drug within the dosing interval of 19 to 23 days could be included in a final analysis if widened to 19-42 days. Most importantly, this included 5 of the 170 patients.

The Statistical Analysis Plan allowed modifications in the protocol(5) where appropriate. but stated that major modifications would be reflected in a protocol amendment. There has never been a formal protocol amendment in all 14 versions of the protocol formalising a dosing interval of 19-42 days. In fact, protocol amendment 5, (on July 24, 2020), done 3 days before the formal start of the phase 2/3 parts of the trial, explicitly state 21-day dosing interval between the 2 doses.

The question arises why it was appropriate to widen the dosing interval of a novel drug and where is the clinical data backing this move?

Is the widening of a dosing interval of a novel drug in the first trial of this drug not considered a major modification?

Earlier phases of this trial also used a 21-day dosing interval(6). Deliberate ambiguity in the protocol was allowed by not defining a number into the words ‘predefined window’ for the dosing interval. The 19–42 day window only made an appearance in the EUA documentation. This calls into question the meaning of the word ‘pre’. When do you define a ‘predefined window’ if it is seemingly defined post hoc? Again, this is explained in great detail in our article.

Where did these patients come from? Another data investigator kindly mapped our 170 patients down to the different investigational sites. One would have expected a greater contribution to 170 from the more densely populated parts of the United States as this is a highly transmissible disease. Argentina contributed 36 cases towards the 170.

Map courtesy of openvaet.org

We also found 6 pairs of sequential numbers in our list. In a true randomised controlled trial, every patient should have equal opportunity to achieve the endpoint of the trial. We invite mathematicians to calculate the probability of 6 pairs of sequential numbers appearing in a list of 170 from a potential population of about 37,000 (final population eligible for analysis) in a true random sample.

Since publishing the initial paper, we have since then analysed the rate of accrual of the 170 population in relation to the data cut-off date of November 14 2020. This is an approximate analysis, as the date of diagnosis was not uniformly documented. At times, I took the date swab was taken as a proxy for date of diagnosis.

Slide provided by Ed Clark and Jeyanthi Kunadhasan

To understand this issue in its context, we must familiarise ourselves with the analysis plan that Pfizer set out in the protocol, paying particular attention to the thresholds for the interim analysis, as well as the bounds of efficacy and futility laid out. For example, if 54 vaccinated subjects had been diagnosed with Covid out of 164 patients in the evaluable population, this drug would have not been declared effective in preventing infection.

With our analysis of the accrual, it begs the questions as to when the interim analysis was done. Why was the drug not declared efficacious when more 62 cases eligible for the endpoint of the trial would have been accumulated approximately in the last week of October 2020? The boundary for futility of the drug at this point was having more then 15 vaccinated in the eligible endpoint population.

In the EUA documentation, it stated the date for data cut-off for the first interim analysis for efficacy was November 4, 2020; when a total of 94 confirmed COVID-19 cases were accrued. We calculated approximately 112 cases would have been accrued by November 4, 2020. The investigators only publicly said that they were unable to do the first interim analysis planned at accrual of 32 eligible cases. Publicly, also, the first interim analysis was done on November 4, 2020. Was interim analysis not done prior to this? Why?

Is there a story in those that did not make it into the 170? The data team at DailyClout.io analysed the excluded trial patients.

Slide courtesy of Jason Morphett

Combining the two, along with some important events in the timeline, we can see leading up the issuance of the EUA, disproportionately more vaccinated patients were excluded from the trial. At a minimum, we need to have access to the patient records of the excluded patients. The biggest spike we see on the graph shows 181 (0.9 per cent) of patients excluded from the vaccine group on Monday November 16, 2020, just after the data cut-off date of November 14, 2020. In the graph below, we also show the exclusions in the trial against the timeline of accrual of the 170 population.

Slide courtesy of Ed Clark and Jeyanthi Kunadhasan

Was the TGA aware of the anomalies identified in the 170 patients that were the basis of the efficacy claim in the EUA? As an anaesthetist who was fired over Covid -19 vaccine mandates, it is even more farcical to me that the patient population upon which my job was taken away, did not even receive the correct dose of the investigational drug. With our analysis, at least 7 to 9 patients should not be part of the final efficacy analysis upon which to base approval of this drug. This would bring it below the final threshold of 164 cases eligible cases.

The basis upon which the EUA was issued needs to be revisited. So many scientific norms have fallen in this pandemic, the conduct of clinical trials being one of them…

1 Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., . . . Gruber, W. C. (2020). Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine383(27), 2603–2615. https://doi.org/10.1056/nejmoa2034577

2 Principles of Epidemiology | Lesson 3 – Section 6. (n.d.). Retrieved from https://www.cdc.gov/csels/dsepd/ss1978/lesson3/section6.html

3 Kunadhasan, J., Clark, E., & Flowers, C. (2022, October 21). Report 42: Pfizer’s EUA Granted Based on Fewer Than 0.4% of Clinical Trial Participants. FDA Ignored Disqualifying Protocol Deviations to Grant EUA. Retrieved from 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/

4 Kunadhasan, J., Clark, E., & Flowers, C. (2022, October 21). Report 42: Pfizer’s EUA Granted Based on Fewer Than 0.4% of Clinical Trial Participants. FDA Ignored Disqualifying Protocol Deviations to Grant EUA. Retrieved from 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/

5 125742_S1_M5_5351_c4591001-interim-mth6-protocol.pdf. (n.d.). Retrieved from https://phmpt.org/wp-content/uploads/2022/03/125742_S1_M5_5351_c4591001-interim-mth6-protocol.pdf

6 Mulligan, M. J., Lyke, K. E., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., . . . Jansen, K. U. (2020). Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature586(7830), 589–593. https://doi.org/10.1038/s41586-020-2639-4

7 Lovelace, B., Jr. (2020, September 4). Pfizer CEO confirms late-stage coronavirus vaccine trial may have results in October. Retrieved from https://www.cnbc.com/2020/09/03/pfizer-ceo-confirms-coronavirus-vaccine-trial-may-have-results-in-october.html

8 Pfizer CEO pushes back against Trump claim on vaccine timing. (2020, October 2). Retrieved from https://apnews.com/article/election-2020-virus-outbreak-donald-trump-business-elections-bba3859d8465c309311bb911af33780f

9 Gruber, M. F. (2020, December 11). EUA Decision Memorandum. Retrieved from https://www.fda.gov/media/144416/download

Source – https://www.spectator.com.au/2022/12/170-patients-that-changed-everything/