Page 152 - pfizervax

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19

In Phase 2/3, the unblinded team supporting the DMC (reporting team), including an
unblinded medical monitor, will review cases of severe COVID-19 as they are received, and
will review AEs at least weekly for additional potential cases of severe COVID-19 and will
contact the DMC in the event that the stopping rule or an alert is met. Specifically, the
unblinded reporting team will contact the DMC chair, who will then convene the full DMC
as soon as possible. The DMC will review all available safety and/or efficacy data at the
time of the review. The DMC will make one of the following recommendations to Pfizer:
withhold final recommendation until further information/data are provided, continue the
study as designed, modify the study and continue, or stop the study. The final decision to
accept or reject the committee’s recommendation resides with Pfizer management and will be
communicated to the committee chairperson in writing.

At any point the unblinded team may discuss with the DMC chair whether the DMC should
review cases for an adverse imbalance of cases of COVID-19 and/or severe COVID-19
between the vaccine and placebo groups (see Section 9.6). In addition, at the time of the IAs
after accrual of at least 62, 92, and 120 cases, the number of severe COVID-19 cases in the
vaccine and placebo groups will be assessed.

Stopping and alert rules will be applied as follows. The stopping rule will be triggered when
the 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%.

The stopping rule and alert rules are illustrated in Table 10 and Table 11, respectively, when
the total number of severe cases is 20 or less. For example, when there are 7 severe cases,
the adverse split has to be 7:0 to stop the study, but a split of 5:2 would trigger the alert rule.
Similarly, when there is a total of 9 severe cases, an adverse split of 9:0 triggers the stopping
rule, while a split of 6:3 or worse triggers the alert rule. The alert rule may be triggered with
as few as 2 cases, with a split of 2:0.

Page 142