key: cord-0920982-hb3hx8nw
authors: Levin, Yotam; Madar Balakirski, Noa; Caraco, Yoseph; Ben-Ami, Eytan; Atsmon, Jacob; Marcus, Hadar
title: Ethics and Execution of Developing a 2nd Wave COVID Vaccine – Our Interim Phase I/II VSV-SARS-CoV2 Vaccine Experience
date: 2021-04-13
journal: Vaccine
DOI: 10.1016/j.vaccine.2021.04.017
sha: 6b771f31e22a705f60f5427a3dc86de5003cb6a9
doc_id: 920982
cord_uid: hb3hx8nw

nan

regulators. Should we continue to maintain (and recruit) for the placebo arms (especially in 24 elderly subjects whom are eligible and have access to an approved and effective vaccine), and if 25 so, for how long should we maintain placebo monitoring? When to trigger unblinding, and which 26 vaccine to offer such unblinded placebo subjects (the approved one, or to request re-consent for 27 our investigational one)? 28 We conclude that placebo is critical for study quality and a follow-up prior to unblinding of 56 29 days maintains a reasonable balance between ethics and execution. The study offers subjects who 30 are unblinded and found on Placebo, to either vaccinate with an approved vaccine outside the 31 study, or to re-consent to the study (with a 1:3 chance of receiving the placebo assigned to that 32 dosing group). 33 Following EUA of two mRNA vaccines in the US, Pfizer-BioNtech and Moderna's, on 34 December 10 th and 17 th 2020, respectively, and their approval by the State of Israel immediately 35 thereafter, Israel has launched perhaps the fastest COVID vaccination campaign (per population) 36 globally. Israel has administered nearly 10 million vaccine doses and fully vaccinated nearly 37 51% of its population, followed by UK (~23%) and the US (~19.7% . If the answer to the above is "yes", after what duration, and upon which trigger, should we 59 unblind and vaccinate such placebo subjects? 60 3. Finally, which vaccines should be offered to such unblinded placebo subjects -the 61 investigational one they originally volunteered for, or a commercial/EUA vaccine that is (or 62 will soon be) available to them? 63 Struggling with these questions and the balancing of subjects' wellbeing vs. the quality of the 64 clinical study (as further elaborated in our own letter to Wendler et al in Science), 6,7 we have 65 attempted to refer to leading regulators and vaccine programs, although this too was quite 66 challenging. In particular, the FDA has not updated its guidance for placebo-controlled efficacy 67 studies to date, and remains in the position that placebo subjects should be followed for "as long 68 as feasible". This approach was recently put to test with the FDA approval of NovaVax's Phase 69 III study, which included a placebo arm (albeit at 2:1 ratio). Pfizer, in its own EUA submission 70 from December 10 th , 2020, has requested to continue to follow-up subjects on placebo for 6 71 months prior to unblinding, setting a relatively long-duration bar compared to its close rival 72 Moderna (which, in its own EUA, seven days later, recommended that all placebo subjects be 73 immunized with the m1273 vaccine, effectively unblinding the study altogether immediately and 74 prior to natural completion). 75 However, in reviewing the strategies proposed or executed by the leading developers of the "first 76 wave" of COVID vaccines, we were also required to attend to our unique situation in which by to be re-randomized into any active dosage arm. Importantly, subjects are notified that they may 95 be re-randomized into placebo arms again (with the same chance of 1:3 to receive the placebo) to 96 ensure study blinding, alongside a commitment that if they are indeed re-randomized to receive 97 placebo they will be unblinded again at Day 56 and referred to receive an approved vaccine. This 98 approach was undertaken in order to maintain the study randomization scheme and blinding, 99 while taking into account the prolonged risk for these double-placebo assignment subjects, and 100 limiting subjects' anxiety for lack of protection. in the population was about 9.6%. However, Israel was undergoing a stringent lock-down, and 117 the sponsor relied on its proficient investigators to provide effective social distancing guidance 118 and education to all subjects -to mitigate said exposure risk. While debating such risks, we 119 voted against limiting placebo to young healthy subjects only, as they are at lower risk for severe 120 COVID-19, and because of the detrimental effect on the quality of the study for the elderly, 121 whom are the primary population to benefit from this vaccine, if registered. An alternative of 122 converting a part of the study to open-label was also considered, however if adopted, would have 123 caused, we felt, irreparable harm to the study's quality. 124 So far, we have unblinded ~80% Phase II subjects. In communicating our protocol amendment 126 and the blinding procedures, the investigators have informed all subjects of the availability of an 127 effective, EUA-approved, vaccine, and the potential risk of being immunized with the 128 investigational yet-to-be-proven, vaccine product. 129 We also would like to report that despite these said challenges, our clinical sites have been able Currently in the case of Israel, one could argue that equity means providing vaccine access for 157 placebo subjects that volunteered to advance science, rather than preventing their prioritization. 158 To conclude, we wish to reiterate the position of Rid et al. on the importance of both equity for 159 vaccine access, 10 as well as the critical importance of maintaining placebo groups' blinding for 160 as long as feasible, to ensure the quality of vaccine development trials. 161 We hereby present our approach to the challenge, which attempts to balance individual risk with 162 the Common Good -without utterly compromising the quality of randomized clinical studies 163 which are the foundation of best clinical practice. 164 Our approach is an interim measure, but it is our opinion that the challenges will persist beyond 165 the 2 nd wave of COVID vaccine development. Indeed, COVID-19 may evolve into new and 166 more challenging variants, and humanity will require additional vaccines and vaccine trials, 167 beyond the ones presently in the late-stage pipeline.

A single dose of recombinant VSV-∆G-173 spike vaccine provides protection against SARS-CoV-2 challenge

Israel's rapid rollout of vaccinations for COVID-19

COVID-19 vaccine trial ethics 179 once we have efficacious vaccines

pursuit of the Common Good

Global Vaccination. eLetter response to

Makers of successful COVID-19 vaccines wrestle with options for placebo 186 recipients

☒ The authors declare that they have no known competing financial interests or personal relationships that could 194 have appeared to influence the work

☐The authors declare the following financial interests/personal relationships which may be considered 197 as potential competing interests