FDA and its vaccines advisory committee are facing ethical and practical conundrums that, unless they are resolved quickly, threaten to undermine the development of COVID-19 vaccines.
The most pressing challenge centers on whether it is acceptable to continue placebo-controlled, blinded trials after a vaccine has been authorized. If there is a need to unblind trials, FDA will need to outline what steps must be taken to ensure that the studies for the authorized or other vaccines can still support regulatory requirements.
The stakes are high. In the worst case, failure to resolve the unblinding problem could mean that the first COVID-19 vaccine would be the only vaccine.
The emergency use authorization (EUA) of a COVID-19 vaccine will create two sets of problems related to placebo-controlled trials. Patients enrolled in the ongoing Phase III trial of the authorized vaccine will want to know whether they received a placebo. Of those who did, some will very likely want to get the vaccine, which would disrupt the ability to gather long-term safety and efficacy comparisons between the vaccine and placebo arms.
The second set of problems involves individuals who have enrolled in trials of other vaccine candidates. Volunteers who have enrolled in a trial of a vaccine candidate that has not received an EUA are likely to want to know if they’ve received a placebo. If so, they may want to drop out of the trial and receive the authorized vaccine. Participants in the vaccine arm of the trial may want to know if it is safe for them to also receive the authorized vaccine.
Vaccine manufacturers, BIO, the Infectious Diseases Society of America (IDSA) and other groups raised concerns about maintaining placebo arms in COVID-19 trials in comments submitted to the docket for the Oct. 22 Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting. The draft agenda includes only about two hours for discussion and recommendations on the full range of topics the committee is considering, so it is unlikely to provide definitive answers on questions about placebo controls.
This is new territory for FDA, with no clear precedent to draw on. However, with the first COVID-19 EUA applications weeks or at most months away, the agency will have to come up with answers quickly.
FDA has seen this problem coming. In its guidance on EUAs for COVID-19 vaccines, FDA stated that it expects that “following submission of an EUA request and issuance of an EUA, a sponsor would continue to collect placebo-controlled data in any ongoing trials for as long as feasible and would also work towards submission of a Biologics License Application (BLA) as soon as possible.”
The guidance also stated that “FDA does not consider availability of a COVID-19 vaccine under EUA, in and of itself, as grounds for stopping blinded follow-up in an ongoing clinical trial.”
The agency suggested that EUA requests “should include strategies that will be implemented to ensure that ongoing clinical trials of the vaccine are able to assess long-term safety and efficacy.” Anticipating the problem, it also asked for strategies for addressing “loss of follow-up information for study participants who choose to withdraw from the study in order to receive the vaccine under an EUA.”
FDA also envisions the need to unblind trials, stating in the guidance on BLAs for COVID-19 vaccines: “Efficacy trials should include contingency plans for continued follow up and analysis of safety and effectiveness outcomes in the event that a safe and effective vaccine becomes available (e.g., as demonstrated in a planned interim analysis or as demonstrated in another clinical trial). In that case, discussion with the agency may be necessary to address ethical arguments to break the blind and offer vaccine to placebo recipients.”
The BLA guidance also proposes one way the authorization or approval of a vaccine could affect subsequent trials of COVID-19 vaccine candidates. “If the availability of a COVID-19 vaccine proven to be safe and effective precludes ethical inclusion of a placebo control group, that vaccine could serve as the control treatment in a study designed to evaluate efficacy with non-inferiority hypothesis testing.”
It is far from clear, however, that non-inferiority trials of COVID-19 vaccines would be feasible. Moreover, the difficulty of doing this could preface pressure on FDA to accept external control arms or real-world data as controls.
Demonstrating non-inferiority to an effective intervention can require very large trials or the acceptance of large confidence intervals around the results. The placebo-controlled Phase III COVID-19 trials already include at least 30,000 participants, and there will be little acceptance of uncertainty about the efficacy of a vaccine to prevent a life-threatening disease.
IDSA is urging FDA to make EUAs contingent on the ability of sponsors to continue placebo-controlled trials.
In its comments, the medical society expressed support for FDA’s statements about the need to continue clinical trials after an EUA.
IDSA added that it is “concerned about the feasibility and ethical questions of keeping study subjects on a placebo after a vaccine is made available via EUA.”
It called on the VRBPAC to “insist that sponsors present a compelling case regarding their ability to continue studies following an EUA before recommending that FDA grant an EUA.”
Companies that are developing COVID-19 vaccines, however, say that is it impossible to maintain blinding after a vaccine has been authorized, and that it is also impossible to prevent participants who received placebo from being vaccinated with an authorized product.
ETHICAL RESPONSIBILITY TO UNBLIND
“As an industry,” BIO stated in its comments, “we have an ethical obligation to make our trial participants aware that a vaccine may be available” after an EUA has been granted.
Jerrold Abraham, a pathology professor at SUNY Upstate Medical University and Arthur Caplan, a bioethicist at NYU Langone Medical Center, made a similar point in a comment published in the Journal of Medical Ethics.
“Ethically, a subject is allowed to quit a trial at any time,” they wrote.
They also stated that if a vaccine has been authorized, participants in trials of that vaccine or of other vaccines have the right to know if they received a placebo, and “they need to be informed of what to do should they wish to subsequently try an approved vaccine.”
Unblinding is particularly important, according to Abraham and Caplan, because the safety considerations for a trial participant who received a placebo are different from someone who received an investigational vaccine candidate. “If a subject got experimental vaccine, there may be more of a chance of having an adverse immune reaction to an additional vaccine that is approved.”
Caplan will make a presentation to the Oct. 22 advisory committee meeting about the ethics of unblinding COVID-19 trials following an EUA.
In its comments about the advisory committee meeting, Pfizer Inc. (NYSE:PFE), which is likely to be among the first companies to seek an EUA for a COVID-19 vaccine, stated that it plans to keep the trial blinded as long as possible, but this will not be possible if and when its product is authorized.
Pfizer is partnering with BioNTech SE (NASDAQ:BNTX) on an mRNA COVID-19 vaccine.
“It is our position that while ensuring the blinded nature of the study as long as possible, Pfizer and BioNTech nevertheless would have an ethical responsibility to inform all study participants about the availability of an Emergency Authorized Vaccine, if authorized, and the eligibility requirements for such a vaccine,” Pfizer stated.
If its vaccine is granted an EUA, Pfizer said it “would propose to amend our ongoing study to allow cross-over of eligible placebo subjects to the active vaccine arm if they wish to do so at any time.”
It added: “The statistical considerations and details regarding the appropriate protocol language, informed consent, and logistics of this process would need to be carefully developed together with the regulatory authority.”
Pfizer urged FDA to consider the use of real-world data to substitute for missing placebo-controlled data. It asked the agency “to be open to other scientifically and statistically sound methods to assess the long-term effectiveness and safety follow-up of recipients of our vaccine candidate (e.g., comparison of standing safety cohorts and registries).”
EUA FOR ONE VACCINE MAY FORCE UNBLINDING OF TRIALS OF OTHERS, J&J SAYS
There is a clear need for multiple COVID-19 vaccines because no single manufacturer can meet the demand in the U.S. or the world, and because vaccines are likely to have different characteristics such as efficacy in specific subpopulations, number of doses, and need for special handling.
Because it will not be possible to authorize all of the COVID-19 vaccines at the same time, it is important for FDA to adopt policies that ensure that the first EUA approvals do not make it impossible to complete trials of other vaccine candidates.
The Janssen unit of Johnson & Johnson (NYSE:JNJ) expressed concerns about the effects of an EUA on its vaccine program. Janssen said it is “evaluating a number of measures aimed at maintaining Phase 3 trial retention, should a COVID-19 vaccine become available before our trial is complete,” it stated in comments to FDA.
Janssen noted that “once the first vaccines are licensed/authorized, this may lead willing volunteers to seek available vaccines over participating in ongoing trials. Participants already enrolled in ongoing trials might withdraw from those trials, preferring to receive an available vaccine.”
This scenario, Janssen warned, could “jeopardize integrity of an ongoing Phase 3 clinical trial if a clinical trial participant decides they want to receive an EUA vaccine; the study may need to be unblinded to ascertain the participant’s randomization schedule.”
In the absence of policies that make it possible to continue to gather data that could support authorization or approval of a vaccine candidate, unblinding could “jeopardize longitudinal follow-up for both safety and efficacy, which in turn can result in serious concerns about the validity and scientific integrity of the affected studies.”
Janssen urged FDA and vaccine sponsors to work together to develop plans for ensuring that the unblinding does not create a de facto monopoly for the first vaccine to receive an EUA.
Janssen raised the prospect of using shared placebo data or external controls to mitigate the loss of placebo-controlled data. “Future FDA workshops on COVID-19 vaccines could include a discussion on collaboration across manufacturers on rules about unblinding ongoing trials and potentially sharing data on participants in the placebo group, and statistical approaches to analyzing results in the event that there are considerable cross-overs from the placebo arm to the treatment/vaccine arm (external controls, self-controlled designs, etc.).”