Early Vaccine Authorization Raises Ethical and Logistical Challenges for Trial Sponsors

Jill Wechsler, Washington Correspondent

The much-anticipated meeting of FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) last month addressed a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection, including policies and data requirements for determining that a pandemic vaccine can be considered safe and effective, particularly when based on more limited, early clinical trial data. A main goal for FDA officials was to reassure the public that it will take all precautions to ensure the safety of any vaccine approved under an Emergency Use Authorization (EUA).

The deliberations may have been shaped by halts in two major vaccine trials at the time due to unspecified safety issues. While studies sponsored by AstraZeneca and Johnson & Johnson’s Janssen unit resumed soon after the meeting, the study pauses were described by researchers as a sign that clinical trial safety systems were working as intended, as the analysts determined the adverse events were unrelated to the test vaccine candidates.

FDA standards for documenting vaccine safety was an important topic for VRBPAC review. The agency’s Center for Biologics Evaluation and Research (CBER) specified in its recent guidance document that it expects an EUA application to provide two months or more of safety data for at least half of the participants in a trial following completion of the full vaccination regimen (see: https://bit.ly/36azRXc). As most serious side effects appear within six weeks of individual vaccination, this timeframe was designed to provide a sufficient period for detecting rare events such as vaccine-induced enhanced respiratory disease and to distinguish such conditions from COVID-19.

Countering vaccine hesitancy

A particularly challenging issue for the advisors was how granting EUA status to an initial product could interfere with further assessment of the vaccine’s safety and with ongoing trials for other preventives. FDA and the expert panel advised that the sponsor of an authorized vaccine should continue blinded follow-up assessments for months following an initial authorization. The aim is to gain further information on vaccine efficacy and side effects, including rare adverse events and fuller comparisons among patient groups with differences in age, sex, comorbidities, and ethnic characteristics. And because information on how long immunity will last will be limited in initial data, both manufacturers and regulators look for additional guidance on determining what data needs to be collected further to indicate when boosters or additional vaccination would be advisable.

However, sponsors raised concerns that it may be unethical to retain trial participants in a placebo arm following EUA approval, raising an important consideration for the research community and health authorities.

At the same time, unblinding a trial could hinder continued development of alternative vaccines, as it would be difficult to enroll new subjects in randomized trials after a vaccine comes to market. Scientists and vaccine developers emphasize that it’s vital for research to continue on multiple preventives, as certain products may affect certain populations differently, and varying formulations may be more suitable for distribution in certain regions.

Most analysts, moreover, expect that some vaccines likely to gain approval in subsequent months may be more effective or provide stronger protection than the early products.

While randomized, placebo-controlled clinical trials are necessary to understand the true effects of a medical product on larger populations, individual participants may gain limited benefit and added risk in the face of a lethal pandemic where the risks are more stark.

An alternative research approach may be to use a newly authorized vaccine as a control in testing subsequent preventives, as a form of noninferiority trial. Such studies may take much longer and cost more to produce results, but could reduce the need for large placebo control arms that deny treatment for thousands.

Jill Wechsler is Applied Clinical Trials' Washington Correspondent