Early Vaccine Authorization Raises Ethical and Logistical Challenges for Trial Sponsors

The much-anticipated meeting of FDA’s vaccine advisory committee this week is slated to address a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection. Although the Vaccines and Related Biological Products Advisory Committee (VRBPAC) will not review an application for any particular product, this panel of virologists and scientists will discuss 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.

Shaping the discussion is the current halt in two major vaccine trials due to unspecified safety issues. US investigators continue to seek more information on patient illness in the AstraZeneca vaccine study announced in early September, although enrollment has restarted for AZ trials in the United Kingdom and other countries. Johnson & Johnson more recently paused its massive COVID-19 vaccine trial due to an “unexplained illness” in a patient. The safety committee for the study has stated by examining whether the ill individual received the vaccine or was in the placebo arm. The sponsors emphasize that these research halts demonstrate their excessive caution and importance of calling on outside monitoring boards to fully investigate such cases.

FDA standards for documenting vaccine safety is an important topic for VRBPAC review, particularly as it relates to granting Emergency Use Authorization (EUA) to an experimental vaccine, an approach that agency officials consider likely and appropriate given the high costs of the pandemic in terms of public health risks and economic hardship. The 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 . As most serious side effects appear within six weeks of individual vaccination, this timeframe is designed to provide a sufficient period for detecting events such as vaccine-induced enhanced respiratory disease and to distinguish such conditions from coronavirus disease.

Sidelining further studies?

A particularly challenging issue for the advisors is the 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 says that the sponsor of an authorized vaccine should continue blinded follow-up assessments for months following an initial distribution, but there some authorities believe that an EUA sponsor should shift all participants in the placebo arm to receive treatment. While that might appear a more ethical decision, it could block efforts 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 of limited information about how long immunity will last from initial vaccines, both manufacturers and regulators look for additional guidance on determining what data need to be collected further to indicate when boosters or additional vaccination would be advisable.

Most analysts expect that some vaccines likely to gain approval in subsequent months may be more effective or provide stronger protection than the early products. However, continued development of alternative vaccines may be hindered by difficulties in enrolling new subjects in randomized trials when a vaccine is on the 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.

These issues raise important ethical considerations for the research community and health authorities. 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. And in the face of a lethal pandemic, the risks are even more stark. An alternative research approach may be to use a newly authorized vaccine as a control in testing subsequent preventives, 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.