Daniel Walsh, Ph.D, MJLST Staffer
The emergence of the SARS-CoV-2 virus has thrown the world into chaos, taking the lives of more than a million worldwide to date. Infection with SARS-CoV-2 causes the disease COVID-19, which can have severe health consequences even for those that do not succumb. An unprecedented number of vaccines are under development to address this challenge. The goal for any vaccine is sterilizing immunity, which means viral infection is outright prevented. However, a vaccine that provides only partially protective immunity will still be a useful tool in fighting the virus. Either outcome would reduce the ability of the virus to spread, and hopefully reduce the incidence of severe disease in those who catch the virus. An effective vaccine is our best shot at ending the pandemic quickly.
For any vaccine to become widely available in the United States, it must first gain approval from the Food and Drug Administration (FDA). Under normal circumstances a sponsor (drug manufacturer) seeking regulatory approval would submit an Investigational New Drug (IND) application, perform clinical trials to gather data on safety and efficacy, and finally file a Biologics License Application (BLA) if the trials were successful. The FDA will review the clinical trial data and make a determination as to whether the benefits of the therapy outweigh the risks, and if appropriate, approve the BLA. Of course, degree of morbidity and mortality being caused by COVID-19 places regulators in a challenging position. If certain prerequisites are met, the FDA as the authority to approve a vaccine using an Emergency Use Authorization (EUA). As pertaining to safety and efficacy, the statutory requirements for issuing an EUA are lower than normal approval. It should also be noted that an initial approval via EUA does not preclude eventual normal approval. Full approval of the antiviral drug remdisivir is an example of this occurrence.
In any specific instance, the FDA must conclude that a reason for using the EUA process (in this case SARS-CoV-2):
can cause a serious or life-threatening disease or condition . . . based on the totality of scientific evidence available . . . including data from adequate and well-controlled clinical trials, if available, it is reasonable to believe that . . . the product may be effective in diagnosing, treating, or preventing [SARS-CoV-2] . . . the known and potential benefits of the product, when used to diagnose, prevent, or treat [SARS-CoV-2], outweigh the known and potential risks of the product . . . .
21 USC 360bbb-3(c). On its face, this statute does not require the FDA to adhere to the full phased clinical trial protocol in grating an EUA approval. Of course, the FDA is free to ask for more than the bare minimum, and it has wisely done so by issuing a set of guidance documents in June and October. The FDA indicated that, at the minimum, a sponsor would need to supply an “interim analysis of a clinical endpoint from a phase 3 efficacy study;” that the vaccine should demonstrate an efficacy of at least 50% in a placebo controlled trial; that phase 1 and 2 safety data should be provided; and that the phase 3 data “should include a median follow-up duration of at least two months after completion of the full vaccination regimen” (among other requirements) in the October guidance.
It is clear from these requirements that the FDA is still requiring sponsors to undertake phase 1, 2, and 3 trials before FDA will consider issuing an EUA, but that the FDA is not going to wait for the trials to reach long term safety and efficacy endpoints, in an effort to get the public access to a vaccine in a reasonable time frame. The Moderna vaccine trial protocol, for example, has a study period of over two years. The FDA also has a statutory obligation to “efficiently review clinical research and take appropriate action . . . in a timely manner.” 21 USC § 393(b)(1).
One method of speeding up the FDA’s assessment of efficacy is a surrogate endpoint. Surrogate endpoints allow the FDA to look at an earlier, predictive metric of efficacy in a clinical trial when it would be impractical or unethical to follow the trial to its actual clinical endpoint. For example, we often use blood pressure as a surrogate endpoint when evaluating drugs intended to treat stroke. The FDA draws a distinction between candidate, reasonably likely, and validated surrogate endpoints. The latter two can be used to expedite approval. However, in its June guidance, the FDA noted “[t]here are currently no accepted surrogate endpoints that are reasonably likely to predict clinical benefit of a COVID-19 vaccine . . . . [and sponsors should therefore] pursue traditional approval via direct evidence of vaccine safety and efficacy . . . .” This makes it unlikely surrogate endpoints will play any role in the initial EUAs or BLAs for any SARS-CoV-2 vaccine.
However, as the science around the virus develops the FDA might adopt a surrogate endpoint as it has for many other infectious diseases. Looking through this list of surrogate endpoints, a trend is clear. For vaccines, the FDA has always used antibodies as a surrogate endpoint. However, the durability of the antibody response to SARS-CoV-2 has been an object of much concern. While this concern is likely somewhat overstated (it is normal for antibody levels to fall after an infection is cleared), there is evidence that T-cells are long lasting after infection with SARS-CoV-1, and likely play an important role in immunity to SARS-CoV-2. It is important to note that T-Cells (which coordinate the immune response and some of which can kill virally infected cells) and B-Cells (which produce antibody proteins) are both fundamental, and interdependent pieces of the immune system. With this in mind, when developing surrogate endpoints for SARS-CoV-2 the FDA should consider whether it is open to a more diverse set of surrogate endpoints in the future, and if so, the FDA should communicate this to sponsors so they can begin to build the infrastructure necessary to collect the data to ensure vaccines can be approved quickly.