Regulatory Decision-making on COVID-19 Vaccines During a Public Health Emergency

Vaccine development and use depend on data-driven assessment of benefits and risks, first by regulatory bodies, and then more subjectively, millions of times over, by individual physicians and patients. Some vaccines have transformed public health (polio, smallpox, measles), whereas others have failed to work (HIV, malaria) or were later found to have important unexpected adverse effects (rotavirus, the 1976 influenza vaccine). Regulatory review of the numerous coronavirus disease 2019 (COVID-19) vaccine candidates will occur under intense clinical, economic, and political pressure. In early August 2020, President Trump predicted that a vaccine could be available before election day. Less than a week later,Russiaclaimedtohavedevelopeditsownvaccineand wasbeginningwidespreadadministrationwithoutcompletion of the large-scale testing that Western countries routinelyrequire,bringingefficacy-riskquestionstoevenwider public attention. Acknowledging the pressure the US Food and Drug Administration (FDA) faces on this front, its leadership has stated that no vaccine would receive formal approval unless it met the agency’s published standards.1 As with drugs, the efficacy and safety of a vaccine are not binary. Each will fall along a gradient and be subject to varying definitions over time. In its June 2020 guidance document, the FDA established its expectation that an approved vaccine would reduce the occurrence or severity of disease in at least 50% of recipients, a standard similar to that for annual influenza vaccines.2 But that criterion could change. If the pandemic surges further, should a vaccine be approvable if it prevents infection in a lower proportionofpeople?Whatifthevaccinesubstantiallyreduces the severity of illness, but not in half of recipients? The FDA also cited the possibility of less conventional approaches. One approach would allow “accelerated approval” of a vaccine based only on antibody levels or another biochemical marker rather than actual clinical outcomes. This could occur if “additional understanding of SARS-CoV-2immunology,andspecificallyvaccineimmune responses that might be reasonably likely to predict protectionagainstCOVID-19, isacquired.”2(p18) Formanyyears, the agency has shown increasing willingness to approve medications based on their capacity to affect surrogate measures such as laboratory test results, rather than demonstrating an effect on clinical disease.3 Such approvals have been made for drugs with extremely limited patient outcome evidence in oncology and muscular dystrophy, among other conditions. Some have argued that extreme clinical need warrants backing away from the FDA’s historicalstandardsrequiringclinicalbenefit.Thistrendcoincides with increasing political popularity of the libertarian “right to try” movement for medications, which advocates that patients should be able to access treatments not approved by the FDA. This approach was likely reflected in the presidential reasoning about unproven COVID-19 treatments: “Try it; what do you have to lose?” Alternatively, the FDA has noted that it could implement an Emergency Use Authorization (EUA) to make a COVID-19 vaccine available even before its full evaluation is completed. This would have seemed implausible but for the agency’s issuance of another COVID19–related decision in March. In the context of the president’s persistent advocacy for hydroxychloroquine, the agency issued an EUA making millions of doses available for this purpose. That decision was eventually rescinded but led to considerable use of the drug, which continues, and the widespread misperception that the FDA had “approved” hydroxychloroquine for this use. TheFDAvaccineguidanceacknowledgedthatanEUA issued before completion of planned clinical trials “could reduce the ability to demonstrate effectiveness of the investigational vaccine in a clinical disease endpoint efficacy trial to support licensure.”2(p19) A similar issue arose with convalescent plasma donated by COVID-19 survivors. The Trump administration established a program to provide convalescent plasma through an “expanded access” program outside ongoing randomized clinical trials, likely reducing enrollment in the studies required to determine if this therapy is effective and safe. A planned FDA EUA for plasma was initially blocked by senior government scientists who cited the lack of adequate efficacy data.4 PresidentTrumpthenexpressedconcernthat influenceswithin the FDA were trying to delay COVID-19–related approvals untilaftertheelectiontoharmhimpolitically.5 Immediately thereafter, the FDA reversed its decision on convalescent plasma and authorized an EUA for it, apparently without additional trial outcome data to justify this move.5 Other concerning regulatory decisions by the FDA at a time of enormous pandemic-driven pressure included its early hesitancy to approve tests to determine the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), followed by widespread authorization of other tests with widely varying accuracy. Just as the question “Does the vaccine work?” does not have a simple yes/no answer, neither does the question “Is the vaccine safe enough?” This will depend on the incidence and prevalence of COVID-19 in a given place and time, as well as the quality of available therapeutics. What about a vaccine that is effective in reducing infection but produces a severe allergic reaction in 1% of recipients? Or one that causes anaphylaxis in 1 in 1000 recipients, or 1 in 10 000? The extremely rare but potentially catastrophic possibility of immune enhancement must also be considered, in which disease is made substantially worse in some patients who receive a vaccine even as it protects others. Finding severe rare adverse events will require the study of tens of thousands VIEWPOINT