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Recent announcements that some Covid-19 vaccines are estimated to be highly effective in the short term provide new hope that vaccination will soon help control the pandemic. The initial release of limited quantities of vaccines that are still under investigation will provide the opportunity to obtain critical data in an ethical manner to improve public health and regulatory decision-making, thereby increasing public and professional confidence in these and other vaccines.
After relatively short follow-up in phase 3 trials, even when the efficacy of the vaccine appears to be high, reliable information on long-term safety and duration of protection will still be needed. Other information gaps will include more comprehensive short-term safety assessments, knowledge of whether vaccine-induced decreased protection can lead to vaccine-enhanced illness if a vaccinated person becomes infected when exposed to SARS-CoV-2, information on protection against clinically serious diseases. forms of Covid-19, and knowledge of any association between the degree of protection and the recipient’s age or coexisting conditions. Even after the first vaccines are available, it will remain important to evaluate additional vaccines to meet global needs.1
On November 6, 2020, we, as participants in a World Health Organization (WHO) ad hoc consultation on the next steps for Covid-19 vaccine evaluation, discussed what additional critical data should be sought to report. normative and policy recommendations for the first success. vaccines and subsequent optimization. A consensus emerged that while it is still feasible and ethical, ongoing studies and others that are about to begin should continue to collect high-quality information using direct randomized comparisons with placebo to address as many data requirements as possible. While vaccine supplies are limited, available vaccines are still under investigation, or public health recommendations for use of those vaccines have not been made, we believe it is ethically appropriate to continue blind follow-up of placebo recipients in existing trials. and randomizing new participants to vaccine or placebo. Furthermore, under these conditions, we believe that trial sponsors are not ethically obligated to stop blinding treatment assignments for participants who wish to obtain a different investigational vaccine. People who enroll in clinical trials for altruistic reasons will likely understand the value of collecting data that will further clarify the safety and efficacy of these vaccines and their appropriate use.
Rather, there was concern that observational data obtained from non-randomized studies after vaccine deployment might give unreliable answers. Observational studies are subject to substantial biases and are much less susceptible to unequivocal interpretation. Its limitations are of particular concern during this public health emergency, because vaccinated and unvaccinated individuals will differ in their risk of exposure to infection and serious disease, in part due to fluctuating attack rates and because during the early phases of deployment of the vaccine, the vaccinated may at particular risk of infection. In these circumstances, even carefully analyzed observational studies can produce misleading answers about safety and efficacy.2.3 Also, unrelated events that occur by chance after vaccination can be incorrectly attributed to the vaccine, and such anecdotes can be deliberately promulgated by groups that oppose vaccination.
Large, placebo-controlled, phase 3 efficacy trials could provide much of the information needed if adequately followed up for long periods of time while random assignments are still blinded. Such a continuation would produce unbiased evidence on the duration of protection and on longer-term safety, including the evaluation of any evidence that the vaccine eventually increases the risk of severe disease (as recently detected by continuous monitoring of recipients of placebo in dengue vaccine studies).4). If there are hazards, you need to identify them; conversely, longer follow-up could reassuringly demonstrate continued protection with little or no adverse consequences, reducing vaccine concerns.
This opportunity for reliable evidence of longer-term effects would be destroyed by early unmasking and immediate vaccination of placebo-assigned participants. Although each participant has the option of performing any available intervention, if a significant number of participants choose not to do so, continued blinded follow-up in a population in which a licensed vaccine is not being implemented could produce important and unexpected findings that would be difficult. to get reliably in any other way.
Therefore, the early deployment of meager doses of vaccines that are still under investigation [EUL] or similar regulatory mechanisms) could bring additional public health benefits if accompanied by firm commitments to blind follow-up of participants in ongoing or future placebo-controlled trials until a licensed vaccine is fully implemented in the population. In some settings, early implementation could instead use the Expanded Access / Compassionate Use (EA / UC) mechanism, whereby recipients are unequivocally informed about the investigational nature of the vaccine. For example, under difficult conditions, the WHO deployed an Ebola vaccine under EA / CU during the recent outbreak in the Democratic Republic of the Congo, ensuring that hundreds of thousands of prioritized people received an investigational vaccine that was in limited supply.4
Because hundreds of millions of people in some priority groups will eventually be vaccinated against Covid-19, the world needs highly reliable evidence of the safety of vaccines that can be directly and convincingly explained to the public. In fact, the ultimate impact of Covid-19 vaccines on a population may depend more on the prevalence of hesitancy or strong aversion to receiving a Covid-19 vaccine than on whether the vaccine is 95%, 80%, or effective. 70%. Current phase 3 studies typically provide controlled data on about 20,000 vaccine recipients and 20,000 placebo recipients. Although these numbers should be sufficient to detect relatively common adverse events, there is a risk that less common but clinically important events will be missed or exaggerated. Because large numbers of people will be vaccinated quickly, vaccination will inevitably appear to be temporarily associated with some rare adverse events. A big and simple test5 To assess serious safety outcomes, in which many participants (even hundreds of thousands) are randomly assigned to the vaccine or placebo and those who receive the placebo are vaccinated only about 2 months later, you could identify any rare but serious side effects short term or show that it exists were neither. Such a trial could be conducted during a period of emergency use or immediately after licensing and could be seen as a fair way to allocate initially limited vaccine supplies.
What about vaccine candidates that are not available for phase 3 study until after effective vaccines have already been implemented in some settings? Additional vaccines with worthwhile efficacy would still be desirable, especially if they could be easily implemented on a large scale or if safety concerns arise with early vaccines. For example, a 70% effective single dose vaccine may be more valuable than a two dose regimen with 90% efficacy and greater implementation challenges. It should be noted that such a vaccine could not be identified without using placebo controls. Participants in such vaccine trials should have access to the standard of care at their location.3 And if the trial is successful, their communities should share in the benefit. Therefore, countries with limited or no access to a known effective vaccine could allow ethically placebo-controlled trials of vaccines of potential relevance to them, even if effective vaccines are already being marketed elsewhere.
Randomized placebo-controlled trials are the foundation of modern clinical decision-making and remain the most effective way to obtain reliable results. If successful, focused attempts to determine protection correlations could materially accelerate the uptake of second-generation vaccines, but alone cannot provide an adequate basis for evaluating safety and efficacy. Early results from clinical trials may be promising, but cannot provide all the necessary reliable data. Non-inferiority randomized trials can provide clinically relevant data in some cases, but at considerable cost for efficiency.
We can address important needs with continuous follow-up of placebo recipients in phase 3 trials, the use of placebo controls in simple and large safety trials, and clinical data from randomized placebo-controlled trials evaluating new vaccines. A concerted global effort to collect such data while still possible would increase the likelihood of reliably identifying multiple vaccines with favorable benefit-risk profiles. These studies would go a long way toward gaining the broad public trust necessary for the widespread acceptance of the vaccine so that we can end this pandemic.
