Recent announcements state that some Kovid-19 vaccines are speculated to have short-term efficacy, providing new hope that vaccination will soon contribute to controlling the epidemic. The initial roll-out of limited amounts of vaccines that are still investigatable will provide an opportunity to obtain ethically significant data to improve regulatory and public health decision-making, thereby increasing public and professional confidence in these and other vaccines .
Relative information on long-term safety and duration of protection will still be needed, even after relatively low follow-up in phase 3 trials, when vaccine efficacy appears to be high. Other information gaps will include more comprehensive assessments of short-term safety, knowing whether weathering for vaccine-induced protection can lead to vaccine-enhanced disease if a vaccine is infected with exposure to SARS-CoV-2, Protection against clinically severe forms of Kovid-19, and knowledge of any associations between the degree of protection and the recipient’s age or co-conditions. Even after the first vaccines became available, it would still be important to evaluate additional vaccines to meet the worldwide needs.1
On November 6, 2020, we, as participants of the World Health Organization (WHO), discuss ad hoc consultation in the next stages of the Kovid-19 vaccine evaluation, what to inform regulatory and policy recommendations for the first successful Important additional data should be looked for. Vaccines and later adaptation. While there has been consensus that this is still feasible and ethical, ongoing studies and others that are about to begin should continue to collect high-quality information using directly randomized comparisons against placebo so that data requirements As possible. While vaccine supplies are limited, available vaccines are still investigatable, or public health recommendations have not been made to use those vaccines, we believe that current trials continue blind follow-up of placebo recipients and new It is appropriate to randomly assign participants to vaccine or placebo. Furthermore, under these conditions, we believe that trial sponsors are not ethically obligated to treat assignments for participants who wish to receive a different investigational vaccine. Those who enroll in clinical trials for altruistic reasons will probably understand the value of collecting data that will advance the safety and efficacy of these vaccines and their proper use.
Conversely, there was concern that observational data obtained from non-dimensional studies after vaccine deployment may provide unreliable answers. Observational studies are subject to substantial biases and little to unclear interpretation. Their limitations during this public health emergency are particularly worrisome, as vaccinated and unvaccinated people will vary in risk of infection and risk of serious illness, partly because of fluctuations in attack rates and because of early vaccination deployment. During the stages, vaccines may occur well. At special risk of infection. Under these circumstances, even carefully analyzed observational studies can provide misleading answers about safety and efficacy.2,3 In addition, coincidentally unrelated events that occur after vaccination may be incorrectly attributed to the vaccine, and such anecdotes may be intentionally promulgated by groups opposing vaccination.
Large, placebo-controlled, phase 3 efficacy trials may provide the necessary information if they have a reasonably long follow-up while randomized assignments are still blind. Such continuity would provide unbiased evidence on the duration of protection and long-term protection, including assessing any evidence of the vaccine and ultimately increasing the risk of severe disease (as in recent dengue vaccine studies of placebo recipients Was found by continuous follow up)4). If there are hazards, they need to be identified; In addition, long-term follow-up may assure continued safety with few vaccines or adverse outcomes, reducing vaccine hesitation.
This opportunity to obtain reliable evidence about the long-term effect would be destroyed by initial unbounding and immediate vaccination of participants assigned to placebo. Although each participant has the option to pursue any available intervention, if a sufficient number of participants do not wish to do so, continuation of blind follow-up in a population in which no licensed vaccine is being deployed is important. And may draw unexpected conclusions that would be difficult. To get reliably in some other way.
Thus, early deployment of rare doses of still-tested vaccines (under the emergency use list) [EUL] Or similar regulatory mechanisms) may bring additional public health benefits if the firm or commit to maintain blind follow-up of participants in ongoing or future placebo-controlled trials as long as a licensed vaccine is fully in the population Do not deploy. In some settings, initial deployment may instead use the Extended Access / Compassionate Use (EA / CU) mechanism, under which recipients are explicitly informed about the nature of the vaccine examined. For example, under conditions, WHO recently deployed an Ebola vaccine under EA / CU during an outbreak in the Democratic Republic of Congo, ensuring that hundreds of thousands of priority individuals 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 Kovid-19, the world needs highly reliable evidence of vaccine safety that can be explained directly and clearly to the public. In fact, the ultimate effect of Kovid-19 vaccines in the population may be more dependent on the prevalence of hesitation or robust dissection to obtain a Kovid-19 vaccine, provided that the vaccine has 95%, 80%, or 70% efficacy. Current Phase 3 studies typically provide controlled data on approximately 20,000 vaccine recipients and 20,000 placebo recipients. While these numbers should be sufficient to detect relatively common adverse events, there is a risk of missing or exaggerating less common but clinically significant events. Because a large number of people will be rapidly vaccinated, vaccination will inevitably appear to be temporarily associated with some unusual adverse events. A big, simple test5 To evaluate serious safety outcomes, in which many participants (even in the hundreds) are randomly assigned to a vaccine or placebo, and those who receive placebo are vaccinated approximately 2 months later. , Which can identify or show any rare but serious short-term side effects. There were no such tests that could be conducted either during the period of emergency use or immediately after licensing and initially viewed as a reasonable way to allocate limited vaccine supplies.
What about vaccine candidates who are not available for Phase 3 studies, unless effective vaccines have already been deployed in some locations? Additional vaccines with meaningful efficacy would still be desirable, especially if they could be easily deployed on a large scale or if safety concerns with vaccines first emerged. For example, a 70% effective single-dose vaccine may be more valuable than a two-dose diet with 90% efficacy and greater implementation challenges. It is noteworthy that such vaccines could not be identified without using placebo controls. Participants in such vaccine trials should have access to standard of care in their place3 And, if the test is successful, their communities should share in the profits. Countries with limited or no use of a known effective vaccine may thus allow placebo-controlled trials of vaccines of potential relevance, even if effective vaccines are already being administered elsewhere.
Randomized, placebo-controlled trials are the basis of modern clinical decision making and remain the most efficient way to obtain reliable results. If successful, focused efforts to detect correlations of preservation may accelerate acceptance of second-generation vaccines, but may not provide an adequate basis for assessing safety and efficacy alone. Initial clinical trial results may offer promise, but they may not provide all the necessary data. Randomized, nonferiority trials may in some cases provide clinically relevant data, but at considerable cost for efficiency.
We can address critical needs with continued follow-up of placebo recipients in phase 3 trials, the use of placebo-controls in large, simple safety trials, and clinical data from placebo-controlled, randomized trials evaluating new vaccines. A global effort to collect such data, while it is still possible to increase the likelihood of reliably identifying multiple vaccines with favorable benefit-risk profiles. These studies will go much further towards earning the broad public confidence necessary for widespread vaccine acceptance so that we can end this epidemic.
Herbert Needleman, MD, a physician-scientist whose lead in consumer products was removed due to research…
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