Reliance on any COVID-19 vaccine that is available under an emergency use authorization (USA for its acronym in English) will depend on the rigor of the clinical criteria, including the length of follow-up, used to assess it. This is stated by a new document published by the scientific journal The New England of Medicine, coinciding with the announcement by the pharmaceutical company Pfizer that plans to start using its vaccine in the United States at the end of November and ensures that it will know if it is effective this month.
The recently published guide by Food and Drug Administration (FDA) -United States government agency responsible for the regulation of food, drugs, cosmetics, medical devices, biological products and blood derivatives- recommends that data from phase 3 studies to support an emergency use authorization – which may result from an interim analysis specified by the protocol – include a median duration of follow-up of at least 2 months after completion of the full vaccination regimen. This recommendation takes into account the likely rapid delivery of a vaccine to millions of healthy Americans and potentially billions more people worldwide.
As specified by the authors of the scientific paper, the deputy director of the Office of Vaccine Research and Review, Center for Biological Research and Evaluation, Food and Drug Administration (FDA), Philip Krause and the director of the Office of Vaccine Research and Review (OVRR) Marion Gruber, an emergency or US application allows the use of unapproved medical products (or unapproved uses of approved medical products) to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by threatening agents, such as COVID-19, in response to a public health and / or emergency declaration for which there are no suitable, approved and available alternatives.
To issue a US, The FDA must determine, among other things, that the known and potential benefits of a product outweigh its known and potential risks and that the product may be effective in preventing, diagnosing, or treating serious or life-threatening cases, diseases or conditions caused by the agent or agents identified in the statement. A favorable risk-benefit determination cannot be made for vaccines that may have only modest improvement or for which there is insufficient data to assess the safety profile. At stake is public confidence in the U.S. response to the pandemic, COVID-19 vaccines, and vaccines in general, all of which are essential to achieving desired public health outcomes.
“The use of an investigational vaccine under an EUA would not be subject to the usual informed consent requirements for clinical investigations; however, vaccine recipients will be provided with an information sheet describing the investigational nature of the product, known and potential benefits and risks, available alternatives, and the option to decline vaccination, ”the scientists warn in the document. .
“To minimize the risk that the use of a vaccine under an emergency authorization will interfere with the long-term evaluation of safety and efficacy in ongoing trials, it will be essential to continue collecting data on the vaccine even after it becomes available under the USA ”, they add.
What is the password? Continuous monitoring of clinical trial participants to further refine efficacy estimates, further assess the potential for increased disease and decreased immunity, and additional active monitoring of safety will be essential to ensure the confidence of the patient. public on a widely administered vaccine. The quality of the data available to inform the ongoing evaluation of the benefits and risks of a vaccine will depend on the ability to continue evaluating the vaccine against a placebo comparator in clinical trials for as long as possible. Furthermore, the evaluation of other potentially superior vaccines will depend on the ability to continue to maintain placebo controls in ongoing trials.
Thus, issuance of a USA should not, in itself, require the unmasking of a COVID-19 vaccine trial and immediate vaccination of placebo recipientsas doing so may jeopardize the approval of these products.
According to the researchers, evaluation of other potentially superior vaccines will depend on the ability to continue to maintain placebo controls in ongoing trials.
When setting the criteria for the USA, regulators determine the amount of data that could support a positive risk-benefit assessment, giving people who want an investigational vaccine the opportunity to gain that benefit while providing confidence that a vaccine is unlikely to cause net harm when used in this way.
From a safety perspective, a median follow-up of 2 months – meaning that at least half of the vaccine recipients in clinical trials have at least 2 months of follow-up – after completing the full vaccination regimen will allow for identification of possible adverse events that were not apparent in the immediate post-vaccination period and will also provide greater confidence in their absence, if none are observed. Adverse events considered plausibly related to vaccination generally begin within 6 weeks of receiving the vaccine.
According to Krause and Gruber, two months of follow-up will provide time for potential immune-mediated adverse events that began within this 6-week period to be observed and evaluated.. In particular, to support the licensing of a vaccine, the FDA generally requires at least 6 months of safety monitoring for serious adverse events and other medically attended adverse events in a sufficient number of vaccinated.
Since some vaccines being evaluated to prevent COVID-19 are based on technologies not previously used in licensed vaccines, a case could be made for longer safety monitoring to support an EUA. A mean follow-up period of at least 2 months after the final dose of the vaccine is justified, however, by the extensive historical experience with adverse events after vaccination, the need for a vaccine to address the current pandemic.
From the perspective of the efficacy of the vaccine, they advance, it will be important to have data to assess whether protection is mediated by early responses such as the presence of IgM and IgG antibodies, which peak on or before 2 to 4 weeks after vaccination, has started to decline. Such an assessment is particularly relevant for coronavirus vaccines, because natural immunity to coronavirus infection is relatively short-lived. Although 2 months of follow-up is not sufficient to fully assess the duration of protection of the vaccine, the substantial decrease in protective responses could begin to manifest itself in the second month. Therefore, a median of 2 months is the shortest follow-up period required to achieve some confidence that any protection against COVID-19 is likely to be more than very short.
The World Health Organization recently proposed a draft of guidelines that require 3 months of efficacy monitoring data before a vaccine can be considered for its Emergency Use List.
To support FDA approval, most vaccine clinical trials include substantially longer follow-up of trial participants to track both safety and efficacy. For example, for herpes zoster vaccines, participants in Shingrix clinical trials were followed for a median of 3.1 years in one study and 3.9 years in another, and participants in Zostavax clinical trials were followed for a median of 1.3 years in one study and 3.1 years in another.
The NEJM document concludes: “Recognizing the severity of the current public health emergency and the importance of making a vaccine available as soon as possible, We believe that a median follow-up of 2 months after completion of the vaccine regimen will provide the necessary safety and efficacy data to support distribution. of an investigational vaccine under an EUA. Reducing this minimum follow-up could destroy the scientific credibility of the decision to authorize any vaccine for use under an EUA in the United States. Appropriate conditions for US issuance for COVID-19 vaccines are expected to be further discussed at the Oct. 22, 2020 meeting of the FDA’s Advisory Committee on Vaccines and Related Biologicals.”.
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