{"id":20189,"date":"2021-04-07T12:35:12","date_gmt":"2021-04-07T12:35:12","guid":{"rendered":"https:\/\/evaggelatos.com\/?p=20189"},"modified":"2021-04-08T09:15:06","modified_gmt":"2021-04-08T09:15:06","slug":"brittish-medical-journal-%ce%bf%ce%b9-%ce%b4%ce%bf%ce%ba%ce%b9%ce%bc%ce%ad%cf%82-%cf%84%cf%89%ce%bd-%ce%b5%ce%bc%ce%b2%ce%bf%ce%bb%ce%af%cf%89%ce%bd-%ce%b4%ce%b5%ce%bd-%ce%b5%ce%af%ce%bd%ce%b1%ce%b9","status":"publish","type":"post","link":"https:\/\/evaggelatos.com\/?p=20189","title":{"rendered":"Brittish Medical Journal: \u039f\u03b9 \u03b4\u03bf\u03ba\u03b9\u03bc\u03ad\u03c2 \u03c4\u03c9\u03bd \u03b5\u03bc\u03b2\u03bf\u03bb\u03af\u03c9\u03bd \u03b4\u03b5\u03bd \u03b5\u03af\u03bd\u03b1\u03b9 \u03c3\u03c7\u03b5\u03b4\u03b9\u03b1\u03c3\u03bc\u03ad\u03bd\u03b5\u03c2 \u03bd\u03b1 \u03c3\u03ce\u03c3\u03bf\u03c5\u03bd \u03b6\u03c9\u03ad\u03c2, \u03bc\u03b1\u03c2 \u03bc\u03b5\u03c4\u03b1\u03c4\u03c1\u03ad\u03c0\u03bf\u03c5\u03bd \u03c3\u03b5 \u03b6\u03ce\u03b1 \u03bb\u03ad\u03b5\u03b9 \u03bf \u03a3\u03bf\u03cd\u03c7\u03b1\u03c1\u03b9\u03c4 \u0392\u03ac\u03c7\u03c4\u03b9"},"content":{"rendered":"<div class=\"panel-pane pane-highwire-article-citation\">\n<div class=\"pane-content\">\n<div id=\"node1036304\" class=\"highwire-article-citation highwire-citation-type-highwire-article\" data-node-nid=\"1036304\" data-pisa=\"bmj;371\/oct21_3\/m4037\" data-pisa-master=\"bmj;bmj.m4037\" data-apath=\"\/bmj\/371\/bmj.m4037.atom\">\n<h1>\u0394\u03ad\u03c3\u03c4\u03b5 \u03c4\u03b7 \u03c3\u03c5\u03bd\u03ad\u03bd\u03c4\u03b5\u03c5\u03be\u03b7 \u03c0\u03bf\u03c5 \u03ad\u03b4\u03c9\u03c3\u03b5 \u03c3\u03c4\u03bf Brighteon \u03c0\u03c1\u03ce\u03c4\u03b1 \u03ba\u03b1\u03b9 \u03bc\u03b5\u03c4\u03ac \u03b4\u03b9\u03b1\u03b2\u03ac\u03c3\u03c4\u03b5 \u03c4\u03bf \u03ac\u03c1\u03b8\u03c1\u03bf \u03b1\u03c0\u03cc \u03c4\u03bf BMJ:https:\/\/www.brighteon.com\/6453f41e-1ccd-4516-a643-3411fdcada94<\/h1>\n<h1 id=\"page-title\" class=\"highwire-cite-title\">Will covid-19 vaccines save lives? Current trials aren\u2019t designed to tell us<\/h1>\n<p><cite class=\"highwire-cite highwire-citation-bmj-article-top\"><span class=\"highwire-cite-journal\">BMJ<\/span> <span class=\"highwire-cite-published-year\">2020<\/span>; <span class=\"highwire-cite-volume-issue\">371<\/span> <span class=\"highwire-cite-doi\"> doi: <a href=\"https:\/\/doi.org\/10.1136\/bmj.m4037\">https:\/\/doi.org\/10.1136\/bmj.m4037<\/a><\/span> <span class=\"highwire-cite-date\">(Published 21 October 2020)<\/span> <span class=\"highwire-cite-article-as\"> Cite this as: <span class=\"italic\">BMJ<\/span> 2020;371:m4037 <\/span> <\/cite><\/p>\n<div>\n<h2>Linked Editorial<\/h2>\n<p>Covid-19 vaccine trial protocols released<\/p>\n<\/div>\n<div>\n<h2>Read our latest coverage of the coronavirus outbreak<\/h2>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div class=\"panel-separator\"><\/div>\n<div class=\"panel-pane pane-highwire-panel-tabs pane-panels-ajax-tab-tabs panels-ajax-tabs-once-processed\">\n<div class=\"pane-content\">\n<ul class=\"tabs inline panels-ajax-tab\">\n<li class=\"first active\"><a class=\"panels-ajax-tab-tab panels-ajax-tabs-once-processed panels-ajax-tabs-first-loaded hw-panels-ajax-tabs-once-processed\" title=\"Article Tab - Article\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037\" data-panel-name=\"jnl_bmj_tab_art\" data-target-id=\"highwire_article_tabs\" data-entity-context=\"node:1036304\" data-trigger=\"\" data-url-enabled=\"1\">Article<\/a><\/li>\n<li><a class=\"panels-ajax-tab-tab panels-ajax-tabs-once-processed hw-panels-ajax-tabs-once-processed\" title=\"Article Tab - Related Articles\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037\/related\" data-panel-name=\"jnl_bmj_tab_related_art\" data-target-id=\"highwire_article_tabs\" data-entity-context=\"node:1036304\" data-trigger=\"related\" data-url-enabled=\"1\">Related content<\/a><\/li>\n<li><a class=\"panels-ajax-tab-tab panels-ajax-tabs-once-processed hw-panels-ajax-tabs-once-processed\" title=\"Article Tab - Info &amp; Metrics\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037\/article-info\" data-panel-name=\"jnl_bmj_tab_info\" data-target-id=\"highwire_article_tabs\" data-entity-context=\"node:1036304\" data-trigger=\"article-info\" data-url-enabled=\"1\">Metrics<\/a><\/li>\n<li><a class=\"panels-ajax-tab-tab panels-ajax-tabs-once-processed hw-panels-ajax-tabs-once-processed\" title=\"BMJ Article Related Rapid Responses\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037\/rapid-responses\" data-panel-name=\"bmj_related_rapid_responses\" data-target-id=\"highwire_article_tabs\" data-entity-context=\"node:1036304\" data-trigger=\"rapid-responses\" data-url-enabled=\"1\">Responses<\/a><\/li>\n<\/ul>\n<\/div>\n<\/div>\n<div class=\"panel-separator\"><\/div>\n<div class=\"panel-pane pane-highwire-panel-tabs-container\">\n<div class=\"pane-content\">\n<div id=\"panels-ajax-tab-container-highwire_article_tabs\" class=\"panels-ajax-tab-container\" data-panels-ajax-tab-preloaded=\"jnl_bmj_tab_art\">\n<div class=\"panels-ajax-tab-wrap-jnl_bmj_tab_art\">\n<div class=\"panel-display panel-1col clearfix\">\n<div class=\"panel-panel panel-col\">\n<div>\n<div class=\"panel-pane pane-highwire-markup\">\n<div class=\"pane-content\">\n<div class=\"highwire-markup\">\n<div id=\"content-block-markup\" data-highwire-cite-ref-tooltip-instance=\"highwire_reflinks_tooltip\">\n<div class=\"article fulltext-view \">\n<div class=\"contributors jquery-once-2-processed\">\n<ol id=\"contrib-group-1\" class=\"contributor-list\">\n<li id=\"contrib-1\" class=\"last\"><span class=\"name\">Peter Doshi<\/span><span class=\"contrib-role\">, associate editor<\/span><\/li>\n<\/ol>\n<p><a class=\"view-more\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#\">Author affiliations<\/a><\/p>\n<ol class=\"corresp-list\">\n<li id=\"corresp-1\" class=\"corresp\"><span class=\"em-link\"><span class=\"em-addr\"><a href=\"mailto:pdoshi@bmj.com\">pdoshi@bmj.com<\/a><\/span><\/span><\/li>\n<\/ol>\n<\/div>\n<div class=\"teaser\">\n<p id=\"p-2\">The world has bet the farm on vaccines as the solution to the pandemic, but the trials are not focused on answering the questions many might assume they are. <strong>Peter Doshi<\/strong> reports<\/p>\n<\/div>\n<p id=\"p-3\">As phase III trials of covid-19 vaccines reach their target enrolments, officials have been trying to project calm. The US coronavirus czar Anthony Fauci and the Food and Drug Administration leadership have offered public assurances that established procedures will be followed.<a id=\"xref-ref-1-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-1\">1<\/a><a id=\"xref-ref-2-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-2\">2<\/a><a id=\"xref-ref-3-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-3\">3<\/a><a id=\"xref-ref-4-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-4\">4<\/a> Only a \u201csafe and effective\u201d vaccine will be approved, they say, and nine vaccine manufacturers issued a rare joint statement pledging not to prematurely seek regulatory review.<a id=\"xref-ref-5-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-5\">5<\/a><\/p>\n<p id=\"p-4\">But what will it mean exactly when a vaccine is declared \u201ceffective\u201d? To the public this seems fairly obvious. \u201cThe primary goal of a covid-19 vaccine is to keep people from getting very sick and dying,\u201d a National Public Radio broadcast said bluntly.<a id=\"xref-ref-6-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-6\">6<\/a><\/p>\n<p id=\"p-5\">Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, said, \u201cIdeally, you want an antiviral vaccine to do two things . . . first, reduce the likelihood you will get severely ill and go to the hospital, and two, prevent infection and therefore interrupt disease transmission.\u201d<a id=\"xref-ref-7-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-7\">7<\/a><\/p>\n<p id=\"p-6\">Yet the current phase III trials are not actually set up to prove either (<a id=\"xref-table-wrap-1-1\" class=\"xref-table\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#T1\">table 1<\/a>).<span style=\"font-size: 18pt;\"><strong> None of the trials currently under way are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths. Nor are the vaccines being studied to determine whether they can interrupt transmission of the virus.<\/strong><\/span><\/p>\n<div id=\"T1\" class=\"table pos-float\">\n<div class=\"table\">\n<div class=\"table-caption\">\n<p><span class=\"table-label\">Table 1<\/span><\/p>\n<p id=\"p-7\" class=\"first-child\">Characteristics of ongoing phase III covid-19 vaccine trials<\/p>\n<div class=\"sb-div caption-clear\"><\/div>\n<\/div>\n<div class=\"table-inline\">\n<div class=\"callout\">\n<ul class=\"callout-links\">\n<li><a class=\"colorbox colorbox-load table-expand-popup init-colorbox-processed cboxElement\" href=\"https:\/\/www.bmj.com\/highwire\/markup\/1036307\/expansion?width=1000&amp;height=500&amp;iframe=true&amp;postprocessors=highwire_figures%2Chighwire_math\" rel=\"gallery-fragment-tables\">View popup<\/a><\/li>\n<li><a class=\"table-expand-inline highwireTablesMarkupProcessor-processed\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037##\" data-table-url=\"\/highwire\/markup\/1036307\/expansion?postprocessors=highwire_figures%2Chighwire_math\">View inline<\/a><\/li>\n<\/ul>\n<\/div>\n<\/div>\n<\/div>\n<div><\/div>\n<\/div>\n<div id=\"sec-1\" class=\"section other1\">\n<h2 class=\"\">Evaluating mild, not severe, disease<\/h2>\n<p id=\"p-13\">In a September interview Medscape editor in chief Eric Topol pondered what counts as a recorded \u201cevent\u201d in the vaccine trials. \u201cWe\u2019re not talking about just a PCR [polymerase chain reaction test]-positive mild infection. It has to be moderate to severe illness to qualify as an event, correct?\u201d he asked.<a id=\"xref-ref-8-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-8\">8<\/a><\/p>\n<p id=\"p-14\">\u201cThat\u2019s right,\u201d concurred his guest, Paul Offit, a vaccinologist who sits on the FDA advisory committee that may ultimately recommend the vaccines for licence or emergency use authorisation.<\/p>\n<p id=\"p-15\">But that\u2019s not right. In all the ongoing phase III trials for which details have been released, laboratory confirmed infections even with only mild symptoms qualify as meeting the primary endpoint definition.<a id=\"xref-ref-9-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-9\">9<\/a><a id=\"xref-ref-10-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-10\">10<\/a><a id=\"xref-ref-11-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-11\">11<\/a><a id=\"xref-ref-12-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-12\">12<\/a> In Pfizer and Moderna\u2019s trials, for example, people with only a cough and positive laboratory test would bring those trials one event closer to their completion. (If AstraZeneca\u2019s ongoing UK trial is designed similarly to its \u201cpaused\u201d US trial for which the company has released details, a cough and fever with positive PCR test would suffice.)<\/p>\n<p id=\"p-16\">Part of the reason may be numbers. Severe illness requiring hospital admission, which happens in only a small fraction of symptomatic covid-19 cases, would be unlikely to occur in significant numbers in trials. Data published by the US Centers for Disease Control and Prevention in late April reported a symptomatic case hospitalisation ratio of 3.4% overall, varying from 1.7% in 0-49 year olds and 4.5% in 50-64 year olds to 7.4% in those 65 and over.<a id=\"xref-ref-13-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-13\">13<\/a> Because most people with symptomatic covid-19 experience only mild symptoms,<a id=\"xref-ref-14-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-14\">14<\/a> even trials involving 30\u2009000 or more patients would turn up relatively few cases of severe disease.<\/p>\n<p id=\"p-17\">In the trials, final efficacy analyses are planned after just 150 to 160 \u201cevents,\u201d\u2014that is, a positive indication of symptomatic covid-19, regardless of severity of the illness.<\/p>\n<p id=\"p-18\">Yet until vaccine manufacturers began to release their study protocols in mid-September, trial registries and other publicly released information did little to dispel the notion that it was severe covid-19 that the trials were assessing. Moderna, for example, called hospital admissions a \u201ckey secondary endpoint\u201d in statements to the media.<a id=\"xref-ref-15-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-15\">15<\/a> And a press release from the US National Institutes of Health reinforced this impression, stating that Moderna\u2019s trial \u201caims to study whether the vaccine can prevent severe covid-19\u201d and \u201cseeks to answer if the vaccine can prevent death caused by covid-19.\u201d<a id=\"xref-ref-16-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-16\">16<\/a><\/p>\n<p id=\"p-19\">But Tal Zaks, chief medical officer at Moderna, told <em>The BMJ<\/em> that the company\u2019s trial lacks adequate statistical power to assess those outcomes. \u201cThe trial is precluded from judging [hospital admissions], based on what is a reasonable size and duration to serve the public good here,\u201d he said.<\/p>\n<p id=\"p-20\">Hospital admissions and deaths from covid-19 are simply too uncommon in the population being studied for an effective vaccine to demonstrate statistically significant differences in a trial of 30\u2009000 people. The same is true of its ability to save lives or prevent transmission: the trials are not designed to find out.<\/p>\n<p id=\"p-21\">Zaks said, \u201cWould I like to know that this prevents mortality? Sure, because I believe it does. I just don\u2019t think it\u2019s feasible within the timeframe [of the trial]\u2014too many would die waiting for the results before we ever knew that.\u201d<\/p>\n<\/div>\n<div id=\"sec-2\" class=\"section other2\">\n<h2 class=\"\">Stopping transmission<\/h2>\n<p id=\"p-22\">What about Hotez\u2019s second criterion, interrupting virus transmission, which some experts have argued<a id=\"xref-ref-17-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-17\">17<\/a> should be the most important test in phase III studies?<\/p>\n<p id=\"p-23\">\u201cOur trial will not demonstrate prevention of transmission,\u201d Zaks said, \u201cbecause in order to do that you have to swab people twice a week for very long periods, and that becomes operationally untenable.\u201d<\/p>\n<p id=\"p-24\">He repeatedly emphasised these \u201coperational realities\u201d of running a vaccine trial. \u201cEvery trial design, especially phase III, is always a balancing act between different needs,\u201d he said. \u201cIf you wanted to have an answer on an endpoint that happens at a frequency of one 10th or one fifth the frequency of the primary endpoint, you would need a trial that is either 5 or 10 times larger or you\u2019d need a trial that is 5 or 10 times longer to collect those events. Neither of these, I think, are acceptable in the current public need for knowing expeditiously that a vaccine works.\u201d<\/p>\n<p id=\"p-25\">Zaks added, \u201cA 30\u2009000 [participant] trial is already a fairly large trial. If you\u2019re asking for a 300 000 trial then you need to talk to the people who are paying for it, because now you\u2019re talking about not a $500m to $1bn trial, you\u2019re talking about something 10 times the size. And I think the public purse and operational capabilities and capacities we have are rightly spent not betting the farm on one vaccine but, as Operation Warp Speed [the US government\u2019s covid-19 vaccine plan] is trying to do, making sure that we\u2019re funding several vaccines in parallel.\u201d<\/p>\n<\/div>\n<div id=\"sec-3\" class=\"section other3\">\n<h2 class=\"\">Debating endpoints<\/h2>\n<p id=\"p-26\">Still, it\u2019s fair to say that most of the general public assumes that the whole point of the current trials, besides testing safety (<a id=\"xref-boxed-text-1-1\" class=\"xref-boxed-text\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#boxed-text-1\">box 1<\/a>), is to see whether the vaccine can prevent bad outcomes. \u201cHow do you reconcile that?\u201d <em>The BMJ<\/em> asked Zaks.<\/p>\n<div id=\"boxed-text-1\" class=\"boxed-text\">\n<p><span class=\"boxed-text-label\">Box 1<\/span><\/p>\n<h3>Safety and side effects<\/h3>\n<p id=\"p-27\">History shows many examples of serious adverse events from vaccines brought to market in periods of enormous pressure and expectation. There were contaminated polio vaccines in 1955, cases of Guillain-Barr\u00e9 syndrome in recipients of flu vaccines in 1976, and narcolepsy linked to one brand of influenza vaccine in 2009.<a id=\"xref-ref-18-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-18\">18<\/a><a id=\"xref-ref-19-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-19\">19<\/a><\/p>\n<p id=\"p-28\"><strong>\u201cFinding severe rare adverse events will require the study of tens of thousands of patients, but this requirement will not be met by early adoption of a product that has not completed its full trial evaluation,\u201d<\/strong> Harvard drug policy researchers Jerry Avorn and Aaron Kesselheim recently wrote in <em>JAMA<\/em>.<a id=\"xref-ref-20-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-20\">20<\/a><\/p>\n<p id=\"p-29\">Covid-19 vaccine trials are currently designed to tabulate final efficacy results once 150 to 160 trial participants develop symptomatic covid-19\u2014and most trials have specified at least one interim analysis allowing for the trials to end with even fewer data accrued.<\/p>\n<p id=\"p-30\">Medscape\u2019s Eric Topol has been a vocal critic of the trials\u2019 many interim analyses. \u201cThese numbers seem totally out of line with what would be considered stopping rules,\u201d he says. \u201cI mean, you\u2019re talking about giving a vaccine with any of these programmes to tens of millions of people. And you\u2019re going to base that on 100 events?\u201d<a id=\"xref-ref-8-2\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-8\">8<\/a><\/p>\n<p id=\"p-31\">Great uncertainty remains over how long a randomised trial of a vaccine will be allowed to proceed. If efficacy is declared, one possibility is that the thousands of volunteers who received a saline placebo would be offered the active vaccine, in effect ending the period of randomised follow-up. Such a move would have far reaching implications for our understanding of vaccines\u2019 benefits and harms, rendering uncertain our knowledge of whether the vaccines can reduce the risk of serious covid-19 disease and precluding any further ability to compare adverse events in the experimental versus the placebo arm.<\/p>\n<p id=\"p-32\">\u201cIt\u2019ll be a decision we\u2019ll have to take at that time. We have not committed one way or another,\u201d Moderna\u2019s Tal Zaks told <em>The BMJ<\/em>. \u201cIt will be a decision where FDA and NIH will also weigh in. And it will be probably a very difficult decision, because you will be weighing the benefit to the public in continuing to understand the longer term safety by keeping people on placebo and the expectation of the people who have received placebo to be crossed over now that it has been proved effective.\u201d<\/p>\n<p><a href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#xref-boxed-text-1-1\">RETURN TO TEXT<\/a><\/p>\n<\/div>\n<p id=\"p-33\">\u201cVery simply,\u201d he replied. \u201cNumber one, we have a bad outcome as our endpoint. It\u2019s covid-19 disease.\u201d Moderna, like Pfizer and Janssen, has designed its study to detect a relative risk reduction of at least 30% in participants developing laboratory confirmed covid-19, consistent with FDA and international guidance.<a id=\"xref-ref-21-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-21\">21<\/a><a id=\"xref-ref-22-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-22\">22<\/a><\/p>\n<p id=\"p-34\">Number two, Zaks pointed to influenza vaccines, saying they protect against severe disease better than mild disease. To Moderna, it\u2019s the same for covid-19: if its vaccine is shown to reduce symptomatic covid-19, it will be confident it also protects against serious outcomes.<\/p>\n<p id=\"p-35\">But the truth is that the science remains far from clear cut, even for influenza vaccines that have been used for decades. Although randomised trials have shown an effect in reducing the risk of symptomatic influenza, such trials have never been conducted in elderly people living in the community to see whether they save lives.<\/p>\n<p id=\"p-36\">Only two placebo controlled trials in this population have ever been conducted, and neither was designed to detect any difference in hospital admissions or deaths.<a id=\"xref-ref-23-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-23\">23<\/a> Moreover, dramatic increases in use of influenza vaccines has not been associated with a decline in mortality (<a id=\"xref-boxed-text-2-1\" class=\"xref-boxed-text\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#boxed-text-2\">box 2<\/a>).<a id=\"xref-ref-26-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-26\">26<\/a><\/p>\n<div id=\"boxed-text-2\" class=\"boxed-text\">\n<p><span class=\"boxed-text-label\">Box 2<\/span><\/p>\n<h3>Not enrolling enough elderly people or minorities<\/h3>\n<p id=\"p-37\">A vaccine that has been proved to reduce the risk of symptomatic disease by a certain proportion should, you might think, reduce serious outcomes such as hospital admissions and deaths in equal proportion.<\/p>\n<p id=\"p-38\">Peter Marks, an FDA official with responsibility over vaccine approvals, recently stated as much about influenza vaccination, which \u201conly prevents flu in about half the people who get it. And yet that\u2019s very important because that means that it leads to half as many deaths related to influenza each year.\u201d<a id=\"xref-ref-24-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-24\">24<\/a><\/p>\n<p id=\"p-39\">But when vaccines are not equally effective in all populations the theory breaks down.<\/p>\n<p id=\"p-40\">If frail elderly people, who are understood to die in disproportionate numbers from both influenza<a id=\"xref-ref-25-1\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-25\">25<\/a> and covid-19, are not enrolled into vaccine trials in sufficient numbers to determine whether case numbers are reduced in this group, there can be little basis for assuming any benefit in terms of hospital admissions or mortality. Whatever reduction in cases is seen in the overall study population (most of which may be among healthy adults), this benefit may not apply to the frail elderly subpopulation, and few lives may be saved.<\/p>\n<p id=\"p-41\">This is hard to evaluate in the current trials because there are large gaps in the types of people being enrolled in the phase III trials (<a id=\"xref-table-wrap-1-2\" class=\"xref-table\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#T1\">table 1<\/a>). Despite recruiting tens of thousands, only two trials are enrolling children less than 18 years old. All exclude immunocompromised people and pregnant or breastfeeding women, and though the trials are enrolling elderly people, few or perhaps none of the studies would seem to be designed to conclusively answer whether there is a benefit in this population, despite their obvious vulnerability to covid-19.<\/p>\n<p id=\"p-42\">\u201cAdults over 65 will be an important subgroup that we will be looking at,\u201d Moderna\u2019s Zaks told <em>The BMJ<\/em>. \u201cThat said . . . any given study is powered for its primary endpoint\u2014in our case covid-19 disease irrespective of age.\u201d<\/p>\n<p id=\"p-43\">Al Sommer, dean emeritus of the Johns Hopkins School of Public Health, told <em>The BMJ<\/em>, \u201cIf they have not powered for evidence of benefit in the elderly, I would find that a significant, unfortunate shortcoming.\u201d He emphasised the need for \u201cinnovative follow-up studies that will enable us to better determine the direct level of protection immunisation has on the young and, separately, the elderly, in addition to those at the highest risk of severe disease and hospitalisation.\u201d<\/p>\n<p id=\"p-44\">One view is that trial data should be there for all target populations. \u201cIf we don\u2019t have adequate data in the greater than 65 year old group, then the greater than 65 year old person shouldn\u2019t get this vaccine, which would be a shame because they\u2019re the ones who are most likely to die from this infection,\u201d said vaccinologist Paul Offit.<a id=\"xref-ref-8-3\" class=\"xref-bibr\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#ref-8\">8<\/a> \u201cWe have to generate those data,\u201d he said. \u201cI can\u2019t see how anybody\u2014the Data and Safety Monitoring Board or the FDA Vaccine Advisory Committee, or FDA decision-makers\u2014would ever allow a vaccine to be recommended for that group without having adequate data.\u201d<\/p>\n<p id=\"p-45\">\u201cI feel the same way about minorities,\u201d Offit added. \u201cYou can\u2019t convince minority populations to get this vaccine unless they are represented in these trials. Otherwise, they\u2019re going to feel like they\u2019re guinea pigs, and understandably so.\u201d<\/p>\n<p><a href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#xref-boxed-text-2-1\">RETURN TO TEXT<\/a><\/p>\n<\/div>\n<\/div>\n<div id=\"ack-1\" class=\"section ack\">\n<h2>Acknowledgments<\/h2>\n<p id=\"p-46\">Sarah Tanveer helped research the design of studies and identify quotations, and Ulrich Keil provided comments on an early draft of this article.<\/p>\n<\/div>\n<div id=\"fn-group-1\" class=\"section fn-group\">\n<h2>Footnotes<\/h2>\n<ul>\n<li id=\"fn-6\" class=\"fn-conflict\">\n<p id=\"p-47\">Competing interests: I co-wrote an op-ed on this topic with Eric Topol, who is quoted in this article, I have been pursuing the public release of vaccine trial protocols, and I co-signed an open letter to the FDA calling for independence and transparency in covid-19 vaccine related decision making.<\/p>\n<\/li>\n<li id=\"fn-7\" class=\"fn-other\">\n<p id=\"p-48\">Provenance and peer review: Commissioned; externally peer reviewed.<\/p>\n<\/li>\n<\/ul>\n<\/div>\n<div id=\"license-1\" class=\"license\">\n<p id=\"p-1\">This article is made freely available for use in accordance with BMJ&#8217;s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.<\/p>\n<p><span class=\"ali-license-ref\"><a href=\"https:\/\/bmj.com\/coronavirus\/usage\" rel=\"license\">https:\/\/bmj.com\/coronavirus\/usage<\/a><\/span><\/p>\n<\/div>\n<div id=\"ref-list-1\" class=\"section ref-list\">\n<h2>References<\/h2>\n<ol class=\"cit-list\">\n<li><a id=\"ref-1\" class=\"rev-xref-ref\" title=\"View reference 1 in text\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#xref-ref-1-1\">\u21b5<\/a>\n<div id=\"cit-371.oct21_3.m4037.1\" class=\"cit ref-cit ref-journal google_scholar_link-processed custom-js-processed\" data-doi=\"10.1001\/jama.2020.15725\">\n<div class=\"cit-metadata\">\n<ol class=\"cit-auth-list\">\n<li><span class=\"cit-auth\"><span class=\"cit-name-surname\">Shah<\/span> <span class=\"cit-name-given-names\">A<\/span><\/span>,<\/li>\n<li><span class=\"cit-auth\"><span class=\"cit-name-surname\">Marks<\/span> <span class=\"cit-name-given-names\">PW<\/span><\/span>,<\/li>\n<li><span class=\"cit-auth\"><span class=\"cit-name-surname\">Hahn<\/span> <span class=\"cit-name-given-names\">SM<\/span><\/span><\/li>\n<\/ol>\n<p><cite>. <span class=\"cit-article-title\">Unwavering Regulatory Safeguards for COVID-19 Vaccines<\/span>. <abbr class=\"cit-jnl-abbrev\">JAMA<\/abbr><span class=\"cit-pub-date\">2020<\/span>. <span class=\"cit-pub-id cit-pub-id-doi\"><span class=\"cit-pub-id-scheme-doi\">doi:<\/span>10.1001\/jama.2020.15725<\/span><span class=\"cit-pub-id-sep cit-pub-id-doi-sep\">.<\/span>\u00a0<span class=\"cit-pub-id cit-pub-id-pmid\"><span class=\"cit-pub-id-scheme-pmid\">pmid:<\/span>32766736<\/span><\/cite><\/p>\n<\/div>\n<div class=\"cit-extra\"><a class=\"cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\" href=\"https:\/\/www.bmj.com\/lookup\/external-ref?access_num=10.1001\/jama.2020.15725&amp;link_type=DOI\">CrossRef<\/a><a class=\"cit-ref-sprinkles cit-ref-sprinkles-medline\" href=\"https:\/\/www.bmj.com\/lookup\/external-ref?access_num=32766736&amp;link_type=MED&amp;atom=%2Fbmj%2F371%2Fbmj.m4037.atom\">PubMed<\/a><a class=\"cit-ref-sprinkles cit-ref-sprinkles-google-scholar cit-ref-sprinkles-google-scholar\" href=\"https:\/\/www.bmj.com\/lookup\/google-scholar?link_type=googlescholar&amp;gs_type=article&amp;author[0]=A+Shah&amp;author[1]=PW+Marks&amp;author[2]=SM+Hahn&amp;title=Unwavering+Regulatory+Safeguards+for+COVID-19+Vaccines&amp;publication_year=2020&amp;journal=JAMA\">Google Scholar<\/a><\/div>\n<\/div>\n<\/li>\n<li><a id=\"ref-2\" class=\"rev-xref-ref\" title=\"View reference 2 in text\" href=\"https:\/\/www.bmj.com\/content\/371\/bmj.m4037#xref-ref-2-1\">\u21b5<\/a>\n<div id=\"cit-371.oct21_3.m4037.2\" class=\"cit ref-cit ref-web google_scholar_link-processed\">\n<div class=\"cit-metadata unstructured\">Cavazzoni P, Marks P, Mayne S, et al. 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\u03ad\u03b4\u03c9\u03c3\u03b5 \u03c3\u03c4\u03bf Brighteon \u03c0\u03c1\u03ce\u03c4\u03b1 \u03ba\u03b1\u03b9 \u03bc\u03b5\u03c4\u03ac \u03b4\u03b9\u03b1\u03b2\u03ac\u03c3\u03c4\u03b5 \u03c4\u03bf \u03ac\u03c1\u03b8\u03c1\u03bf \u03b1\u03c0\u03cc \u03c4\u03bf BMJ:https:\/\/www.brighteon.com\/6453f41e-1ccd-4516-a643-3411fdcada94 Will covid-19 vaccines save lives? Current trials aren\u2019t designed to tell us BMJ 2020; 371 doi: https:\/\/doi.org\/10.1136\/bmj.m4037 (Published 21 October 2020) Cite this as: BMJ 2020;371:m4037 Linked Editorial Covid-19 vaccine trial protocols released Read our latest coverage of the &hellip; <\/p>\n<p><a class=\"more-link btn\" href=\"https:\/\/evaggelatos.com\/?p=20189\">\u03a3\u03c5\u03bd\u03ad\u03c7\u03b5\u03b9\u03b1 \u03b1\u03bd\u03ac\u03b3\u03bd\u03c9\u03c3\u03b7\u03c2<\/a><\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[72,85,68],"tags":[141,159,122,92,106],"class_list":["post-20189","post","type-post","status-publish","format-standard","hentry","category-72","category-85","category-68","tag-141","tag-159","tag-122","tag-92","tag-106","item-wrap"],"_links":{"self":[{"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/posts\/20189","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=20189"}],"version-history":[{"count":4,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/posts\/20189\/revisions"}],"predecessor-version":[{"id":20212,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/posts\/20189\/revisions\/20212"}],"wp:attachment":[{"href":"https:\/\/evaggelatos.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=20189"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=20189"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=20189"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}