tag:theconversation.com,2011:/ca-fr/topics/phase-3-trial-86641/articlesPhase 3 Trial – La Conversation2021-10-06T05:48:40Ztag:theconversation.com,2011:article/1692462021-10-06T05:48:40Z2021-10-06T05:48:40ZTake-at-home COVID drug molnupiravir may be on its way — but vaccination is still our first line of defence<p>The Australian government has <a href="https://www.pm.gov.au/media/interview-david-koch-sunrise-15">pre-purchased 300,000 courses</a> of an experimental antiviral oral drug called molnupiravir.</p>
<p>Interim results announced by the company, US pharmaceutical Merck, show the drug halved the number of patients who ended up in hospital due to COVID. No patient who took the drug died from the virus.</p>
<p>But the drug isn’t yet available for dispensing from pharmacies because it hasn’t received approval from Australia’s drug regulator, the <a href="https://tga.gov.au">Therapeutic Goods Administration</a> (TGA).</p>
<p>If approved it can be used in the community to prevent patients with mild symptoms from developing more severe disease.</p>
<p>Until then, there will be no legal, effective and safe treatments that people with COVID can take at home to keep them out of hospital. As such, we need to continue our push to get maximum vaccination coverage within the community.</p>
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Read more:
<a href="https://theconversation.com/stopping-blocking-and-dampening-how-aussie-drugs-in-the-pipeline-could-treat-covid-19-162349">Stopping, blocking and dampening – how Aussie drugs in the pipeline could treat COVID-19</a>
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<h2>What is molnupiravir?</h2>
<p>Molnupiravir is an experimental antiviral drug that acts against a range of respiratory viruses, including the virus that causes COVID.</p>
<p>For COVID, the instructions for creating more virus are contained in the <a href="https://www.medicinenet.com/rna_virus/definition.htm">virus’ RNA</a>. This RNA needs to be read and copied to make new virus particles.</p>
<p>Molnupiravir works by disrupting the replication of the virus. It does this by <a href="https://www.nature.com/articles/s41594-021-00651-0">mimicking two natural compounds called cytidine and uridine</a> that are needed to make RNA. When the body tries to replicate the virus it incorporates molnupiravir into the RNA structure instead of versions of cytidine and uridine. The result is the accumulation of mutations in the virus RNA which then prevent it from causing illness.</p>
<p>This type of technology isn’t new. In fact, we have been using chemotherapy drugs that mimic RNA and DNA ingredients for over 50 years. One drug, called <a href="https://www.healthdirect.gov.au/medicines/brand/amt,3626011000036107/fluorouracil-dbl">fluorouracil</a> works by preventing DNA production inside cancer cells by mimicking the DNA ingredient thymine.</p>
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<h2>Results of the clinical trial</h2>
<p>Last week Merck announced interim results of a phase 3 clinical trial of molnupiravir.</p>
<p>The company found the drug significantly <a href="https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/">reduced the risk of hospitalisation or death</a> in patients who took the drug when compared with patients who took a placebo treatment. In fact, the results were so good, an independent data monitoring committee recommended the trial be stopped early.</p>
<p>Overall, the drug reduced hospitalisations and deaths by around 50%. While 14.1% of patients who took placebo ended up in hospital, only 7.3% of molnupiravir patients had the same outcome. </p>
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Read more:
<a href="https://theconversation.com/what-is-sotrovimab-the-covid-drug-the-government-has-bought-before-being-approved-for-use-in-australia-165802">What is sotrovimab, the COVID drug the government has bought before being approved for use in Australia?</a>
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<p>The results were even better with regard to the death rates. No patient who took molnupiravir died, while eight patients in the placebo group did die.</p>
<p>Importantly, while the clinical trial demonstrated efficacy of the drug, it was also able to show molnupiravir is safe. The rate of side effects was nearly the same in both the molnupiravir and placebo groups. Earlier clinical trials found there are no serious side effects with the drug. The most common, mild effects were <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092915/">headache and diarrhea</a>.</p>
<p>We have to wait for the full data to be released and checked in order to be fully confident in the drug. But the results seem to indicate molnupiravir may be useful for the early treatment of COVID to prevent the development of serious disease and hospitalisation.</p>
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<h2>How it will be used</h2>
<p>Molnupiravir will be able to be taken orally by patients at home after they receive a prescription from their doctor. </p>
<p>A course of treatment will be eight 200 milligram capsules a day for five days; four capsules in the morning and four capsules in the afternoon. A patient can choose whether they want to take the medicine with or without food, as it doesn’t appear to affect the medicine in the body. </p>
<p>It’s unclear whether a positive COVID test will be required before a prescription can be issued. This is something that will be decided by the TGA.</p>
<p>Health Minister Greg Hunt <a href="https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/minister-hunts-press-conference-in-melbourne-on-4-october-2021-with-an-update-on-vaccination-rollout-and-covid-19-treatment">said he encourages Merck to apply for registration</a> of the drug, and the TGA has stated it’s willing to <a href="https://www.tga.gov.au/media-release/tga-grants-provisional-determination-merck-sharp-dohmes-antiviral-covid-19-treatment-molnupiravir">receive an application for provisional registration</a> at which time they can evaluate the data themselves.</p>
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Read more:
<a href="https://theconversation.com/could-a-simple-pill-beat-covid-19-pfizer-is-giving-it-a-go-160988">Could a simple pill beat COVID-19? Pfizer is giving it a go</a>
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<p class="fine-print"><em><span>Associate Professor Wheate in the past has received funding from the ACT Cancer Council, Tenovus Scotland, Medical Research Scotland, Scottish Crucible, and the Scottish Universities Life Sciences Alliance. He is Fellow of the Royal Australian Chemical Institute and a member of the Australasian Pharmaceutical Science Association. Nial is science director of the medicinal cannabis company Canngea Pty Ltd, a board member of the Australian Medicinal Cannabis Association, and a Standards Australia committee member for sunscreen agents.</span></em></p>Merck announced preliminary data suggesting the drug reduced the risk of hospitalisation and death by 50%.Nial Wheate, Associate Professor of the Sydney Pharmacy School, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1517742020-12-09T16:52:50Z2020-12-09T16:52:50ZOxford COVID-19 vaccine: newly published results show it is safe – but questions remain over its efficacy<figure><img src="https://images.theconversation.com/files/373935/original/file-20201209-23-e3rhma.jpg?ixlib=rb-1.1.0&rect=142%2C0%2C5235%2C3487&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/medicine-vaccination-healthcare-concept-doctor-wearing-1817163167">Syda Productions/Shutterstock</a></span></figcaption></figure><p>Full interim analysis of the safety and efficacy of the Oxford COVID-19 vaccine – developed in partnership with AstraZeneca – has been <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32661-1/fulltext">published in the Lancet</a>. This paper represents the most comprehensive set of results from any of the phase 3 trials of COVID-19 vaccines to date. </p>
<p>These are still only interim results, meaning they show only how the ongoing phase 3 trial has progressed so far. The final results may differ. But what this analysis reveals is how the Oxford team calculated <a href="https://www.bbc.co.uk/news/health-55040635">its vaccine’s efficacy</a>, which it announced in late November.</p>
<p>This interim analysis included 11,636 people, of whom 7,548 were in the UK and 4,088 in Brazil. All participants received two injections, but as has been <a href="https://www.nytimes.com/2020/11/25/business/coronavirus-vaccine-astrazeneca-oxford.html">widely reported</a>, one of the UK groups received a half dose rather than a full dose for the initial injection. This has made analysing the effects of this vaccine more complicated than it probably will be for others in the late stages of testing. </p>
<p>Importantly, the evidence that the vaccine is safe is convincing. There were 175 severe adverse events reported in the trials, and these were actually more common in the control group (which received either saline or a meningococcal vaccine) than with those receiving the COVID-19 vaccine.</p>
<p>Three of these events were judged to be possibly related to either the experimental or control vaccine. They included a case of <a href="https://www.mayoclinic.org/diseases-conditions/transverse-myelitis/symptoms-causes/syc-20354726">transverse myelitis</a>, a rare but serious spinal inflammatory disorder, in someone in the vaccine group, a case of <a href="https://www.hopkinsmedicine.org/health/conditions-and-diseases/hemolytic-anemia">haemolytic anaemia</a> in someone in the control group, and a further person who developed a fever of over 40°C. As yet we don’t know whether this person received the COVID-19 vaccine or a control. </p>
<p>Across the study, ten patients became sufficiently ill with COVID-19 to require hospitalisation, but all were in the control arm. </p>
<h2>Calculating efficacy</h2>
<p>The headline figure given for the overall efficacy of this vaccine is 70.4%. This is lower than the equivalent efficacy reported by Pfizer (<a href="https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine">94%</a>) and Moderna (<a href="https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-primary-efficacy-analysis-phase-3-cove-study">94.1%</a>) for their vaccines. </p>
<p>Both Pfizer and Moderna have based their estimates on rather bigger trials than the Oxford vaccine and so their estimates are likely to be more precise. But we still need to be able to see the full publication of their results in peer-reviewed journals before we can make valid comparisons between the efficacy and safety of the three vaccines. But a lower efficacy does run the risk of leaving a higher proportion of the vaccinated population unprotected.</p>
<p>But the most difficult issue with the Oxford/AstraZeneca study is that it has pooled analysis of the vaccine’s efficacy from three separate trials. The UK-based arm of the trial was in effect two studies. One study used two standard-dose injections and the other a half dose followed by a standard dose. A third study in Brazil used two standard doses. </p>
<p>These different dosing strategies produced very different efficacy readings. Averaging efficacy across everyone involved in all three studies combined produces the 70.4% figure – but this doesn’t truly reflect the efficacy of the vaccine in either dosing scenario.</p>
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<img alt="Ampoules of COVID-19 vaccine" src="https://images.theconversation.com/files/373941/original/file-20201209-18-1bbvdgj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/373941/original/file-20201209-18-1bbvdgj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/373941/original/file-20201209-18-1bbvdgj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/373941/original/file-20201209-18-1bbvdgj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/373941/original/file-20201209-18-1bbvdgj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/373941/original/file-20201209-18-1bbvdgj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/373941/original/file-20201209-18-1bbvdgj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Delivering a smaller first dose of the vaccine may increase its efficacy – but more testing of this dosing regimen is needed to be sure.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/ampoules-covid19-vaccine-on-laboratory-bench-1696929460">M-Foto/Shutterstock</a></span>
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<p>Both standard-dose study arms gave similar estimated efficacies – 60.3% in the UK and 64.2% in Brazil. Combined, the efficacy of these two standard-dose trials was 62.1%. By contrast, the low-dose regimen indicated an efficacy of 90%. This finding would place the Oxford vaccine close to the reported efficacies of the Pfizer and Moderna vaccines.</p>
<p>But how reliable is this estimate of what is, in effect, a subgroup within the study? Breaking analysis down in this way to look at outcomes in specific groups <a href="https://handbook-5-1.cochrane.org/chapter_9/9_6_2_what_are_subgroup_analyses.htm">can be appropriate</a> in randomised controlled trials – but it increases the risk of what looks like positive findings simply being down to chance. </p>
<p>This sort of practice is “particularly unreliable” and “can produce spurious results”, <a href="https://www.journalslibrary.nihr.ac.uk/hta/hta5330#/abstract">experts have noted</a>. I would add that one needs to be even more cautious when subgroup analyses produce unexpected results – which is exactly what has happened here, as the low-dose regimen <a href="https://www.theguardian.com/uk-news/2020/nov/23/oxford-covid-vaccine-hit-90-success-rate-thanks-to-dosing-error">stemmed from an accident</a>. Additional testing of the low-dose regimen is needed.</p>
<p>A further issue is that the study arm that yielded the 90% estimate was only conducted with people under 55 years old and almost exclusively with people of white ethnicity. By contrast, the burden of serious disease and death from COVID-19 tends to fall on older people and those from <a href="https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/908434/Disparities_in_the_risk_and_outcomes_of_COVID_August_2020_update.pdf">Black and Asian ethnic groups</a> and the priority populations for immunisation in the UK are <a href="https://www.gov.uk/government/publications/covid-19-the-green-book-chapter-14a">largely over 55 years old</a>. </p>
<p>Given their increased vulnerability, knowing whether older people respond well to this vaccine is important. Problematically, we know that <a href="https://immunityageing.biomedcentral.com/articles/10.1186/s12979-019-0164-9">older people</a> often do not respond as well as younger people to vaccination. On the other hand, in another recent <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32466-1/fulltext">Lancet paper</a> from the Oxford Vaccine Group, groups of participants aged 18-55, 56-69 and 70+ were all found to have similar levels of antibodies after receiving the standard-dose regimen, suggesting that it will be similarly effective across all ages. </p>
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<img alt="An older man getting vaccinated" src="https://images.theconversation.com/files/373951/original/file-20201209-13-k4nwhx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/373951/original/file-20201209-13-k4nwhx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=397&fit=crop&dpr=1 600w, https://images.theconversation.com/files/373951/original/file-20201209-13-k4nwhx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=397&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/373951/original/file-20201209-13-k4nwhx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=397&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/373951/original/file-20201209-13-k4nwhx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=499&fit=crop&dpr=1 754w, https://images.theconversation.com/files/373951/original/file-20201209-13-k4nwhx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=499&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/373951/original/file-20201209-13-k4nwhx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=499&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">We still don’t know for sure exactly how effective the vaccine might be in over-55s.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/vaccination-older-adults-population-group-high-1862057209">Studio Romantic/Shutterstock</a></span>
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<p>But we don’t know yet what the effect of the seemingly more efficacious low-dose regimen is in over-55s. So as well as needing further trials of the low-dose regimen, they also need to include older people and Black and Asian people. Only then can we be sure that it is effective across different groups.</p>
<p>We also do not yet know for certain how effective any of the COVID-19 vaccines will be at preventing asymptomatic infection or transmission of the virus. But the Oxford vaccine’s phase 3 results do suggest that immunisation with the vaccine will generate some downward pressure on transmission.</p>
<p>Getting the development and testing of the Oxford vaccine this far is an incredible achievement – and the vaccine will undoubtedly become a major tool in our ability to combat the current pandemic. The vaccine is safe and effective, albeit maybe not as effective as the two other leading candidates from Pfizer and Moderna. The low-dose regimen may have an efficacy closer to these other vaccines, but we need more data to be sure.</p><img src="https://counter.theconversation.com/content/151774/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Paul Hunter receives funding from National Institute for health Research, World Health Organization and The European Regional Development Fund. </span></em></p>We need more data on the low-dose, high-dose regimen used in one arm of the trial, which may make the vaccine more effective.Paul Hunter, Professor of Medicine, University of East AngliaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1502702020-11-23T22:42:41Z2020-11-23T22:42:41ZHow pharma can build trust in COVID-19 vaccines: Transparency on trials and side-effects<figure><img src="https://images.theconversation.com/files/370843/original/file-20201123-21-7rxk7n.jpg?ixlib=rb-1.1.0&rect=103%2C0%2C2505%2C2164&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A woman walks by graffiti reading 'No vaccine, No tracking, No COVID', in Montréal on Aug. 16, 2020.
</span> <span class="attribution"><span class="source">THE CANADIAN PRESS/Graham Hughes</span></span></figcaption></figure><p>Promising results from large clinical trials testing three vaccines to prevent COVID-19 bring us a step closer to a widely available vaccine. </p>
<p>On Nov. 9, Pfizer’s <a href="https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against#:%7E:text=The%20Phase%203%20clinical%20trial,racially%20and%20ethnically%20diverse%20backgrounds">interim analysis</a> from its Phase 3 vaccine trial revealed it prevented 90 per cent of COVID-19 cases. (The vaccine’s efficacy was revised to 95 per cent in a recent <a href="https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine">more complete analysis of the data</a>.) Just one week later, Moderna announced <a href="https://www.nih.gov/news-events/news-releases/promising-interim-results-clinical-trial-nih-moderna-covid-19-vaccine">interim results</a> from its own Phase 3 trial: its vaccine conferred 94.5 per cent protection against illness. </p>
<p>On Nov. 23, AstraZeneca reported an <a href="https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html">interim analysis</a> from two separate Phase 3 trials that looked at two dosing regimens. Its COVID-19 vaccine, developed with the University of Oxford in the United Kingdom, was 70 per cent efficacious overall, with one dosage regimen protecting against the disease 90 per cent of the time.</p>
<p>But a vaccine that works is useless if people are unwilling to take it. </p>
<h2>Vaccine hesitancy</h2>
<p>Polling in the United States and Canada reveals increasing distrust of COVID-19 vaccines. This distrust threatens the widespread uptake of the vaccine required to bring an end to the pandemic.</p>
<p>The proportion of <a href="https://morningconsult.com/2020/11/16/coronavirus-vaccine-willingness-mid-november/">Americans surveyed</a> who “would get a potential coronavirus vaccine” has dropped to 52 per cent in November from 72 per cent in April. Notably, the November poll was conducted after Pfizer’s announcement.</p>
<p>A similar trend is seen in Canada. In July, 46 per cent of <a href="http://angusreid.org/canada-covid-19-vaccine/">Canadians polled</a> indicated they would get vaccinated “as soon as possible,” 32 per cent would “wait for others to go first and immunize later,” and 14 per cent would not get vaccinated. After Pfizer’s announcement, Canadians surveyed were slightly more reluctant: only 40 per cent would get a vaccine right away, while 36 per cent would wait.</p>
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<a href="https://images.theconversation.com/files/370882/original/file-20201123-17-1rdjja2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A woman in jeans and a denim shirt sits on the end of an exam table in a medical exam room." src="https://images.theconversation.com/files/370882/original/file-20201123-17-1rdjja2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/370882/original/file-20201123-17-1rdjja2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/370882/original/file-20201123-17-1rdjja2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/370882/original/file-20201123-17-1rdjja2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/370882/original/file-20201123-17-1rdjja2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/370882/original/file-20201123-17-1rdjja2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/370882/original/file-20201123-17-1rdjja2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Jennifer Haller waits in an exam room before being given a shot in the first-stage study of Moderna’s coronavirus vaccine on March 16, 2020, at the Kaiser Permanente Washington Health Research Institute in Seattle. Haller was the first person to receive the shot.</span>
<span class="attribution"><span class="source">(AP Photo/Ted S. Warren)</span></span>
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<p>The World Health Organization defines vaccine hesitancy as “the reluctance or refusal to vaccinate despite the availability of vaccines,” and has identified it as a <a href="https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019">leading threat to global health</a>. While vaccine hesitancy is a complex social phenomenon, with COVID-19 it is clear that the <a href="https://www.pewresearch.org/science/2020/09/17/u-s-public-now-divided-over-whether-to-get-covid-19-vaccine/">rapid pace of vaccine development</a> and its <a href="https://www.ctvnews.ca/health/coronavirus/scientists-raise-alarm-over-signs-of-vaccine-hesitancy-1.5152604">perceived politicization</a> are driving distrust. </p>
<h2>Transparency builds trust</h2>
<p>As vaccine developers and sponsors of ongoing trials, pharmaceutical companies are uniquely situated to help <a href="https://www.msn.com/en-us/video/superbowl-chiefs/modernas-covid-19-vaccine-and-public-trust/vp-BB1b4ud3">promote public trust</a> in COVID-19 vaccines. </p>
<p>Pharma must ensure greater transparency in vaccine trials. Transparency will allow independent scientists to assess the rigour of trial designs and the reliability of results. Further, transparency may increase public understanding of and confidence in vaccine development. </p>
<p>Pharma has taken some steps in the right direction.</p>
<p>In September, nine companies developing COVID-19 vaccines issued a public pledge to be bound by science — not politics. They affirmed that vaccine development will be guided by “high ethical standards and sound scientific principles” and that applications for regulatory approval will only be made “after demonstrating safety and efficacy through a Phase 3 clinical study.”</p>
<p>Subsequently, four companies (<a href="https://s3.amazonaws.com/ctr-med-7111/D8110C00001/52bec400-80f6-4c1b-8791-0483923d0867/c8070a4e-6a9d-46f9-8c32-cece903592b9/D8110C00001_CSP-v2.pdf">AstraZeneca</a>, <a href="https://www.jnj.com/coronavirus/covid-19-phase-3-study-clinical-protocol">Johnson & Johnson</a>, <a href="https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf">Moderna</a> and <a href="https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-11/C4591001_Clinical_Protocol_Nov2020.pdf">Pfizer</a>) took the unusual step of making the protocols for their Phase 3 vaccine trials public. The protocol is the detailed plan for the trial, and it contains information on recruitment of volunteers, vaccine administration, participant followup and statistical analysis. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/370883/original/file-20201123-17-1n8b6sw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A man wearing a hat and a face mask gets an inject from a health-care worker out of frame." src="https://images.theconversation.com/files/370883/original/file-20201123-17-1n8b6sw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/370883/original/file-20201123-17-1n8b6sw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=361&fit=crop&dpr=1 600w, https://images.theconversation.com/files/370883/original/file-20201123-17-1n8b6sw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=361&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/370883/original/file-20201123-17-1n8b6sw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=361&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/370883/original/file-20201123-17-1n8b6sw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=453&fit=crop&dpr=1 754w, https://images.theconversation.com/files/370883/original/file-20201123-17-1n8b6sw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=453&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/370883/original/file-20201123-17-1n8b6sw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=453&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A volunteer is injected with AstraZenica’s COVID-19 vaccine candidate at the Chris Hani Baragwanath hospital in Soweto, Johannesburg, South Africa on June 24, 2020.</span>
<span class="attribution"><span class="source">(AP Photo/Siphiwe Sibeko)</span></span>
</figcaption>
</figure>
<p>Two companies (<a href="https://www.covid19vaccinetrial.co.uk/participate-oxford">AstraZeneca</a> and <a href="https://www.modernatx.com/sites/default/files/u1421/Moderna_mRNA-1273-P301-Informed-Consent.pdf">Moderna</a>) additionally made available consent documents provided to volunteers.</p>
<p>But pharma must go further.</p>
<h2>Data monitoring committees</h2>
<p>Phase 3 trials have independent <a href="https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-data-monitoring-committees_en.pdf">data monitoring committees</a> that review in real time any serious adverse events and trends in accumulating data. Traditionally, the membership of these committees is confidential, and their work is done in secret. </p>
<p>Of the data monitoring committees overseeing current COVID-19 vaccine trials, we know next to nothing. This may be business as usual, but in the face of a global pandemic, business as usual is not good enough.</p>
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Read more:
<a href="https://theconversation.com/canadas-covid-19-vaccine-task-force-needs-better-transparency-about-potential-conflicts-of-interest-147323">Canada’s COVID-19 Vaccine Task Force needs better transparency about potential conflicts of interest</a>
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<p>Membership of data monitoring committees should be public. Trust would be enhanced by knowledge that people making key decisions about safety in COVID-19 trials have the requisite expertise, and they are not encumbered by conflicts of interest.</p>
<h2>Adverse events</h2>
<p>On Sept. 8, AstraZeneca’s vaccine trials were <a href="https://www.statnews.com/2020/09/08/astrazeneca-covid-19-vaccine-study-put-on-hold-due-to-suspected-adverse-reaction-in-participant-in-the-u-k/">paused due to a serious adverse event</a>. The next day, while a <a href="https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/statement-on-astrazeneca-oxford-sars-cov-2-vaccine-azd1222-covid-19-vaccine-trials-temporary-pause.html">press release</a> referred only to a “single event of an unexplained illness,” AstraZeneca’s CEO revealed in a <a href="https://www.statnews.com/2020/09/09/astrazeneca-covid19-vaccine-trial-hold-patient-report/">phone call to investors</a> that the adverse event involved a woman hospitalized with transverse myelitis, an inflammation of the spinal cord.</p>
<p>One month later, Johnson & Johnson’s Phase 3 vaccine trial <a href="https://www.statnews.com/2020/10/12/johnson-johnson-covid-19-vaccine-study-paused-due-to-unexplained-illness-in-participant/">was paused</a> “due to an unexplained illness in a study participant.” No further details would be provided, said a company representative: “We must respect this participant’s privacy.”</p>
<p>If one were seeking to inflame distrust in vaccine trials, it is difficult to imagine a more effective strategy.</p>
<p>Pharma should publicly disclose details of any serious adverse event in a vaccine trial. Given the global attention focused on these trials, a pause — and the obvious inference that something bad has happened — is certain to become international news. In trials involving tens of thousands of people, sufficient details of the adverse event can be released without imperilling participant privacy. </p>
<p>Revealing the steps taken to investigate the adverse event and the reasons for restarting the trial are an opportunity to reinforce the careful oversight of vaccine trials and reassure an anxious public.</p>
<h2>Open access to data</h2>
<p>Finally, pharma should commit to making <a href="https://doi.org/10.1136/bmj.j2372">de-identified participant data from vaccine trials publicly available</a> as soon as possible. This allows independent scientists to investigate and confirm the reliability of analyses. In the case of discrepant interpretations, these can be mediated and resolved in plain view.</p>
<p>Responding to COVID-19 vaccine hesitancy requires unprecedented — and no doubt uncomfortable — transparency from pharma. But the <a href="https://doi.org/10.1038/d41586-020-02738-y">stakes could not be higher</a>: “History has shown that once public trust in vaccines has been compromised it is difficult to win back.”</p><img src="https://counter.theconversation.com/content/150270/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Charles Weijer consults with Cardialen, Eli Lilly & Company, and Research Triangle Institute (RTI) International.</span></em></p>COVID-19 vaccines are at risk of being undermined by vaccine hesitancy. Pharma must take steps to ensure transparency in data monitoring committees and trial data to build public trust in vaccines.Charles Weijer, Professor of medicine, epidemiology & biostatistics, and philosophy, Western UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1460912020-09-22T18:59:19Z2020-09-22T18:59:19ZHow and when will we know that a COVID-19 vaccine is safe and effective?<figure><img src="https://images.theconversation.com/files/358194/original/file-20200915-20-141c8is.jpg?ixlib=rb-1.1.0&rect=26%2C66%2C4415%2C3856&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">How much longer must society wait for a vaccine?</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/hourglass-inside-syringe-artwork-royalty-free-illustration/488635523?adppopup=true">ANDRZEJ WOJCICKI/Getty Images</a></span></figcaption></figure><p>With COVID-19 vaccines currently in the final phase of study, you’ve probably been wondering how the FDA will decide if a vaccine is safe and effective.</p>
<p>Based on the status of the <a href="https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html">Phase 3 trials</a> currently underway, it is unlikely that the results of these trials will be available before November. But it is likely that not just one but several of the competing COVID-19 vaccines will be shown to be safe and effective by the end of 2020. </p>
<p><a href="https://scholar.google.com/citations?hl=en&user=6yMIM1MAAAAJ&view_op=list_works&sortby=pubdate">I am a scientist and infectious diseases specialist</a> at the University of Virginia, where I care for patients with COVID-19 and conduct research on the pandemic. I am also a member of the World Health Organization Expert Group on COVID-19 Vaccine Prioritization. </p>
<h2>What is the status of COVID-19 vaccines in human clinical trials?</h2>
<p><a href="https://partners.mediasite.com/mediasite/Play/968f633a874c4f1a80c368496f49d4661d">Phase 3 studies are underway</a> for the Moderna and BioNTech/Pfizer vaccines, the Oxford/AstraZeneca viral vector vaccine and now the <a href="https://www.washingtonpost.com/health/2020/09/23/coronavirus-vaccine-jj-single-shot/">Johnson & Johnson viral vector vaccine</a>. </p>
<p>Each of these vaccines uses the SARS-CoV-2 spike glycoprotein, which the virus uses to infect cells, to trigger the immune system to generate protective antibodies and a cellular immune response to the virus. Protective antibodies act by preventing the spike glycoprotein from attaching the virus to human cells, thereby neutralizing the SARS-CoV-2 virus that causes COVID-19.</p>
<p>In the case of <a href="https://theconversation.com/coronavirus-a-new-type-of-vaccine-using-rna-could-help-defeat-covid-19-133217">Moderna’s nucleic acid vaccine</a>, the messenger RNA encoding the spike glycoprotein is encased in a fat droplet – called a liposome – to protect the mRNA from degradation and enable it to enter cells. Once these instructions are inside the cells, the mRNA is read by the human cell machinery and made into many spike proteins so that the immune system can respond and begin producing antibodies against this coronavirus. </p>
<p>The Oxford/AstraZeneca and <a href="https://www.jnj.com/johnson-johnson-initiates-pivotal-global-phase-3-clinical-trial-of-janssens-covid-19-vaccine-candidate">Johnson & Johnson</a> vaccines use a different strategy to activate an immune response. Here an adenovirus found in chimpanzees shuttles the instructions for manufacturing the spike glycoprotein into cells.</p>
<p><a href="http://doi.org/10.1126/science.abc5312">Phase 1 and 2 studies by pharmaceutical companies Janssen and Merck</a> also use viral vectors similar to the Oxford/AstraZeneca and J&J vaccines, while vaccines by Novavax and GSK-Sanofi use the actual spike protein itself. </p>
<h2>Animal tests show the vaccines provide protection from coronavirus infection</h2>
<p>Studies in animal models of COVID-19 provide convincing evidence that vaccination with the spike glycoprotein will protect from COVID-19. Experiments have show that when the immune system is shown the spike protein – which alone cannot trigger disease – the immune system will generate an antibody response that protects from infection with SARS-CoV-2.</p>
<p><a href="https://doi.org/10.1038/s41591-020-1070-6">In studies in hamsters</a> an adenovirus viral vector – the approach used by Oxford/AstraZeneca, for example – was used to immunize with the Spike glycoprotein. When the hamsters were infected with SARS-CoV-2 they were protected from pneumonia, weight loss and death.</p>
<p><a href="http://doi.org/10.1126/science.abc6284">In nonhuman primates</a>, DNA vaccines – which deliver the gene for the spike glycoprotein – reduced the amount of virus in the lungs. Animals that produced antibody that prevented virus attachment to human cells were most likely to be protected.</p>
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<figcaption><span class="caption">History of vaccines: Smallpox to SARS-CoV-2.</span></figcaption>
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<h2>What have the early Phase 1 and 2 studies in humans shown?</h2>
<p>Overall, <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2026920?query=featured_coronavirus">vaccination has triggered a more potent neutralizing antibody response</a> than even that seen in patients recovering from COVID-19. </p>
<p>This has also been the case for <a href="http://doi.org/10.1056/NEJMoa2022483">Moderna’s vaccine currently in Phase 3 trials</a> and for vaccines from <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31611-1/fulltext">CanSino Biologics and Oxford/ AstraZeneca.</a> </p>
<h2>What side effects have been observed?</h2>
<p><a href="https://doi.org/10.1016/S0140-6736(20)31605-6">Physicians have recorded</a> <a href="https://doi.org/10.1016/S0140-6736(20)31604-4">mild to moderate reactions</a> <a href="http://doi.org/10.1056/NEJMoa2022483">when the subjects were observed</a> up to 28 days after vaccination. These side effects included mild pain, warmth and tenderness at the site of injection, and fever, fatigue, joint and muscle pain. </p>
<p>But Phase 1 and 2 studies are by small by design, with just hundreds of participants. So these trials will not be large enough to detect uncommon or rare side effects. </p>
<p>The emphasis on safety as the primary goal was recently demonstrated in the Phase 3 Oxford/AstraZeneca vaccine trial <a href="https://www.nature.com/articles/d41586-020-02594-w">where one vaccinated individual developed inflammation of the spinal cord</a>. It isn’t clear whether the vaccine caused this reaction – it might be a new case of multiple sclerosis unrelated to the vaccine – but the Phase 3 trial was halted in the U.S. until more is known.</p>
<h2>How is the FDA ensuring that a vaccine will be safe yet quickly produced?</h2>
<p>The <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-and-licensure-vaccines-prevent-covid-19">FDA has issued guidance for industry</a> on the steps required for developing and ultimately licensing vaccines to prevent COVID-19 – these are the same rigorous safety standards required for all vaccines.</p>
<p>There are, however, ways to speed the process of approval that are centered on “platform technology.” What this means is that if a vaccine is using an approach such as an adenovirus that has previously been shown to be safe, it may be possible for a company to use previously collected data on toxicity and pharmacokinetics to fast-track clinical trial approval. </p>
<p>While speed and safety may appear conflicting goals, it is also encouraging to note that the <a href="https://www.wsj.com/articles/covid-19-vaccine-developers-prepare-joint-pledge-on-safety-standards-11599257729">rival vaccine manufacturers have jointly pledged</a> not to bow to any political pressures to rush vaccine approval, but to maintain the most rigorous safety standards. </p>
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<figcaption><span class="caption">How to develop a vaccine, quickly.</span></figcaption>
</figure>
<h2>How protective does a vaccine need be to receive FDA approval?</h2>
<p>The FDA has set the bar for the primary endpoint of a Phase 3 trial of 50% protection for approval of a COVID-19 vaccine. </p>
<p>Protection is defined as protection from symptomatic COVID-19 infection, defined as laboratory-confirmed SARS-CoV-2 infection plus symptoms such as fever or chills, cough, shortness of breath, fatigue, muscle aches, loss of taste or smell, congestion or runny nose, diarrhea, nausea or vomiting. </p>
<p>This means that an effective vaccine is considered one that will reduce the number of infections in vaccine recipients by half. This is the <a href="https://doi.org/10.1016/S0140-6736(20)31821-3">minimal protection that is anticipated to be clinically useful</a>. That is, in part, because lower levels of efficacy could paradoxically increase COVID-19 infections if it leads vaccinated people to decrease mask wearing or social distancing because they think they are completely protected.</p>
<p>Since a vaccine might be more effective at preventing severe COVID-19, the FDA instructs that <a href="https://www.fda.gov/media/139638/download">protection from severe COVID-19</a> should be a secondary endpoint.</p>
<h2>How many people have to be vaccinated to know if a vaccine works in Phase 3?</h2>
<p>The current Phase 3 trials are enrolling 30,000-40,000 subjects. Most of these participants will receive the vaccine and some a placebo.</p>
<p>When, exactly, the results of Phase 3 studies will be released depends in large part on the rate of infection in the placebo recipients. The way that these vaccine studies work is that they test if naturally acquired new coronavirus infections are lower in the group that received the vaccine compared with the group receiving the placebo. </p>
<p>So while it is good news that COVID-19 infections have dropped recently in the U.S. from <a href="https://www.nytimes.com/interactive/2020/us/coronavirus-us-cases.html?auth=login-email&login=email">70,000 to 40,000 cases per day</a>, this drop in new infections may slow the vaccine studies.</p>
<h2>Will Emergency Use Authorization fast-track vaccine?</h2>
<p>In an emergency such as we are faced with the COVID-19 pandemic, with approximately 700 new deaths and 40,000 new cases per day right now, the FDA is authorized to allow the use of unapproved products for the diagnosis, treatment and prevention of disease. That includes a vaccine.</p>
<p><a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-and-licensure-vaccines-prevent-covid-19">The standard approval process for vaccines</a> can require more than one year of observation after vaccination. If the short-term safety is good and the vaccine works to prevent COVID-19, then the vaccine should be approved for use under an Emergency Use Authorization while it is still being studied.</p>
<p>Under Emergency Use Authorization, the FDA will <a href="https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization">continue to collect information</a> from the companies producing the vaccines for benefit and harm, including surveillance for vaccine-associated enhanced respiratory disease or other potentially rare complications that might be observed in only one in a million.</p>
<h2>What should we expect in terms of approvals?</h2>
<p>I expect that the FDA will approve several vaccines by the end of 2020 under its Emergency Use Authorization authority so that vaccination can begin immediately, starting with high-risk groups including first responders, health care personnel, and the elderly and those with preexisting medical conditions. </p>
<p>This will be followed rapidly with <a href="https://theconversation.com/video-who-should-get-a-covid-19-vaccine-first-146285">roll-out of vaccination</a> to the population at large, while all of the time the FDA and vaccine manufacturers will continue to monitor for side effects and work to improve upon these first vaccines. This process is <a href="https://www.usatoday.com/story/news/health/2020/09/02/covid-19-vaccine-rollout-plan-united-states-worries-experts/5694037002/">expected to take months</a>.</p>
<p>It may not be life back to normal next year, but all signs point to a healthier 2021.</p>
<p><em>This article was updated on September 25 with information on the Johnson & Johnson vaccine trial.</em></p><img src="https://counter.theconversation.com/content/146091/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>William Petri receives funding from the NIH and the Bill & Melinda Gates Foundation.</span></em></p>Several vaccines are in Phase 3 trials. So when will we know whether any of these will protect against COVID-19?William Petri, Professor of Medicine, University of VirginiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1458822020-09-09T17:09:26Z2020-09-09T17:09:26ZThe Oxford vaccine trial has been paused, but this is no reason to panic<figure><img src="https://images.theconversation.com/files/357275/original/file-20200909-20-m5srs6.jpg?ixlib=rb-1.1.0&rect=432%2C10%2C5613%2C4074&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/study-covid19-infection-male-doctor-examines-1705078219">F8 studio/Shutterstock</a></span></figcaption></figure><p>The much-anticipated phase 3 trial of the University of Oxford’s coronavirus vaccine has been paused following a <a href="https://www.statnews.com/2020/09/08/astrazeneca-covid-19-vaccine-study-put-on-hold-due-to-suspected-adverse-reaction-in-participant-in-the-u-k/">suspected adverse reaction</a> in one of its participants. </p>
<p>As developing a successful vaccine has been widely touted as a way to <a href="https://theconversation.com/how-effective-does-a-covid-19-coronavirus-vaccine-need-to-be-to-stop-the-pandemic-a-new-study-has-answers-142468">end the pandemic</a>, this will feel like a blow for many people desperate to get back to normal life.</p>
<p>But how worried should we be? Is the suspension of this trial a major setback in the research effort to find a solution? At this stage, it is difficult to say. What it does show is that the trial is fulfilling one of its main purposes – to rigorously test the safety of the vaccine in a large number of people.</p>
<h2>How vaccine testing works</h2>
<p>During development a vaccine goes through <a href="https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html">multiple rounds of testing in humans</a>, known as phases. A phase 1 trial is run with small groups of participants to show that the vaccine is generally safe to give to people. A phase 2 trial then tests the vaccine in larger groups of people, to see if it stimulates an immune response and therefore is likely to benefit patients.</p>
<p>But it is the phase 3 trial that gives the answers we all really want to know – whether the vaccine will work in the population of interest by protecting them from disease, what side-effects there will be if it is given to lots of people, and whether ultimately the vaccine should be licensed for clinical use.</p>
<p>There are a number of possible ways to run a phase 3 trial, but generally a randomised controlled trial (RCT) design is used. This randomly assigns participants to one of two groups: the active group, who get the vaccine being tested, or the control group, who get an inactive vaccine called a placebo. The aim is to show statistically that the active vaccine is more beneficial than the placebo. </p>
<figure class="align-center ">
<img alt="A person receiving an injection in their arm." src="https://images.theconversation.com/files/357276/original/file-20200909-14-wlouuc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/357276/original/file-20200909-14-wlouuc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/357276/original/file-20200909-14-wlouuc.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/357276/original/file-20200909-14-wlouuc.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/357276/original/file-20200909-14-wlouuc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/357276/original/file-20200909-14-wlouuc.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/357276/original/file-20200909-14-wlouuc.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">In the US arm of the trial, one-third of participants are receiving a saline injection as a control.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/selective-focus-end-syringe-while-needle-556416004">DonyaHHI/Shutterstock</a></span>
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<p>This randomisation is also often “double-blinded”, meaning that neither the participants nor the researchers know which group each participant is in. This prevents researchers intentionally or unintentionally biasing their results out of optimism that their new vaccine will work. Blinded RCTs are considered the gold standard for testing any vaccine or drug.</p>
<p>However, as most RCTs are blinded – including Oxford’s phase 3 trial – researchers cannot easily determine whether any adverse medical events suffered by participants are due to the vaccine being tested or some other cause. This is because they do not know which participants have received the vaccine and which are in the placebo group.</p>
<h2>Safety monitoring</h2>
<p>To get around this problem, blinded trials almost always have an independent, unblinded, data safety monitoring committee (DSMC). Its job is to monitor all the participants to see whether those in the active group are having more medical complications than those in the placebo group.</p>
<p>All medical complications caused by any means – including accidents – are reported to the DSMC, which then considers whether the “adverse events” are connected to the vaccine. Sometimes this isn’t clear, and so the DSMC can request that the trial is stopped while an event is investigated. This is what seems to have happened with the Oxford vaccine trial.</p>
<p>Quite often adverse events are found not to be related to the vaccine being tested. Instead they may be caused by unrelated health conditions, diseases or infections. Alternatively, complications might be connected to the vaccine, but occur so infrequently that the DSMC may not consider them to be a significant risk to the other participants in the trial.</p>
<p>Without any further details, it is very difficult to assess the significance of the adverse event that has been detected in the Oxford trial. But it is important to note that halting trials for this reason is fairly common. Indeed, it shows that the trial is doing precisely what it is meant to – closely monitoring participants to ensure that all, and any, adverse events are detected and investigated.</p>
<p>We all probably hope that upon investigation the independent DSMC will find that this adverse event is manageable, and thus that the trial can soon restart. But even if this proves not to be the case, it is important to remember that any lessons learned from this trial will be carried forward for future vaccine development.</p>
<p>It is also important to remember that the Oxford vaccine is only one of <a href="https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines">nine COVID-19 vaccines</a> currently in phase 3 trials, and that <a href="https://www.acsh.org/news/2020/06/11/clinical-trial-success-rates-phase-and-therapeutic-area-14845">six in ten</a> vaccines put through trials are ultimately unsuccessful. Even if in a worst case scenario this adverse event means that development of the Oxford vaccine has to stop, there are still grounds for optimism that a successful vaccine will be developed soon.</p><img src="https://counter.theconversation.com/content/145882/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Simon Kolstoe does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Stoppages of clinical trials are a normal part of the testing process, and show that patient safety is being taken seriously.Simon Kolstoe, Senior Lecturer in Evidence Based Healthcare and University Ethics Advisor, University of PortsmouthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1443322020-08-12T12:00:59Z2020-08-12T12:00:59ZA COVID-19 vaccine needs the public’s trust – and it’s risky to cut corners on clinical trials, as Russia is<figure><img src="https://images.theconversation.com/files/352381/original/file-20200811-20-179mzzz.jpg?ixlib=rb-1.1.0&rect=187%2C22%2C743%2C551&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">On Aug. 11, Russian President Vladimir Putin announced that a coronavirus vaccine developed in the country has been registered for use.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/photo-shows-vials-of-vaccine-called-gamcovidvac-in-moscow-news-photo/1228002428?adppopup=true">Russian Health Ministry/Handout/Anadolu Agency via Getty Images</a></span></figcaption></figure><p>Russia’s announcement that a <a href="https://www.politico.com/news/2020/08/11/russia-coronavirus-vaccine-putin-daughter-393455">fast-tracked COVID-19 vaccine</a> is registered there, with plans for quick distribution in the general population this fall, is being <a href="https://www.nature.com/articles/d41586-020-02386-2">condemned by scientists worldwide</a>.</p>
<p>Findings from scientific studies of this vaccine, named “Sputnik V,” are not available. Large safety and efficacy trials <a href="https://sputnikvaccine.com/about-vaccine/clinical-trials/">are only now getting underway</a>. But despite only two months of preliminary testing in people, Russian President Vladimir Putin called the vaccine “<a href="https://www.bbc.com/news/world-europe-53735718">quite effective</a>” and it’s <a href="https://www.bloomberg.com/news/articles/2020-08-11/putin-says-russia-has-registered-world-s-first-covid-19-vaccine">received regulatory approval</a>.</p>
<p>In other places, notably the <a href="https://www.weforum.org/agenda/2020/06/vaccine-development-barriers-coronavirus/">United States, China and the European Union</a>, even as <a href="https://www.nationalgeographic.com/science/health-and-human-body/human-diseases/coronavirus-vaccine-tracker-how-they-work-latest-developments-cvd/">researchers rush to develop vaccines</a>, they continue to publish studies of these vaccines at a more measured pace than is happening in Russia.</p>
<p>As an <a href="https://scholar.google.com/citations?user=RNembkwAAAAJ&hl=en&oi=ao">epidemiologist who studies vaccine hesitancy and vaccine-preventable disease</a>, I’m concerned about this news from Russia. After essential workers and high-risk groups are vaccinated, I would want to be among the first in line for an approved COVID-19 vaccine, but the medical research system must make sure any vaccine is safe and effective before distributing it to the population at large.</p>
<h2>Clinical trials have a valuable role</h2>
<p>Before any drug, vaccine or medical device is licensed for use in the general population, it needs to go through <a href="https://www.historyofvaccines.org/content/articles/vaccine-development-testing-and-regulation">several rounds of large-scale testing</a>. These studies are designed to make sure the intervention is safe and effective, and to understand what the appropriate dosage will be.</p>
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<p>Under normal conditions, the research required to bring a vaccine to market <a href="https://doi.org/10.1186/s12961-020-00571-3">can take decades</a>. For example, before the HPV vaccine was <a href="https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5920a4.htm">licensed in the U.S. in 2006</a>, a phase III clinical trial <a href="https://doi.org/10.1016/S0140-6736(09)61248-4">enrolled 18,644 participants in 2004-2005</a>, a phase II clinical trial had <a href="https://doi.org/10.1016/S0140-6736(04)17398-4">enrolled 1,113 participants in 2000</a>, and the laboratory studies that led to a vaccine candidate had been <a href="https://doi.org/10.2147/tcrm.2006.2.3.259">published in the early 1990s</a>.</p>
<p>In the face of the coronavirus pandemic, scientists around the globe are focusing their efforts on developing a COVID-19 vaccine. <a href="https://www.knowablemagazine.org/article/health-disease/2020/getting-covid-19-vaccine-quickly-and-safely">They’re working at an</a> <a href="https://theconversation.com/what-needs-to-go-right-to-get-a-coronavirus-vaccine-in-12-18-months-136816">unprecedented pace to move through the necessary clinical trials</a> to end up with a safe and effective vaccine. One of the most time-consuming parts of clinical trials is enrolling participants, and pharmaceutical companies have <a href="https://doi.org/10.1186/s12961-020-00571-3">sped up this process</a> by lining up volunteers early, obtaining important baseline data from them even before a vaccine candidate is available.</p>
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<figcaption><span class="caption">Here’s how drugs are tested and approved in the U.S.</span></figcaption>
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<h2>Problems if the vaccine is released too early</h2>
<p>Carefully conducted clinical trials are necessary to identify any problems with the vaccine. For example, studies of a new type of measles vaccine in the early 1990s found that it was <a href="https://apps.who.int/iris/bitstream/handle/10665/228552/WER6748_357-361.PDF">detrimental to baby girls</a>, and so it was never licensed to the general population. The existing measles or measles-mumps-rubella vaccine available in the U.S. and other countries is <a href="https://www.cdc.gov/vaccinesafety/vaccines/mmr/mmr-studies.html">highly safe and effective</a>. </p>
<p>It could also be that the vaccine is not effective in some categories of people. Phase I and II clinical trials have small sample sizes and may not include individuals from high-risk groups. For example, a recently published phase II clinical trial of a COVID-19 vaccine <a href="https://doi.org/10.1016/S0140-6736(20)31605-6">excluded obese people, those with chronic diseases and pregnant women</a>. However, these are all groups that should be able to get the vaccine in the future. More studies, including phase III trials, are necessary to discover if the vaccine works in the general population. Preliminary results should be <a href="https://www.reuters.com/article/us-health-coronavirus-vaccines-explainer/when-will-a-coronavirus-vaccine-be-ready-idUSKCN2571H2">available by the end of 2020</a>.</p>
<p>The concern is that by introducing the vaccine early, without adequate testing of safety, effectiveness and dosing, the population may be presented with a vaccine which is not safe or not effective, and with little information on which vaccine schedule is best.</p>
<p>Food and Drug Administration Commissioner Dr. Stephen Hahn has said the FDA <a href="https://www.mercurynews.com/2020/08/10/commissioner-fda-wont-cut-corners-on-covid-19-vaccine/">will not “cut corners”</a> in approving a COVID-19 vaccine in the U.S. despite an accelerated program, <a href="https://abcnews.go.com/Politics/public-health-experts-scientists-confident-vaccine-process-criticism/story?id=72216320">dubbed Operation Warp Speed</a>.</p>
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<a href="https://images.theconversation.com/files/352382/original/file-20200811-14-292m13.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="archival photo of packing vials of polio vaccine into boxes" src="https://images.theconversation.com/files/352382/original/file-20200811-14-292m13.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/352382/original/file-20200811-14-292m13.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=492&fit=crop&dpr=1 600w, https://images.theconversation.com/files/352382/original/file-20200811-14-292m13.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=492&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/352382/original/file-20200811-14-292m13.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=492&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/352382/original/file-20200811-14-292m13.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=619&fit=crop&dpr=1 754w, https://images.theconversation.com/files/352382/original/file-20200811-14-292m13.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=619&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/352382/original/file-20200811-14-292m13.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=619&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">In 1956, boxes of polio vaccine were rushed for delivery, but only after clinical trials concluded and it was approved by the FDA.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/indianapolis-in-at-the-eli-lilly-and-company-plant-in-the-news-photo/514874700?adppopup=true">Bettmann via Getty Images</a></span>
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<h2>Rushing to market</h2>
<p>But is there ever an ethical reason to release a vaccine early, even without going through all phases of clinical trials?</p>
<p>Although it would be wonderful to get a vaccine into the population quickly, there could be substantial downsides if researchers and manufacturers cut corners. Imagine a vaccine that often had serious side effects that weren’t caught in small trials before it was widely administered.</p>
<p>[<em>Research into coronavirus and other news from science</em> <a href="https://theconversation.com/us/newsletters/science-editors-picks-71/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=science-corona-research">Subscribe to The Conversation’s new science newsletter</a>.]</p>
<p>An untested vaccine wouldn’t just harm the people vaccinated. If negative perceptions about the safety or efficacy of a COVID-19 vaccine spread throughout the population, it could limit how many people are willing to get the shot and perpetuate disease transmission.</p>
<p>Trust in vaccination programs is crucial. Russia, in fact, provides an important historical example. In the 1990s, trust in the country’s public health system rapidly decreased, and rates of diphtheria-tetanus-pertussis vaccination fell as a result. A large outbreak of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640235/?tool=pmcentrez&report=abstract">diphtheria then spread through eastern Europe</a>, leaving over 4,000 people dead.</p>
<p>Hasty rollout of a COVID-19 vaccine could prime people not only to not trust the COVID-19 vaccine, but also to doubt vaccination and public health systems as a whole. </p>
<p>Vaccinations should be developed by impartial scientists and evaluated by nonpartisan government officials. By cutting red tape, procedures can be prioritized and sped up, but they must not be skipped.</p><img src="https://counter.theconversation.com/content/144332/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Abram L. Wagner receives funding from the NIH and NSF. </span></em></p>As Russia fast tracks a coronavirus vaccine, scientists worry about skipped safety checks – and the potential fallout for trust in vaccines if something ends up going wrong.Abram L. Wagner, Research Assistant Professor of Epidemiology, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1381972020-06-02T12:13:49Z2020-06-02T12:13:49ZFrom the research lab to your doctor’s office – here’s what happens in phase 1, 2, 3 drug trials<figure><img src="https://images.theconversation.com/files/334221/original/file-20200512-66644-10tznjn.jpg?ixlib=rb-1.1.0&rect=43%2C0%2C4800%2C3140&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Finding a cure for the coronavirus requires more than anecdotal evidence.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/doctor-wearing-ppe-or-isolation-grown-suite-for-royalty-free-image/1208754898?adppopup=true">Skaman306/Moment via Getty Images</a></span></figcaption></figure><p>For COVID-19, like all illnesses, the drugs and vaccines to treat or prevent the disease must be backed by rigorous evidence. <a href="https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies">Clinical trials</a> are the source of this evidence. </p>
<p>With vaccines and drugs for the coronavirus already entering human testing, it is important to know what the different phases of clinical trials are testing for. <a href="https://keck.usc.edu/faculty-search/mindy-aisen/">I am a neurologist</a> with the <a href="https://keck.usc.edu/atri/">Alzheimer’s Therapeutic Research Institute</a> at the University of Southern California. Our team has been developing and overseeing all phases of clinical trials for decades. I am here to help you understand this complicated and important process. </p>
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<h2>Preclinical trials</h2>
<p>The earliest indications about whether an intervention is effective and safe come from preclinical trials. This research is done in the laboratory using cells or animals.</p>
<p>Researchers can get some information about safety and efficacy of a treatment from preclinical trials, but the results do not say whether what they are testing is safe or works in people. </p>
<p>Once a treatment shows promise in preclinical trials, researchers begin the process of working through the phases that have been established by the <a href="https://www.fda.gov/patients/drug-development-process/step-3-clinical-research">U.S. Food and Drug Administration</a>. These phases are designed <a href="https://www.fda.gov/science-research/science-and-research-special-topics/clinical-trials-and-human-subject-protection">to do two things</a>: protect patients during the process and make sure that the drug or treatment works. </p>
<h2>Phase 1 trials</h2>
<p>Phase 1 trials are <a href="https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies">focused on safety</a>. Researchers monitor kidney, liver, hormone and cardiac functions to look for adverse affects in human volunteers. They also look for biological signs of efficacy related to what they are hoping to treat. For example, if a trial was testing a vaccine, researchers might monitor immune activity to see if it increases.</p>
<p>Phase 1 clinical trials <a href="https://www.nia.nih.gov/health/what-are-clinical-trials-and-studiesand">typically take around two months</a> and involve small numbers of participants, usually 20 to 100 healthy volunteers or people with the condition that the intervention may treat. Researchers give the participants a range of medication dosages to help determine the lowest possible effective but safe dose. Some, but not all, phase 1 studies are randomized and placebo controlled, meaning that some portion of the subjects are given the real treatment and some <a href="https://www.nia.nih.gov/health/placebos-clinical-trials">get a placebo</a> that does nothing. Neither the subject nor clinician knows who is receiving which treatment. </p>
<p>Drugs that pass phase 1 trials can be considered likely safe, but whether they work or not still remains to be seen.</p>
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<a href="https://images.theconversation.com/files/334227/original/file-20200512-66681-pk6env.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/334227/original/file-20200512-66681-pk6env.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/334227/original/file-20200512-66681-pk6env.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=384&fit=crop&dpr=1 600w, https://images.theconversation.com/files/334227/original/file-20200512-66681-pk6env.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=384&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/334227/original/file-20200512-66681-pk6env.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=384&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/334227/original/file-20200512-66681-pk6env.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=483&fit=crop&dpr=1 754w, https://images.theconversation.com/files/334227/original/file-20200512-66681-pk6env.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=483&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/334227/original/file-20200512-66681-pk6env.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=483&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Once people are used in the testing process, the U.S. Food and Drug Administration gets involved.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/the-outside-of-the-food-and-drug-administration-news-photo/496532228?adppopup=true">Al Drago/CQ Roll Call via Getty Images</a></span>
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<h2>Phase 2 trials</h2>
<p>In phase 2 trials, researchers focus on seeing if the treatment works, finding the safest effective dose and determining what symptoms, tests or outcomes are the best measures of efficacy of the treatment. Determining the best measures of success is important for designing the final stage of testing.</p>
<p>All phase 2 trials are randomized and placebo controlled.</p>
<p>This stage of research can take months to years, and only about <a href="https://www.fda.gov/patients/drug-development-process/step-3-clinical-research">one-third of drugs in phase 2 trials make it to the next phase</a>.</p>
<p>In phase 2 trials, researchers give the drug to hundreds of subjects and watch for safety through regular testing. To measure effectiveness, researchers look at clinical responses such as the length of illness, severity of the illness or survival rates. Direct measures of a disease – such as the amount of virus in a person’s cells – are also monitored, as well as <a href="https://dx.doi.org/10.1177%2F1535370217750088">biomarkers</a> – signals in the body that researchers <a href="https://www.clinicaltrials.gov/ct2/show/NCT04322513">know are changed by the targeted disease</a>.</p>
<p>At this point, the researchers will use all the information they have gained to design the phase 3 trial. They decide what measures to use, the doses to test and the type, or <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cohort">cohort</a>, of people to test. </p>
<p>If there is evidence in either phase 1 or phase 2 that the drug or vaccine is unsafe or ineffective, the teams will stop the trial. </p>
<h2>Phase 3 trials</h2>
<p>Phase 3 trials are where researchers look to see if people that get the treatment are statistically better off than those don’t. The trials are randomized and placebo controlled, and use the measures of success chosen from the phase 2 trial. Phase 3 trials are also designed to find any rare side effects of a treatment. </p>
<p>In order to get statistically meaningful data, phase 3 trials are big, normally including a few hundred to 3,000 people. </p>
<p>This is the final step before a drug is approved for public use. After a phase 3 trial is finished, the FDA puts together a panel of independent scientists to review the data. The panel decides, based on evidence of success and prevalence of side effects, if the benefits of the drug outweigh the risks enough to approve it for widespread use.</p>
<p>According to the FDA, only <a href="https://www.fda.gov/patients/drug-development-process/step-3-clinical-research">25%-30% of drugs in phase 3 trials get approved</a>.</p>
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<a href="https://images.theconversation.com/files/338641/original/file-20200529-78867-1mjk2mt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/338641/original/file-20200529-78867-1mjk2mt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/338641/original/file-20200529-78867-1mjk2mt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/338641/original/file-20200529-78867-1mjk2mt.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/338641/original/file-20200529-78867-1mjk2mt.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/338641/original/file-20200529-78867-1mjk2mt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/338641/original/file-20200529-78867-1mjk2mt.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/338641/original/file-20200529-78867-1mjk2mt.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Neither the researchers, physicians nor patients know whether they are handing real drugs or placebos for randomized placebo-controlled clinical trials.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/drug-research-doctor-working-in-hospital-writing-a-royalty-free-image/959237242?adppopup=true">krisanapong detraphiphat/Moment via Getty Images</a></span>
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<h2>Phase 4 trials</h2>
<p>Phase 4 trials are used to test approved treatments for the same medical condition but in a different dose or time frame or group of people. For example, a phase 4 trial could be used to test if a drug that’s already approved for adults is safe and effective for children.</p>
<p>When a drug that’s been approved for one purpose is studied for a different medical condition – for example, testing the malaria drug hydroxychloroquine as a potential treatment for COVID-19 – this is not a phase 4 trial. This is a phase 2 or 3 trial because it is designed to answer those early questions about how well the treatment works for the new condition.</p>
<h2>A critical eye for medical news</h2>
<p>News headlines are full of <a href="https://www.msn.com/en-us/money/markets/coronavirus-live-updates-oxford-readying-a-phase-2-vaccine-trial-cases-surge-in-india/ar-BB14smVc">trial results concerning COVID-19 interventions</a>. It’s easy to get excited when reading about a new drug or vaccine. But early successes do not guarantee a treatment will work.</p>
<p>COVID-19, like <a href="https://www.actcinfo.org/projects/">Alzheimer’s</a>, is a complex disease, and clinical trials to test treatments are particularly challenging, with highly variable outcomes. The process for drug and treatment approval is long, but is designed to guarantee that what a physician gives you will do help, not hurt, you.</p>
<p>[<em>You need to understand the coronavirus pandemic, and we can help.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=upper-coronavirus-help">Read The Conversation’s newsletter</a>.]</p><img src="https://counter.theconversation.com/content/138197/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mindy Aisen does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Drugs and vaccines to fight the coronavirus are already in clinical trials. It is important to understand the difference between each step in this process as efforts to fight COVID-19 continue.Mindy Aisen, Clinical Professor of Neurology, University of Southern CaliforniaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1368162020-05-08T12:21:15Z2020-05-08T12:21:15ZWhat needs to go right to get a coronavirus vaccine in 12-18 months<figure><img src="https://images.theconversation.com/files/333429/original/file-20200507-49556-zcna08.jpg?ixlib=rb-1.1.0&rect=0%2C22%2C7238%2C4616&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A coronavirus vaccine is coming, but when?</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/syringes-and-injectable-medications-royalty-free-image/1161382041?adppopup=true"> Francesco Carta fotografo/Moment via Getty Images</a></span></figcaption></figure><p>I, like many Americans, miss the pre-pandemic world of hugging family and friends, going to work and having dinner at a restaurant. A protective vaccine for SARS-Cov2 is likely to be <a href="https://doi.org/10.1002/emmm.201403876">the most effective public health tool</a> to get back to that world. </p>
<p>Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, cautiously estimates that a vaccine could be available in <a href="https://www.npr.org/sections/coronavirus-live-updates/2020/04/30/848478507/fauci-says-its-doable-to-have-millions-of-doses-of-covid-19-vaccine-by-january">12 to 18 months</a>. </p>
<p>I am a <a href="https://scholar.google.com/citations?user=-pDNdhcAAAAJ&hl=en&oi=sra">professor of microbiology and immunology</a> and study how the immune system develops. I think Dr. Fauci’s estimate is an optimistic one, but possible. </p>
<p>Traditional vaccine development is a long and complicated process. Only about 6% of vaccine candidates are eventually <a href="https://doi.org/10.1371/journal.pone.0057755">approved for public use</a>, and the process takes <a href="https://doi.org/10.1371/journal.pone.0057755">10.7 years, on average</a>.</p>
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<a href="https://images.theconversation.com/files/333426/original/file-20200507-49579-1khxvcw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/333426/original/file-20200507-49579-1khxvcw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/333426/original/file-20200507-49579-1khxvcw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/333426/original/file-20200507-49579-1khxvcw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/333426/original/file-20200507-49579-1khxvcw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/333426/original/file-20200507-49579-1khxvcw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/333426/original/file-20200507-49579-1khxvcw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/333426/original/file-20200507-49579-1khxvcw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Anthony Fauci is estimating a coronavirus vaccine will be developed faster than any other vaccine in history.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Virus-Outbreak-Trump/711244f1bb2e4e219041e8f99dc7b552/247/0">AP Photo/Patrick Semansky</a></span>
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<p>But these are not traditional times. Researchers around the world are <a href="https://doi.org/10.1038/d41573-020-00073-5">innovating the process of vaccine development</a> in real time to develop a vaccine as fast as possible. So how close are we to a vaccine?</p>
<h2>A step-by-step process</h2>
<p>Vaccines prevent disease by boosting a person’s natural immune response against a microbe that they have <a href="https://www.cdc.gov/vaccines/vpd/vpd-vac-basics.html">not encountered before</a>. There are a number of different types of vaccines in development for SARS-CoV-2 and they fall into three broad categories: <a href="https://theconversation.com/labs-are-experimenting-with-new-but-unproven-methods-to-create-a-coronavirus-vaccine-fast-134319">traditional killed-virus vaccines, protein-based vaccines and gene-based vaccines</a>. No matter the type, every single vaccine candidate must go through the same vetting process before it can be put into use. </p>
<p>Once researchers have developed a potential candidate, they begin the first step of testing in laboratories, called preclinical studies. Scientists use laboratory animals to examine if the candidate vaccine induces an immune response to the virus and to check whether the vaccine causes any obvious medical problems. </p>
<p>Once a vaccine is proven safe in animals, researchers begin human testing. This is where the <a href="https://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/BiologicsLicenseApplicationsBLAProcess/ucm133096.htm">federal Food and Drug Administration</a> begins to regulate the process. </p>
<p>Phase 1 studies test for safety and proof-of-concept. Researchers give a small number of human volunteers the vaccine. Then they look for medical problems and see if it induces some sort of immune response.</p>
<p>In Phase 2 studies, researchers give the vaccine to hundreds of volunteers to determine the optimal vaccine composition, dose and vaccination schedule.</p>
<p>The final step before a vaccine is approved by the FDA for broad use is a Phase 3 trial. These involve <a href="https://doi.org/10.1191%2F0962280204sm356ra">thousands of volunteers</a> and provide data on how good the vaccine is at preventing infection. These large trials will also uncover rarer side effects or health issues that may not show up in the smaller trials. </p>
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<a href="https://images.theconversation.com/files/333435/original/file-20200507-49569-11xpm4z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/333435/original/file-20200507-49569-11xpm4z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/333435/original/file-20200507-49569-11xpm4z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/333435/original/file-20200507-49569-11xpm4z.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/333435/original/file-20200507-49569-11xpm4z.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/333435/original/file-20200507-49569-11xpm4z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/333435/original/file-20200507-49569-11xpm4z.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/333435/original/file-20200507-49569-11xpm4z.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Some side effects are rare, so testing must be thorough before a vaccine is approved.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/doctor-giving-patient-injection-in-volunteer-clinic-royalty-free-image/573103329?adppopup=true">Jose Luis Pelaez Inc/DigitalVision via Getty Images</a></span>
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<p>If in any of these phases a vaccine candidate appears to be ineffective or cause harm to people, the researchers must start over with a new candidate.</p>
<p>After a vaccine candidate successfully completes these clinical trials, a medical regulatory panel in the FDA looks at the evidence, and if the vaccine is effective and safe, approves it for general use. Experts estimate that the whole process costs between <a href="https://www.passporthealthusa.com/2018/02/how-much-does-it-cost-to-develop-a-new-vaccine/">US$1 billion and $5 billion</a>.</p>
<p>But approval is not the only hurdle. As has been demonstrated by the <a href="https://www.nytimes.com/2020/04/15/us/coronavirus-cases-update-live.html">severe lack of coronavirus testing</a>, easy and fast production of a test or vaccine is as critical as having one that works.</p>
<p>Both clinical efficacy and ease of production must be considered when asking how long until a vaccine is ready.</p>
<h2>Current promising candidates</h2>
<p>As of April 30, 2020, there were eight vaccine candidates currently in Phase 1 (or joint Phase 1/Phase 2) clinical trials and 94 vaccines candidates <a href="https://www.who.int/who-documents-detail/draft-landscape-of-covid-19-candidate-vaccines">in preclinical studies</a>.</p>
<p>Three of the eight are <a href="http://www.chictr.org.cn/showprojen.aspx?proj=52227">traditional vaccines</a> that use <a href="https://clinicaltrials.gov/ct2/show/NCT04352608?term=Sinovac&cntry=CN&draw=2&rank=9">inactivated</a> or killed virus. Two of the others are <a href="http://www.chictr.org.cn/showprojen.aspx?proj=51154">protein-based</a> vaccines that use a <a href="https://clinicaltrials.gov/ct2/show/NCT04324606?term=vaccine&cond=covid-19&draw=2&rank=3">modified cold virus to deliver the protein</a> that will stimulate the immune response.</p>
<p>The final three vaccines in Phase 1 or 2 trials, and the only two in the U.S., are gene-based vaccines. To me, these seem like the most promising.</p>
<p>Gene-based vaccines contain a gene or part of a gene from the virus that causes COVID-19, but not the virus itself. When a person is injected with one of these vaccines, their own cells read the injected gene and make a protein that is a part of the coronavirus. This one protein isn’t dangerous by itself, but it should trigger an immune response that would lead to immunity from the coronavirus.</p>
<p><a href="https://theconversation.com/labs-are-experimenting-with-new-but-unproven-methods-to-create-a-coronavirus-vaccine-fast-134319">Gene-based vaccines</a> come in DNA form, like the vaccine <a href="https://clinicaltrials.gov/ct2/show/NCT04336410?term=inovio&cond=covid-19&draw=2&rank=1">in Phase 1 clinical trials</a> from Inovio Pharmaceuticals in the U.S., or in RNA form, like the vaccine in a simultaneous Phase 1/Phase 2 trial from the <a href="https://www.clinicaltrialsregister.eu/ctr-search/search?query=BNT162-01">German company BioNTech</a> and the vaccine in Phase 1 trials from the <a href="https://clinicaltrials.gov/ct2/show/NCT04283461?term=vaccine&cond=covid-19&draw=2&rank=4">U.S.-based Moderna</a>.</p>
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<a href="https://images.theconversation.com/files/333438/original/file-20200507-49589-2ug3wp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/333438/original/file-20200507-49589-2ug3wp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/333438/original/file-20200507-49589-2ug3wp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/333438/original/file-20200507-49589-2ug3wp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/333438/original/file-20200507-49589-2ug3wp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/333438/original/file-20200507-49589-2ug3wp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/333438/original/file-20200507-49589-2ug3wp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/333438/original/file-20200507-49589-2ug3wp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Gene-based vaccines are unproven, but offer effective protection and ease of production.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/hepatitis-b-viruses-and-dna-illustration-royalty-free-illustration/758308151?adppopup=true">KATERYNA KON/SCIENCE PHOTO LIBRARY via Getty Images</a></span>
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<p>No gene-based vaccines have ever been approved for human use, but DNA vaccines are used on <a href="https://dx.doi.org/10.1038%2Fnrg2432">animals</a>, and a few were in <a href="https://doi.org/10.1056/NEJMoa1708120">clinical trials</a> for <a href="https://www.technologyreview.com/2016/08/02/158531/us-government-starts-test-of-zika-vaccine-in-humans/">the Zika virus</a>.</p>
<p>In the past, researchers have struggled to develop DNA vaccines that produce strong immune responses, but new techniques <a href="https://doi.org/10.1586/erv.11.188">look promising</a>. RNA vaccines tend <a href="https://doi.org/10.1038/nrd.2017.243">to be more effective</a> in animal studies but have also required innovations before human use. It may be that the time of <a href="https://dx.doi.org/10.1038%2Fnrg2432">gene-based vaccines has arrived</a>.</p>
<p>Another benefit of gene-based vaccines is that manufacturers would likely be able to produce large amounts <a href="https://dx.doi.org/10.3389%2Ffimmu.2019.00594">much faster than traditional vaccines</a>. DNA and RNA vaccines would also be <a href="https://dx.doi.org/10.1038%2Fnrg2432">more shelf–stable than conventional vaccines</a> since they don’t use ingredients like cell components or chicken eggs. This would make distribution, especially to rural areas, easier.</p>
<h2>Still a long road to implementation</h2>
<p>The three gene-based vaccines and the five other candidates face many challenges before you or I will be vaccinated. The fact that they are in Phase 1 and 2 trials is encouraging, but the very point of clinical trials is to reveal any problems with a vaccine candidate.</p>
<p>And there are a <a href="https://doi.org/10.1101/021543">lot of potential problems</a>. The preclinical results in laboratory animals might not translate well to people. The level of immune protection might be low. And people may react adversely when injected with the vaccine.</p>
<p>Any coronavirus vaccine could also produce a dangerous reaction called immune enhancement, where the vaccine actually worsens the symptoms of a coronavirus infection. This is rare, but <a href="https://doi.org/10.1073/pnas.2005456117">has happened with past vaccine candidates</a> for dengue fever and other viruses.</p>
<p>So, how long before we have a vaccine against the COVID-19 virus? </p>
<p>No vaccines have made it through Phase 1 or Phase 2 trials yet, and Phase 3 trials generally take between one and four years. If researchers get lucky and one of these first vaccines is both safe and effective, we are still at least a year away from knowing that. At that point manufacturers would need to start producing and distributing the vaccine at a massive scale. </p>
<p>It is unclear what percent of the population would need to be vaccinated against SARS-CoV-2, but in general, you need to immunize between 80% and 95% of the population to have effective <a href="https://doi.org/10.1093/cid/cir007">herd immunity</a>. Depending on what the virus does in the coming months, that might not be necessary, but if it is, that’s 260-300 million people in the U.S. alone.</p>
<p>Researchers are doing everything they can to develop a vaccine as fast as possible while still making sure it is effective and safe. Manufacturers can help by preparing flexible systems that could be ready to produce whichever candidate gets across the finish line first.</p>
<p>If everything goes well, Fauci’s 12- to 18-month prediction may be right. If so, it will be thanks to the tireless work of scientists, the support of international organizations and manufacturers all innovating and working together to fight this virus. </p>
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<p class="fine-print"><em><span>Marcos E. García-Ojeda receives funding from the Howard Hughes Medical Institute (HHMI) Inclusive Excellence Grant Intiative.</span></em></p>Vaccine development is usually a long process. The coronavirus pandemic is forcing researchers to innovate and test potential vaccines faster than ever before.Marcos E. García-Ojeda, Professor of Molecular and Cell Biology, University of California, MercedLicensed as Creative Commons – attribution, no derivatives.