Virus World

Experts are concerned that the company has not been more forthcoming about two participants who became seriously ill after getting its experimental vaccine. AstraZeneca revealed details of its large coronavirus vaccine trials on Saturday, the third in a wave of rare disclosures by drug companies under pressure to be more transparent about how they are testing products that are the world’s best hope for ending the pandemic. Polls are finding Americans increasingly wary of accepting a coronavirus vaccine. And scientists inside and outside the government are worried that regulators, pressured by the president for results before Election Day on Nov. 3, might release an unproven or unsafe vaccine. “The release of these protocols seems to reflect some public pressure to do so,” said Natalie Dean, a biostatistician and expert in clinical trial design for vaccines at the University of Florida. “This is an unprecedented situation, and public confidence is such a huge part of the success of this endeavor.” Experts have been particularly concerned about AstraZeneca’s vaccine trials, which began in April in Britain, because of the company’s refusal to provide details about serious neurological illnesses in two participants, both women, who received its experimental vaccine in Britain. Those cases spurred the company to halt its trials twice, the second time earlier this month. The studies have resumed in Britain, Brazil, India and South Africa, but are still on pause in the U.S. About 18,000 people worldwide have received AstraZeneca’s vaccine so far.

AstraZeneca’s 111-page trial blueprint, known as a protocol, states that its goal is a vaccine with 50 percent effectiveness — the same threshold that the Food and Drug Administration has set in its guidance for coronavirus vaccines. To determine with statistical confidence whether the company has met that target, there will have to be 150 people ill with confirmed coronavirus among participants who were vaccinated or received placebo shots. However, the plan anticipates that a safety board will perform an early analysis after there have been just 75 cases. If the vaccine is 50 percent effective at that point, it might be possible for the company to stop the trial early and apply for authorization from the government to release the vaccine for emergency use. In allowing only one such interim analysis, AstraZeneca’s plan is more rigorous than the others that have been released, from Moderna and Pfizer, Dr. Eric Topol, a clinical trials expert at Scripps Research in San Diego, said in an interview. Moderna allows two such analyses, and Pfizer four. He said the problem with looking at the data too many times, after a relatively small number of cases, is that it increases the odds of finding an appearance of safety and efficacy that might not hold up. Stopping trials early can also increase the risk of missing rare side effects that could be significant once the vaccine is given to millions of people. Dr. Topol said AstraZeneca’s plan, like those of Moderna and Pfizer, had a problematic feature: All count relatively mild cases of Covid-19 when measuring efficacy, which may hamper efforts to determine whether the vaccine prevents moderate or severe illness.

Such plans are not usually shared with the public “due to the importance of maintaining confidentiality and integrity of trials,” Michele Meixell, a spokeswoman for AstraZeneca, said in a statement. The company has released few details about the two cases of serious illness in its trial. The first participant received one dose of the vaccine before developing inflammation of the spinal cord, known as transverse myelitis, according to a participant information sheet for AstraZeneca’s vaccine from July. The condition can cause weakness in the arms and legs, paralysis, pain and bowel and bladder problems. The case prompted a pause in AstraZeneca’s vaccine trials to allow for a safety review by independent experts. A company spokeswoman told the Times last week that the volunteer was later determined to have a previously undiagnosed case of multiple sclerosis, unrelated to the vaccine, and that the trial resumed shortly thereafter. Transverse myelitis can sometimes be the first sign of multiple sclerosis, which involves more complex symptoms. But the myelitis alone can also occur after the body encounters an infectious agent like a virus. The company said it had not confirmed a diagnosis in the second case, a participant who got sick after the second dose of the vaccine. A person familiar with the situation who spoke with The Times on the condition of anonymity said the participant’s illness had been pinpointed as transverse myelitis. The trial was paused again on Sept. 6 after she fell ill. The condition is rare, but serious, and experts said that finding even one case among thousands of trial participants could be a red flag. Multiple confirmed cases, they said, could be enough to halt AstraZeneca’s vaccine bid entirely...

The biotech, among the furthest along in coronavirus vaccine development, is the first developer to share the so-called study protocol of its large Phase 3 trial. Moderna on Thursday took the unusual step of making public the detailed study plan for the company's large coronavirus vaccine trial, becoming the first developer in late-stage testing to do so amid calls for greater transparency by researchers and public health experts. The so-called study protocol, a lengthy document that's typically closely kept while testing is ongoing, gives outside observers a better sense of how the trial is being run. Most importantly, the plans help clarify how — and when — an independent committee in charge of reviewing data from the study would determine whether the vaccine is safe and effective. "We want to ensure that what we know is shared with the public, with the media, with clinicians who aren't part of the company so we can develop confidence," said Stéphane Bancel, Moderna's CEO, in an interview. "Submitting the protocol online is another step," he added. "We want the world to know they can trust us."

Trust has been in short supply, however. As Moderna and fellow coronavirus frontrunnners Pfizer and AstraZeneca have raced through early-stage testing, scrutiny of the companies and their clinical programs has ratcheted up. All three are now studying their experimental shots in late-stage trials involving tens of thousands of volunteers each. Their rapid progress has brought concerns that they, or regulators, may rush to declare a vaccine ready for use before having sufficient data in hand to prove their shots are safe and effective. In the U.S., the question is intensely political, as President Donald Trump has said a vaccine could be available before election day on Nov. 3. Government officials, including the head of the Trump administration's vaccine initiative, have indicated that's unlikely, although Pfizer anticipates the first results from its Phase 3 trial could come by the end of October. Moderna expects an initial readout from its late-stage study a little later, likely in the latter half of November, Bancel said. The company recently slowed enrollment to ensure it recruits a more diverse group of trial volunteers. 

But that timeline could still slip, should infection rates in the U.S. decline further. Moderna's trial, as with the others, measures vaccine effectiveness by comparing the number of COVID-19 cases in vaccinated participants to those who received placebo, meaning the study's outcome is dependent on infections occurring. Moderna had previously said that an independent data monitoring committee would compare the vaccine to placebo at two interim time points, when 53 and 106 cases were confirmed. The principal comparison will take place after 151 cases. The trial protocol shared by the biotech Thursday fills in some missing details on how the committee will conduct those analyses. Summary statistical plans included in the protocol, for instance, indicate the vaccine would need to be more than 70% effective for the trial to be considered positive at the first interim data check. The trial would not be stopped early in the event of a positive interim analysis, according to the protocol. The protocol also reveals statistical assumptions Moderna made to design its study, such as what percentage of participants will develop COVID-19, as well as how the data monitoring committee will convene and report its recommendations to a study oversight group. That group consists of representatives from the company and two government agencies that have helped fund and test its vaccine...

Study Protocol available at:

https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf

The companies hope to earn the trust of the public and of scientists who have clamored for details of the studies.  Two drug companies that are leading the race to develop coronavirus vaccines bowed to public pressure on Thursday, abandoning their traditional secrecy and releasing comprehensive road maps of how they are evaluating their vaccines. The companies, Moderna and Pfizer, revealed details about how participants are being selected and monitored, the conditions under which the trials could be stopped early if there were problems, and the evidence researchers will use to determine whether people who got the vaccines were protected from Covid-1. Moderna’s study will involve 30,000 participants, and Pfizer’s 44,000.  Companies typically share these documents after their studies are complete. The disclosures while the trials are still underway, a rare move, are aimed at addressing growing suspicion among Americans that President Trump’s drive to produce a vaccine before the election on Nov. 3 could result in a product that was unsafe.  The plan released by Moderna on Thursday morning included a likely timetable that could reach into next year for determining whether its vaccine works. It does not jibe with the president’s optimistic predictions of a vaccine widely available to the public in October.

Pfizer’s plan does not appear to estimate when its results could be available. Its chief executive has said repeatedly that the company hopes to have an answer as early as October. Moderna has said only that it could have a result before the end of the year. Moderna’s 135-page plan, or protocol, indicated that the company’s first analysis of early trial data might not be conducted until late December, though company officials now say they expect the initial analysis in November. In any case, there may not be enough information then to determine whether the vaccine works, and the final analysis might not take place until months later, heading into the spring of next year. Moderna’s timeline meshes with the cautionary estimates from many researchers, including Dr. Robert R. Redfield, the director of the Centers for Disease Control and Prevention, who told senators on Wednesday that a vaccine would not be widely available until the middle of next year. Hours later, Mr. Trump sharply contradicted him, making unsubstantiated projections that a vaccine could become widely available weeks from now. On Wednesday, Joseph R. Biden Jr., the Democratic presidential nominee, said in Wilmington, Del., that the process used to evaluate and approve a vaccine would have to be “totally transparent” to win public confidence. He has said that Mr. Trump’s calls for companies and regulators to speed the process have shaken the public’s faith in vaccines and that politics has no place in vaccine development. Researchers in particular have been urging vaccine makers to share the detailed blueprints of their studies so that outside experts can evaluate them. At least one expert, after reading the plans, has already raised questions about the way the trials were designed. “I want to acknowledge a good deed done,” said Peter Doshi, who is on the faculty at the University of Maryland School of Pharmacy in Baltimore and an editor with The BMJ, a medical journal. He previously requested the plans from Moderna and Pfizer. “They have opened up, for the first time, the ability for researchers not involved in the trial to form their own independent judgment about the design of this study.”

Until now, none of the nine companies that are testing vaccines in large clinical trials had released this level of detail. Moderna, AstraZeneca and Pfizer, which is collaborating with the German company BioNTech, are among the front-runners in the global race to produce a vaccine to fight the pandemic. A spokeswoman for AstraZeneca said the company intended to publish its protocol shortly. Novavax, which is expected to start a large, advanced clinical trial later this year, also did not comment. Johnson & Johnson, which has said it plans to begin a large trial this month, said it would have “more information to share” when the trial starts.AstraZeneca’s trial was stopped temporarily because of serious illness in a participant. It has resumed in Britain and Brazil, but not in the United States. Earlier studies of both vaccines in small numbers of people found that after the second shot, they developed so-called neutralizing antibodies, which can inactivate the virus in lab tests. The vaccines also produced a favorable response involving T-cells, another part of the immune system...