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The biotech company Moderna released a 135-page document on Thursday detailing how it is conducting the late-stage trial of its coronavirus vaccine and how safety and efficacy will be determined.
The paper suggests that the first analysis of the trial data may not take place until the end of December, and that there may not be enough information to determine whether the vaccine works. Subsequent analyzes, scheduled for March and May, are more likely to provide an answer.
Those timelines dovetail with the cautious estimates of many researchers and contrast sharply with President Trump’s predictions that a vaccine will be widely available before the end of this year.
Scientists have asked vaccine manufacturers to share their study plans, known as protocols, so that outside experts can evaluate them. So far, none of the nine companies that are testing vaccines in late-stage clinical trials have.
Moderna, AstraZeneca and Pfizer, which collaborates with the German company BioNTech, are among the pioneers in the global race to produce a vaccine to fight the pandemic.
The AstraZeneca trial was temporarily stopped due to a serious illness in one participant. It has resumed in Britain, but not in the United States.
Pfizer said Saturday that it planned to expand its trial to 44,000 participants from 30,000, but still expected to have efficacy results by the end of October.
Both Moderna and Pfizer / BioNTech use genetic material from the virus, known as mRNA, to drive cells in the body to produce a fragment of the virus that will train the immune system to fight infection.
Moderna’s chief medical officer, Dr. Tal Zaks, said his company was the first of the coronavirus vaccine manufacturers to publish its protocol, and that drug companies were generally reluctant to do so, for competitive reasons.
“I am proud to do that,” he said in an interview. “I don’t think there is much that we are revealing that has not been talked about yet, but let the public be the judge of that.”
Aware of the public’s caution and skepticism about vaccines, Dr. Zaks said Moderna consulted an outside ethics expert who informed the company that the only way to gain trust was to be “transparent to the point of discomfort”.
It also sought to address the investigators’ complaints about the lack of disclosure.
“If what you want to do is see the protocol, here,” Dr. Zaks said.
The move could encourage other vaccine manufacturers to do the same, Dr. Stéphane Bancel, Moderna’s chief executive, said in an interview.
Dr. Eric Topol, a clinical trial expert at Scripps Research in San Diego, congratulated the company for sharing the information, but said he was disappointed by some of the details. For example, the company intends to include in its data people who developed relatively mild cases of Covid-19. Dr Topol said more convincing evidence of the vaccine’s efficacy would be produced if the company counted only moderate to severe cases.
Furthermore, the protocol allows for the possibility of stopping the trial early after a relatively small number of cases. Stopping early could lead to an exaggerated perception of the efficacy of the vaccine, and it could also overlook safety concerns that could become significant later if the vaccine is given to millions and millions of people.
“Take the time, the extra weeks,” Dr. Topol said. “No shortcuts. No one will regret it. I have been conducting clinical trials for decades. I don’t know if there has ever been one more important than this. I wish it were done right and not stopped sooner.”
Moderna’s protocol launch coincided with a call Thursday morning with investors to discuss the company’s work on the coronavirus, research into other vaccines, and its plans to begin developing flu vaccines.
The company’s coronavirus vaccine, developed in collaboration with scientists at the National Institutes of Health, was the first to be tested in humans. The Phase 3 study now underway has enrolled more than 25,000 of the 30,000 planned volunteers, and Dr. Zaks said that enrollment should be completed in the next few weeks.
About 28 percent of the participants are black, Latino, or from other populations that have been particularly affected by the disease. A diverse enrollment has been considered essential to ensure that the findings apply to people of as many backgrounds as possible.
Half of the participants receive the vaccine and half a placebo injection consisting of salt water, and neither the volunteers nor the doctors treating them know who gets which. Two injections are needed, four weeks apart. The participants are then monitored to see if they develop symptoms of Covid-19 and test positive for the virus.
Side effects of the vaccine are also tracked, and participants record symptoms in electronic diaries, take their own temperatures, visit the clinic and receive regular phone calls to assess their condition. In previous studies, the vaccine has caused transient reactions such as arm pain, fever, chills, muscle and joint pain, fatigue, and headaches.
To determine the efficacy of the vaccine, Covid-19 cases are counted only if they occur two weeks after the second injection. Some patients have already passed two weeks after the second injection, but Dr. Zaks said he did not know if any of the trial participants had contracted the disease yet.
A total of 151 cases, spread out between the vaccine and placebo groups, would be enough to determine whether the vaccine is 60 percent effective. The Food and Drug Administration has set the bar at 50 percent.
But if the vaccine turns out to be very effective and a statistically significant difference emerges between the two groups with fewer than 151 cases, the efficacy could be demonstrated earlier, Dr. Zaks said.
The numbers will be watched by a panel of independent experts selected by the National Institutes of Health. The same group will also supervise several other trials.
The panel, called the data safety monitoring board, will conduct its first analysis of the efficacy data after 53 cases have occurred.
Mr. Bancel said the company would publicly report the results of this so-called interim analysis, and the next one, when they are carried out.
The safety board may also suspend the trial if there is evidence that a participant may have been harmed, as was the case recently in the AstraZeneca vaccine study.
Dr. Zaks and Mr. Bancel said that the first analysis would probably not take place before November. In theory, the vaccine could be effective at that time, although the odds of proving 60 percent effective in the first analysis are not high, Dr. Zaks said.
If the data is inconclusive, the panel will look again after there have been a total of 106 cases. If there is still no response, the next and final analysis will take place after 151 people hire Covid.
The time it takes to reach any of those case counts depends on the trajectory of the pandemic and the likelihood that participants are exposed to the virus.
It will likely take five months from the start of the study, when the first participant received the first injection, to reach 53 cases, eight months to reach 106, and 10 months to reach 151, the protocol says. Those estimates depend on certain assumptions being correct, including that over a six-month period, the incidence of Covid in the placebo group will be 0.75 percent.
The study began in late July, which would suggest that the first interim analysis may not occur until late December and the last in late May.
Regardless of whether the vaccine is effective or not, the health of the participants will be monitored for two years after the second injection, the protocol says.
Moderna and other companies have already started to make their vaccines “at risk,” that is, financial risk, because if trials find that the products don’t work, they will have to be scrapped. Both Moderna and Pfizer have projected that millions of doses will be ready by early 2021. But the world’s population is 7 billion and everyone will need two doses.
“In the first half of next year, at least maybe until Labor Day next year, I anticipate that the world will be hugely limited in supply, which means there won’t be enough vaccines to vaccinate everyone,” Bancel said.
