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Moderna Shares the Blueprint for Its Coronavirus Vaccine Trial Moderna and Pfizer Reveal Secret Blueprints for Coronavirus Vaccine Trials
(about 11 hours later)
The biotech company Moderna released a 135-page document on Thursday that spells out the details of how it is conducting the late-stage trial of its coronavirus vaccine, and how safety and efficacy will be determined. 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 document suggests that the first analysis of the trial data may not be conducted until late December, and that there may not be enough information then to determine whether the vaccine works. Subsequent analyses, scheduled for March and May, are more likely to provide an answer. 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-19.
Those timelines mesh with the cautionary estimates from many researchers, and stand in sharp contrast to President Trump’s predictions that a vaccine will become widely available before the end of this year. Moderna’s study will involve 30,000 participants, and Pfizer’s 44,000.
Scientists have been calling on vaccine makers to share their study plans, known as protocols, so that outside experts can evaluate them. Until now, none of the nine companies that are testing vaccines in late-stage clinical trials have done so. 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.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.
AstraZeneca’s trial stopped temporarily because of serious illness in a participant. It has resumed in Britain, but not in the United States. AstraZeneca did not respond to inquiries about whether it would now disclose its study plan. 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.
Pfizer said on Saturday that it planned to expand its trial to 44,000 participants from 30,000, but that it still expected to have efficacy results by the end of October. 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.
Both Moderna and Pfizer/BioNTech use genetic material from the virus, known as mRNA, to prompt cells in the body to make a fragment of the virus that will train the immune system to fight off an infection.
Dr. Tal Zaks, Moderna’s chief medical officer, said that his firm was the first of the coronavirus vaccine makers to release its protocol, and that pharmaceutical companies were usually reluctant to do so, for competitive reasons. 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.
Dr. Tal Zaks, chief medical officer for Moderna, the first coronavirus vaccine maker to release its detailed plan, said pharmaceutical companies were usually reluctant to do so, for competitive reasons.
“I’m proud of doing that,” he said in an interview. “I don’t think there’s much there that we’re disclosing that hasn’t already been spoken to, but let the public be the judge of that.”“I’m proud of doing that,” he said in an interview. “I don’t think there’s much there that we’re disclosing that hasn’t already been spoken to, but let the public be the judge of that.”
Cognizant of public wariness and skepticism about vaccines, Dr. Zaks said Moderna consulted an outside ethics expert who advised the company that the only way to win trust was to be “transparent to the point of discomfort.” Dr. Zaks said Moderna had consulted an outside ethics expert who advised the company that the only way to win trust was to be “transparent to the point of discomfort.”
He also sought to address researchers’ complaints about the lack of disclosure. In a statement, Pfizer said it did not usually did not release its protocols, adding, “We recognize, however, that the COVID-19 pandemic is a unique circumstance and the need for transparency is clear.”
“If what you want to do is see the protocol — here,” Dr. Zaks said. Dr. Eric Topol, a clinical trial expert at Scripps Research in San Diego, gave Moderna “big kudos” for sharing its plan but said that he was disappointed that Moderna intended to include in its data people who had developed relatively mild cases of Covid-19. He said more compelling evidence of the vaccine’s effectiveness would be produced if the company counted only moderate to severe cases.
The action might encourage other vaccine makers to do the same, Stéphane Bancel, Moderna’s chief executive, said in an interview. Moderna’s plan also allows for the possibility of stopping the trial early after a relatively small number of cases, potentially leading to an exaggerated perception of the vaccine’s efficacy and missing safety problems that could turn out to be significant later if the vaccine were given to millions of people, he said.
Dr. Eric Topol, a clinical trial expert at Scripps Research in San Diego, gave the company “big kudos” for sharing the information, but said that 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 compelling evidence of the vaccine’s effectiveness would be produced if the company counted only moderate to severe cases. Dr. Topol was more critical of Pfizer’s plan because it allowed even milder cases than Moderna’s to be counted and provided more opportunities to stop the trial early based on few cases, which he called troubling.
In addition, 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 vaccine’s efficacy, and could also miss safety problems that could turn out to be significant later if the vaccine is given to millions and millions of people.
“Take the time, the extra weeks,” Dr. Topol said. “No shortcuts. Nobody will regret it. I’ve been doing clinical trials for decades. I don’t know if there’s ever been a more important one than this one. I’d like to see it done right, and not stopped early.”“Take the time, the extra weeks,” Dr. Topol said. “No shortcuts. Nobody will regret it. I’ve been doing clinical trials for decades. I don’t know if there’s ever been a more important one than this one. I’d like to see it done right, and not stopped early.”
Moderna’s protocol release coincided with a call Thursday morning with investors to discuss the company’s coronavirus work, research on other vaccines and its plans to begin developing flu vaccines.
The company’s coronavirus vaccine, developed in collaboration with scientists from 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 its intended 30,000 volunteers, and Dr. Zaks said the enrollment should be complete in the next few weeks. In both Moderna’s and Pfizer’s studies, half of the participants receive the vaccine, and half receive a placebo shot consisting of salt water, with neither the volunteers nor the doctors treating them knowing who gets which. Two shots are needed, four weeks apart for Moderna and three weeks apart for Pfizer. The participants are then monitored to see if they develop symptoms of Covid-19 and test positive for the virus.
About 28 percent of the participants are Black, Latino or from other populations that have been particularly hard hit by the disease. A diverse enrollment has been considered essential to make sure that the findings apply to people from as many backgrounds as possible. Side effects of the vaccines are also tracked. In earlier studies, both vaccines have caused transient reactions like a sore arm, fever, chills, muscle and joint pain, fatigue and headaches.
Half the participants receive the vaccine, and half a placebo shot consisting of salt water, with neither the volunteers nor the doctors treating them knowing who gets which. Two shots are needed, four weeks apart. Then the participants are monitored to see if they develop symptoms of Covid-19 and test positive for the virus. To determine the vaccine’s efficacy, Moderna counts Covid-19 cases only if they occur two weeks after the second shot. Pfizer starts counting them seven days after the second shot.
Side effects of the vaccine are also tracked, with participants recording symptoms in electronic diaries, taking their own temperatures, making clinic visits and receiving periodic phone calls to assess their condition. In earlier studies the vaccine has caused transient reactions like a sore arm, fever, chills, muscle and joint pain, fatigue and headaches. A total of 151 cases of Covid-19 from among the tens of thousands of people participating in the trial — spread between the vaccine and placebo groups — would be enough to determine whether the Moderna vaccine is 60 percent effective. Pfizer’s case count for 60 percent efficacy is 164. The Food and Drug Administration has said any coronavirus vaccines must be at least 50 percent effective.
To determine the vaccine’s efficacy, Covid-19 cases are counted only if they occur two weeks after the second shot. Some patients are already two weeks beyond the second shot, but Dr. Zaks said he did not know if any trial participants had contracted the disease yet. Many outside researchers have been watching for details about how the trials could be stopped early, given the push to bring a vaccine to market as soon as possible.
A total of 151 cases — spread 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. That could happen only when outside panels of experts examine the data while the trials are underway. If the vaccine is extremely effective, they could stop the trial because it would be unethical to continue giving some participants a placebo.
But if the vaccine turns out to be highly effective, with a statistically significant difference emerging between the two groups with fewer than 151 cases, efficacy could be proved sooner, Dr. Zaks said. The panel, called a data-safety monitoring board, will perform its first analysis of Moderna’s efficacy data once 53 cases of Covid-19 have been diagnosed. Pfizer’s first analysis will be done after 32 cases.
The numbers will be watched by a panel of independent experts picked by the National Institutes of Health. The same group will also monitor several other trials. The board could recommend stopping the Moderna trial after 53 cases if it was found to be 74 percent effective. In the case of Pfizer, the effectiveness would need to be better than about 77 percent.
The panel, called a data-safety monitoring board, will perform its first analysis of the efficacy data once 53 cases have occurred. Moderna has two more analysis points; Pfizer has three.
Mr. Bancel said the company would report publicly on the results of this so-called interim analysis, and the next one, when they are conducted. Dr. Topol said studies often allowed only one look at the data partway through, and he had sharp words for Pfizer’s use of three.
“It’s programming the trial to have so many looks that it might stop early,” he said.
Moderna’s chief executive, Stéphane Bancel, said the company would report publicly on the results of the first so-called interim analysis, and the next one, when they are conducted. Pfizer has said that it will share information about the analyses only if a decision is made that the trial should be stopped, either because it is very effective or because it does not appear to be working.
The safety board can also put the trial on hold if there is evidence that a participant may have been harmed, as occurred recently in AstraZeneca’s vaccine study.The safety board can also put the trial on hold if there is evidence that a participant may have been harmed, as occurred recently in AstraZeneca’s 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 found effective at that point, though the odds of demonstrating 60 percent effectiveness at the first analysis are not high, Dr. Zaks said. Dr. Zaks and Mr. Bancel said in interviews that the first analysis would probably not take place before November. In theory, the vaccine could be found effective at that point, though the odds of that are not high, Dr. Zaks said.
If the data are not conclusive, the panel will look again after there have been a total of 106 cases. If there is still no answer, the next and final analysis will occur after 151 people contract Covid. If the data are not conclusive, the panel would look again after there had been a total of 106 cases. If there were still no answer, the next and final analysis would occur after 151 people had contracted Covid.
How long it takes to reach any of those case counts depends on the trajectory of the pandemic and how likely participants are to be exposed to the virus.How long it takes to reach any of those case counts depends on the trajectory of the pandemic and how likely participants are to be exposed to the virus.
It will probably take five months from the study start — when the first participant received the first shot — to reach 53 cases, eight months to reach 106 and 10 months to reach 151, the protocol states. Those estimates depend on certain assumptions being correct, including that in a six-month period, the incidence of Covid in the placebo group will be 0.75 percent. Whether or not the vaccine is effective, the participants’ health will be monitored for two years after the second shot, the plan stated.
The study began in late July, which would suggest that the first interim analysis may not occur until late December, and the final one in late May. Moderna and other companies have already begun making their vaccines “at risk,” meaning financial risk, because if the products are found not to work, they will have to be thrown away. Both Moderna and Pfizer have projected that millions of doses will be ready early in 2021. But the world’s population is seven billion, and for a number of these vaccines, everyone would need two doses.
Regardless of whether the vaccine is effective or not, the participants’ health will be monitored for two years after the second shot, the protocol states. “In the first half of next year, at least maybe until Labor Day next year, I anticipate that the world is going to be massively supply-constrained, meaning not enough vaccine to vaccinate everybody,” Mr. Bancel of Moderna said.
Moderna and other companies have already begun making their vaccines “at risk,” meaning financial risk, because if the trials find that the products do not work, they will have to be thrown away. Both Moderna and Pfizer have projected that millions of doses will be ready early in 2021. But the world 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 is going to be massively supply-constrained, meaning not enough vaccine to vaccinate everybody,” Mr. Bancel said.
His timetable seemed in line with one suggested on Wednesday by Dr. Robert Redfield, the director of the Centers for Disease Control and Prevention, who told a Senate committee that a vaccine would not be widely available until the middle of next year. Just hours later, the president publicly contradicted Dr. Redfield, saying he was mistaken.
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