The morning after the world learned that a carefully controlled clinical trial of a coronavirus vaccine had been halted last week due to safety concerns, the company’s chief executive revealed that a person given the vaccine had experienced severe neurological symptoms.
But the remarks were not public. Instead, AstraZeneca’s chief executive, Pascal Soriot, spoke at a closed-door meeting organized by J.P. Morgan, the investment bank.
AstraZeneca said on Saturday that an outside committee has cleared the trial in Britain to start over, but the company has not yet provided details on the patient̵
Another leader in the vaccine race, Pfizer, made an equally concise announcement on Saturday: The company proposes to expand its clinical trial to include thousands more participants, but has provided few other details about its plan, including how which would determine the effectiveness of the vaccine in its larger study.
It is standard for pharmaceutical companies to withhold the details of clinical trials until they are completed, tenaciously protecting their intellectual property and competitive advantage. But these are extraordinary times, and now there is growing protest among independent scientists and public health experts who are pushing companies to be much more open to the public in the midst of a pandemic that has already killed more than 193,000 people in the states. United. States.
These experts say American taxpayers have a right to know more as the federal government has committed billions of dollars to vaccine research and purchase of vaccines once they are approved. And greater transparency could also help bolster vacillating public confidence in vaccines at a time when a growing number of Americans fear President Trump will press federal regulators to approve a vaccine before it proves safe and effective.
“Trust is in short supply,” said Dr. Harlan Krumholz, a cardiologist and health researcher at Yale University in New Haven, Connecticut, who has spent years soliciting companies and academic researchers to share more evidence with outside scientists. “And the more they can share, the better.”
Last week, nine pharmaceutical companies, including AstraZeneca and Pfizer, pledged to “stay with the science” and rigorously control any vaccine for the coronavirus, an unusual deal among competitors. But the researchers said the joint statement lacked a promise to share more critical details about their research with the public and the scientific community.
None of the three companies with coronavirus vaccines in advanced clinical trials in the United States have made public the protocols and statistical analysis plans for those trials – the detailed road maps that could help independent scientists better understand how the trials were designed and keep the companies accountable if they deviate from their plans. In some cases, crucial details about how studies were set up, such as at what points an independent board can review the first results of a study or under what conditions a study might be stopped early, have not been made public.
“We have never had such an important clinical trial – or a series of clinical trials – in recent history,” said Dr. Eric Topol, professor of molecular medicine at Scripps Research in La Jolla, California, and long-time expert on evidence. “Everything should be transparent.”
Public confidence in the results of drug companies and the rigor of federal regulators will be key to convincing Americans to get vaccinated. An increasing number of people are skeptical. A poll by the Kaiser Family Foundation last week found that nearly two-thirds of Americans – 62 percent – are concerned that the Food and Drug Administration is rushing to approve a coronavirus vaccine without making sure it’s safe and effective, under pressure. Mr. Trump’s policy.
Pharmaceutical companies are counting on their vaccine research to help them rebuild a reputation that has been tarnished by soaring drug prices and the role of industry in fueling the opioid epidemic.
In an effort to restore public confidence, the top regulators of the F.D.A. Thursday took the extremely unusual step of pledging in a USA Today article to uphold the scientific integrity of the treatment and vaccine evaluation process and to maintain agency independence.
Representatives of the three companies with vaccine candidates in large advanced studies in the United States – Moderna, Pfizer and AstraZeneca – said they have released many details on the tests.
Pfizer said in a statement that the novelty of the virus and the rapidly evolving nature of the coronavirus crisis meant that the protocol needed to be flexible “to allow us to improve the evaluation of the vaccine’s potential safety and efficacy.” The company said it will publish the full study protocol as part of its submission to a medical journal “which will include results, enrollment criteria and final number of enrolled participants.”
On Saturday, Pfizer said it would ask the F.D.A. for permission to expand its trial to 44,000 participants, from its initial goal of 30,000. But the announcement raised new questions about how the company could have known the results by its end-October target, with so many new entrants. Pfizer spokesperson Amy Rose said: “We will not talk about the timing or details of any interim analysis.”
AstraZeneca did not initially report that a participant’s disease had stopped its clinical trials around the world. Studies were suspended last Sunday, but were not reported until the news broken by STAT on Tuesday. The company has not yet disclosed the patient’s illness that led to the hiatus, although it did discuss the medical condition of another participant who developed multiple sclerosis in July, which led to another brief halt in the trial. That disease was determined not to be vaccine related.
The company said that Mr. Soriot’s appearance at J.P. Morgan was part of a long-planned event that largely discussed the company’s business prospects, with a few questions about the process. The New York Times reported that the patient developed symptoms consistent with transverse myelitis or inflammation of the spinal cord.
An AstraZeneca spokesperson, Michele Meixell, said that while trial sponsors were required to inform physicians running clinical trial sites if an “unexplained event” occurred, “it is not common practice for those breaks to be reported to the outside the clinical community involved in a trial – including the media – in order to protect the privacy of individual participants and maintain the integrity of the trial. “
There is a precedent for greater transparency. The large Recovery study conducted by the University of Oxford in the UK – which helped determine that the steroid dexamethasone reduces deaths in patients with Covid-19 – has published its test protocol and statistical analysis plans.
Although the broad lines of vaccine trial projects have been made available – even on a federal clinical trial registry – the crucial details remain a mystery.
For example, Pfizer’s chief executive said the company could apply to the F.D.A. for emergency clearance of his vaccine as early as October. But the company did not say how many times – and at what point in the study – it will allow an independent review committee to review the study data to assess whether the evidence for safety and efficacy is strong enough to stop the study early and request a review. ’emergency approval from federal regulatory authorities.
And none of the companies have published the criteria they will use to determine when these outside councils would recommend stopping the trial, which could happen if the vaccine showed overwhelming effectiveness, if it showed it didn’t protect against Covid-19, or if it did. related to serious security problems.
These so-called interim analyzes are of intense interest, as they are the only way in which late stage trials can be stopped early.
Company executives provided some evidence when they spoke at discussion groups or at investor conferences or in press releases. But researchers looking for clues had to sift through transcripts, videos and articles posted online, rather than looking at the documents provided by the companies.
The lack of transparency is unacceptable, several researchers said, as the federal government has multi-billion dollar deals with each of the companies.
“Look, we paid for it,” said Saad B. Omer, the director of the Yale Institute for Global Health. “So it’s reasonable to ask.”
A federal clinical trial registry specifies the number of study participants, who should be included and excluded from the study, and the key outcomes. But it only skims the surface, Dr. Krumholz said. “The protocols are much more detailed.”
Peter Doshi, who is a lecturer at the University of Maryland School of Pharmacy in Baltimore and editor of The BMJ, a medical journal, said he recently requested the protocols from Pfizer, Moderna, and AstraZeneca. None of the companies shared them, he said.
“I guess most of the public would like to believe that all scientists share their data, that this process is open for scrutiny by the scientific community,” said Dr. Doshi, which helped drug manufacturers share study records with researchers. “It just isn’t true.”
Dr Doshi said the protocols could help researchers answer important questions about the studies and possibly criticize them. For example, can studies determine whether the vaccine can prevent Covid-19 and complications in high-risk groups such as the elderly? When researchers test for coronavirus, how do they explain the false results?
Other independent scientists said they were eager to look at the statistical analysis plans of the evidence, which would guide them in analyzing the results.
“Frankly, I’d like to know what they plan to do and how they plan to do it,” said Dr. Judith Feinberg, vice president of medical research at West Virginia University in Morgantown.
By making these documents public, outside experts said they would be able to hold companies accountable if they changed the way they analyzed the results.
“There are no downsides” to sharing documents, said Dr. Paul A. Offit, a professor at the University of Pennsylvania in Philadelphia who serves in the F.D.A. advisory committee that will review coronavirus vaccines. “People are nervous about these vaccines. I think it helps to be transparent. “
Dr Omer said he was in favor of companies issuing protocols and analysis plans, but also said he feared that, in the wrong hands, technical documents could be misinterpreted.
“You can’t mess with that kind of thing,” he said. In the long run, however, he said it was a benefit for companies to allow qualified researchers to evaluate the plans.
If the independent researchers agreed that the tests were set up correctly – and Dr Omer said he expected it would – this could help improve their credibility. They can say, “Hold your horses. No need to jump up and down.”