Vaccine-makers keep safety details quiet, alarming scientists

The morning after the world learned that a closely watched clinical trial of a coronavirus vaccine had been halted last week over safety concerns, the company’s chief executive disclosed that a person given the vaccine had experienced serious neurological symptoms.

But the remarks were not public. Instead, the chief executive, Pascal Soriot of AstraZeneca, spoke at a closed meeting organised by J P Morgan, the investment bank.

AstraZeneca said Saturday that an outside panel had cleared its trial in Britain to begin again, but the company still has not given any details about the patient’s medical condition, nor has it released a transcript of Soriot’s remarks to investors, which were reported by the news outlet STAT and later confirmed by an analyst for J P Morgan.

Another front-runner in the vaccine race, Pfizer, made a similarly terse announcement Saturday: The company is proposing to expand its clinical trial to include thousands more participants, but it gave few other details about its plan, including how it would determine the effectiveness of the vaccine in its larger study.

It is standard for drug companies to withhold details of clinical trials until after they are completed, tenaciously guarding their intellectual property and competitive edge. But these are extraordinary times, and now there is a growing outcry among independent scientists and public health experts who are pushing the companies to be far more open with the public in the midst of a pandemic that has killed more than 193,000 people in the United States.

These experts say American taxpayers are entitled to know more since the federal government has committed billions of dollars to vaccine research and to buying the vaccines once they are approved. And greater transparency could also help bolster faltering public confidence in vaccines at a time when a growing number of Americans fear President Donald Trump will pressure federal regulators to approve a vaccine before it is proved safe and effective.

“Trust is in short supply,” said Dr Harlan Krumholz, a cardiologist and health care researcher at Yale University in New Haven, Connecticut, who has spent years prodding companies and academic researchers to share more trial data with outside scientists. “And the more that they can share, the better off we are.”

Last week, nine pharmaceutical companies, including AstraZeneca and Pfizer, pledged to “stand with science” and rigorously vet any vaccine for the coronavirus — an unusual pact among competitors. But the researchers said that missing from the joint statement was 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 the independent scientists better understand how the trials were designed and hold the companies accountable if they were to deviate from their plans. In some cases, crucial details about how the trials have been set up — such as at what points an independent board can review early study results or under what conditions a trial could be stopped early — have not been made public.

“We’ve never had such an important clinical trial — or series of clinical trials — in recent history,” said Dr Eric Topol, a professor of molecular medicine at Scripps Research in La Jolla, California, and a longtime expert on clinical trials. “Everything should be transparent.”

Public confidence in the drug companies’ findings and federal regulators’ rigor will be critical in persuading Americans to get vaccinated. A growing number of people are sceptical. A poll by the Kaiser Family Foundation last week found that nearly two-thirds of Americans — 62% — are worried that the Food and Drug Administration will rush to approve a coronavirus vaccine without making sure it is safe and effective, under political pressure from Trump.

Pharmaceutical companies are counting on their vaccine research to help them rebuild reputations that have been tarnished by soaring drug prices and the industry’s role in fuelling the opioid epidemic.

In an effort to restore public trust, senior regulators at the FDA took the highly unusual step of promising in a USA Today op-ed piece Thursday to uphold the scientific integrity of the process of evaluating treatments and vaccines and to maintain the agency’s independence.

Representatives for the three companies with vaccine candidates in large, advanced trials in the United States — Moderna, Pfizer and AstraZeneca — said they had released many details about the trials.

Pfizer said in a statement that the novelty of the virus and the fast-moving nature of the coronavirus crisis had meant that the protocol had to be flexible “to enable us to enhance the evaluation of the potential vaccine’s safety and efficacy.” The company said it would publish the full protocol from the trial as part of its submission to a medical journal “that will include results, enrollment criteria and final number of participants enrolled.”

On Saturday, Pfizer said it would ask the FDA for permission to expand its trial to 44,000 participants, from its initial target of 30,000. But the announcement raised new questions about how the company would be able to know the results by its goal of the end of October with so many new participants. A Pfizer spokeswoman, Amy Rose, said, “We are not going to speak to timing or specifics of any interim analyses.”

AstraZeneca did not initially report that a participant’s illness had halted its clinical trials around the world. The studies were paused Sept 6 but not reported until the news was broken by STAT on Tuesday. The company still has not disclosed the patient’s illness that led to the pause, even though it has discussed the medical condition of another participant who developed multiple sclerosis in July, which led to another brief halt of the trial. That illness was determined to be unrelated to the vaccine.

The company said that Soriot’s appearance at the J P Morgan meeting was part of a long-planned event and that he largely discussed the company’s business outlook, with a few questions about the trial. The New York Times has reported that the patient developed symptoms consistent with transverse myelitis, or inflammation of the spinal cord.

A spokeswoman for AstraZeneca, Michele Meixell, said that while trial sponsors were required to notify the doctors operating clinical trial sites if an “unexplained event” occurred, “it is not common practice for those pauses to be communicated beyond 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 precedent for greater transparency. The large Recovery trial being run by the University of Oxford in Britain — which helped determine that the steroid dexamethasone reduces deaths in patients with COVID-19 — has published its trial protocol and statistical analysis plans.

While the broad outlines of the vaccine trial designs have been made available — including on a federal clinical trial registry — crucial details remain a mystery.

For example, Pfizer’s chief executive has said the company could apply to the FDA for emergency authorisation of its vaccine as early as October. But the company has not said how many times — and at what point in the trial — it will allow an independent review board to examine its study data to evaluate whether the evidence of safety and efficacy is strong enough that it can stop the trial early and apply for an emergency approval from federal regulators.

And none of the companies have published the criteria they will use to determine when these outside boards would advise stopping the trial, which could happen if the vaccine showed overwhelming efficacy, if it showed that it did not protect against COVID-19 or if it was linked to serious safety issues.

These so-called interim analyses are the subject of intense interest because they are the only way that late-stage trials could be halted early.

Company executives have provided some trial details when they have spoken on discussion panels, at investor conferences or in news releases. But researchers looking for clues have had to comb through transcripts, videos and articles posted online rather than examine documents that the companies provided.

The lack of transparency is unacceptable, several researchers said, given that the federal government has billion-dollar deals with each of the companies.

“Look, we paid for it,” said Saad Omer, director of the Yale Institute for Global Health. “So it’s reasonable to ask for it.”

A federal clinical trial registry details the number of trial participants, who should be included and excluded from the study, and the main outcomes. But it only skims the surface, Krumholz said. “The protocols are much more detailed.”

Peter Doshi, who is on the faculty at the University of Maryland School of Pharmacy in Baltimore and is an editor with 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 imagine most of the public would like to believe scientists are all sharing their data, that this process is open to scrutiny among the scientific community,” said Doshi, who has helped pressure drugmakers to share trial records with researchers. “Just not true.”

Doshi said the protocols could help researchers answer important questions about the studies and possibly to critique them. For example, can the trials determine whether the vaccine can prevent COVID-19 and complications in high-risk groups like older adults? When the researchers test for the coronavirus, how do they account for false results?

Other independent scientists said they were eager to examine the trials’ statistical analysis plans, which would guide them in analysing the results.

“Frankly, I would love to know what they’re planning to do and how they’re planning to do it,” said Dr Judith Feinberg, vice chairwoman for research in medicine at West Virginia University in Morgantown.

By making these documents public, outside experts said they would be able to hold the companies accountable if they changed the way they analysed the results.

“There’s no downside” to sharing the documents, said Dr Paul Offit, a professor at the University of Pennsylvania in Philadelphia who serves on the FDA advisory committee that will review coronavirus vaccines. “People are skittish about these vaccines. I think it helps to be transparent.”

Omer said he was in favour of the companies releasing the protocols and analysis plans, but he said he also worried that, in the wrong hands, the technical documents could be misinterpreted.

“You cannot kid around with this kind of stuff,” he said. In the long run, however, he said it was to the companies’ advantage to allow qualified researchers to evaluate the plans.

If independent researchers agreed the trials were set up properly — and Omer said he expected that would be the case — that could help enhance their credibility. They can say, “Hold your horses. No need to jump up and down.”

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