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In September, as Pfizer and partner BioNTech were quickly advancing a study of their Covid-19 vaccine, dozens of well-known academics sent an open letter to Pfizer’s CEO with a simple plea: Please slow down and collect more data.

It was not until Nov. 20 that the data were submitted to the Food and Drug Administration.

Now, as the FDA prepares to convene a group of outside advisers on Thursday to review the data, and recommend whether the vaccine should be broadly used, many experts are voicing the opposite opinion. What, they ask, is taking so long?

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Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said the process has been halting and hesitant.

“The next two months are going to be bad,” Gellad said. “A vaccine that is highly likely to be effective and highly likely to be safe could have an impact.” 

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“I would hope the EUA is 75% written at this point,” he said, referring to the emergency use authorization the agency is widely expected to issue.

On Wednesday, the United Kingdom became the first country to clear the Pfizer vaccine. Over the past week, FDA Commissioner Stephen Hahn has been called to the White House twice to explain why the vaccine could not be authorized more quickly. Those urging speed point to the two-dose vaccine’s incredibly strong short-term efficacy — it prevents 95% of symptomatic Covid-19 cases, at least based on a few months’ data — and that it appears safe overall. 

With more than 2,000 Americans dying from Covid-19 daily, they argue, what was the risk of trying it sooner?

The FDA has said in multiple public forums that it could not have moved any faster. The agency’s staff “were eating turkey sandwiches on Thanksgiving while reviewing documents,” Peter Marks, who heads the FDA center conducting the vaccine reviews, said on a Thursday webcast run by the Journal of the American Medical Association. 

Additionally, members of an FDA advisory committee that will convene Thursday to review the data and issue its recommendations, have expressed no desire to meet sooner. STAT spoke to four members of the panel and all said the agency should not try to move any faster. 

“It takes a few months usually to review these kinds of data, and now this has been shortened to a few weeks,” said Hana El Sahly, a researcher at the Baylor College of Medicine who normally chairs the FDA’s vaccine advisory committee, but who is recused this time because of her involvement with a vaccine developed by Moderna, expected to be before the panel on Dec. 17. “I just can’t see this amount of work being compressed significantly much more than it’s already been compressed.”

Cody Meissner, a Tufts Children’s Hospital vaccinologist who serves on the committee, said his concern is that “the process is too fast, not that it’s not fast enough.”

“I understand completely why people want a vaccine sooner, but they wouldn’t want a vaccine sooner if it wasn’t safe,” he said.

A STAT review of the process of vaccine development reveals only three ways it could have been further sped up. The first, and biggest, revolves around an FDA decision to require two months of safety data for half the patients in a study before a company asked for authorization. Had it settled for less data, a vaccine likely would have been authorized quicker.

The FDA might have also been able to save some time if it evaluated data on the vaccines on a rolling basis, instead of getting all of the information — in Pfizer’s case, tens of thousands of pages — at once. (Regulators in the U.K. accepted Pfizer’s data on a rolling basis, but the FDA argues that the processes were simply very different.)

Lastly — and perhaps least consequently — the FDA could have turned around the data for its advisory committee more rapidly, holding the meetings on, say, Dec. 3 and Dec. 10, instead of Dec. 10 and Dec. 17. 

Why is the review of the data taking so long? The FDA takes the raw data that companies provide and reanalyzes them, often picking apart statistical calculations made by manufacturers. Among regulators the world over, there is no similar direct check on the data produced by pharmaceutical manufacturers. 

This type of analysis, routine for new drug approvals at the FDA, is not legally necessary for emergency use authorizations during a pandemic. But given that Covid-19 vaccines could be given to hundreds of millions of people, the agency decided a thorough review was needed. In an interview with the Wall Street Journal, Hahn, the FDA commissioner, said staffers are working long hours in parallel seeking to prepare.

To insiders at the FDA, even the current timeline seems insanely compressed; one insider said that when Marks, the center director, first stated it publicly regulators were shocked.

“Our folks nearly fainted at the start of this when Peter [Marks] stood up in public and said when we get an EUA application we can turn it around in a few weeks,” the staffer said. “That itself was a heart-stopping moment. Now people are motivated to do that because the vaccine is looking like it has serious efficacy and it’s a public health crisis, but it doesn’t mean that there’s a fast way to do that.”

The EUA process, which allows for clearances based on far less data than a traditional approval, does not have a provision for rolling applications.

What’s more, the FDA said in a statement, “rolling review” does not have the same meaning at the European Medicines Agency as in the U.S. “The EMA does not have access to the same scope of data for an investigational product that the FDA has while the product is under development,” the statement said. The FDA said it has “tremendous insight” into the manufacturing processes and preclinical and clinical research that the EMA rolling review would provide.

Another point of delay was Pfizer’s decision to drop its initial interim analysis, which would likely have occurred in late November. This would have allowed an outside committee to peek at the efficacy results when there were 32 cases of symptomatic Covid. Instead, the company decided to conduct the analysis after 62 cases; by the time that plan was formalized, there had actually been 94 cases.

But many experts believe it would have been a mistake to analyze the data after 32 cases. It could have been clear a vaccine was effective, but not clear whether its efficacy was 60% or 90% — and there would have been little safety data.

“If an EUA had been issued by some regulatory authority based on 30 cases, we would not know much about that vaccine,” said Jesse Goodman, a former FDA chief scientist and a professor at Georgetown University.

Even when Pfizer had much more data — and evidence of greater than 90% efficacy — the drug giant still couldn’t file. 

That’s because of the FDA’s decision, announced quietly on Oct. 6 in the prelude to an earlier FDA advisory committee, to tell vaccine makers not to ask for an EUA until half the patients in their studies had been followed for two months. Setting the threshold slightly lower would have saved time, but meant less safety data.

At an FDA advisory panel held on Oct. 22, experts convened by the FDA said resoundingly that they would favor conducting the studies for longer, and collecting more data. At the time of the Oct. 6 decision, that approach was met with resistance from the White House, which was pushing for a faster approval.

The debate was shaped, in part, by widespread worries that even lower standards might hold the day. In May, Scott Gottlieb, who was the FDA commissioner early in the Trump administration, and Luciana Borio, whose name is being floated as a potential FDA commissioner in a Biden administration, co-authored a Wall Street Journal op-ed saying that immune response data alone should not be used as the basis of an approval. (Almost all experts agree, and it wasn’t.) In August, 400 vaccine experts signed a letter cautioning the FDA to make sure sufficient data were collected. 

Wherever the FDA landed, it was going to draw fire. And by any account, the process has been far faster than normal.

“During a pandemic and an emergency, the passion and concern about public health and our patients is admirable, but it’s kind of like the heat of battle and people can lose their perspective,” said Goodman, the former FDA chief scientist. “And I think that’s why a strong science-based regulatory agency is so important.”

  • The FDA should be ashamed of itself with regards to its vaccine approval approach.
    1) An EUA should be exactly that. Why is the FDA insisting on re-analysing all the company’s data (which no other authority globally EVER does) AND holding a meeting of its advisory committee? NEITHER are required for a vaccine EUA! Of course for the full approval this should be done but in very high risk cohorts there is no reason they couldn’t have skipped these steps and given emergency use authorisation;
    2) There is no real rationale for why the FDA chose to require two full months of safety follow up data for the median vaccine recipient. This has never been a requirement for other vaccines. Again this should have been waived for very high risk cohorts;
    3) The FDA should have been receiving data on a rolling basis. The decision not to do this is inexplicable.
    Literally the FDA have wasted weeks at minimum. Tens and tens of thousands of lives will be lost due to their lackadaisical approach to their critical role in this pandemic.

    • What is incredible is that they don’t seem to be able to see the dreadful irony in what they have been doing. “We are making sure the vaccine is safe before we approve it.” What possible flaw in the vaccine could cause it to kill 15% of nursing home residents who contract the virus?

      Policies, at their best, are codified wisdom. The EUA policies may have wisdom for many situations, but I don’t understand the wisdom of making an all or nothing approval decision right now. Here is how you could do it: approve it for people in nursing homes and health professionals age 60 and above (or who have risk factors). Then engage in nitpicking of the raw data for the general public. Even if you just want to say, “take it at your own risk while we work to approve it.”

      This clearly raises the scientific question of: Is there empirical data to show that regulatory bodies such as the FDA improve public health? We see quite clearly this year that you could add many deaths and disability to the negative effects of having such an agency that could wipe out many potential benefits at other times. Has this type of question been explored scientifically? All treatments have risks and benefits, and bodies that engage in public health regulation are a form of treatment. Have they been shown to be effective?

  • I’d argue that the FDA could have sped up the approval process by separating the topics of efficacy and safety. They could have asked Pfizer to submit the part of their application dealing with efficacy immediately after their 11/9 announcement (which almost certainly could have come on 11/2, if it hadn’t been delayed due Pfizer shutting its labwork down for, presumably, political reasons). Get the efficacy portion of the evaluation done, while waiting for two months of safety data, which didn’t arrive until the second half of November.

  • The last word in this sentence is a typo:

    “Another point of delay was Pfizer’s decision to drop its initial interim analysis, which would likely have occurred in late November.”

    The sentence should read:

    “Another point of delay was Pfizer’s decision to drop its initial interim analysis, which would likely have occurred in late October,” as we can see from Mr. Herper’s 11/9 article on the Pfizer vaccine:

    https://www.statnews.com/2020/11/09/covid-19-vaccine-from-pfizer-and-biontech-is-strongly-effective-early-data-from-large-trial-indicate/

    “Gruber said that Pfizer and BioNTech had decided in late October that they wanted to drop the 32-case interim analysis. At that time, the companies decided to stop having their lab confirm cases of Covid-19 in the study, instead leaving samples in storage. The FDA was aware of this decision. Discussions between the agency and the companies concluded, and testing began this past Wednesday [the day after the election]. When the samples were tested, there were 94 cases of Covid in the trial. The DSMB met on Sunday.

    “This means that the statistical strength of the result is likely far stronger than was initially expected. It also means that if Pfizer had held to the original plan, the data would likely have been available in October, as its CEO, Albert Bourla, had initially predicted.”

    Pfizer shut down processing samples until the day after the election in order to not know that it had reached its published interim analyses points of 32 and 62 cases. Presumably, by halting processing it was hoping to avoid shareholder lawsuits for secretly changing its protocol from what it had published.

    Almost certainly, if not for the shutdown, Pfizer could have announced on the day before the election that its vaccine had achieved efficacy in a 32 case analysis, and possibly in a 62 case analysis.

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