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Regulation

Expanding access to COVID-19 vaccines

Imminent release of interim data will force FDA to make tough decisions about pre-approval access to COVID-19 vaccines

Imminent release of interim data will force FDA to make tough decisions about pre-approval access to COVID-19 vaccines

Oct 31, 2020 | 3:35 AM GMT

As lightning-quick vaccine development comes close to catching up with a runaway pandemic, FDA must quickly decide how it will respond to the first clear signs that a vaccine candidate may be effective.  

Former senior agency officials are advocating that FDA respond to favorable interim data from COVID-19 trials by allowing expanded access rather than by issuing emergency use authorizations. The goal is to gain more control over the launch of the first COVID-19 vaccines. 

Expanded access, its proponents contend, would be less likely than EUA to cause sponsors to unblind Phase III trials. They also believe the pathway makes it possible for a narrowly defined population to receive the vaccine, preserves the integrity of ongoing Phase III trials, and reduces the potential for unexpected adverse effects to sap public confidence in all COVID-19 vaccines. 

By allowing for a more gradual rollout while additional data are collected about efficacy and safety, granting expanded access would make it easier to pull the plug if unexpected safety issues arise. 

Proponents of EUAs argue that that attempting to use expanded access for large-scale distribution of a vaccine would create legal and logistic nightmares, adding disastrous confusion to an already precarious situation. They also contend that the benefits attributed to expanded access can all be obtained through EUAs. 

Even if an EUA is issued before the end of the year, supply constraints will limit the scale of COVID-19 vaccine dissemination for several months, and there are mechanisms for prioritizing distribution that do not require expanded access. 

During the Oct. 22 meeting of the Vaccines and Related Biologic Products Advisory Committee (VRBPAC), Philip Krause, deputy director of the Office of Vaccines Research and Review at FDA’s Center for Biologics Evaluation and Research (CBER), said the decision of whether to recommend approval or authorization of a COVID-19 vaccine involves a “balance between looking at people’s rights to take something where it is determined the benefits might exceed the risks, while also making sure we don’t interfere with the public good associated with continuing to evaluate that vaccine and other vaccines, while also making sure that people are not taking vaccines that might actually harm them.”

VRBPAC did not reach a consensus about how to balance these interests, but members did ask FDA if expanded access could help.

FDA Commissioner Stephen Hahn is considering the expanded access option, individuals who have spoken with him and who have been briefed on the agency leadership’s deliberations told BioCentury.

“I’m pleased to see FDA considering the use of its expanded access authorities for distributing initial doses of experimental COVID vaccines outside of clinical trials,” Luciano Borio, former acting FDA Chief Scientist, told BioCentury. “Even if interim analysis from the ongoing Phase III trials reveal a certain vaccine provides at least short-term protection, there may be insufficient information on safety, longer-term protection, and impact on diverse populations. An EUA would likely hinder the ability to collect the remaining crucial information.”

However, the same factors that make expanded access attractive to its advocates — in particular the slower rollout and informed consent,  which emphasizes the experimental nature of the vaccine — are concerns for those who believe rapid uptake is essential for getting COVID-19 under control. 

At least one vaccine sponsor, Moderna Inc. (NASDAQ:MRNA), appears to have a strong economic incentive to seek an EUA rather than expanded access, and other sponsors are likely to be leery of a pathway that comes with increased responsibilities.

While expanded access is being debated at FDA, and some VRBPAC members are voicing concerns about widespread access based on interim data, Operation Warp Speed and vaccine developers are racing forward with plans that are predicated on EUA based on interim readouts.

There are no signs that they are contemplating a pivot to expanded access, and if interim data show high levels of efficacy, they certainly are not aiming to defer launches for months until the trials are completed.

Buying blinded time

Pfizer Inc. (NYSE:PFE) and Moderna will receive the first interim analyses of Phase III COVID-19 vaccine trials in November. Both companies have made it clear that they would seek EUAs based on positive interim results, and both have signaled that they believe an EUA would create an ethical obligation to unblind their trials and allow participants who received placebo to obtain the authorized vaccine. 

Moncef Slaoui, chief scientific adviser to Operation Warp Speed, told BioCentury he expects two vaccines to receive EUAs in 2020 or early 2021, and VRBPAC members have been asked to reserve three dates in November and three in December to meet to discuss EUA applications.

FDA officials described at the VRBPAC meeting guidance the agency has given vaccine developers that indicates that an EUA could be issued based on an interim analysis that demonstrates at least a 50% efficacy in preventing COVID-19 with a confidence interval of 30% or more, along with at least a median of two months of safety data.

However, speaking on an interview on Tuesday streamed by JAMA, VRBPAC member Paul Offit said he and other committee members oppose granting an EUA to any COVID-19 vaccine based on interim data.

Offit, a professor of pediatrics at Children’s Hospital of Philadelphia, said he wants to wait for the trials to be completed and that an EUA should not be issued based on the smaller number of events that accrue at the time of an interim readout. He did not say how many or which VRBPAC members share his view, nor did he express this opinion at the VRBPAC meeting.

FDA seemed to have been taken by surprise by statements from vaccine developers proposing unblinding of trials following an EUA. 

“Issuance of an EUA should not in and of itself require unblinding of a COVID-19 vaccine,” Marion Gruber, director of CBER’s Office of Vaccines Research and Review, told VRBPAC. “We are concerned about the risk that use of the vaccine under an EUA would interfere with long-term assessment of safety and efficacy in ongoing trials and potentially even jeopardize product approval, not only of the first vaccines but maybe even follow-on vaccines.”

Vaccine sponsors that feel an ethical obligation to allow participants who received placebo to cross over to access an authorized vaccine may try to finesse the controversy by committing to delaying unblinding until vaccines are widely available. This would likely occur after the trials had been completed.

Jesse Goodman, former CBER director and former chief scientist at FDA, believes FDA should consider expanded access for COVID-19 vaccines based on interim data. Expanded access, he told BioCentury, “is more typically done while definitive trials are being done, and unlike an EUA, it might not create the imperative in some people’s minds to unblind trials.”

Goodman is director of the Georgetown University Center on Medical Product Access, Safety and Stewardship.

While CBER’s Krause did not endorse use of the expanded access pathway for COVID-19 vaccines, he did note at the VRBPAC meeting that FDA could be more comfortable limiting expanded access to a specific population than it would be in tightly defining who could receive a vaccine under an EUA.

“If an interim analysis suggests efficacy, one could start with expanded access and as one gathers data perhaps move to an EUA,” Krause told the VRBPAC. “Of course, there are some complexities there [but] under an expanded access one surely would have a very high degree of control over who could get the vaccine.”

Alison Bateman-House, assistant professor in the Division of Medical Ethics at NYU Langone Health, told BioCentury access to COVID-19 vaccines should be restricted to individuals who are not eligible for the trials. “Expanded access will provide access more narrowly than would an EUA, and that is appropriate, as anyone who is not excluded from the trials should participate in a trial in order to get access to an unapproved vaccine candidate.”

Differences in perception

However they implement unblinding, Pfizer’s and Moderna’s statements indicate that the companies consider an EUA a signal that FDA has determined that a vaccine is safe and effective, which makes it unethical to deny access to trial participants who received placebo. And government officials, including President Donald Trump and HHS Secretary Alex Azar, have publicly conflated authorization with approval.

Even though products that have received an EUA are investigational under FDA regulations, the widespread perception that an EUA is equivalent to approval has reignited interest in granting early access to vaccines through expanded access, which would include measures to ensure that recipients are aware that products haven’t been approved.  

Expanded access protocols must receive approval from an IRB and individuals must sign informed consent documents explaining that safety and efficacy have not been established.

“Expanded access is in the center of the spectrum that goes from research to unrestricted clinical treatment,” Jess Rabourn, CEO of WideTrial, a third-party sponsor of group-level expanded access programs, told BioCentury. “EUA is closer to the treatment end of the spectrum.”

“I think of emergency use as therapy,” Arthur Caplan, head of the Division of Medical Ethics at New York University School of Medicine and co-chair of the Vaccine Working Group on Ethics and Policy, told BioCentury. “It is FDA saying ‘here’s something that may save you.’ Expanded access is more like research.”

While a vaccine offered under expanded access may seem riskier to the public than one that has received an EUA, FDA would require similar data for either pathway. The safety and efficacy requirements would be “highly similar” for an EUA or expanded access, Fink told the VRBPAC.

Fink made it clear at the advisory committee meeting that FDA staff had considered expanded access for COVID-19 vaccines and decided that an EUA was more appropriate. “Operationally speaking, an expanded access use protocol for a vaccine would add some complexities and that is why emergency use authorization is being considered primarily as the mechanism for addressing the public health emergency.”

Goodman acknowledged that the informed consent process could be a barrier to vaccine uptake, but argued that could be an acceptable risk compared to the potential for an EUA to disrupt ongoing trials. “If we don’t learn which vaccine works best, or we miss an unexpected safety or efficacy problem and it takes a year to sort it out, the harm done could be much greater than the number of people who would get a vaccine in two or three months.”

Resisting expanded access

While Caplan is in favor of using expanded access to grant pre-approval access to COVID-19 vaccines, he noted that compared with an EUA, expanded access puts more responsibility in the hands of the manufacturers because they are in control of the protocol.

“The manufacturers will be in the driver’s seat, not FDA, and it is manufacturers that are subject to reputational risk if they ask for expanded access and things go south,” he said.

There are reasons beyond reputation for some companies to resist expanded access.

Moderna and Pfizer did not respond to requests for comments from BioCentury about the use of expanded access instead of EUAs for their COVID-19 vaccines.

Under its contract with the U.S. government, Moderna will receive a payment of up to $300 million if it produces 100 million doses of its mRNA-1273 COVID-19 vaccine candidate and has received an EUA or BLA by Jan. 31, 2021, according to an SEC filing. The filing does not indicate what payment Moderna would receive if its vaccine is made available through expanded access.

Vaccine sponsors could argue that rather than asking FDA to restrict access to an unapproved vaccine through an expanded access protocol, it would be more appropriate to allow CDC’s Advisory Committee on Immunization Practices (ACIP) to make prioritization recommendations. That is the process Warp Speed envisions. 

Aversion to EUAs may dissipate as winter drives Americans into their homes and the pandemic worsens. Even sooner, the political winds may blow in public confidence in FDA.

“I think post-election, should Biden win there will be more willingness to trust the regulator,” said Caplan. That trust, coupled with worsening of the pandemic, could lead to a sense that “we have to do the same thing we do with dying cancer patients, we can’t wait for all the data before we provide access.” 

If there is promising interim data, the combination of a desperate public, increased trust in government and resistance to expanded access from sponsors and Operation Warp Speed could lead FDA to opt for EUAs. 

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