By Jacob S. Sherkow, Lisa Larrimore Ouellette, Nicholson Price, and Rachel Sachs
Recently, Pfizer and BioNTech and Moderna announced that they are seeking full FDA approval for their mRNA COVID-19 vaccines—filing, in FDA parlance, a Biologics License Application (BLA). Johnson & Johnson plans to file its own BLA later this year. But currently, all three vaccines are being distributed under a different FDA mechanism, the Emergency Use Authorization (EUA). What’s the difference, under the hood, between these two mechanisms? Why would these companies want to go through the BLA process? And what tools can policymakers use to make the EUA to BLA shift better?
What’s the difference between an EUA and a BLA?
A Biologics License Application, or BLA, is FDA’s standard “full approval” mechanism for biological products, including therapeutics and vaccines. A company seeking a BLA for its product must demonstrate that the product is “safe, pure, and potent,” which generally means completing robust, well-controlled clinical trials. A company receiving a BLA for their product can introduce the product into interstate commerce and market it for its approved uses. A BLA also has no defined end date—assuming no significant problems emerge, the product can stay on the market indefinitely.
By contrast, an Emergency Use Authorization, or EUA, is just that—an authorization to distribute an otherwise unapproved product (or an approved product for an unapproved use) during an emergency formally declared by the Secretary of Health & Human Services. Both the substantive and procedural rules surrounding an EUA differ from those surrounding a BLA (or the BLA counterpart for small-molecule drugs, a New Drug Application or NDA). Substantively, the standard for granting an EUA is whether, “based on the totality of scientific evidence available,” “it is reasonable to believe that the product may be effective” and that the “known and potential benefits… outweigh the known and potential risks.” Procedurally, an EUA lasts only as long as the underlying emergency. Further, the FDA may “revise or revoke” an EUA if the substantive evidence for granting it no longer exists.
In the context of prescription drugs intended to treat COVID-19, the EUAs granted by the FDA typically did not require the completion of robust, well-controlled clinical trials. Further, several of these EUAs have been revised or revoked subsequently (such as hydroxychloroquine and convalescent plasma). But for COVID-19 vaccines, the FDA has applied a higher standard.
Specifically, the FDA has published multiple guidance documents that describe both what the agency is specifically looking for in vaccines authorized under an EUA and how that differs from the requirements for submitting a full BLA. A June 2020 guidance for COVID-19 vaccines laid out requirements for companies to conduct full-scale clinical trials before submitting EUA paperwork. Each vaccine manufacturer enrolled tens of thousands of participants in randomized clinical trials, similar if not virtually identical to what would have been done for outright license approval. As the agency later explained in more detailed EUA guidance, because these vaccines are “intended to be administered to millions of individuals, including healthy people, to prevent disease,” the FDA planned to apply different standards to the authorization of vaccines than to the authorization of treatments for patients who were already ill with COVID-19.
However, a comparison of these two guidance documents reveals important differences between what is required of companies submitting applications for an EUA and their subsequent BLA. Two stand out. First, the FDA wants to see longer follow-up of trial participants, particularly at least six months of safety data (compared to the two months required for EUA submission). Second, the FDA needs more detailed chemistry, manufacturing, and control data (including requiring facility inspections) in a BLA submission. The agency has indicated that working through this vast amount of data will take “months.”
Why would vaccine manufacturers go through the BLA process?
Pfizer-BioNTech, Moderna, and other vaccine manufacturers have already sold billions of vaccine doses—many even before any vaccines received an EUA—so why would they go through the expense of filing for a BLA? Although a BLA would not increase rewards under existing contracts, it could increase demand for the vaccine in ways that lead to additional government purchases for at least six reasons.
First, a recent U.S. survey found that 32% of unvaccinated adults say they would be more likely to get a vaccine that had full FDA approval. Reducing vaccine hesitancy would also have a social benefit that exceeds any private rewards to Pfizer or Moderna.
Second, although there is a strong legal argument that employers may mandate vaccines under EUAs, including guidance from the EEOC, some commentators have raised concerns about the practice. Some employers and schools are thus waiting for full approval before mandating the shots. The U.S. military will also consider a vaccine mandate after approval.
Third, because EUAs are authorized, not approved, physicians do not appear to have the ability to prescribe authorized products off-label. Full approval, however, allows physicians to do just that, and it’s possible that some physicians and parents could choose to vaccinate children under 12 off-label even before the clinical trial results come out. Pfizer has said that they’re hoping to have data from children as young as 2 by September or October, which could be relevant to the agency as it decides on the grant of full approval.
Fourth, an approved BLA likely would make it harder for new vaccines to receive EUAs. The FDA has statutory authority to grant an EUA only if “there is no adequate, approved, and available alternative,” so if Pfizer’s or Moderna’s approvals are granted and are deemed both “adequate” and sufficiently “available” for the intended populations, an EUA couldn’t be granted. To be sure, there are strong arguments (for instance) that the existing mRNA vaccines may not be sufficiently “available” for particular populations when compared to a product like J&J’s, a one-dose vaccine without the mRNA vaccines’ particular storage needs. But the agency has already taken steps toward limiting future EUA requests, suggesting that these factors may be more difficult to satisfy in the future.
Fifth, EUAs last only as long as the public health emergency that prompted them. Although COVID-19 continues to devastate countries around the world, the pandemic appears to be winding down in the United States as vaccination becomes more widespread. Approval will allow manufacturers to continue marketing their vaccines even after the officially declared emergency ends. Relatedly, manufacturers that receive full approval of their vaccines will have an easier time receiving approval for post-pandemic boosters to address new variants if COVID-19 becomes endemic.
Finally, a full stamp of approval from the FDA might help the rollout of the approved vaccines in other countries. The FDA is unusual among health regulators in requiring companies to submit raw data so that the agency can conduct its own statistical analyses, and other organizations like the WHO often rely on the FDA’s expertise—although the FDA is not the WHO’s National Regulatory Authority (NRA) of record for any of the COVID-19 vaccines so far. The Pfizer-BioNTech and Moderna vaccines are still not approved or authorized in many countries; perhaps FDA approval will help.
What can policymakers learn from the experience with EUAs and BLAs for COVID-19 vaccines?
The experience of EUAs and forthcoming BLAs for COVID-19 vaccines has useful lessons for policymakers going forward.
First, resistance to mandates of EUA products, and public reactions more generally, suggest that full FDA approval—in this case, a BLA—remains important in the eyes of the public and those setting corporate and local policy. Whatever the various challenges that have arisen to the public’s trust in the FDA (and however the FDA responds), there is more skepticism of things that haven’t yet gotten the agency’s official stamp of approval. That matters, and it’s worth the effort to maintain that public trust (in addition to public trust more generally). Other companies should be encouraged to seek approval, and as we have noted above, they have substantial incentives to do so. Policymakers can and should continue that encouragement. This includes raising thresholds for or discouraging EUAs once a vaccine is approved through a BLA, as the agency has begun to do.
Second, despite the benefits of BLAs, the experience of COVID-19 has demonstrated exactly why EUAs create a complementary pathway. Put simply, typical BLAs, especially for vaccines, require much longer to gather, submit, and review important data. Given the timing of clinical trials, no BLA could have been approved until this summer; without EUAs, vaccines would have been delayed for at least several months, at the cost of countless lives. Public hesitancy in the face of EUA products shouldn’t dim the immense benefits of swift action. It is useful both to have flexibility to get products on the market quickly when needed—but also to have the incentives carried by full approval to drive the creation of the high-quality data needed for long-term trust.
Third and finally, the flexibility of EUAs is important to manage carefully. Quick authorization should also allow quick deauthorization when products don’t work or have minimal benefits. Knowing when to reverse course depends on the FDA ensuring that EUAs come with careful guidance and rules on generating and analyzing data as products are used in the clinic. Good data prompted the quick revocation of hydroxychloroquine’s EUA, a clear win. It took much longer to gather data showing that convalescent plasma was similarly unhelpful. Ensuring the collection of data, rapid reevaluation when necessary, and appropriate standards in the first place (like the FDA’s helpful guidance on heightened vaccine EUA standards in summer 2020) will help the public know that even though full approval is the gold standard, EUA-authorized products are still as data-supported as possible given the need for speed.
EUAs and BLAs are both important parts of the FDA’s box of policy tools. Getting the contours of each right, reevaluating their complementary roles when necessary, ensuring the collection of good data throughout the process, and clearly communicating to the public will all help ensure those tools are as effective as possible.
This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.
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