Friday, July 10, 2020

How will the FDA’s new COVID-19 vaccine guidance affect development efforts?

Policymakers are expectantly awaiting the development of a COVID-19 vaccine, which they view as critical to future management of the pandemic. A number of pharmaceutical companies have jumped into the vaccine race, moving at record speed, with several vaccines already about to enter Phase III trials. Last week, the Food and Drug Administration (FDA) released a guidance document on the development of new vaccines for COVID-19. In this post, we review the FDA’s new guidance, consider the ways in which the FDA must attempt to balance risk and access in this context, and address the critical question of patient access to future approved vaccines.

What does the FDA’s COVID-19 vaccine guidance do?

The FDA’s June 30 guidance broadly details the agency’s requirements for clinical trials of COVID-19 vaccines. These include considerations for trials’ designs and subject populations, measures of efficacy, statistical considerations, and safety thresholds, among other requirements. Notably, the guidance is the first from the FDA to establish such measures for a COVID-19 vaccine specifically. Besides providing vaccine developers, well, guidance for vaccine development, guidances issued early in the development process also bind the FDA to its own evidentiary mast against the siren song of political pressure. (In this way, guidances, too, can serve as an instrument in augmenting public trust.) 

The guidance clearly specifies current areas of scientific uncertainty and expresses what evidence the agency is looking for and how to obtain it. For example, the guidance admits that “[u]nderstanding of SARS-CoV-2 immunology, and specifically vaccine immune responses that might predict protection against COVID-19, is currently limited and evolving”—and, as a consequence, the goal of COVID-19 vaccine trials is not necessarily to demonstrate immunogenicity but “efficacy in protecting humans from SARS-CoV-2 infection and/or disease.” 

More specifically, the June 30 guidance notes a preference for vaccine trials with a 1:1 randomization of vaccine candidate:placebo, rather than trials investigating multiple different treatment arms. It also encourages following up with study participants for “at least” one or two years to determine the length of protection provided by the vaccine as well as to watch for potential adverse events. And the guidance suggests using a lab-confirmed SARS-CoV-2 infection as a trial’s primary endpoint, with incidences of severe COVID-19 as at least a secondary endpoint. The guidance also acknowledges the racial disparity in COVID-19 outcomes by “strongly encouraging” enrolling racial and ethnic minorities in any vaccine clinical trials. Developing a vaccine that is less effective when administered to Black patients, for example, would only exacerbate differential COVID-19 outcomes and contribute to health inequities.

More controversially, however, the guidance pegs studies’ primary efficacy endpoint at “at least 50%”—a far cry from the 90%+ efficacy for vaccines against polio or HPV. This means, of course, that at least some vaccinated individuals (including high-risk individuals) would become infected. At the same time, an efficacy endpoint of 50% is not unheard of for vaccine development, and is used routinely for seasonal influenza vaccines. In cases like the flu, the goal is not necessarily to inoculate everyone, but to flatten the curve enough (i.e., to bring down R0) so that transmission is effectively halted. Mandating a coronavirus vaccine to demonstrate 90%+ efficacy while the pandemic rages would be allowing the perfect to be the enemy of the good.

For now, Moderna, a vaccine developer relatively far along in the approval process, has delayed part of its trial, seemingly to conform to the guidance. Moderna’s technology—an RNA-based vaccine approach—is novel and has its fair share of skeptics. But the guidance, like all good guidances, has the salutary effect of committing the FDA and developers to a common set of principles and evidence to the usher development of important therapeutics.

How does the FDA use its information-forcing powers to balance risk and access in the COVID-19 vaccine context?

The FDA doesn’t just regulate to ensure that new products are safe and effective; a key part of its role is to require and shape the production of costly information about the products it regulates. Professor Rebecca Eisenberg has argued persuasively that the FDA is an innovation agency, not just a consumer protection agency, and this information-forcing role is central to that purpose. It is difficult and expensive to generate information about health-care innovations, whether therapeutic drugs, medical devices, or vaccines. In the face of manufacturers’ incentives to underproduce this information, the FDA steps in to require a certain amount before it will allow products to be marketed. The amount of information required is debatable—as we have previously discussed, requiring more information decreases the risk of the FDA making a mistake during the approval process but delays patients’ access. This role is particularly important in a pandemic, where urgency colors every new biomedical development but high quality information is still needed, not least because errors can be particularly costly in terms of both medical outcomes and public trust

The guidance’s specific requirements (e.g., 1:1 vaccine:placebo, 1-2 year follow-up, specified endpoints) are an effort to ensure that the information generated about a vaccine is robust enough to merit approval and the likely widespread use that will follow. Ideally, as multiple candidates are taken through clinical trials, developers will learn more about the virus and more about effective development efforts. The FDA may require more and better information to approve later vaccines, both because firms (and the FDA) have more experience, but also because once the first vaccine is on the market, the need for a second vaccine is not quite as desperate. That said, the FDA has suggested that accelerated approval—a faster and easier approval pathway—may be more likely later after more is known about how the virus works. More vaccines will still be needed, but the agency can afford to be slightly pickier with each approved vaccine, and correspondingly to demand better evidence of efficacy and safety (for instance, once an approved vaccine exists, non-inferiority trials for later vaccines would look for an efficacy within 10%).

One crucial step the FDA could take to improve the information produced in vaccine trials would be to facilitate the sharing of information about failures in vaccine development. In the ordinary course of drug development, failures are minimally shared, as knowledge of dead ends not to follow is considered valuable confidential business information. Keeping failures secret in the COVID-19 vaccine development efforts would be a terrible waste, particularly as the clinical landscape is already littered with inefficiency and duplication. The European Medicines Agency already exercises a similar authority more generally.

The FDA’s role of ensuring that developers generate high quality information about safety and efficacy is in some tension with another prominent government initiative: Operation Warp Speed. Operation Warp Speed is an effort to speed the development of therapeutics and vaccines as much as possible, but part of that effort means that the government (particularly BARDA, the Biomedical Advanced Research and Development Authority) will be picking winners and supporting particular candidates—long before they have the sort of information the FDA is looking for. The FDA is correspondingly emphasizing its independence from other efforts; the information required to approve a vaccine seemingly does not change based on the mechanics of Operation Warp Speed or other government efforts. Nevertheless, and with good reason, the firms operating under Operation Warp Speed will be using the FDA’s guidance to shape their development efforts.

If the FDA approves a COVID-19 vaccine, how will the United States pay for it?

The FDA’s rigorous requirements and stated reluctance to issue a vaccine EUA have been described as throwing cold water on the goal of having a COVID-19 vaccine in 2020. Experts suggest that even summer 2021 is an aggressive goal, requiring tremendous duplicative spending and a lot of luck. But while an effective COVID-19 vaccine remains aspirational, politicians, patient advocates, and pharmaceutical innovation experts have been worrying about vaccine cost since the early stages of the pandemic. We think it would be helpful if these discussions distinguished between affordability—the out-of-pocket costs to patients that can pose barriers to access—and the separate question of overall financial incentive for developers, recognizing that pharmaceutical profits and public health are not incompatible.

Any FDA-approved vaccine will likely be free for Americans who want it. The push for adoption of U.S. vaccines typically comes from the CDC’s Advisory Committee on Immunization Practices (ACIP), which formed a COVID-19 work group in April to create an independent framework for assessing vaccines and to review early clinical trial data. The Affordable Care Act requires insurers to cover ACIP-recommended vaccines with no cost-sharing (at least as long as it is not overturned). As we have previously discussed, HHS has also used CARES Act funding to create a COVID-19 Uninsured Program Portal, which will cover any FDA-approved vaccine for uninsured Americans, when available. The Trump administration stated in June that any COVID-19 vaccine will be free for “any American who is vulnerable, who cannot afford the vaccines.” It seems likely to us that Congress will allocate additional funding for vaccine coverage if necessary, including to ensure that patients are not billed for the health care provider’s administration of the vaccine (in addition to the product itself).

But free at the point of sale to patients need not—and should not—mean free to the U.S. government. Vaccine development is tremendously expensive, requiring customized manufacturing facilities that usually take many years to build. Having any chance of meeting 12-to-18-month development timelines requires building these factories now for promising candidates, with recognition that most will have to be abandoned as unrecoverable sunk costs when clinical trials do not pan out. Vaccines are also less profitable than repeat-use treatments, and political pressure often pushes profits even lower. But vaccines can have huge positive externalities for society beyond the benefits provided to individual vaccinated patients—as illustrated by the enormous daily costs of COVID-19 that an effective vaccine would eliminate.

The conventional solution for this kind of market failure in innovation policy is to supplement market rewards with public funding—and the federal government is indeed putting substantial sums into COVID-19 vaccine development. A $1.6 billion contract with Novavax was announced Tuesday, following pledges of “up to $1.2 billion” to AstraZeneca and about $1 billion more divided among Moderna, Johnson & Johnson, Merck, and Sanofi. Some commentators have pointed to this funding as justification for compulsory licenses or price caps on successful vaccines. But the goal of this funding is to correct for market rewards that are insufficient to motivate companies to build facilities at-risk, before a vaccine candidate's efficacy is known; decreasing market-based incentives would subvert this goal and exacerbate this market distortion. Total public funding for COVID-19 vaccine development so far is less than the daily social cost of the pandemic in the United States alone. If this funding speeds vaccine development even slightly, it will have been worth it.

Indeed, in addition to laying out guidance for the standards that will be used for vaccine approval, the federal government should consider committing now to reimbursement rates for an approved vaccine, akin to what it has done for advanced COVID-19 diagnostic testing technologies. As multiple scholars have noted, an effective COVID-19 vaccine is the kind of technological problem that lends itself well to an innovation challenge prize known as an advance market commitment (AMC), in which the government commits to paying a certain amount per vaccinated person, under certain assumptions about the vaccine’s effectiveness that align with the FDA’s guidance. Even though an entirely new prize system isn’t politically likely, wide-scale government purchasing can replicate most of the benefits of market-based prize systems like AMCs. Committing to a profitable reimbursement rate could provide additional motivation to get working COVID-19 vaccines into Americans’ arms more quickly.

The legal and policy issues arising in the context of vaccines for COVID-19 are not entirely unique to the vaccine context. The federal government has already faced questions around the FDA’s approval standards, regulating in the face of uncertainty, and ensuring access to other new healthcare technologies for COVID-19, such as drugs and diagnostics. But the particular facts underlying the development of new vaccines counsel in favor of solutions to this problem that differ from those the federal government has already considered. Now, several months into COVID-19’s spread into the United States, federal policymakers should work to ensure that plans specifically encouraging innovation into and access to vaccines are developed and implemented.

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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