How do we encourage innovation on “long COVID”?

By Jacob S. Sherkow, Lisa Larrimore Ouellette, Nicholson Price, and Rachel Sachs

Since the pandemic began, numerous recovered COVID-19 patients have reported having “long COVID”: COVID-19 symptoms persisting well beyond the underlying viral infection period. Whether such a condition is specific to COVID-19, or more generally a form of “post-acute sequelae”—or even a discernable condition—has bedeviled scientists and clinicians alike. The fact remains, though, that likely millions of people in the U.S. alone will continue to report a variety of challenging symptoms more than 6 months after they’re infected. Despite this magnitude of reports, confusion regarding defining the condition and identifying its etiological basis has presented significant challenges to innovating treatments for it. In this post, we explore some of the current evidence surrounding “long COVID,” some of the difficulties in developing long COVID treatments, and how policymakers can move things along.

What’s the current evidence for long COVID and how prevalent is it?

Figuring out what long COVID is has proved frustratingly elusive. The CDC uses “long COVID”—or “post-COVID conditions”—as an umbrella term for a range of health problems experienced 4 or more weeks after infection, including shortness of breath, fatigue, “brain fog,” “post-exertional malaise,” cough, headache, diarrhea, dizziness, changes in smell, and more. Guidance from the UK’s National Institute for Health and Care Excellence (NICE) draws a distinction between “ongoing symptomatic COVID-19” from 4 to 12 weeks after infection, and “post-COVID-19 syndrome” for symptoms that continue for more than 12 weeks. In November 2021, NICE published detailed evidence reviews on defining post-COVID-19 syndrome and the most prevalent symptoms, both of which noted the low quality of the existing evidence base. In particular, most long COVID studies are cross-sectional retrospective surveys of self-reported symptoms, which increases the risk of recall bias. These studies have also almost exclusively been conducted in high-income countries, and survey respondents are not even representative of the populations within those countries: they have mostly been white, female, and of higher socioeconomic status.

SARS-CoV-2 is not the only virus that results in long-term reported symptoms—generally known as “post-acute sequelae”—although the risk of sequelae after COVID-19 appears higher than the risk after influenza, suggesting that long COVID might not just be a general post-viral complication. But the lack of a consistent case definition has confounded studies, and the risk of biased surveys was recently illustrated by a recent French study that suggested that reporting long COVID symptoms “may be associated more with the belief in having been infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection.” Some researchers have thus focused on more objective markers of persistent clinical symptoms, which still leaves “many available hypotheses” to explain COVID’s long-term effects—to the understandable frustration of patients who are looking for more answers from the medical community.

An improved clinical understanding of what long COVID is—and how to treat it—will become even more important as people recover from the massive Omicron wave that has been circling the globe. While few long COVID cases result in hospitalization, some are serious, and they may put further strain on an already splintering healthcare system. Long COVID is also affecting many individuals’ ability to go back to work—in some cases, due to cognitive impairments—and may be exacerbating the current labor shortage. Patients are also desperate for treatments and sometimes turning to ineffective “alternative” therapies, which could create additional health risks.

What are the innovation challenges for developing therapies for long COVID?

Developing therapies for long COVID involves several interlinked challenges relating to definitions, reimbursement, clinical trials, competing incentives, and non-excludable treatments.

Perhaps the biggest challenge involves concretely defining long COVID. Medicine is typically bad at defining chronic conditions with variable and often non-specific symptoms using diagnostic exclusionary criteria—that is, when it’s difficult to say exactly what counts as having the disease (and what counts as being successfully treated). Not knowing the etiology (the causal pathway) of a disease makes it difficult to develop drugs for the disease, all things being equal. This parallels some of the failures of developing treatments for Alzheimer’s: it’s not clear what the molecular basis of the disease is (i.e., what causes Alzheimer’s) or whether it’s truly a single “disease” or a collection of diseases with potentially different treatments. For long COVID, the lack of a known mechanism (though scientists are starting to learn more) is also linked to unfortunately widespread skepticism and under-reporting, which is likely to reduce incentives for developers. Diffuse, hard-to quantify symptoms have long had trouble winning developer attention, as individuals who suffer from endometriosis, for instance, have known for far too long.

Second, and relatedly, because long COVID is not a well defined condition, reimbursement is more challenging. Reimbursement can function as both a private and a public source of incentives for development, whether deliberately or not. If a condition is poorly defined and not readily reimbursable, that decreases the incentives to develop treatments for it in the first place.

Third, clinical trials on possible treatments are likely to be both expensive and long. Trials are likely to be expensive because they would need to be large when the endpoint is relief from non-specific symptoms. Controls may also be difficult to recruit, since so many people have been infected by COVID by now. This is especially true because of the length of trials likely needed; if long COVID is defined by having several months of symptoms, for how long must symptoms remit to achieve an endpoint?  Long trials unfortunately tend to discourage therapeutic innovation. 

Fourth and finally, there is some evidence that non-excludable treatments work to help treat long COVID, including exercise, occupational therapy, and cognitive therapy. R&D on these treatments is likely to be underincentivized by existing innovation institutions. And to the extent these are successful and become the standard treatment, they’ll compete with excludable therapies—and accordingly diminish the incentives to develop them in the first place.

What can policymakers do to support innovation related to long COVID?

A first item on which policymakers have already made progress in supporting innovation related to long COVID is to expand access to insurance and care for those experiencing its symptoms. As we have written previously, ensuring that patients have access to health insurance (which provides reimbursement for treatments and services) can serve itself as an innovation incentive for pharmaceutical companies. The 2010 passage of the Affordable Care Act and its guarantee that insurers cannot discriminate against patients with pre-existing conditions (such as having previously had COVID-19) are a key step in this direction. HHS’s more recent guidance that long COVID can qualify as a disability for purposes of anti-discrimination laws is also helpful. 

But more could be done on this front. One step that could be taken is for the Social Security Administration to add long COVID to its list of qualifying conditions, which would assist patients in becoming eligible for Medicaid or Medicare benefits. 

A second item is for policymakers to invest in research enabling scientists to learn more about the long-term effects of COVID-19. In December 2020, Congress provided $1.15 billion to study long COVID, and in February 2021 the NIH launched an initiative to use this funding. This support was extended by the American Rescue Plan, and in fall 2021 NIH awarded nearly $470 million to study these issues. This research could provide physicians with novel ideas for treatment in the short-term, and pharmaceutical companies with potential drug targets in the more medium-term. But it will be important to ensure that these research efforts are accessible to patients broadly, not only those who may have the connections and resources to travel to large academic medical centers. 

Third, policymakers could consider additional ways to support the development of treatments for long COVID. Existing market-based reward incentives may be sufficient to encourage the development of novel prescription drugs or medical devices, but as noted above, they may be less effective at encouraging the development of information about the efficacy of non-excludable interventions like exercise. Trials on non-pharmaceutical interventions for long COVID might be directly supported by public funding, given the lack of private incentives to do so. 

Fourth and finally, policymakers could support ongoing efforts to repurpose existing drugs that might be effective in treating long COVID. For similar reasons as above, pharmaceutical companies may have limited incentives to test their old drugs for new conditions. But, just as some existing medications have been effective in treating COVID-19, the same may be true for long COVID. Direct funding of trials or advance purchase commitments may be useful in this area. 

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

How does pregnancy factor into COVID-19 innovation?

By Nicholson Price, Rachel Sachs, Jacob S. Sherkow, and Lisa Larrimore Ouellette

Pregnant people are at increased risk of severe illness from COVID-19, but they have been largely excluded from clinical trials, the process of testing vaccines’ and treatments’ safety and efficacy. They’re consequently left in a bind: there’s not great evidence about the safety and efficacy of products they can take to be safe from COVID-19. This lack of information might be part of the explanation for low vaccine uptake among pregnant people, particularly women of color. And while this lack of data isn’t particularly novel with respect to drug development, generally—we’re historically bad at generating robust safety data for pregnant people—failing to do so for COVID-19 seems to have outsized public health consequences. What’s behind this ongoing exclusion? And how should policymakers consider including pregnant people in COVID-19 clinical trials and beyond?

How have pregnant people been included (or not) in COVID-19 innovation?

As we’ve discussed before, clinical trial design is an important and complex consideration in drug development, and the stakes are even higher in a pandemic. Broadly, clinical trial design for new therapies and vaccines is governed by a patchwork of FDA regulations, guidance documents, agency practice, and best practices. While the FDA ultimately has significant oversight over a given clinical trial’s design—it can, for example, reject “protocol amendments” after a design has been approved—a trial’s overarching design is up to the developer. While there are no direct sanctions for departing from a given clinical trial guidance, developers often hew to the FDA’s advice lest the agency reject their product applications.

To minimize complications on the path toward approval, developers have historically sought mostly healthy, non-elderly men for clinical trials when possible; developers have long shied away from including pregnant subjects. The reasons for this reluctance are manifold. Pregnancy is a complex medical condition on many fronts, including anatomically and endocrinologically. Measuring drug metabolism—pharmacokinetic/pharmacodynamic modeling (PK/PD)—during pregnancy is also difficult. Beyond these scientific reasons, there are also social barriers, such as paternalism; pregnant people were long classified as “vulnerable” in human subjects research, with corresponding limits on when they could participate in clinical trials. That rule was finally changed in 2017 after substantial criticism and reform effort—but exclusion from clinical trials frequently remains the norm. Even after the FDA issued a new draft guidance on including pregnant people in clinical trials in 2018, it retained a default presumption that they’ll otherwise be excluded.

Pregnancy is complex, too, because of difficulties in measuring therapies’ and vaccines’ effects on fetuses and born children. Aside from patent birth defects—the thalidomide disaster in Europe casts a long shadow over testing drugs on pregnant people—there are significant complexities in designing (and funding) long-term studies to measure investigative products’ effects. These include the challenge of developing standard measures of “normal” children at different (and shifting) ages. Expectant parents, too, may be reluctant to subject their soon-to-be born children to experimental products and, even if they’re on board during an earlier stage of pregnancy, may drop out during the course of the study, making obtaining statistical robustness a challenge. There’s also complexities on how long to obtain data about born children: A year after birth? Two? Until adulthood? Beyond? For truly novel therapies, there may not be clear enough answers.

These challenges regarding designing clinical trials to incorporate pregnant people are particularly acute for COVID-19 therapies and vaccines, where speed to market is at a financial and public-health premium. This is true even for products authorized under an emergency use authorization, or EUA, rather than through one of the FDA’s traditional approval pathways. Pregnant people were consequently excluded from the first vaccine clinical trials and too few people in the trial got pregnant during trials to include them in a statistically robust manner. Even preclinical data on the COVID-19 vaccines and pregnancy was limited. More recently, pregnant people were excluded from molnupiravir trials because of concerns about birth defects.

With that said, there is some recent movement to include pregnant people in clinical trials for COVID-19 vaccines. Phase 2/3 clinical trials began in February 2021 for Pfizer/BioNTech and Janssen and included pregnant people. There have also been larger observational studies, including Moderna’s ongoing observational trial, the v-safe smartphone app study, and a Harvard SPH-affiliated registry to observe pregnant people in COVID-19 trials. But these enrolled only a tiny fraction of the number needed to conclusively demonstrate safety and efficacy in the pregnant population. (Nonetheless, all observational results thus far show no particular issues for pregnant people taking any of the FDA-authorized COVID-19 vaccines.) 

Why is it important to include pregnant people in clinical trials, including for COVID-19?

Physicians and experts at the World Health Organization and CDC have been among those calling for change and arguing for greater inclusion of pregnant people in trials—with appropriate precautions—particularly for COVID-19. Two important reasons for inclusion are worth emphasizing.

First, pregnant people are not immune from illness—they often get sick with all sorts of diseases, including COVID-19, which is known to be more dangerous in pregnancy. If pregnant people are going to be prescribed medications if they become ill with COVID-19, or vaccinated against the virus, it’s difficult to justify a system in which clinical trials are purposefully designed not to generate information about how those drugs and vaccines will work (and whether they might cause particular problems) in pregnant people. This challenge has been referred to as the “pregnant people’s paradox.” At least some pregnant people have stated that they chose not to become vaccinated against COVID-19 out of concern over the impacts on the health of their pregnancies, suggesting that including pregnant people in the vaccine trials and generating safety information ahead of time might have helped to combat vaccine hesitancy in this high-risk population. Mixed messages from public health agencies may have complicated this situation for patients.

Second, as a matter of societal health equity, we should generally want information about how drugs and vaccines work across all swaths of the population. Pregnant people are people too and should not be excluded from trials as a matter of course, even if their inclusion renders the trial more complex. The historic underrepresentation of women in general—not just pregnant people—from clinical trials has been well-documented, and there is a lack of research in general into issues that predominantly or disproportionately affect women (such as endometriosis). This lack of study and understanding is problematic for everyone.

How can policymakers encourage clinical trials for pregnant people going forward? 

Widespread exclusion of pregnant people from clinical trials represents a market failure of our current biomedical innovation system. Manufacturers designing clinical trials exclude pregnant people because the costs to the company—including potential risks—are estimated to exceed the private benefits, even if the social benefits are much larger. These costs to developers include (1) added complications and uncertainty for clinical trials process (such as those suggested by the FDA), (2) a potentially lower likelihood of being authorized or approved due to those complications, and (3) the substantial PR (and potential liability) risk if clinical trials result in harm to pregnant people. 

As for other market failures, policymakers interested in addressing this failure can turn to other types of government interventions. Fortunately, they have a large innovation policy toolkit to choose from, which is similar to the toolkit we have previously discussed for encouraging pediatric trials.

First, the FDA could encourage more inclusive clinical trials through regulatory mandates. As long as the FDA continues to not require the inclusion of pregnant people as a condition for authorization or approval, companies will not feel pressure to do so. As explained above, the FDA grants sponsors substantial freedom in clinical trial design, and trial sponsors do not always follow guidance the agency does issue—which has been a longstanding problem in many areas, including for the representation of diverse racial populations in trials. The FDA and its counterparts abroad are beginning to address these problems, in moves the FDA recently described as a global “paradigm shift.” Whether the agency will issue regulations with more teeth or more forceful guidance remains to be seen.

Second, grantmaking agencies like the NIH could provide direct grant funding for clinical trials in pregnant people. For example, MOMI-VAX is an observational study conducted by the NIH that started in summer 2021. Funding could also be provided to other entities with interest in conducting clinical trials, such as healthcare payers who want to avoid paying for interventions that are harmful or ineffective.

Third, Congress could increase the incentives for product sponsors to study their products in pregnant populations by decreasing the cost through targeted tax incentives or increasing the benefits through added regulatory exclusivity. For example, orphan drugs for rare diseases are incentivized through a combination of a 25% credit for clinical trial expenses and seven years of exclusivity, on top of additional grant funding. And Congress has provided six months of added pediatric exclusivity—on top of other exclusivity periods—for companies that conduct pediatric trials of their products. Both statutes have been subject to significant criticism, such as for limited dissemination of pediatric trial results, but have also been successful in incentivizing the targeted type of R&D.

Development of safe and effective treatments and vaccines for the pregnant population is an important public health issue, for COVID-19 and beyond—and as with many areas of underdeveloped medical information, a variety of policy tools could be used by different government institutions to help address the problem. 

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

How would the proposed American Pandemic Preparedness Plan help address underinvestment in pandemic-related innovation?

By Jacob S. Sherkow, Lisa Larrimore Ouellette, Nicholson Price, and Rachel Sachs

Historically, the United States’ preparedness for a pandemic is like Charles Dudley Warner’s aphorism on the weather: everybody talks about it but no one ever does anything. Before COVID-19 struck, it was clear that the threat of a pandemic was real and that the world was not ready. As one of many examples, a September 2019 report from the Global Preparedness Monitoring Board (GPMB)—an expert group convened by the World Bank and WHO—concluded that “there is a very real threat of a rapidly moving, highly lethal pandemic of a respiratory pathogen killing 50 to 80 million people and wiping out nearly 5% of the world’s economy.” Perhaps the tragedy of the current crisis will provide sufficient motivation to better prepare for next time.

As a step in this direction, earlier this month the Biden administration released a twenty-seven page American Pandemic Preparedness Plan—with a $65 billion price tag—to provide the United States with “broad and deep protection against biological threats, ranging from the ongoing and increasing risk of pandemic disease, to the possibility of laboratory accidents and the deliberate use of bioweapons.” These include, of course, several innovation policy commitments to encourage the development of pandemic-related tools for COVID-19 and beyond. What are those commitments? How do they work—or would have worked—for COVID-19? And what does this say about innovation policy more generally?

What innovation policies does the Plan contemplate?

The American Pandemic Preparedness Plan is built around five pillars supporting the U.S. response to a future pandemic: (I) Transforming our Medical Defenses, (II) Ensuring Situational Awareness, (III) Strengthening Public Health Systems, (IV) Building Core Capabilities, and (V) Managing the Mission. Within each of these areas, the Plan lays out more specific goals to be achieved. As a whole, these goals involve many sectors of the federal government and envision a holistic response to—or anticipation of—future pandemics. Although it is not possible to include here a complete list of the many goals included in the Plan, we highlight several that are related to the innovation policy issues we have considered in our blog posts over the last year and a half.

Pillar I, Transforming our Medical Defenses ($41 billion), focuses on the types of health technologies we have considered in several prior posts: vaccines, therapeutics, and diagnostics. Within each of these categories, the Plan includes aims targeted at developing, distributing, and administering these technologies, recognizing the need for governmental support all along this process. The Plan does include specific benchmarks for several of these aims—for instance, noting the need to “[e]nable design, testing, and review of a safe and effective vaccine … within 100 days after the recognition” of an emerging threat. But others are framed more generally at this time, and are not tied to specific time or quality benchmarks. 

Pillar II, Ensuring Situational Awareness ($5.4 billion), is intended to improve our ability to detect potential pandemic threats as early as possible and monitor their spread and evolution. Some of the Plan’s specific proposals in this area take inspiration from relatively new strategies used in forecasting the spread of COVID-19, such as the use of “environmental sequencing” including wastewater sampling to detect the level of virus circulating in a community. The Plan also aims to track viral variants and the potential impact those variants might have on the types of technologies prioritized elsewhere in the Plan.

Pillar III, Strengthening Public Health ($9.3 billion), aims to both modernize our public health infrastructure to manage biological threats and establish the international infrastructure to do so. Several of these proposals relate to the types of knowledge infrastructure or human infrastructure considered in previous Biden Administration proposals. For instance, the Plan intends not only to strengthen the public health workforce and its ability to engage in evidence-based communication, but also to invest in public health laboratories and their digital infrastructure to enable data sharing across stakeholders. 

Pillar IV, Building Core Capabilities ($8.8 billion), includes a broader range of goals, intending to (1) support the availability of personal protective equipment, (2) restore and expand the United States’ pandemic stockpiles, (3) prevent laboratory accidents and deter bioweapons development, and (4) improve regulatory capacity for a wide range of health technologies. Some of these proposals may take inspiration from other countries which have successfully implemented some of these strategies. 

Pillar 5, Managing the Mission ($0.8 billion), envisions the creation of a “U.S. Mission Control” for our pandemic preparedness. Mission Control would have the ability to “manage, integrate, and ensure accountability” for our pandemic preparedness and response, in a way that should have the ability to avoid at least some of these issues going forward.

It is difficult to say which of these pillars the Plan prioritizes, though one indication is certainly the amount of proposed funding dedicated to each area. Out of a proposed budget of $65 billion, the Plan allocates $24.2 billion to its various vaccine goals, and another $11.8 billion to therapeutics and $5 billion to diagnostics, such that more than 60% of the proposed budget goes toward Transforming Medical Defenses (Pillar I). To be sure, these are also extremely capital-intensive endeavors, and it is surely more expensive to fund the development and manufacturing of novel, highly adaptable vaccines than it is to create a federal Mission Control (at $0.8 billion). Nonetheless, it seems that the American Pandemic Preparedness Plan is one largely centered on healthcare technologies. 

How do these policies address failures highlighted by the COVID-19 pandemic?

Despite the success in developing effective vaccines and therapeutics against COVID-19, some of the American Pandemic Preparedness Plan’s vision arises from perceived weaknesses of the U.S. innovation ecosystem that have been highlighted by the ongoing pandemic.

First, across the five pillars, the Plan reflects a commitment to more pandemic-related R&D funding, particularly for basic research. The federal government already invests heavily in basic research; as noted in the Plan, the success of COVID-19 vaccine developed built on decades of “fundamental scientific research, spurred by the emergence of SARS and MERS, [which] provided detailed knowledge about coronaviruses, including revealing which protein to target and how to stabilize it.” But the Plan also notes that most viruses that infect humans are less well understood than coronaviruses, and the GPMB report faulted the world for “insufficient R&D investment and planning,” including for vaccines, broad-spectrum antivirals, and targeted therapeutics like monoclonal antibodies. The Plan thus reflects the latest in a long tradition of public support for basic research in the United States in response to destabilizing events, from World War II until now.

Second, the Plan indicates an understanding that developing drugs and vaccines requires more than additional funding: it also requires the infrastructure to rapidly determine whether they are effective. We have previously explained the benefits of the UK’s RECOVERY trial, which used size, speed, randomization, and simplicity to quickly determine which COVID-19 interventions were most effective, avoiding the wasteful use of drugs in inconclusive trials (or outside of any trial at all). Pillar IV calls for the promotion of “efficient, large-scale clinical trials networks” that could be used during pandemic situations, which may have been inspired by RECOVERY. National-level coordination of clinical trials may also help standardize trials in ways that make it easier to compare the relative efficacy of different interventions.

Third, the Plan recognizes that pandemic-related R&D doesn’t stop once a product is developed: figuring out how to scale up manufacturing and equitable distribution of any health-related technology entails its own challenges, contributing to the concern that the U.S. healthcare system is “all breakthrough, no follow-through.” For everything from masks to vaccines to therapeutic antibodies, COVID-19 has repeatedly exposed insufficient attention to both manufacturing bottlenecks and distribution hurdles. The Plan includes provisions to address these failures: Pillar I includes funding not just for vaccine, therapeutic, and diagnostic development but also production and distribution. Pillar III will help rebuild our crumbling public health infrastructure, including at the state and local level. Pillar IV includes funding to improve the manufacturing of PPE and to improve supply chains for medical products. We have previously described the need to build infrastructure for the next pandemic; these appear to be steps in the right direction.

Fourth, the Plan at least acknowledges the importance of equitable distribution, with funding “to mitigate the health inequities exacerbated during a public health emergency, including prioritizing allocation of public health emergency response resources … to vulnerable and under-served communities.” As we have explained in prior posts, COVID-19 has highlighted the degree to which legal institutions are complicit in creating a healthcare system with disparities by race, gender, and class, and hopefully efforts to strengthen U.S. pandemic preparedness can help address these challenges.

Finally, the Plan would promote greater coordination of our pandemic response. As we have written about previously, the lack of interagency coordination in many areas was detrimental in our response to the COVID-19 pandemic. Establishment of a Mission Control hopefully would smooth coordination among relevant agencies—including NIH, CDC, BARDA, FDA, CMS, DoD, DoE, and VA—while providing greater sharing of expertise among them.

What is missing from the American Pandemic Preparedness Plan?

While the Plan has much to laud, it seems to focus on a relatively classic view of innovation policy where the government’s role is to spend on technological research, mostly basic but also applied. Largely left out are other spaces where the past two years have shown profound lapses in both knowledge and capacity.

Most notably, the Plan focuses strongly on technological ends: vaccines, therapeutics, diagnostics, and the like. These products embody classic knowledge goods that are easy to hold up and celebrate. But there are a host of other knowledge goods which are also crucial in combating pandemics, including knowledge about tailoring medical practice or hospital coverage or evaluating the effectiveness of non-technological interventions like wearing masks or social distancing. In criticizing global underinvestment in pandemic-related R&D, the GPMB report cited not just traditional vaccines and drugs, but also non-pharmaceutical interventions, including public safety protocols. This information is crucial but largely nonexcludable—that is, difficult for innovators to keep others from using (and therefore difficult for private actors to use to make a profit). Useful but nonexcludable innovation should typically receive more government attention, not less, because the private market is expected to underinvest in such nonexcludable goods. 

In addition, the Plan leaves relatively untouched the arsenal of private incentives that help drive biomedical innovation. Nothing describes modifications to patents (which have received substantial blame during the pandemic, some of it misplaced). No funds seem directed to prizes or tax credits or other solutions that drive private investment. And while there are gestures to public-private partnerships, the vast majority of the Plan seems to center on direct government spending. Effective innovation policy—especially for an unknown pandemic that may not operate like COVID-19 and require a suite of different approaches—likely requires a broader diversity of mechanisms. 

Overall, the Plan is a laudable effort to prepare the U.S.—and the world—better for the next pandemic. To be sure, it leaves out some areas where the current pandemic has encountered notable failures, especially with regard to nonexcludable knowledge goods. But the perfect can be the enemy of the good—and the Plan is good! While there is room for improvement, it’s a giant step in the right direction. Congress has a lot on its plate, but the Plan is worthy of its attention—sooner rather than later.

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

How does the CDC’s Advisory Committee on Immunization Practices impact innovation and access to COVID-19 vaccines?

By Rachel Sachs, Jacob S. Sherkow, Lisa Larrimore Ouellette, and Nicholson Price

In previous blog posts in this series, we have explored the roles different federal agencies, including the NIH, FDA, and CMS, play in the development and distribution of new healthcare technologies in the fight against COVID-19. But we have devoted much less attention to the CDC and its Advisory Committee on Immunization Practices (ACIP), which has a key role to play in the distribution of vaccines, including those against COVID-19. In this post, we explain the role played by ACIP, discuss several important COVID-19 vaccine decisions ACIP has been involved in, and consider what ACIP’s processes might teach policymakers more generally about innovation and access to health technologies.

What role does ACIP play in enabling access to vaccines?

ACIP, first established in 1964, is an Advisory Committee housed within the CDC. The CDC has tasked ACIP with providing “advice and guidance to the Director of the CDC regarding use of vaccines and related agents for effective control of vaccine-preventable diseases in the civilian population of the United States.” ACIP reviews any new vaccine—or new vaccine indication—approved or authorized by the FDA, but their task is distinct from the FDA review process. For example, a vaccine licensed by the FDA may be recommended by ACIP more narrowly than its labeled indication, such as only for use based on risk factors like traveling to certain countries. ACIP also considers health equity and cost-effectiveness in recommending vaccine schedules, which do not factor into the FDA’s decision.

Like the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC)—which we’ve described in an earlier post—ACIP is governed by the Federal Advisory Committee Act, including the requirements of open meetings and public involvement. Like VRBPAC, ACIP is an expert body, with members bringing different areas of expertise (such as immunology, virology, and public health), and one member “who provides perspectives on the social and community aspects of vaccination.” But ACIP has greater authority than VRBPAC. The FDA doesn’t have to convene advisory committees (though it has chosen to use VRBPAC for many important COVID-19 vaccine decisions), and the FDA can make decisions that contradict advisory committee recommendations (as it does over one-fifth of the time, including recently for the controversial Alzheimer’s drug Aduhelm). In contrast, ACIP must review every new vaccine, and its decisions have legal effects for vaccine access.

Most notably, the Affordable Care Act (ACA) requires vaccines recommended by ACIP to be covered by private insurers with no cost sharing. The Vaccines for Children (VFC) program, which we’ve written about, also provides ACIP-recommended vaccines at no cost to eligible children. Public and private insurers can still choose to cover vaccines without ACIP recommendations; for example, after the FDA’s authorization of a third COVID-19 vaccine for immunocompromised patients, CMS announced that Medicare recipients could receive a booster at no cost without waiting for ACIP to review the issue. But ACIP’s recommendation triggers important coverage mandates, particularly for patients not on public insurance. Like CMS, ACIP thus plays an important role in governing access to new health technologies—and this market-setting role also affects the incentives to create new vaccines in the first place.

In addition to considering whether a vaccine should be recommended for U.S. populations, Professor Jason Schwartz has explained that ACIP also has played a “traditional role by establishing guidelines for … vaccine prioritization and deployment,” for which issues of health equity are paramount. For example, ACIP issued prioritization recommendations for H1N1 vaccines in July 2009, and for vaccines that have faced temporary shortages. Because of the importance of its role in the U.S. vaccine innovation ecosystem, ACIP has faced ongoing debates about its independence and potential financial conflicts of interest, but it has generally preserved a “reputation as an inclusive and credible voice on vaccination.”

How has ACIP been called upon to make important decisions during the COVID-19 pandemic?

ACIP has played several critical roles in the recommendation and accessibility of vaccines during the pandemic. Most recently, after a public meeting, ACIP recommended third doses of mRNA vaccines (i.e., “booster shots”) for immunocompromised individuals and other groups sensitive to waning vaccine efficacy following the FDA’s reissuance of the vaccines’ EUAs to include third doses for patients “who have undergone solid organ transplantation” or “who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise.” Because there was no FDA advisory committee meeting concerning third doses—originally not included in the mRNA vaccines’ EUAs—ACIP’s meeting was an important place to lay out publicly available information on the doses’ necessity, such as how organ transplant patients’ antibody responses differ from patients with other immunocompromising conditions. ACIP’s meeting also covered important questions, such as how to define who is “immunocompromised.” ACIP also addressed practical concerns such as how such information should be presented and validated, and whether booster shots—given the current combination of vaccine shortages and refusals—will promote equity. 

ACIP was also instrumental in lifting the mid-April “pause” on distributing doses of the Johnson & Johnson vaccine. Back in mid-April, both the FDA and CDC recommended halting the distribution of the J & J vaccine over concerns related to cerebral venous sinus thrombosis (CVST), a rare type of blood clot. ACIP then convened two meetings to assess the relative risk, including one the day after its parent agency and the FDA’s announcement. A second meeting, after ACIP received more information about the relative incidence of CVST—especially as compared to the effectiveness of the J & J vaccine and the effects of COVID-19—resulted in ACIP voting to lift the pause, which both the FDA and CDC shortly agreed to thereafter. ACIP’s advisory role thus was critical in controlling access to FDA-authorized vaccines.

Beyond these recent examples, many are likely familiar with ACIP as initially establishing recommendations about “phasing” the initial doses of the vaccines in the early days of their authorization. While thirty states put ACIP’s recommendations for the initial prioritization phase into practice, most states diverged from ACIP’s framework in later prioritization phases. While somewhat controversial, at least at the time, ACIP’s “work has long included the identification of priority groups for vaccine allocation when supplies are limited,” and it was unclear whether ACIP would take a back seat to the FDA, the CDC, or the White House prior to the vaccines’ authorization. This was complicated by competing allocation mechanisms proposed, separately, by the White House and the National Academies of Science, Engineering and Medicine. States’ buy-in to ACIP’s protocol (at least initially) likely speaks to ACIP’s trustworthiness and independence—important attributes when issues regarding vaccine access are increasingly politicized.

What lessons might policymakers learn from ACIP’s processes about innovation and access to new healthcare technologies?

ACIP’s public process demonstrates the value of transparency in making decisions with substantial public import. The deliberations, and the information involved in making decisions, are widely available to members of the public, which, ideally, helps increase public trust and increase legitimacy. Some other decisional bodies have done a similar job of maintaining transparency, like VRBPAC, which has also held public meetings with available background information. The transparency of ACIP and VRBPAC stands in contrast to some other pandemic-related agency decisionmaking, such as the leaked internal slide deck that provides the primary insight into the CDC’s decision to reimpose mask mandates after the rise in Delta infections. Transparency is unlikely to solve every issue pertaining to vaccine access and refusal. But opacity does no one any good.

Second, and also like VRBPAC, ACIP is an expert body, and its process highlights the importance of relying on scientific expertise to make key scientific policy decisions. As noted above, its members bring different areas of expertise—though like for VRBPAC and the Biden Administration’s COVID-19 task force, social scientists are notably absent. Nevertheless, involving a wide array of scientific and epidemiological experts has helped lead ACIP to make better decisions with better claims to legitimacy. 

Third, these two features—transparency and scientific expertise—are particularly important in maintaining public trust under conditions of uncertainty: when the science changes, policy should change too. But it’s best to persuasively justify those changes to convince the public they are indeed the right choices. COVID-19 has been a rapidly changing pandemic and ACIP’s measured and public involvement in decisions about how to distribute vaccines—including how many doses to allocate and how to account for variant evolution—has been helpful to the public, agencies, and vaccine manufacturers. Transparency and expertise help demonstrate that these policy evolutions are considered and careful, and not fly-by-night reversals for political reasons.

Finally, from an innovation and access standpoint, it is worth noting that ACIP plays a role that is often underappreciated in the standard biopharmaceutical innovation story. While it does not approve or authorize vaccines like the FDA, ACIP complements the FDA by bridging the policy space between market access and market uptake for vaccines. It is a trust repository—and, consequently, a driver of demand—in helping determine which products make it into widespread adoption and which are consigned to relatively infrequent use. ACIP’s role here stands in stark contrast to the ongoing debates over the expensive Alzheimer’s drug Aduhelm, approved by the FDA in a hotly debated and criticized process. Now a constellation of other actors are deciding whether to recommend, use, or pay for the drug at all, demonstrating a lack of trust in the drug’s approval process. ACIP, however, takes these sorts of equity, cost-effectiveness, and public health considerations into account. In the context of arguments about whether the FDA should consider cost or public health in its own decisions, and about the appropriate role of other gatekeepers and their independence from FDA decisions, it is worth considering whether an ACIP-like entity might be equally useful in other biomedical innovation contexts.

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

What’s happening with proposals for a WTO waiver of COVID-related IP?

By Nicholson Price, Rachel Sachs, Jacob S. Sherkow, and Lisa Larrimore Ouellette

If COVID-19 were a pandemic movie, we’d be very close to the end since we’ve identified several excellent vaccines; the conventional biomedical innovation narrative often ends with the product being fully developed. But we’ve still got a long way to go with COVID-19, and the biggest challenge is getting the vaccines to billions more people (and getting them to take the vaccines, but that’s a separate topic). Only 0.3% of global doses have been administered in low-income countries, many of which are confronting severe outbreaks. A staggering 1 million infections were reported in Africa in just one month, with few vaccines in sight. By some estimates, much of the world’s population won’t be vaccinated until well into 2023. Amid pledges of sharing vaccines, perhaps the most prominent policy debate today is about waiving intellectual property rights to COVID-19 technologies, including vaccines. In this post we explain what’s being proposed, what’s happening with the waiver negotiations, and what impact these negotiations might have.

What does TRIPS require at baseline? 

Negotiations over the intellectual property rights supporting COVID-19 technologies are taking place against the backdrop of the World Trade Organization (WTO) Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). The TRIPS Agreement creates obligations for WTO member states (with exceptions for least-developed countries). For example, member states must provide inventors with the opportunity to obtain patents that last for 20 years from the date of filing, and must provide for patent protection for pharmaceutical products, rather than processes alone.

Only member states can enforce TRIPS obligations. Members who wish to initiate dispute resolution proceedings against other countries they believe are violating TRIPS may do so through the WTO’s dispute resolution mechanism, with possible trade sanctions as a remedy. But since December 2019, the WTO’s Appellate Body—charged with hearing appeals and resolving inconsistent settlement panel rulings—has lacked a quorum. As a result, the WTO’s ability to resolve disputes and engage in enforcement is now limited, as dispute resolutions are only binding if neither party appeals or the appeal is resolved. The Trump Administration spent years blocking any potential nominees to the appeals panel, and thus far, the Biden Administration has done the same.

TRIPS Article 31 and 31bis do permit member states to engage in compulsory licensing, permitting either “use by the government or other third parties authorized by the government,” as long as certain conditions are met, including “adequate remuneration” paid to the rightholder. Originally, TRIPS only permitted compulsory licensing for domestic production—and although many countries did have the ability to produce their own pharmaceuticals, not all did. In the COVID-19 context, for instance, most countries currently lack facilities with capacity to produce COVID-19 vaccines. Africa, for example, currently only has three existing facilities with vaccine substance manufacturing capacity, one each in Egypt, Tunisia, and Senegal, though others are planned. None currently make mRNA-LNP vaccines.

In 2005, an amendment to the TRIPS Agreement was approved (though it was first agreed to in 2003 and not formally ratified until 2017) that would enable member states to produce a pharmaceutical product subject to a compulsory license solely for purposes of export to another eligible member state. In theory, this provision would allow a country with current capacity to manufacture COVID-19 vaccines to issue a compulsory license for the production and export of the vaccines to developing countries. But the procedures established by the amendment were complicated, and the amendment has only been used once—in 2007, when Rwanda used it to import HIV medications manufactured in Canada.

To be sure, formal WTO sanctions are not the only deterrent to compulsory licenses. Countries who engage in compulsory licensing also may worry about unilateral action outside WTO procedures—such as pressure exerted by the United States through its Special 301 Report—as well as retaliation from companies who are the subject of those licenses. In 2007, after Thailand issued compulsory licenses on a number of HIV-AIDS medications, Abbott Laboratories—the manufacturer of one of those drugs—retaliated by declaring that it had “elected not to introduce new medicines” into the country. 

How would the IP waiver proposal work and how are negotiations progressing?

In October 2020, two WTO members, India and South Africa, proposed a waiver of certain provisions of the TRIPS Agreement, namely, Sections 1 (copyrights), 4 (industrial designs), 5 (patents), and 7 (trade secrets) of Part II of TRIPS. The stated aim of the waiver was to “meet the growing supply-demand gap” of COVID-19 related medical products through the “unhindered global sharing of technology and know-how in order that rapid responses for the handling of COVID-19 can be put in place on a real time basis.” That is, by removing TRIPS requirements for domestic IP enforcement, affected countries could—according to the proposal—more easily manufacture COVID-19 related medical products. The basis for such a proposal was stated as stemming in part from “several reports about intellectual property rights hindering or potentially hindering timely provisioning of affordable medical products to the patients,” namely, two newspaper articles (one from Bloomberg, the other from the Louisville Courier Journal) about N95 mask shortages early in the pandemic. (Both articles focused on the N95 mask shortage early in the pandemic and whether the Defense Production Act could have been invoked to increase their supply. We previously wrote an explainer about the Defense Production Act and the mask shortage.) 

The biggest surprise in subsequent IP waiver discussions, perhaps, is the support from the U.S. Trade Representative, the agency responsible for negotiating trade agreements. On May 5, the USTR announced the Biden Administration’s support for waiver of WTO rules for vaccine-related IP and the U.S.’s participation in “text-based negotiations” at the WTO. India and South Africa’s broader IP waiver proposal, as of May 18, had 62 co-sponsors, and an amended version of the proposal was submitted to the WTO on May 25. 

India and South Africa’s waiver, as currently proposed, is expansive. It is not limited to vaccines, but includes any “health product technologies” used for the “prevention, treatment or containment of COVID-19.” The waiver would last for 3 years, although termination would not be automatic but instead require an agreement of the General Council, i.e., WTO consensus to end the waiver period. (This would make ending the waiver just as difficult as enacting it.) Mechanically, the waiver would not automatically end covered IP rights in any given country; rather, it would allow member states to engage in certain IP practices—diminishing of trade secrets, issuing compulsory licenses—or change their domestic IP laws without the threat of being haled into a WTO dispute. The extent to which countries would change their domestic laws remains unclear. But countries could not use WTO enforcement mechanisms to curtail such practices.

Implementing a WTO waiver is easier said than done. WTO decision-making normally involves the consensus of all 164 members. Currently, consensus seems unlikely given the opposition by Germany (home to CureVac and BioNTech), South Korea, Switzerland, Japan, the UK, and Australia, among others. Theoretically, if consensus cannot be reached, WTO rules permit waiver proposals based on a vote by three-fourths of all members (i.e., 123 countries) if floated by the WTO’s Ministerial Conference, but this is exceptionally rare: “[I]n practice, almost no matter has been decided by voting.” And even if the voting option were pursued, as of this writing, the number of WTO members supporting IP waiver is only about half of the votes needed. 

Negotiations also take time. TRIPS Council members have been negotiating the waiver proposal in June and July, with plans to report to the WTO General Council July 27-28—but the informal negotiations paused without obvious progress as the negotiators recessed until September. It seems unlikely that negotiations will be concluded before the next Ministerial Conference (November 30 to December 3 in Geneva). And even if some version of IP waiver makes it through the WTO in December, national-level implementation would take additional time.

What impact would a WTO IP waiver have?

The importance of the waiver proposal has been contested by academics. Over 180 IP faculty signed a letter in support of the waiver, stating that “existing provisions within the TRIPS Agreement are not sufficient in a pandemic context, whereby global access to vaccines produced at speed and scale is in all our interests.” If the costs of negotiating licenses with separate IP rightsholders or seeking compulsory licenses is deterring firms with manufacturing capacity, an IP waiver could reduce these problems (assuming national action to subsequently alter IP rights). On the other hand, a different group of IP faculty have argued that “IP rights might so far have played an enabling and facilitating rather than hindering role in overcoming Covid-19, and that the global community might not be better off by waiving IP rights, neither during nor after the pandemic.” 

As we have explained, for COVID-19 vaccines, a waiver of patent rights alone would likely have little impact. Jorge Contreras has argued that “the main benefit of the waiver could be in the area of non-patent IP,” such as a country attempting to “mandate that foreign companies operating in the country disclose their proprietary manufacturing, storage, and testing information to local producers under a compulsory license.” To be clear, waiving trade secret laws related to COVID-19 vaccines would not automatically lead to sharing of manufacturing information, training of personnel, or access to scarce raw materials. These are significant barriers, as detailed by Christopher Rowland in his Washington Post account of Pfizer’s manufacturing troubles. Nor is it clear how a mandatory disclosure obligation would work against a recalcitrant manufacturer; there are few, if any, guides. As Contreras notes, mandatory trade secret transfer “would be unprecedented in the international arena.”

An IP waiver is not the only international proposal for expanding access to COVID-related technologies. The G20 has floated a voluntary IP licensing scheme. The EU has issued its own WTO proposal that focuses on limiting export restrictions, expanding domestic manufacturing production, and operationalizing the sharing of manufacturing information and licensing. Wealthy countries like the United States can also donate excess supply—and help purchase additional doses for the rest of the world (though some barriers exist). As we stated in August of last year: “[T]he economic and public health impact of COVID-19 counsels that whatever risk exists from payers overpaying for a patent-protected COVID-19 vaccine is a mere rounding error compared to the enormous harm—both economic and human—from the pandemic. If Pfizer stands to reap $2 billion to end a scourge that has already claimed 700,000 lives and stands to cost $82 trillion globally, it’ll be worth it.” Since then, the number of lives claimed has increased nearly six-fold, and vaccine distribution has become an international tragedy. Expanding global access to effective COVID-19 vaccines should be an urgent priority for policymakers in the United States and abroad—no matter which policies end up helping us get there.

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

Why do differences in clinical trial design make it hard to compare COVID-19 vaccines?

By Lisa Larrimore Ouellette, Nicholson Price, Rachel Sachs, and Jacob S. Sherkow

The number of COVID-19 vaccines is growing, with 18 vaccines in use around the world and many others in development. The global vaccination campaign is slowly progressing, with over 3 billion doses administered, although the percentage of doses administered in low-income countries remains at only 0.3%. But because of differences in how they were tested in clinical trials, making apples-to-apples comparisons is difficult—even just for the 3 vaccines authorized by the FDA for use in the United States. In this post, we explore the open questions that remain because of these differences in clinical trial design, the FDA’s authority to help standardize clinical trials, and what lessons can be learned for vaccine clinical trials going forward.

What were the key differences in how clinical trials were run for COVID-19 vaccines?

Clinical trials for COVID-19 vaccines differed along a surprising number of dimensions based on manufacturer choices: the number of doses, the spacing between multiple doses, the amount of vaccine per dose, the patients studied, and the endpoints tested. Because the trials were conducted at different places and at different times, the prevalence of COVID-19 variants also differed. These differences matter because clinical trials are the best source of rigorous information about vaccine efficacy, and differences in the way those trials were conducted limits the ability to compare the vaccines meaningfully.

Doses administered. Vaccines are given in one or two doses. The J&J vaccine was studied and is administered in one dose (indeed, many people sought out J&J for this reason), but J&J is now studying the effect of a booster shot. When the Pfizer-BioNTech and Moderna vaccines were initially tested, a first dose was followed by a relatively weak immune reaction, and a second dose triggered a strong reaction. The Oxford-AstraZeneca and Novavax vaccines showed the same pattern. Nevertheless, rigorous evidence about the performance of two-dose vaccines after only a single dose is lacking, because that scenario was not tested in the pivotal clinical trials. 

Dose spacing. Two-dose vaccines were administered at significantly different intervals. Moderna was tested at a four-week interval, Pfizer-BioNTech and Novavax at three weeks. Oxford-AstraZeneca was the only prominent vaccine where trials included different spacing between doses (for a small number of patients), testing four- to twelve-week intervals. They found that longer inter-dose gaps provoked a greater immune response, which was used as support for the UK’s controversial Dec. 30 decision to expand the gap between doses—including for the Pfizer-BioNTech vaccine where changing the dose spacing hadn’t been tested. A later study found that an increased gap for Pfizer boosted immune response in the elderly. The United States saw similar proposals to expand the gap between doses to get more people vaccinated (with at least one dose) faster, but evidence for the real-world effects remains unknown—because, as the CDC has emphasized, a longer gap was not tested. 

Vaccine per dose. Vaccines differed substantially in the amount of vaccine per dose in clinical trials—and consequently in the amount of vaccine given to patients. For instance, Moderna vaccines were tested with 100 micrograms of mRNA per dose, while Pfizer-BioNTech was tested with 30 micrograms per dose. Would Moderna be effective with lower doses? In January the FDA said changes to dosing or schedule were “premature and not rooted solidly in the available evidence.” In February, Moderna published results from a Phase 2 trial showing that half-doses of 50 micrograms were as good as full-doses at generating a strong immune response, but experts cautioned against extrapolating immunogenicity data to make conclusions about real-world performance.

Study populations. Vaccines were studied in different populations, based in part on recruitment efforts and in part on trials being conducted in different countries. Globally, for instance, the J&J patient population was 45% Hispanic and/or Latinx, Pfizer-BioNTech 26% and Moderna 20%. Given disparities in COVID-19 impact on different communities, disparities in vaccine access, and a history of biased clinical trial populations, balanced vaccine demographics are particularly important. Population age also differed, though less starkly (even setting aside pediatric trials); 25% of Moderna’s patients were 65 or older, but only 21% of Pfizer-BioNTech’s. (Notably, even knowing whether the comparisons are apples to apples is nontrivial; Moderna’s reported age breakdown was 18-65/older, Pfizer’s was 16-18/16-55/55+/65+/75+, and J&J’s was under/over 60). 

Endpoints. Manufacturers also chose different endpoints for their clinical trials. What were the endpoints? Pfizer-BioNTech measured efficacy against any symptomatic infection beginning seven days after the second vaccine dose. Moderna also measured any symptomatic infection, but not until two weeks after the second dose. And J&J measured cases both at two and four weeks after its single dose—but counted only cases of moderate-to-severe COVID-19 (including a positive test). These differences make it difficult to compare even topline results. 

Variants. Finally, clinical trials occurred at different times and in different countries—which means that the prevalence of viral variants also differed. Pfizer-BioNTech’s and Moderna’s vaccines were tested before variants of concern were widely circulating, making it harder to know how effective they are against variants. J&J’s vaccine, on the other hand, was tested in South Africa when the Beta variant was spreading there, and it showed lower efficacy in preventing infection in South Africa (57%) than in the United States (72%), though still strong protection (85%) against severe illness. Three months ago we described the existing data on vaccines and variants, including the lack of clinical trial evidence for most vaccine/variant combinations. Studies from England and Scotland suggest Pfizer and AstraZeneca vaccines offer somewhat reduced protection against infection by the highly transmissible Delta variant, but similar protection against severe illness. But these studies are not randomized controlled clinical trials.

What legal authority does the FDA have to help standardize clinical trials?

As we discussed in our last post, the FDA’s decision whether to grant either emergency use authorization (EUA) or full approval under a Biologics License Application (BLA) is based on standards specified by statute. But the FDA has also published a range of regulations and guidance documents governing the clinical trial process. These requirements do compel some standardization throughout the drug development timeline, though some requirements are more procedural than substantive (such as the submission of clinical data in standard formats). 

More substantively, even though the FDA has been pushing clinical trials “in the direction of standardization” since before World War II, many important scientific aspects of the clinical trials process remain up to sponsors’ discretion. The pharmaceutical companies themselves choose, in their best scientific judgment, the right dosage and route of administration for their new products. In the case of the COVID-19 vaccines, the FDA was unlikely to second-guess the manufacturers’ choice of one versus two-dose vaccines, the spacing of those vaccines, or the dosage within each vaccine. 

From the perspective of generating comparative clinical effectiveness information, these decisions (about dosage and spacing) may be less important than decisions about clinical trial design, including enrollment and the selection of appropriate endpoints. The FDA did release helpful guidance in June 2020 to explain what it would be looking for in the development of COVID-19 vaccines. The FDA “strongly encourage[d]” sponsors to enroll “populations most affected by COVID-19, specifically racial and ethnic minorities.” Although the agency did not require sponsors to meet certain benchmarks for the diversity of their trials, Moderna did slow the enrollment of their trial briefly to ensure that their trial population was more representative of the U.S. public, after initially enrolling fewer people of color than anticipated.

The FDA also specified important features of the clinical trial design, including appropriate endpoints. Noting that “[s]tandardization of efficacy endpoints across clinical trials may facilitate comparative evaluation of vaccines,” the FDA recommended that “either the primary endpoint or a secondary endpoint… be defined as virologically confirmed SARS-CoV-2 infection” with one or more specified symptoms, and that sponsors should also evaluate severe COVID-19, defined as confirmed infection plus particular indicators of severity. Despite the FDA’s efforts to standardize these endpoints, though, the manufacturers chose—and were approved to use—endpoints which cannot be compared in a straightforward way.

Another feature of the COVID-19 pandemic may have given the government as a whole more visibility into and oversight of the clinical trials process here: Operation Warp Speed. Although the FDA does work with sponsors throughout the development process, the development of COVID-19 vaccines featured a particularly high level of government involvement and coordination of clinical trials for companies opting in to that process (as Moderna and other companies did). In theory, Warp Speed could have used that funding to attempt to exert a greater degree of standardization over the clinical trials involved here.

What lessons can be learned for vaccine clinical trial design going forward?

Greater standardization of clinical trial design could have made the existing COVID-19 vaccines more comparable. But standardization also has costs. Compelling the standardization of trials on less than ideal or ambiguous endpoints, for example, would allow easier comparisons at the cost of less informative studies. Standardization of treatment protocols—say, the number of days between shots for two-dose vaccines—would yield some comparative insights but would diminish opportunities for optimization, essentially variations that yield information about improving vaccine candidates under trial. For the COVID-19 vaccines, we still don’t know the optimal number of weeks between doses, and standardizing a given time-period from the outset would have done little to elucidate that. Ditto for the optimal dose of the vaccine, be it, for example, 100 or 30 micrograms of mRNA, or something greater, smaller, or in between. 

At the same time, compelling each manufacturer to test these variations would have come at the cost of losing statistical power and increasing the time before vaccines could be authorized—a tragedy in a pandemic where more than 10,000 lives are lost each day. Vaccine developers were able to create multiple safe and effective vaccines on an unprecedented timeline in no small part because of the simple trial designs. So, while the lack of standardization is easy to critique, the triumph of studying these vaccines under immense time pressure should be lauded.

That doesn’t mean there are no future opportunities to improve. Additional trials will be needed to resolve a variety of open scientific questions about the vaccines and the virus, such as whether boosters are needed to combat variants, as well as the safety and effectiveness of the vaccines in pediatric populations. A recent Perspective in Nature calls for a similar strategy, to design post-licensure clinical trials “addressing vaccine effectiveness, including the level of protection of both vaccinated and non-vaccinated individuals in entire targeted populations.” Making the most of these studies—and making the results comparable across vaccines—will require some effort at standardization, balanced with the need to deliver more vaccine to low-income countries without being exploitative.

While the FDA and other regulators shouldn’t necessarily micromanage trials, especially for novel technology, agencies could learn from the successes of a large-scale, umbrella clinical trial: RECOVERY. The initial vaccine trials did not have an adaptive, multi-arm design, but now that several vaccines are available, future trials perhaps should have such an adaptive design. The WHO’s 2018 plan for designing vaccine trials during a public health emergency noted the advantages of trials with “multiple vaccine candidates and a control comparator arm” and “adaptive strategies to drop poorly performing candidates.” Going forward, especially with testing on pediatric populations, this could include differing dosing options for a single vaccine.

While these lessons are directed to the COVID-19 vaccines, they should be broadly generalizable, including to non-vaccine interventions. A lack of comparative effectiveness data for the COVID-19 vaccines exists precisely because these problems exist more generally. Thinking through their solutions now should help us for the next pandemic. As the saying goes, researchers investigating clinical trial design shouldn’t let a serious crisis go to waste.

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

What’s the difference between vaccine approval (BLA) and authorization (EUA)?

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.