Person receiving vaccine.

Why Do Differences in Clinical Trial Design Make It Hard to Compare COVID-19 Vaccines?

Cross-posted from Written Description, where it originally appeared on June 30, 2021. 

By Lisa Larrimore OuelletteNicholson PriceRachel 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.

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Emergency department entrance.

“Stick to the Science”? FDA, Ethics, and Pandemics

Cross-posted from COVID-19 and The Law, where it originally appeared on February 8, 2021. 

By

Throughout the current pandemic, Dr. Anthony Fauci and other public health experts have called on the government to “stick to the science.” This was at the same time that former President Donald Trump repeatedly undermined scientific expertise and prioritized political interests over responsible public health practices. Yet the particular ways in which the Trump administration mishandled the pandemic can divert attention from more fundamental challenges confronting government actors in any emergency — challenges that respect for science alone is insufficient to address. These challenges concern the norms guiding regulators’ exercise of their power under the law, as well as the proper role of values in public health and public policy more broadly.

FDA has struggled throughout COVID-19 to maintain high standards of integrity, including independence from undue political influence. We see this most clearly in the decisions FDA has faced in applying its power to issue emergency use authorizations (EUAs) for medical countermeasures against COVID-19. FDA’s experience using its emergency powers during COVID-19 speaks to the complex relationship between science and ethics in health policy — between empirical fact finding and normative questions involving ethics and public values.

This post reflects on the ethical implications of FDA’s use of its emergency powers, and suggests opportunities for greater accountability and more systematic decision-making by health regulators moving forward.

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Patient receives Covid-19 vaccine.

What’s the Difference Between Vaccine Approval (BLA) and Authorization (EUA)?

Cross-posted from Written Description, where it originally appeared on June 3, 2021. 

By Jacob S. SherkowLisa 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?

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people waiting in a line.

How the Government Can Prevent Individuals from Using Wealth to Cut the Vaccine Line

Cross-posted from COVID-19 and The Law, where it originally appeared on January 27, 2021. 

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Since the Food & Drug Administration granted emergency use authorization for the COVID-19 vaccines produced by Pfizer-BioNTech and Moderna in December 2020, there have been many debates on vaccine allocation and prioritization.

As noted by Harvard Law School Professor Glenn Cohen in a recent interview with Annie Kapnick for the COVID-19 and The Law series, the issue of vaccine distribution is “complicated” because of competing factors decision-makers must consider. The relative weights placed on these factors has led to very different prioritization schemes. Initially, the Centers for Disease Control and Prevention (CDC) recommended a hybrid plan that appeared to prioritize individuals who were most likely to contract the virus (e.g., first responders, grocery store workers) over individuals most vulnerable to severe symptoms or death from the virus if contracted (e.g., individuals over the age of 65 not in long-term care facilities). In the United Kingdom, the prioritization groups were primarily based on vulnerability. Similarly, when looking more narrowly at the various plans being implemented at the state level in the United States, there are high degrees of variation.

This post does not seek to evaluate the merits of these or other specific vaccine allocation plans. Rather, it will address a risk that all plans likely face: the potential of individuals using their wealth and access to “cut the line” and be vaccinated ahead of schedule.
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Syringe being filled from a vial. Vaccine concept illustration.

From 9/11 to COVID-19: A Brief History of FDA Emergency Use Authorization

Cross-posted from COVID-19 and The Law, where it originally appeared on January 14, 2021. 

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The ongoing fight against COVID-19 has thrown a spotlight on the Food and Drug Administration (FDA) and its power to grant emergency use authorizations (EUAs). EUA authority permits FDA to authorize formally unapproved products for temporary use as emergency countermeasures against threats to public health and safety.

Under § 564 of the Food, Drug, and Cosmetic Act (FD&C Act), use of FDA’s EUA authority requires a determination that an emergency exists by secretaries of the Department of Homeland Security, the Department of Defense, or the Department of Health and Human Services (HHS), as well as a declaration by the HHS Secretary that emergency circumstances exist warranting the issuance of EUAs. Each issuance of an EUA requires that FDA conclude that:

  • it is reasonable to believe that a given product “may be effective” as an emergency countermeasure,
  • the known and potential benefits of authorization outweigh the known and potential risks, and
  • no formally approved alternatives are available at the time.

Annie Kapnick’s post on COVID-19 and FDA’s EUA authority provides a helpful overview of FDA’s emergency powers and their use in response to the pandemic. A brief look at the history of FDA’s emergency powers, including key events leading up to their enactment — Thalidomide, swine flu, AIDS, and 9/11 — offers perspective on the situation facing FDA today and its implications for the future. The history of EUA illustrates how its use today against COVID-19 involves fundamental questions about the role of public officials, scientific expertise, and administrative norms in times of crisis.

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Washington, USA- January13, 2020: FDA Sign outside their headquarters in Washington. The Food and Drug Administration (FDA or USFDA) is a federal agency of the USA.

COVID-19 and the FDA Emergency Use Authorization Power

By Anne Kapnick

The Food and Drug Administration (FDA) is responsible for protecting public health by regulating the production, distribution, and consumption of food, cosmetics and drugs.[1] In the healthcare arena (the focus of this post), the FDA strives to ensure the safety, efficacy, and security of drugs, biological products, and medical devices.[2] The FDA also ensures that the “public get[s] the accurate, science-based information they need to use medical products and foods to maintain and improve their health.”[3] This blog post provides an overview of the FDA’s emergency authorization powers, analyzes the extent of their usage in the COVID-19 pandemic, and concludes by flagging potential concerns regarding the FDA’s management of this vast power.

Under normal circumstances, the FDA medical product approval process is rigorous and requires a high level of scrutiny. However, in times of emergency, like a nationwide pandemic, the FDA has certain tools it can use to make important medical countermeasures available quicker. One such tool is the Emergency Use Authorization (EUA) authority. Under § 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the FDA commissioner is allowed to temporarily authorize unapproved medical products or unapproved uses of approved medical products during certain types of emergencies—such expedited approval methods are known as an EUA. [4]

The FD&C Act §564 has three requirements for issuing an EUA: (1) the determination that an emergency exists by one of three specified cabinet members[5]; (2) the declaration of an emergency justifying the authorization of an EUA by the secretary of Health and Human Services (HHS)[6]; and (3) a finding by the FDA that specified statutory criteria have been met for the medical product in question. The third requirement, the FDA’s specified criteria, requires evaluating these products based on the best available evidence, weighing associated risks against potential benefits. For example, the FDA must conclude that it is reasonable to believe the product may be effective, that the known benefits outweigh the known risks, and that there is no adequate, approved, and available alternative.[7] Once an EUA is issued, it can be amended and may be revoked if the criteria for issuance are no longer met or if revocation is appropriate to protect public health or safety.[8] An EUA does not equate to FDA approval.

The FDA was quick to activate its emergency use powers for managing the COVID-19 pandemic.[9] On February 4, 2020, the HHS Secretary determined, pursuant to § 564, that COVID-19 is a public health emergency that “has a significant potential to affect national security or the health and security of United States citizens living abroad.”[10] On the basis of this determination, the Secretary subsequently declared that “circumstances exist justifying the authorization of emergency use of in vitro diagnostics for the detection and/or diagnosis of COVID-19 (February 4, 2020), personal respiratory protective devices (March 2, 2020), and other medical devices, including alternative products used as medical devices (March 24, 2020).”[11]

According to the FDA’s website, in response to the COVID-19 pandemic it has issued EUAs for an entire range of medical countermeasures including for: (1) in vitro diagnostic products, (2) personal protective equipment and related devices, (3) ventilators and other medical devices, and (4) drug and biological products. As of October 21, 2020, the FDA has 337 active COVID-19 related EUAs, comprised of:

  • 284 active EUAs for in vitro diagnostic products (this includes diagnostic and serology/antibody tests);[12]
  • 22 active EUAs for personal protective equipment and related devices;[13]
  • 26 active EUAs for ventilators and other medical devices;[14] and
  • 5 active EUAs for drug and biological products.[15]

In addition, there are at least 6 EUAs which have been revoked since the beginning of the pandemic.[16]

The scope and magnitude of the FDA’s use of its emergency authorization power during the COVID-19 pandemic is massive when compared with past emergencies. Based on data from the FDA’s website, the FDA issued only 38 EUAs during the Zika, Ebola, MERS, and Avian Flu emergencies combined. The below table summarizes the data:    

 

Emergency Current EUAs Terminated or Revoked EUAs Total EUAs
Coronavirus Disease 2019 (COVID-19) 337 (284 diagnostic) 6 (3 diagnostic) 344
Zika Virus 14 (14 diagnostic)[17] 6 (6 diagnostic) 20
Ebola Virus 10 (10 diagnostic)[18] 3 (3 diagnostic)[19] 13
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) 2 (2 diagnostic)[20] 0[21] 2
Avian Influenza (H7N9) 3 (3 diagnostic) 0 3

 

So far during the COVID-19 pandemic, the FDA has issued nearly 10x the number of EUAs issued in previous emergencies. As is evident from the above data, the vast majority (85%) of the EUAs issued during the COVID-19 pandemic concern diagnostic products. All of EUAs issued in prior emergencies were categorized as diagnostic products. This makes sense intuitively because the process for FDA approval of diagnostics is less rigorous than for therapeutics given the relative risks.

Given the unique nature of the virus that causes COVID-19, experts agree that rapid detection and widespread testing capabilities are necessary to control the spread of the pandemic. Because testing is such an integral countermeasure for controlling this virus, the FDA has focused extensively on “accelerat[ing] the availability of novel coronavirus (COVID-19) tests developed by laboratories and commercial manufacturers for the duration of the public health emergency.”[22] However, the sheer scale of the FDA’s emergency use powers should give us pause—especially when most of these tests are manufactured by profit-seeking corporations who have the financial incentive to push products out ahead of their competitors through the EUA process, before full reliability can be established.

Take, for example, Chembio Diagnostic Systems, Inc.’s DPP COVID-19 IgM/IgG System, which received emergency authorization on April 14, 2020 to detect IgM and IgG antibodies against SARS-CoV-2 (the virus which causes COVID-19) in blood specimens.[23] Chembio’s antigen diagnostic test sat on the market for three months before the FDA revoked its EUA on the grounds that “its performance may be both inconsistent and lower than that described in the request for Authorization.”[24] Chembio was one of the first companies to receive an EUA for an antibody test during the COVID-19 pandemic. The FDA noted that after analyzing subsequent data disclosure from the company and independent researchers, there were performance concerns about the accuracy of the test because it generated a higher than expected rate of false results.[25] The revocation letter further notes that “the risk to public health from the false test results makes EUA revocation appropriate to protect the public health or safety.”[26] Chembio Diagnostics Inc. is a public company. Its stock price rose from $4.70 on March 2, to a year-to-date peak of $15.54 on April 24 (following its EUA approval), before dropping to $3.89 on June 17 following the FDA’s revocation.[27] The stock price reflects the real value the EUA had in the market.

There are, of course, safeguards in the FDA emergency use process for in vitro diagnostic products. The FDA issued guidance outlining its policies for EUA diagnostic tests in February, and has revised this policy three times.[28] These policies help serve as a regulatory roadmap for manufacturers and assist in streamlining the EUA process.[29] One interesting case study is the FDA’s changed guidance on antibody testing. Before issuing the revised guidance, the FDA had released a letter warning to healthcare providers noting the limitations of antibody testing and why those tests results should not be used as the sole basis to diagnose COVID-19. As part of the revised policies, the FDA “provided specific performance threshold recommendations for specificity and sensitivity for all serology test developers.”[30] The FDA noted that as the pandemic progressed, the FDA had improved it understanding of the performance and expectations required for COVID-19 serology (antibody) tests, and that while a higher level of flexibility may have been appropriate in March, they now had sufficient understanding of antibody test performance and could set higher and more definitive standards.[31] At the time the FDA issued its revised guidance, 12 antibody tests had been authorized under individual EUAs.[32] The FDA subsequently revoked 2 (or 17%) of those tests on the grounds that they were now considered ineffective under the new guidelines.[33]

At the beginning of this pandemic, the FDA was faced with an urgent need to diagnose and treat individuals in order to prevent the spread of COVID-19. Section 564 of the FD&C Act provides the FDA with much needed flexibility in order to promote timely access to critical medical products. The impetus of the EUA power is that in extraordinary circumstances, we cannot always afford to wait for all the evidence to emerge. The FDA has also demonstrated that it is willing to adapt as it learns new information, but there are future questions and implications to explore once this pandemic is controlled. Most importantly, will the FDA’s extensive use and revision of emergency authorizations erode or undermine trust in FDA processes in the future? How rigorous should the continued review process be following an EUA, and who should bear that burden—the FDA, the company, or independent researchers? Are the current controls sufficient to safeguard consumer welfare and confidence? Does the consumer have enough information to make an informed decision about their testing options? Do we fully understand the risk of inaccurate diagnostic devices on public health? And finally, should there be greater hurdles for emergency authorization of diagnostic devices?

 

[1] See What We Do, U.S. Food and Drug Administration, https://www.fda.gov/about-fda/what-we-do (last visited Oct. 21, 2020).

[2] Id.

[3] Id.

[4] See Emergency Use Authorization, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization (last visited Oct. 21, 2020).

[5] This determination can be made by the secretaries of the Department of Homeland Security, the Department of Defense, or the Department of Health and Human Services. See Food, Drug, and Cosmetics Act § 564(b), 21 U.S.C. § 360bbb–3(b).

[6] Note that the §564 declaration of emergency is different from a determination of public health emergency under PHS Act §319 and a declaration of a public health emergency under the PREP Act.

[7] See Food, Drug, and Cosmetics Act § 564(c), 21 U.S.C § 360bbb–3(c).

[8] Id.

[9] The first U.S. cases of nontravel–related COVID-19 were confirmed on February 26 and 28, 2020. See CDC Confirms Possible Instance of Community Spread of COVID-19 in U.S., Centers for Disease Control and Prevention (Feb. 26, 2020),  https://www.cdc.gov/mmwr/volumes/69/wr/mm6922e1.htm.

[10] See Emergency Use Authorization, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization (last visited Oct. 21, 2020).

[11] https://www.fda.gov/medical-devices/emergency-use-authorizations-medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices

[12] See Emergency Use Authorization, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization (last visited Oct. 21, 2020).

[13] Id.

[14] Id.

[15] Id.

[16] See Emergency Use Authorization–Archived Information, U.S. Food and Drug5 Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization-archived-information#covid19 (last visited Oct. 21, 2020).

[17] See Emergency Use Authorization, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization (last visited Oct. 21, 2020).

[18]Id.

[19] See Emergency Use Authorization–Archived Information, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization-archived-information#covid19 (last visited Oct. 21, 2020).

[20] See Emergency Use Authorization, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization (last visited Oct. 21, 2020).

[21] While 2 EUAs expired, they have been reissued, and thus have current counterparts. See Emergency Use Authorization–Archived Information, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization-archived-information#covid19 (last visited Oct. 21, 2020).

[22] See Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised), U.S. Food and Drug Administration (May 11, 2020), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-coronavirus-disease-2019-tests-during-public-health-emergency-revised.

[23] Id.

[24] Revocation of Authorization of Emergency Use of an In Vitro Diagnostic Device for Detection of Antibodies Against SARS-CoV-2, the Virus That Causes Coronavirus Disease 2019 (COVID-19), U.S. Food and Drug Administration (July 14, 2020), https://www.federalregister.gov/documents/2020/07/14/2020-15138/revocation-of-authorization-of-emergency-use-of-an-in-vitro-diagnostic-device-for-detection-of.

[25] See id.

[26] Id.

[27] Chembio Diagnostics, Inc. (CEMI), yahoo! Finance, https://finance.yahoo.com/quote/CEMI/.

[28] See Emergency Use Authorization, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization (last visited Oct. 21, 2020).

[29] See Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised), U.S. Food and Drug Administration (May 11, 2020), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-coronavirus-disease-2019-tests-during-public-health-emergency-revised.

[30] Anand Shah and Jeff Shuren, Insight into FDA’s Revised Policy on Antibody Tests: Prioritizing Access and Accuracy, U.S. Food and Drug Administration (May 4, 2020), https://www.fda.gov/news-events/fda-voices/insight-fdas-revised-policy-antibody-tests-prioritizing-access-and-accuracy.

[31] See id.

[32] See id.

[33] See Emergency Use Authorization–Archived Information, U.S. Food and Drug Administration, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization-archived-information#covid19 (last visited Oct. 21, 2020).

 

This post was originally published on the COVID-19 and the Law blog.

Annie Kapnick graduated from Harvard Law School in May 2021.