As research into COVID-19 treatments and vaccines continues to progress, Bass, Berry & Sims attorneys Clint Hermes and Nikki Wethington authored an article for the American Bar Association (ABA) discussing the public policy dilemma facing the Food and Drug Administration (FDA) as it must balance the need for controlled clinical trials to demonstrate safety and efficacy of these treatments and vaccines against the need to make these products available quickly.
The authors outline the benefits of well-controlled clinical trials as well as two mechanisms available to the FDA to permit the treatment and use of medical investigational products that have not yet been approved. These mechanisms include expanded access (sometimes called “compassionate use”) and Emergency Use Authorizations (EUAs). “Both of these mechanisms can, under appropriate circumstances, provide doctors with tools that, although unproven, might benefit patients who lack alternatives to fight serious diseases,” the authors explained. “When deployed widely, however, they both have the potential to disrupt the clinical trials needed to generate evidence to determine whether these products are safe and effective.”
In considering expanded access or EUAs to meet the public health emergency’s need, the FDA and drug developers must balance their desire to respond quickly with requirements to determine the treatment is safe and actually works. To get product approval, the FDA requires applicants to demonstrate a drug’s efficacy and safety based on “substantial evidence,” which is typically established by two well-controlled clinical trials. However, these can present challenges in a crisis due to the time needed and criteria that must be met to participate in a clinical trial. While clinical trials produce the best data to determine safety and efficacy, that high quality data takes time to generate, and some people are hesitant to participate in the control (standard of care or placebo) arms of these studies.
As of publication, the FDA had examined several treatments as candidates for the expanded access or EUA processes, and the articles discusses a few that illustrate the public policy balancing act at issue, including, for example convalescent plasma treatment IND run by the Mayo Clinic and vaccine research. For vaccines, the FDA stated it would hold developers to a higher standard the “may be effective” bar set by the statute authorizing EUAs.
The full article, which also discusses the process for approving early access to COVID-19 treatments, is titled “Balancing Hope and Proof: Investigational Products During the COVID-19 Pandemic,” and was published in the December 2020 issue of Health Lawyer, a publication of the ABA’s Health Law Section and is available to members. The full content is also provided below and used with permission from ABA.
Balancing Hope and Proof: Investigational Products During the COVID-19 Pandemic
originally published in December 2020 issue of Health Lawyer, a publication of the ABA’s Health Law Section
On October 2, 2020, the White House announced that President Trump received an investigational antibody cocktail (REGN-COV2) for COVID-19 made by Regeneron Pharmaceuticals, Inc. REGN-COV2 is still in clinical trials and has not been approved for any use by the Food and Drug Administration (FDA). In general, the federal Food, Drug, and Cosmetic Act (the Act) prohibits “new” drugs and biological products (such as antibodies and vaccines) from being introduced or delivered for introduction into interstate commerce without prior approval from the FDA.1 A commonly understood exception to this prohibition is that new drugs may be shipped for FDA-regulated clinical trials under an Investigational New Drug application (IND) pursuant to 21 C.F.R. Part 312. President Trump, however, did not participate in the clinical trials studying REGN-COV2. So how did he get this experimental product?
There are two principal mechanisms the FDA has at its disposal to permit the use of unapproved products in certain circumstances outside of clinical trials: expanded access (sometimes called “compassionate use”) and Emergency Use Authorizations (EUAs).2 Both of these mechanisms can, under appropriate circumstances, provide doctors with tools that, although unproven, might benefit patients who lack alternatives to fight serious diseases. When deployed widely, however, they both have the potential to disrupt the clinical trials needed to generate evidence to determine whether these products are safe and effective.
This article provides a brief overview of this dilemma and how the FDA is approaching it during the COVID-19 pandemic.
Overview of Pathways to Access Experimental Treatments
The FDA has long facilitated access to investigational drugs for patients with serious or immediately life threatening diseases or conditions when those patients lack therapeutic alternatives. The terms “serious disease or condition” and “immediately life threatening disease or condition” have lengthy regulatory definitions,3 but the FDA has considered COVID-19 to qualify in light of the public health emergency and national emergency declared by the secretary of Health and Human Services4 and the president,5 respectively. Under the FDAs current regulations, there are three categories of expanded access, depending on the size of the treatment population (e.g., individual patients, intermediate-size patient populations, or widespread use). In addition, because of the declaration of a public health emergency, the FDA may allow unapproved medical products or unapproved uses of approved medical products to be used to diagnose, treat, or prevent COVID-19 under an EUA.6 In general, EUAs expire at the end of the public health emergency unless they are revoked earlier.
Both of these pathways have additional regulatory or statutory requirements and are available only at the discretion of the investigational product manufacturer. Importantly, to authorize expanded access, the FDA must determine that expanded access to the drug for the requested use will not interfere with the initiation, conduct, or completion of clinical trials that could support marketing approval of the drug. Generally, patients must be ineligible or otherwise unable to enter ongoing clinical trials to receive the drug under expanded access (e.g., geographically unable to access a study site). The FDA determines whether an expanded access use will interfere with clinical trials based on the information provided by the sponsor of the clinical trial7 in its expanded access submission. If the information provided by the sponsor is not adequate for the FDA to make this determination, the FDA may ask the sponsor for additional information. For example, before authorizing a treatment ND for a drug for which clinical trials are ongoing, the FDA may ask the sponsor to explain how the sponsor will ensure that the treatment IND will not interfere with the accrual of patients in the clinical trials and how the sponsor will determine whether interference is occurring if such information is not provided in the expanded access submission. More specifically, the FDA may ask the sponsor to submit with its IND a comprehensive investigational plan with a timetable and milestones (if it has not done so already) so that the FDA can periodically assess whether the treatment IND is affecting accrual of patients in the clinical trials or other parameters related to the pace of drug development.8
There is no similar explicit requirement under the EUA framework, and only a small number of pre-COVID-19 EUAs have been issued,9 but the FDA did express similar concerns in COVID-19 vaccine guidance issued in June 2020, noting:
[i]ssuance of an EUA for a COVID-19 vaccine prior to the completion of large randomized clinical efficacy trials could reduce the ability to demonstrate effectiveness of the investigational vaccine in a clinical disease endpoint efficacy trial to support licensure, and such clinical disease endpoint efficacy trials may be needed to investigate the potential for vaccine-associated ERD [Enhanced Respiratory Disease]. Thus, for a vaccine for which there is adequate manufacturing information, issuance of an EUA may be appropriate once studies have demonstrated the safety and effectiveness of the vaccine but before the manufacturer has submitted and/or FDA has completed its formal review of the biologics license application.10
Evidence-Generating Benefits of Clinical Trials v. Speed of Availability under Expanded Access or EUA
While a public health emergency can highlight the need for programs like expanded access and EUAs, the FDA and drug developers must balance their desire to respond quickly to emerging pathogens with the public health requirement to determine (1) whether drugs and other biological products are safe and (2) whether these drugs and other biological products actually work.
Ordinarily, the FDA requires an applicant to demonstrate that a drug is effective based on “substantial evidence” and that the drug is safe. Most often, this is established by two well-controlled clinical trials.11 FDA regulations describe the characteristics of an adequate and well-controlled clinical tria1.12 While a variety of designs can meet the requirements, the general idea is that they should be randomized, involve sufficient controls, and enroll enough patients to provide high-quality data to distinguish the effect of a drug from any other potential influences (e.g., placebo effect).13 By contrast, expanded access protocols and EUAs involve fewer patients, few controls, and as a result provide fewer and less reliable data.
Currently, there are over 2,000 potential treatments for COVID-19 in clinical trials globally, a number that has led to calls for a centralized, coordinated coalition for COVID-19 research. These proposals are motivated, in part, by the desire to streamline research and therefore increase the speed with which reliable data is obtained and to avoid overuse of EUA in particular.14 While clinical trials produce the best data to determine safety and efficacy, the various requirements necessary to obtain that high quality data present drawbacks for participants, especially when those participants are facing a life-threatening disease. Clinical trial enrollees must meet certain criteria to participate, and the trials take time and involve extensive follow-up.15 In addition, participants may receive a placebo instead of the product being investigated. So it’s easy to see why, when alternative pathways like expanded access and EUAs become available, patients are less willing to enroll in clinical trials. It’s also easy to see why, especially during a public health crisis, the FDA and drug manufacturers want to use these pathways to provide greater access to potentially promising treatments. But doing so undoubtedly impedes the progress of clinical trials and can ultimately make clinical trials impossible to finish. In those cases, the United States must wait for data from other countries to determine whether experimental treatments that are being widely used are in fact effective.16
COVID-19 has provided multiple case studies that demonstrate how this balancing act can play out in real time.
Mayo Convalescent Plasma Program
At the onset of the COVID-19 pandemic, a number of randomized, controlled clinical trials began to test the efficacy of convalescent plasma to treat COVID-19.17 In April 2020, the FDA worked with the Mayo Clinic to develop an expanded access program for convalescent plasma therapy to treat COVID-19.18 The program involved more than 70,000 patients but did not include the controls that would be in place in a clinical trial. In August 2020, the FDA issued an EUA for the convalescent plasma therapy on the basis that it met the statutory requirements that the product “may be effective.”19 At the time, leading public health officials, including Dr. Francis Collins, Director of the National Institutes of Health, and Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, questioned the data, which at the time had not yet been peer reviewed. When the EUA was issued, many raised concerns about how a widespread EUA would impact the ability of researchers to enroll participants in clinical trials to ultimately demonstrate the efficacy of the product.20 In the interim, a research team in India published the results of a clinical trial that found convalescent plasma therapy to be ineffective, though other researchers have noted some flaws in the study’s design.21 In the United Kingdom, the RECOVERY trial has enrolled over 2,000 participants, and is currently thought to be the best opportunity to determine the efficacy of convalescent plasma treatment for COVID-19.22 The data from the Mayo Clinic EUA, on the other hand, will not be considered determinative.
Development of a COV1D-19 Vaccine
In an effort to expedite the availability of a COVID-19 vaccine, the FDA is considering issuing an EUA for potential COVID-19 vaccines currently in development. In October 2020, it convened a meeting of its Vaccines and Related Biological Products Advisory Committee (VRBPAC) to seek input on this approach. VRBPAC members expressed concerns with an EUA for a COVID-19 vaccine, citing the risks this approach would pose for vaccine clinical trials currently underway. Members were worried not only about the ability of a vaccine to ultimately receive full FDA approval based on robust efficacy data, but also about the importance of data from a well-controlled clinical trial to provide convincing safety data for the public. Members noted that public trust of the drug development process, and vaccines in particular, is already low and raised concerns that a misstep would result in long-term consequences for the relationship between the public, the FDA, and the scientific research community. While the FDA intends to hold vaccine manufacturers to a higher EUA standard than the “may be effective” statutory floor, VRBPAC members expressed concern about how the process surrounding the EUAs already issued in connection with COVID-1923 (the EUA for hydroxychloroquine was subsequently revoked24 and the efficacy of convalescent plasma is in question25) has muddied the waters for the public in an already confusing process. Committee members suggested that if any shortened pathway were to be used, expanded access or a modified, stricter version thereof, would be a preferable route as it would require the continuation of robust clinical trials.26
Subsequently, Pfizer and BioNTech,27 Moderna,28 AstraZeneca and the University of Oxford29 have announced promising interim results from Phase 3 clinical trials. Each of these vaccines, and others still in earlier phases of the clinical trial process, functions differently and, in some cases, require multiple doses.30 As of the writing of this article, Pfizer and BioNTech and Moderna have each completed the efficacy portions of their clinical trials and applied for an EUA with the FDA on November 20, 202031 and November 30, 202032 respectively. The VRBPAC will meet on December 10, 2020 to discuss the Pfizer – BioNTech EUA application and on December 17, 2020 to discuss the Modern application. The FDA released a Federal Register Notice on November 27, 2020 with respect to the Pfizer and BioNTech EUA application and will be accepting comments until December 9, 2020.33
These developments have predictably increased optimism with respect to COVID-19, and various parties are beginning to speculate more seriously about when the general public could receive doses.34 Myriad logistical hurdles to distributing and administering these vaccines exist, and the Department of Defense, Centers of Disease Control and Prevention, and the Department of Health and Human Services are working in connection with state and local health departments to plan for distribution and administration of the vaccines.35
Logistical hurdles aside, it is important to note that the preliminary data is just that, preliminary; the data has not yet been peer reviewed, and there are other unanswered questions.36 Those unanswered questions become more difficult to resolve in a traditional EUA paradigm, especially when considered alongside emerging reports of trial participants eager to confirm they have received the vaccine and not a placebo contemplating dropping out of the tria1.37 The VRBPAC is facing the unenviable task of weighing the need for continued analysis of the data from these vaccine trials against the backdrop of surging numbers of COVID-19 cases across the country.
Clearly tremendous incentives exist to widely distribute safe and effective treatments for COVID-19. This need and desire for speed must be balanced, however, against the need for robust data to determine safety and efficacy and maintaining, or even rebuilding, public trust in the drug development process.
This article was submitted for publication on December 1, 2020 and does not reflect additional updates that may have followed.
1. See 21 U.S.C. § 331(d), 355(a). New drugs are drugs not generally recognized as safe and effective for their intended uses. 21 U.S.C. § 321(p). Biological products are considered drugs under the Act for these purposes.
2. Federal and state “right to try” laws are rarely used, do not involve the FDA, and are not discussed here.
3. 21 C.F.R. § 312.300(b).
4. Determination that a Public Health Emergency Exists (Jan. 31, 2020), https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-nCoV.aspx.
5. Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak (Mar. 13, 2020), https://www.whitehouse.gov/presidential-actions/proclamation-declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/.
6. 21 U.S.C. § 360bbb(2).
7. A clinical trial sponsor is the person, company, institution, group, or organization that oversees or pays for a clinical trial and collects and analyzes the data.
8. Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, US. Department of Health and Human Services, Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers, Guidance for Industry (2017), available at https://www.fda.gov/media/85675/download.
9. FDA issued EUAs in connection with Zika Virus, Ebola Virus, Middle East Respiratory Syndrome Coronavirus and H1N1 outbreaks. See Emergency Use Authorization – Archived Information, MCM Legal Regulatory and Policy Research (Oct. 22, 2020), available at https://www.fda.gov/emergency preparedness-and-response/mcm-legal-regulatory and-policy framework/emergency use-authorization-archived-information.
10. Center for Biologics Evaluation and Research, U.S. Department of Health and Human Services, Emergency Use Authorization for Vaccines to Prevent COVID-19 – Guidance to Industry 2017), available at https://www.fda.gov/media/142749/download.
11. The FDA will also consider types and combinations of trials, such as large, multi-center clinical trials. Center for Biologics Evaluation and Research, US. Department of Health and Human Services, Emergency Use Authorization for Vaccines to Prevent COVID-19 – Guidance to Industry 2017) available at https://www.fda.gov/media/142749/download.
12. 21 C.F.R. § 314.126.
14. Badley, A., Farrugia, G. and Mihaljevic, T, Needed: A National Coalition to Coordinate COVID-19 Clinical Trials, STAT+ (2020). https://www.statnews.com/2020/10/26/needed-a-national-coalition-to-coordinate-covid-19-clinical-trials/.
15. Thomas, K and Weiland, N., As Trump Praises Plasma, Researchers Struggle to Finish Critical Studies, New York Times (Aug. 28, 2020), available at https://www.nytimes.com/2020/08/04/health/trump-plasma.html.
16. See e.g. Caplan, A., We don’t know if convalescent plasma is effective against Covid-19. With the emergency authorization, we might never know, STAT (Aug. 24, 2020), available at https://www.statnews.com/2020/08/24/trump-opened-floodgates-convalescent-plasma-too-soon/.
17. Convalescent plasma therapy is antibody rich plasma donated by those who have recovered from a particular disease, in this instance, COVID-19. This form of treatment has been used in other outbreaks, including during the 1918 influenza pandemic and recent Ebola outbreaks. See Caplan, A., We don’t know if convalescent plasma is effective against Covid-19. With the emergency authorization, we might never know, STAT (Aug. 24, 2020) available at https://www.statnews.com/2020/08/24/trump-opened-floodgates-convalescent-plasma-too-soon/.
18. Food and Drug Administration, U.S. Department of Health and Human Services, FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID-19 Treatment, Another Achievement in Administration’s Fight Against Pandemic (2020), available at https://www.fda.govinews-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment.
20. Thomas, K and Weiland, N., As Trump Praises Plasma, Researchers Struggle to Finish Critical Studies, New York Times (Aug. 28, 2020), available at https://www.nytimes.com/2020/08/04/health/trump-plasma.html.
21. Kelland, K, Don’t Give Up on COVID-19 Plasma, Experts Say, After Study Finds No Benefit, Healthcare and Pharma, Reuters (Oct. 22, 2020), available at https://www.reuters.com/article/us-health-coronavirus-plasma/blood-of-recovered-covid-19-patients-shows-little-benefit-as-treatment-idUSKBN27738R.
22. Wickware, C., Hospitalised COVID-19 patients first in UK to receive antibody treatment in RECOVERY Trial, The Pharmaceutical Journal (Oct.19, 2020), available at https://www.pharmaceutical-journal.com/news-and-analysis/news/hospitalised-covid-19-patients-first-in-uk-to-receive-antibody-treatment-in-recovery-tria1/20208461.article.
23. Cohen, J., ‘There’s only one chance to do this right’—FDA panel wrestles with COVID-19 vaccine issues, Science (Oct. 23, 2020), https://www.sciencemag.org/news/2020/10/there-s-only-one-chance-do-right-fda-panel-wrestles-covid-19-vaccine-issues.
24. Doglin, E., Core Concept: The pandemic is prompting widespread use—and misuse—of real-world data, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STAFFS OF AMERICA (Oct. 21, 2020), available at https://wwwpnas.org/content/early/2020/10/20/2020930117.
25. Caplan, A., supra n. 16.
26. Cohen, J., supra n. 23.
27. Pfizer and BioNTech Announce Vaccine Candidate Against Covid-19 Achieved Success in First Interim Analysis from Phase 3 Study (Nov. 9, 2020), https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against.
28. Modern’s COVID-19 Vaccine Candidate Meets its Primary Efficacy Endpoint in the First Interim Analysis of the Phase 3 COVE Study (Nov. 16, 2020), https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy.
29. AZD1222 Vaccine Met Primary Efficacy Endpoint in Preventing COVID-19 (Nov. 23, 2020), https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222h1r.html.
30. Saplakogu, Here are the Most Promising Coronavirus Candidates out There, LiveScience (Nov. 25, 2020), https://www.livescience.com/most-promising-coronavirus-vaccine-candidates.html.
31. Pfizer and BioNTech to Submit Emergency Use Authorization Request Today to The U.S. FDA For Covid-19 Vaccine (Nov. 20, 2020), https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-emergency-use-authorization.
32. Modern Announces Primary Efficacy Analysis in Phase 3 COVE Study for Its COVID-19 Vaccine Candidate and Filing Today with U.S. FDA for Emergency Use Authorization (Nov. 30, 2020), https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-primary-efficacy-analysis-phase-3-cove-study.
33. Vaccines and Related Biological Products Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments 85 Fed. Reg. 76082 (Nov. 27, 2020).
35. Simunachi, L., Operation Warp Speed Refines Vaccine Delivery Plan, https://www.defense.gov/Explore/News/Artide/Artide/2423700/operation-warp-speed-refines-vaccine-delivery-plan/.
36. Lee, B., How Effective Will Covid-19 Coronavirus Vaccines Be? 8 Reasons It’s Too Early To Tell, Forbes (Nov. 27, 2020), https://www.forbes.com/sites/brucelee/2020/11/27/how-effective-will-covid-19-coronavirus-vaccines-be-5-reasons-its-too-early-to-tell/?sh=2bb526da1617.
37. Winkler, R., COVID-19 Vaccine Studies may Suffer as Trial Participants Consider Dropping Out, Wall Street Journal (Nov. 27, 2020), https://www.wslcom/articles/covid-19-vaccine-studies-may-suffer-as-volunteers-consider-dropping-out-11606485601.