With COVID-19 cases rising across the world, there is a tremendous sense of urgency to develop, test, and approve a variety of therapeutic and preventive interventions for the disease, including safe and effective vaccines. The health and economic costs of the pandemic have been astronomical. There is wide agreement on the pressing need to open up economies, jobs, and schools as soon as doing so is safely possible – and the swift production of a vaccine offers the most promising way to do that.
There is legitimate disagreement, however, on what level of evidence should be sufficient to justify an “emergency authorization”[1] for use of a vaccine by federal regulators. Such an authorization would allow the use of a novel vaccine that has shown early promise but that has not been through complete, rigorous testing for safety and efficacy. The 2004 law[2] that allows the U.S. Food and Drug Administration (FDA) to issue such Emergency Use Authorizations (EUA) during national emergencies requires only that “it is reasonable to believe that the product may be effective.” This low bar offers useful regulatory flexibility in an emergency, but risks being misused. In particular, using the EUA mechanism to encourage widespread adoption of an inadequately tested vaccine outside of clinical trials would be a mistake. How this process is – and should be – handled is especially fraught at a time of considerable pressures to politicize science and public health in dangerous ways.
The Pressure to Approve
Federal regulators have already come under intense political pressure to grant emergency use authorization for novel therapeutics for COVID-19. Examples have included hydroxychloroquine, which received an EUA from the FDA on March 28, 2020,[3] and remdesivir, which received an EUA on May 1, 2020.[4] But the revocation of the EUA for hydroxychloroquine in June, 2020,[5] just weeks after it was issued, illustrates the potential risks of using the EUA authority based on inadequate data and in response to political pressure. Very soon after the EUA was issued, further data emerged showing that hydroxychloroquine provided no benefit to patients with COVID-19 and could be harmful,[6] with the harm for some patients leading to death.
As the response to the COVID-19 pandemic has become increasingly politically polarized, there is growing concern that scientific findings might be hidden, manipulated, or manufactured for political purposes. In this regard, recent attacks[7] on federal regulatory and public health agencies and the career scientists in them have been alarming. The muzzling, intimidation, and forcing out or firing of scientists responsible for assessing evidence of the safety and efficacy of investigational drugs and vaccines directly threatens the integrity of the review process and undermines public health during the spread of a deadly, global pandemic. As concerning, these actions also harm public and professional trust in the process itself. This harm is already manifesting in rising rates of mistrust in any potential COVID-19 vaccines: a September 2020 Pew Research Center nationally representative U.S. survey,[8] for example, found an alarming 77 percent of those surveyed believed that it is very or somewhat likely a COVID-19 vaccine will be approved in the United States before its safety and effectiveness are fully understood.
As the response to the COVID-19 pandemic has become increasingly politically polarized, there is growing concern that scientific findings might be hidden, manipulated, or manufactured for political purposes.
Such mistrust may in turn erode confidence in other vaccines and treatment. As we have seen in prior epidemics, such as the Ebola virus disease outbreaks beginning in 2014, such distrust can result not only in poor uptake of effective treatments or vaccines, but even in community violence and resistance to other essential measures to contain an infectious illness.
In short, pressuring scientists to meet a political timeline poses an existential threat to the fundamental human right to benefit from the outcomes of medical science and to protection from infectious disease. Moreover, because shrouding political agendas in medical pseudo-science has a tragic history in the United States and around the world, health professionals today hold a profound obligation to guard against any politically motivated misuse of science.
Considerations for the Authorization of a COVID-19 Vaccine
Three major elements are essential to consider in decisions on authorizing use of a novel vaccine intended to protect against COVID-19.
- Ensuring safety is as important as ensuring efficacy. Any medication or vaccine that will be given to large numbers of healthy people must be carefully tested for safety as well as efficacy. The world learned this lesson through witnessing the deaths and deformities of thousands of babies only 70 years ago from the hasty approval of thalidomide. Safety concerns have already arisen with COVID-19 vaccine candidates, with two efficacy trials experiencing FDA-mandated pauses[9] while safety indicators are being assessed. While a great deal is known about vaccine science – and it bears reinforcing that existing, FDA-approved vaccines are safe and effective – it is equally important to recognize that some proposed COVID-19 vaccines are being built using novel methods, some are being tested by companies with no prior track record of bringing a vaccine safely to market, and all COVID-19 vaccines will be novel in that there are no prior vaccines against a coronavirus for humans.
- Corners cannot be cut in vaccine development and testing cannot be rushed. While steps can be taken to safely speed production and distribution of novel vaccines, development and testing of vaccines is one of the most scientifically and technically challenging processes in medical and biological science. To find safe and effective vaccines against COVID-19 requires multiple essential steps. First, it requires the engagement of many scientific teams working at the boundaries of molecular understanding and technology. Second, it requires testing and monitoring tens of thousands of volunteers from diverse populations – with different rates, intensities, and sources of exposure, among other epidemiological factors – over many months. This is necessary to ascertain whether one or several of the candidate vaccines are both safe and effective in achieving clinical outcomes, such as reduction of COVID-19 infections, disease severity, or mortality.
- Research on individuals without full informed consent and rigorous research oversight is unethical. Physicians and scientists who knowingly use inadequately tested interventions on human beings without appropriate oversight and/or without the full, informed consent of participants violate core principles of medical ethics, which were developed in the wake of appalling Nazi medical crimes against institutionalized and disabled people, stigmatized and powerless populations, and concentration camp inmates in the 1930s and 1940s. Authorization to use a vaccine before it is proven safe and effective would comprise de facto experimentation on those receiving the vaccine prior to completion of full testing. The reliability and completeness of the testing and approval processes are therefore of absolute importance.
The International Rush to Market
There is currently an international effort underway to develop, test, and manufacture safe and effective COVID-19 vaccines. The United States, through its Operation Warp Speed, has chosen to implement a series of large-scale Phase III safety and efficacy trials of five vaccine candidates. It is also pre-purchasing large volumes (100 million doses) of a sixth, the Pfizer vaccine. All these candidates were selected, as is appropriate, based on early phase safety and immunogenicity studies (Phase I and II vaccine trials in human volunteers). Phase III efficacy trials are underway. The major time-saving approach for the United States has been to simultaneously incentivize manufacture of the multiple candidate products, such that if a candidate is safe and effective, it may be immediately available at some scale.
Health professionals today hold a profound obligation to guard against any politically motivated misuse of science.
Other countries have bypassed this proven and essential pathway. Russia has approved a candidate vaccine without conducting a Phase III randomized controlled trial[10] for safety or efficacy. Russia’s Sputnik 5 vaccine is thus an untested product, and its use outside of clinical trials is an abuse of medical ethics, public health, and human rights. China has also begun immunizations in its armed forces personnel without Phase III efficacy and safety testing.[11] This, too, should be seen as inherently unethical and is a special case, since military personnel are often subject to immunization without consent for military preparedness reasons. The fact that many military personnel cannot realistically refuse vaccination means any vaccines given to soldiers must be fully vetted — not experimental.
An EUA for a U.S. vaccine prior to full safety and efficacy testing would risk putting the United States in the same category of a country violating fundamental safety and scientific principles around medical research ethics. Moreover, doing so with one vaccine candidate could also undermine other vaccine trials still underway or planned. This could have disastrous consequences by delaying the testing and use of a proven safe and effective vaccine, an essential tool that all agree will be required to control the COVID-19 pandemic.
A U.S. Failure of Governance
Many prominent practitioners and medical scientists have criticized the handling of the COVID-19 pandemic in the United States, saying, for example, that its national political leaders have “taken a crisis and turned it into a tragedy.”[12] This failure arose out of these leaders’ “refusal to look at the evidence and act accordingly”[13] and a “shameful record of interference in health and science agencies — thus undermining public trust in the very institutions that are essential to keeping people safe.”[14] A recent editorial in the Journal of the American Medical Association noted the “immense”[15] pressure on the FDA to authorize a vaccine prior to full testing for safety and efficacy, noting that “some clinicians, public health officials, and members of the public [are] bewildered about what is actually happening and concerned that vaccines will be made available before safety and effectiveness are fully established.”
To date, the U.S. response to COVID-19 represents a serious failure of governance. Much of this failure stems from the politicization of science and public health.
To ensure public and clinician trust in any vaccine that is approved, it will be essential both to support the regular scientific review process for a novel vaccine and to buttress transparency and communication about the evidence underlying any approved vaccine. This will mean ensuring full public access to data on safety and efficacy, as well as disclosure of all communications about safety and efficacy from the relevant vaccine trial Data Safety Monitoring Boards and with the FDA and Centers for Disease Control and Prevention (CDC) review committees. Finally, no vaccine should be approved by the U.S. Department of Health and Human Services or FDA leadership that has not been approved by both the FDA review committee and the CDC review committee.
To date, the U.S. response to COVID-19 represents a serious failure of governance.[16] Much of this failure stems from the politicization of science and public health. Political considerations must not be allowed to taint the process of ensuring the safety and efficacy – and subsequent equitable access to and distribution of – vaccines and therapeutics to prevent and mitigate harms from COVID-19. Allowing short-term political aims to drive the hasty approval of a potential vaccine could pose a significant danger to the American people and to the whole of humanity. Both in the United States and in countries throughout the world, it will only be possible to successfully contain, prevent, and treat communicable diseases – or any public health challenge – if there is public confidence in the integrity and transparency of the scientific process.
Endnotes
[1] Office of the Commissioner, “Emergency Use Authorization,” U.S. Food and Drug Administration, accessed October 29, 2020, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization.
[2] Project BioShield Act of 2004, 42 U.S.C. 243 et seq. (2004), accessed October 29, 2020, https://www.govinfo.gov/content/pkg/PLAW-108publ276/pdf/PLAW-108publ276.pdf.
[3] “Frequently Asked Questions on the Emergency Use Authorization (EUA) for Chloroquine Phosphate
and Hydroxychloroquine Sulfate for Certain Hospitalized COVID-19 Patients,” U.S. Food and Drug Administration, accessed on October 29, 2020, https://www.fda.gov/media/136784/download.
[4] Gilead Sciences, Inc., “Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Veklury® (remdesivir),” U.S. Food and Drug Administration, October 2020, accessed October 29, 2020, https://www.fda.gov/media/137566/download.
[5] Denise Hinton, Letter Revoking Emergency Use Authorization for
Emergency Use of Chloroquine Phosphate and Hydroxychloroquine, U.S. Food and Drug Administration, June 15, 2020, accessed October 29, 2020, https://www.fda.gov/media/138945/download.
[6] Center for Drug Evaluation and Research, “FDA Cautions Use of Hydroxychloroquine/Chloroquine for COVID-19,” U.S. Food and Drug Administration, updated July 1, 2020, accessed October 29, 2020, https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or.
[7] Michelle M. Mello, “Attacks on Public Health Officials During COVID-19,” Journal of the American Medical Association, JAMA Network, August 25, 2020, accessed October 29, 2020, https://jamanetwork.com/journals/jama/fullarticle/2769291.
[8] Alec Tyson, Courtney Johnson, and Cary Funk, “U.S. Public Now Divided Over Whether To Get COVID-19 Vaccine,” Science & Society, Pew Research Center, September 18, 2020, accessed October 29, 2020, https://www.pewresearch.org/science/2020/09/17/u-s-public-now-divided-over-whether-to-get-covid-19-vaccine/.
[9] Amanda Heidt, “COVID-19 Vaccine Trial Pauses After Adverse Reaction,” Scientist, September 9, 2020, accessed October 29, 2020, https://www.the-scientist.com/news-opinion/covid-19-vaccine-trial-pauses-after-adverse-reaction-67917.
[10] Sarah Caddy, “Russian SARS-CoV-2 Vaccine,” British Medical Journal, August 24, 2020, accessed October 29, 2020, https://www.bmj.com/content/370/bmj.m3270.
[11] Lili Pike, “China Has Quietly Vaccinated More than 100,000 People for Covid-19 before Completing Safety Trials,” Vox, September 11, 2020, accessed October 29, 2020, https://www.vox.com/2020/9/11/21431416/coronavirus-vaccine-china-sinopharm-sinovac-emergency-authorization.
[12] Editorial, “Dying in a Leadership Vacuum,” New England Journal of Medicine, October 8, 2020, accessed October 29, 2020, https://www.nejm.org/doi/full/10.1056/NEJMe2029812.
[13] The Editors, “Scientific American Endorses Joe Biden,” Scientific American, October 1, 2020, accessed October 29, 2020, https://www.scientificamerican.com/article/scientific-american-endorses-joe-biden1/.
[14] Editorial, “Why Nature Supports Joe Biden for US President,” Nature News, October 14, 2020, accessed October 29, 2020, https://www.nature.com/articles/d41586-020-02852-x.
[15] Howard Bauchner, “Reassuring the Public and Clinical Community About the Scientific Review and Approval of a COVID-19 Vaccine,” Journal of the American Medical Association, JAMA Network, October 6, 2020, accessed October 29, 2020, https://jamanetwork.com/journals/jama/fullarticle/2770681.
[16] Eric C. Schneider, “Failing the Test – The Tragic Data Gap Undermining the U.S. Pandemic Response,” New England Journal of Medicine, October 8, 2020, accessed October 29, 2020, https://www.nejm.org/doi/full/10.1056/nejmp2014836.