The Ethics of Continuing Placebo in SARS-CoV-2 Vaccine Trials | Infectious Diseases | JAMA | JAMA Network
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Viewpoint
December 14, 2020

The Ethics of Continuing Placebo in SARS-CoV-2 Vaccine Trials

Author Affiliations
  • 1Department of Bioethics, The Clinical Center, National Institutes of Health, Bethesda, Maryland
  • 2Center for Communicable Disease Dynamics, Department of Epidemiology, Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 3Weill Cornell Medical College, New York, New York
JAMA. 2021;325(3):219-220. doi:10.1001/jama.2020.25053

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to rage, developing safe and effective vaccines is critically important. With unprecedented speed, multiple candidate vaccines are now being evaluated in placebo-controlled clinical trials that have enrolled hundreds of thousands of participants.

According to Pfizer-BioNTech and Moderna, interim analyses after approximately 2 months of follow-up suggest their vaccines are 90% to 95% effective at preventing SARS-CoV-2 infection, although no peer review of the data has been conducted to date. Both companies now claim they have an “ethical obligation” to offer vaccine as soon as possible to all participants who received placebo, considering the strong results and participants’ contribution to the research.1,2

This Viewpoint argues that given limited vaccine supply for at least several months, only the participants receiving placebo who would be eligible for vaccination outside the trial should be offered access to the vaccines at this point. The argument is explored in the US context, setting aside ethical questions about global vaccine distribution.

If the US Food and Drug Administration grants an Emergency Use Authorization for the vaccines, as appears likely at the time of writing, the supply of vaccines will initially be limited. Government officials project that at most 40 million doses will be available in December 2020.3 This amount would be sufficient to vaccinate 20 million people, a fraction of what would be needed to protect the population. Priorities for vaccination therefore need to be set.

Several ethical frameworks for prioritizing groups for vaccination have been developed, with significant overlap between frameworks (eAppendix in the Supplement). For example, the Advisory Committee on Immunization Practices to the Centers for Disease Control and Prevention has identified 4 priority groups with a view to maximizing benefits and minimizing harms, promoting justice, and mitigating health inequities: health care personnel, other essential workers, adults with high-risk medical conditions, and adults aged 65 years or older.4 Decisions about continuing coronavirus vaccine trials should be consistent with these ethical frameworks.

Under conditions of vaccine scarcity, 2 ethical reasons conflict with offering vaccine to all participants in the placebo group. First, this would result in a major loss of valuable research data without eliminating undue risks to participants who continue in the placebo group of the trials. Second, health and health equity gains would decrease because participants in the placebo group would be given vaccine even when they have not been prioritized for vaccination outside the trial.

Data about the long-term safety and efficacy of vaccines are essential to support their full licensure and their intended widespread, government-financed use. For example, important uncertainties remain about the duration of the high protective efficacy of the vaccines; whether measures of immune function, such as neutralizing antibody titers, predict any waning of immunity; whether enhanced disease occurs following vaccine waning; and the safety and effectiveness of vaccines in different demographic groups as well as long-term safety. The best way to resolve these uncertainties is to continue placebo-controlled trials, given the substantial risks of bias in observational studies of vaccine effectiveness,5 especially under rapidly changing circumstances.

Crucially, if all participants in the placebo groups of vaccine trials were offered vaccine, valuable research data would be lost even though continued placebo use would not necessarily expose participants to undue risks. A key question for evaluating participants’ risks is whether they are eligible for vaccination outside the trial. Although policies will differ by state, they should be guided based on the various ethical frameworks that have been developed, such as the framework from the Advisory Committee on Immunization Practices.4 If participants are not eligible for vaccination outside the trial, continuing in the placebo group would not make them worse off than they should have been outside of participating in the trial.6 The risks of continuing their participation in the placebo group could therefore be justified, provided the trials yield valuable research data and participants are encouraged to minimize the risks of SARS-CoV-2 infection.7 In contrast, if participants are eligible for vaccination outside the trial, continuing in the placebo group would make them significantly worse off than they should have been outside of participating in the trial. The risks to these participants seem difficult to justify; in any case, they could simply withdraw from the study and seek vaccination outside the trial.

Careful statistical adjustments would have to be made for removing participants in the placebo group, perhaps with an “intent-to-continue” analysis of only those who are not eligible for vaccination outside the trial. There currently is limited information on how many participants in the ongoing trials would be offered vaccine because they belong to the identified top priority groups for vaccination. The proportion could be less than 10% if health care personnel (estimated at 21 million, 6% of the population)4 are prioritized exclusively in the first months of vaccine availability. The proportion could be greater if other priority groups are also eligible for immediate vaccine access. However, even with a reduced trial cohort, important data could be gathered, especially if SARS-CoV-2 infection rates remain high and several months of additional follow-up are possible.

The second ethical reason against offering vaccine to all participants in the placebo groups of the trials is that this would yield lower health and health equity gains from vaccination overall if participants do not belong to the identified priority groups. With a projected vaccine supply for at most 20 million people through the end of 2020,3 there will initially be barely enough vaccine to vaccinate even the top priority group identified across all ethical frameworks: the estimated 21 million health care personnel.4 Thus, if all participants in the placebo groups in the Pfizer-BioNTech trial (currently n = 43 651; placebo group, n = 21 828) and Moderna trial (n = 30 000; placebo group, n = 15 000) were offered vaccine, this would mean that currently up to 36 828 health care personnel or other individuals who have higher priority than the participants could not be vaccinated. The resulting loss of benefits could be significant.

Participants who received placebo in the vaccine trials have made an essential contribution to testing vaccine safety and efficacy. Notably, they made this contribution without any promise during the consent process that they would later be prioritized for vaccination.8 Participants in the placebo groups who are not eligible for vaccination outside the trial should not be placed ahead of groups that have been prioritized across ethical frameworks. Above all, this would fail to maximize benefits and minimize harms because participants in the placebo groups who are not health care personnel do not have an instrumental role in the pandemic response, and participants younger than 65 years or without high-risk medical conditions benefit less from being vaccinated. Nevertheless, participants’ research contributions could be partially recognized by offering the first vaccine doses to the participants in the placebo groups who belong to the identified priority groups for vaccination.

Based on these ethical and scientific considerations, the following practical steps are recommended. Sponsors and investigators should inform participants about the encouraging interim results, including whether an Emergency Use Authorization for the vaccines has been granted. They should then offer vaccine to participants in the placebo groups of clinical trials who would be eligible for vaccination outside the trial. Crossover to the vaccines should happen as part of the trial, so that follow-up data on immune responses and potential breakthrough infections can still be gathered. All other participants should remain blinded to whether they received vaccine or placebo in the trial and should be informed that while vaccine supplies are limited, vaccine is being offered only to the participants in the placebo group who would be eligible for vaccination outside the trial. These participants should be encouraged to remain enrolled in the trial to generate valuable research data while engaging in physical distancing, mask wearing, and other strategies to minimize the risk of SARS-CoV-2 infection. These participants should also be reminded that they have the right to withdraw from the trial without penalty. Finally, these recommendations should be revisited frequently with respect to the importance of continuing placebo-controlled trials and the degree of vaccine scarcity, especially as more vaccine doses and potentially other vaccines become available.

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Article Information

Corresponding Author: Annette Rid, MD, Clinical Center Department of Bioethics, National Institutes of Health, 10 Center Dr, Bldg 10, Room 1C118, Bethesda, MD 20892 (annette.rid@nih.gov).

Published Online: December 14, 2020. doi:10.1001/jama.2020.25053

Conflict of Interest Disclosures: Dr Lipsitch reported receipt of honoraria/consulting fees from Merck, Affinivax, Sanofi Pasteur, Bristol Myers Squibb, and Antigen Discovery; receipt of research funding (institutional) from Pfizer; and provision of unpaid scientific advice to Janssen, AstraZeneca, One Day Sooner, and COVAXX (United Biomedical). No other disclosures were reported.

Funding/Support: This work was supported in part by the Clinical Center Department of Bioethics, which is in the Intramural Program of the National Institutes of Health.

Role of the Funder/Sponsor: The funder had no role in the preparation, review, or approval of the manuscript or decision to submit the manuscript for publication.

Disclaimer: The views expressed herein are those of the authors and do not necessarily reflect the policies of the National Institutes of Health or the US Department of Health and Human Services.

References
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Branswell  H. Pfizer may be within days of filing emergency authorization request for Covid-19 vaccine. STAT News. Published November 17, 2020. Accessed December 2, 2020. https://www.statnews.com/2020/11/17/pfizer-may-be-within-days-of-filing-emergency-authorization-request-for-covid-19-vaccine/
2.
Grady  D. Early data show Moderna’s coronavirus vaccine is 94.5% effective. New York Times. Published November 16, 2020. Accessed December 2, 2020. https://www.nytimes.com/2020/11/16/health/Covid-moderna-vaccine.html
3.
Sun  LH. First 6.4 million doses of Pfizer’s coronavirus vaccine could go out in mid-December. Washington Post. Published November 24, 2020. Accessed December 2, 2020. https://www.washingtonpost.com/health/2020/11/24/vaccine-plan-first-doses/
4.
Bell  BP, Romero  JR, Lee  GM.  Scientific and ethical principles underlying recommendations from the Advisory Committee on Immunization Practices for COVID-19 vaccination implementation.   JAMA. 2020;324(20):2025-2026. doi:10.1001/jama.2020.20847PubMedGoogle ScholarCrossref
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Lipsitch  M, Jha  A, Simonsen  L.  Observational studies and the difficult quest for causality: lessons from vaccine effectiveness and impact studies.   Int J Epidemiol. 2016;45(6):2060-2074. doi:10.1093/ije/dyw124PubMedGoogle Scholar
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Wendler  D, Ochoa  J, Millum  J, Grady  C, Taylor  HA.  COVID-19 vaccine trial ethics once we have efficacious vaccines.   Science. Published online December 3, 2020. doi:10.1126/science.abf5084PubMedGoogle Scholar
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Rid  A, Wendler  D.  A framework for risk-benefit evaluations in biomedical research.   Kennedy Inst Ethics J. 2011;21(2):141-179. doi:10.1353/ken.2011.0007PubMedGoogle ScholarCrossref
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Herper  M. Pfizer says placebo patients will eventually get its Covid-19 vaccine; the question of when is complicated. STAT News. Published November 12, 2020. Accessed December 2, 2020. https://www.statnews.com/2020/11/12/pfizer-says-placebo-patients-will-eventually-get-its-covid-19-vaccine-the-question-of-when-is-complicated/
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    5 Comments for this article
    EXPAND ALL
    Fascinating Article. COVID-19 Vaccine Placebo Groups.
    Gary Ordog, MD, DABEM, DABMT | County of Los Angeles, Department of Health Services, (ret.)
    Thank you for the fascinating article, one of my favorites of the year. This is a ground-breaking ethical discussion. My thought immediately, was that these people should be moved to the front of the vaccine line because they basically risked their lives and received nothing in return except pride. But on further thinking and discussion with others I believe that you are correct. The big variable is that we don't know who these people are. They could be all front line workers who are going to be first in line anyway. They are very brave, risking their lives, "drawing the short straw," and perhaps now having to wait in a long line for the vaccine in order to benefit the experiment. Wow, I am glad I am not making this decision! I think that the placebo group deserves something great, although their pride in knowing that they helped save humanity may be better than anything that the government can give them.
    CONFLICT OF INTEREST: None Reported
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    The Perspective Was Incomplete
    Conrad Swartz, Ph.D., M.D. | Southern Illinois University School of Medicine
    It is in the interest of society to attract volunteer subjects for such studies. Allowing study participants who had received placebo to receive active vaccine earlier than otherwise after the trial is concluded serves as a precedent for reinforcing volunteering for future studies. This consideration appears important.

    Beyond this there is a major ethical shortcoming in the first rationalization in the essay claiming ethical value to withholding the vaccine from volunteers who received placebo. If the informed consent process did not mention that active vaccine may be withheld after the initial trial is concluded, to gather additional outcome
    data, informed consent was not obtained for the study extension--and the study extension fails to conform with expected conduct of ethical studies. In other words, deliberately withholding the vaccine from them may be wrongful.

    Other perspectives may have been similarly overlooked in this review of ethics.
    CONFLICT OF INTEREST: None Reported
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    Verbal Assurances From Physicians Conducting Trials
    Pete Foley, PhD Chemistry | Independent Researcher/Consultant
    A critical data point that this article does not take into account is that in at least one trial the placebo group were verbally assured that they would offered vaccine as soon as the FDA cleared the vaccine. I specifically asked for clarification on this from the physician leading the study in my area, as I didn't want my wife and I to be trapped on a placebo when the vaccine became available. I was also told by a nurse administering the second vaccine that she was looking forward to switching us all from the placebo. I assume that we weren't the only trial participants who were given either overt or implied assurances. The consent documentation was unclear on this, which is why I asked for additional clarification, but it certainly did not mention that active vaccine may be withheld after the initial trial is concluded. Given this, I find it hard to find any ethically valid rationale for not offering vaccine to all participants in the placebo group
    CONFLICT OF INTEREST: Participant in SARS-CoV-2 Vaccine Trial (specific trial not disclosed to respect NDA)
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    Reality Check
    Thomas Slater, BS, MBA | Pfizer Phase 3 Trial Participant
    As a 78-year-old male in the placebo arm of Pfizer’s phase 3 trial I would like to respond to this article on a personal level and to the two “ethical” arguments presented.

    The article states “Notably, they made this contribution without any promise during the consent process that they would later be prioritized for vaccination.” I was told at the start of the trial that if I was in the placebo arm of the trial that we would be eligible (non-conditionally) for the vaccine once the EUA was awarded. Pfizer also issued a statement to that effect
    in November.

    After the EUA was issued, I contacted the trial clinic on December 14, the day this article was published, and talked to my clinician who indicated I was number 15 on her list of participants and, given the 50/50 odds of my having received placebo, would probably be about the 7th or 8th to be called. She indicated they had to get some additional training and new procedures so it would probably be the 18th or 21st when I could receive the vaccine.

    On December 15, Pfizer appeared to renege on those promises, limiting the vaccination option to “those who would qualify for vaccination if they were not part of the clinical trial.” 

    Taking the article’s second argument first, when it comes to health and equity gains you can get a hundred different frameworks or priority lists from an equal number of informed qualified sources. Look at all the frameworks floated after Pfizer submitted their trial info, a number of which included the placebo group.

    The Advisory Committee’s framework is presented as the gold standard. While there is logic to it, the framework was selected in large part for ease of implementation. Note the omission of minorities, particularly older ones, who are at risk for severe disease and death more than the average health care worker.

    It may not be practical to implement a framework that is sufficiently granular to provide true health equity across the population, but to hold the Advisory Committee’s framework as the holy grail against which placebo group members are found wanting is absurd. To quote Dr Fauci, “You put yourself at risk to prove that something works, so that everybody could use it. When you have efficacy as high as this, the case becomes stronger.” (1)

    Also, how much additional distortion of health equity is created by directing 44,000 doses (about 0.2% of the total 20 million Pfizer doses available in December) to the placebo group? Clearly, there is no material distortion of health equity even if you consider the placebo group undeserving.

    The article’s first argument against vaccinating the placebo group really contains two separate points, loss of data and no harm done to the placebo group. The only data loss referenced (safety, efficacy, etc.) in this and similar articles is not derived from the placebo group. It comes from the treatment group. Worried about control group comparison data? The U. S. has had a 330 million placebo cohort in place for a year.

    As to no harm done to the placebo group, that is only measured against the artificial construct of the framework. I live in the real world with real infection and death rates. The CFR for my age and gender group is roughly similar to playing Russian Roulette with 6 shot revolver. Anyone want those odds?

    Reference

    1. https://www.nytimes.com/2020/12/02/health/covid-vaccine-placebo-group.html
    CONFLICT OF INTEREST: I am participant in Pfizer's phase 3 trail (placebo group)
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    Input From a Clinical Trial Participant
    Samrat Shenbaga, MBA | None
    Similar to another commenter, I am currently enrolled in the vaccine trial for one of the approved COVID vaccines. It has been a tremendous scientific accomplishment to have two vaccines administered to Americans already. The scientists, trial facilitators, and trial participants must be congratulated on their unbelievable efforts -- this is nothing short of landing on the moon.

    I concur with the article's argument that there is no ethical requirement to vaccinate the placebo arm before their priority group is due. I am a healthy 45 year old male and definitely do not intend to cut
    in line ahead of front line workers, people at much higher risks etc. -- I've waited 9 months and can wait another 3.

    However, I am perplexed by the resistance to fully unblind the trials (and the two companies have different philosophies with Pfizer's being much more restrictive). Keeping trials blinded to this point clearly demonstrated efficacy. The stated goal of continued blinding is to monitor for long-term side effects and longevity of efficacy. I have personally corresponded with the experts who recommended against unblinding -- and I cannot get a straight answer on how the study of these effects will be helped by keeping in the dark people injected with saline water. On the contrary, I would think it would be better to reset the clock with the placebo patients as quickly as possible to enable data collection. The other big benefit of unblinding the trial is that 22k volunteers who received the vaccine can rest easy -- not telling them is denying them the opportunity to visit an elderly parent in a nursing home they have not seen for 9 months. And the last issue with keeping the trial blinded is that it removes any incentive for future and current trial participants. By not telling me now which arm I am in, there are two effects: a) a reduction in any moral obligation I feel to continue on the trial, and b) When my turn is up, I have to weigh the risks of driving an hour to the clinical trial site versus just hopping over to the local CVS.

    I am no scientist but from the real world of a person in the trial I cannot see any harm in fully and immediately unblinding the trials. I am not asking to cut in line. But the argument of keeping trial participants in the dark in the name of data collection feels counter-intuitive. Placebo patients will drop in numbers very quickly anyway as the trials wanted more participants from categories with high exposure (healthcare workers, frontline people). And it will only have the effect of participants dropping out and not trusting the system in the future for other trials. The current scientific opinion appears to be based on traditional clinical trial design. A higher consideration should be placed on the availability of real world data (over a million people have already received the vaccine). It is also important to consider what motivates clinical trial participants. There is an implicit assumption by many that the participants just want to cut in line which is highly inaccurate. I was motivated by the personal suffering and death of those close to me. Converting clinical trial participants to mere data points is an unfortunate turn of events.
    CONFLICT OF INTEREST: None Reported
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