Hamlet in the times of COVID19

“…Whether 'tis nobler in the mind to suffer

The slings and arrows of outrageous fortune,

Or to take arms against a sea of trouble

And by opposing end them.”

-William Shakespeare

The big question facing ethicists, researchers, and regulators around the world post-December 2020-

• Should the placebo arm in current COVID19 vaccines studies be discontinued?
• Should the next round of COVID Vaccine studies use a placebo or active control?

The scientific rationale for continued use of placebo arms as stated by experts are as follows-

a.  All* COVID19 vaccine EUD’s (Emergency Use Designation)/ EUA’s (Emergency Use Authorization) are based on interim results. (Based on 6-month data). The long-term safety and efficacy are still under study. The fears of virus variants and decreasing efficacy with time are coming true with each fresh COVID19 wave.

*(Note: On 23 Aug 2021, US FDA granted 'Approval' to the Pfizer-BioNTech COVID-19 Vaccine. This vaccine up till this date had an EUA)

b.  Key questions on long term efficacy that require answers are-

• Duration of high/ sufficient vaccine efficacy
• What will happen to disease presentation and severity in vaccinated populations?
• Variability in different demographic groups- e.g., immunocompromised
• Variability of effect as new virus strains emerge (on vaccinated and unvaccinated populations)

c.  EUD approvals have considered a pre-specified safety milestone over a short period. Extended observation for long-term safety events is still a necessity. These safety concerns with the vaccine include-

• Rare adverse events
• Delayed adverse events

The ethical rationale for using a placebo is becoming increasingly blurred and complex as the COVID19 scenario evolves. The debate started as the first interim analysis of studies became public knowledge, and companies started applying for EUA/EUD. The WHO issued a guideline on 18 Dec 2020.

There are major ethical concerns for including placebo arms in COVID19 vaccine studies moving forward. According to international guidelines in research, placebo arms are justified if there is NO effective treatment / best-proven intervention. However, none of these guidance’s (before WHO 2020) were outlined considering Emergency use authorizations.

Placebo arm, according to these guidelines, is justified under the following circumstances:

1. No proven treatment exists.
2. Scientifically sound reasons that the use of placebo is necessary to assess safety and efficacy.

a.      without placing the placebo group under additional risks

b.      will result in no more than a minor increase above minimal risk to the participant, and risks are minimized

3. As an added intervention to an established effective intervention.

The Declaration of Helsinki or the CIOMS guideline does not specifically mention vaccine studies. The WHO set up an expert panel that came out with a report in 2014 specifically addressing the use of placebos in vaccine trials. (much before COVID19)

(a) no efficacious and safe vaccine exists and

(b) the vaccine under consideration is intended to benefit the population in which the vaccine is to be tested

(c)  when an efficacious vaccine exists, provided the risk-benefit profile of the trial is acceptable

• the study question cannot be answered with an active-controlled trial design; and
• the risks of delaying or foregoing an existing efficacious vaccine are adequately minimized or mitigated; and
• the use of a placebo control is justified by the potential public health or social value of the research; and
• the research is responsive to local health needs

These conditions were simpler to interpret in the pre-COVID19 Vaccine EUA/EUD era ( pre-Dec 2020). Since then, two things have happened-

a)      Increasing number of vaccines have received EUA/EUD with efficacy between 70-95% for infections and >90% for severe infections/ hospitalizations.

b)     Vaccine inequity has emerged:

• Between countries
• Within population groups because of staggered vaccine rollouts

The WHO ACT-Accelerator Ethics & Governance Working Group (ACT: Access to COVID-19 Tools- developed a policy to address and guide COVID19 Vaccine studies- ‘Emergency Use Designation of COVID-19 candidate vaccines: Ethical considerations for current and future COVID-19 placebo-controlled vaccine trials and trial unblinding. The document released in Dec 2020 recommends-

1.      Trial participants at substantial risk of infection with the coronavirus SARS-CoV-2 and severe COVID-19 morbidity or mortality—such as healthcare workers at high to very high risk of acquiring and transmitting the disease and people above 65 years of age. Such participants should be offered the option to use the EUD vaccine if they wish to.

2.      Investigators should explain the scientific benefit of continued trial participation and the implications of unblinding to such trial participants (for them as individuals and the study)

a.      The issuance of EUD is based on early interim findings and is time-limited in nature.

b.      Such status can be withdrawn by regulators should interim evidence later suggest that the potential risks of the vaccine outweigh its potential benefits.

c.      Promising early interim data may be based on apparent efficacy in homogenous groups that are not representative of all target groups for the candidate vaccine and provide limited insight into vaccine efficacy and safety over time.

3.      Participants should then be offered the opportunity to be unblinded so that they can make an informed decision about whether to withdraw from the trial and access a EUD vaccine

4.      Trial participants who are not deemed to be at substantial risk of SARS-CoV-2 infection and COVID-19 morbidity or mortality and who do not meet prevailing eligibility criteria to access a candidate vaccine granted a EUD should be informed of the scientific benefits of continuing with the trial and should be encouraged to remain enrolled, with full acknowledgment of their right to withdraw from a trial at any point, without penalty.

5.      If the participant wishes to exit the study, the following steps need to be undertaken-

a. Investigators and sponsors should abide by the participants' requests.

b. Sponsors should establish unblinding eligibility criteria and the implications of unblinding for trial participants.

c.  After withdrawing from a trial, participants should be followed up as part of an observational study, should they agree.

6.      If the participant assigned to the intervention arm of a COVID-19 vaccine trial wishes to access a different EUD approved vaccine-

a.      Investigator should counsel the participants that no scientific data currently supports such administration. (However, this scenario is rapidly changing as studies with mix and match vaccines are being published)

b.      If the participant still insists, they should be followed up as part of an ongoing monitoring strategy of the study. Data from such participants should be analyzed for safety and effectiveness outcomes.

Counterpoints to such selective approach in placebo-controlled COVID19 vaccine studies:

The WHO policy was released in Dec 2020. Since then, many things have changed. In the current (Aug 2021) scenario, there are significant limitations to such a strategy:

a)      In countries where access to vaccines is easy, or all adults are now eligible to be vaccinated, this approach may result in significant study withdrawals and loss of long-term data. In such regions, the only unvaccinated populations present are those with vaccine hesitancy who, as it is, will not participate in studies.

b)     Countries where significant vaccine shortages are present, such an approach will result in an ethical challenge at a global level. Why should such countries/populations face the negative fallout /disadvantage of vaccine inequity while contributing to vaccine research?

What about future studies? Why don’t we switch to active control studies?

Swinging to active control trials with EUD approved vaccines is difficult. At present, there are challenges to even this approach.

a. In a global vaccine shortage/ inequity scenario, how do you procure vaccines for the control arm?

b. Will such procurement of EUD vaccines be justifiable when there are large population groups still unvaccinated?

c. Will active controls not serve as an inducement in countries with vaccine shortages?

As can be seen, the solution to the ethical dilemma to use or not to use a placebo does not have a one size fits all solution, especially in the rapid changes in COVID19 scenarios across countries and within countries. These questions will become more pertinent because COVID19 Vaccine studies are still needed.

1.      To overcome short supplies by having more vaccine candidates available

2.      Data is emerging of varying efficacy over time of current vaccines. There is already talk about booster doses.

3.      This pandemic does not have a short-term expiry date. New strains are emerging.

What do you think? Share your thoughts in the comments.

REFERENCES:

1.        Singh, J.A., Kochhar, S., Wolff, J. et al. Placebo use and unblinding in COVID-19 vaccine trials: recommendations of a WHO Expert Working Group. Nat Med 27, 569–570 (2021). https://doi.org/10.1038/s41591-021-01299-5

2.        Emergency Use Designation of COVID-19 candidate vaccines: Ethical considerations for current and future COVID-19 placebo-controlled vaccine trials and trial unblinding (Policy Brief- 18 Dec 2020- WHO)

3.        International Ethical Guidelines for Health-related Research Involving Humans (2016) https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf

4.        Declaration of Helsinki- https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/

5.        Rid A, Lipsitch M, Miller FG. The Ethics of Continuing Placebo in SARS-CoV-2 Vaccine Trials. JAMA. 2021;325(3):219–220. doi:10.1001/jama.2020.25053

6.        Dal-Ré, R., Orenstein, W. & Caplan, A.L. Being fair to participants in placebo-controlled COVID-19 vaccine trials. Nat Med 27, 938 (2021). https://doi.org/10.1038/s41591-021-01338-1

7.        Ivan Sisa, Estefania Noblecilla, Fadya Orozco; Rationale to continue approving placebo-controlled COVID-19 vaccine trials in LMICs. CORRESPONDENCE| VOLUME 397, ISSUE 10277, P878, MARCH 06, 2021 https://doi.org/10.1016/S0140-6736(21)00357-3

8.        Jenna Rose Stoehr, et al.; Ethical Considerations for Unblinding and Vaccinating COVID-19 Vaccine Trial Placebo Group Participants; Front. Public Health, 24 June 2021. https://doi.org/10.3389/fpubh.2021.702960