Open access peer-reviewed chapter

Perspective Chapter: Ethics of Using Placebo Controlled Trials for Covid-19 Vaccine Development in Vulnerable Populations

Written By

Lesley Burgess, Jurie Johannes Jordaan and Matthew Wilson

Submitted: 10 February 2022 Reviewed: 01 April 2022 Published: 05 May 2022

DOI: 10.5772/intechopen.104776

From the Edited Volume

Current Topics in SARS-CoV-2/COVID-19 - Two Years After

Edited by Alfonso J. Rodriguez-Morales

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When clinical trials are conducted in vulnerable communities such as those found within low-to-middle-income-countries (LMICs), there is always the risk of exploitation or harm to these communities during the course of biomedical research. Historically, there have been multiple instances where significant harm was caused. Various organisations have proposed guidelines to minimise the risk of this occurring, however, questionable clinical trials are still conducted. Research Ethics Committees have an additional duty of care to protect these vulnerable populations. During the Covid-19 pandemic the ongoing use of placebo-controlled trials (PCTs), even after approval of a safe and efficacious vaccine, is a topic of great debate and is discussed from an ethical and moral perspective.


  • Covid-19
  • research ethics
  • clinical trials
  • equity
  • placebo
  • randomisation

1. Introduction

Randomised control trials have existed in medicine since the 1940s [1]. Many iterations of guidelines to govern their use in research to protect vulnerable populations that have historically been abused for the betterment of science. Unfortunately, with a concept as abstract as ethics in clinical research, there is no universal consensus, and one may argue for or against their use with equal vigour depending on the specific circumstances of the trial [1, 2, 3, 4, 5].

Ethics of conducting clinical trials, particularly placebo-controlled trials (PCTs) in low-to-middle-income-countries (LMICs), is controversial. The emergence of placebo-controlled vaccine clinical trials against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has renewed interest in the debate. According to the World Bank Group (2021) [6], LMICs are defined as countries in the developing world with a gross national income per capita of $1046–$4095. The need for clinical trials to be conducted in LMICs is paramount to bridging the health gap, a concept so starkly highlighted in the recent pandemic. Medical research in these countries requires proper adjudication and protection to maximise benefits and deter potential harm [7].

Pharmaceutical companies tend to pursue these communities, capitalising on lower costs, fewer restrictions, and weaker local standards [8]. In 2008, the United States Food and Drug Administration (FDA) published its decision to abandon the Declaration of Helsinki (DoH) as an ethical guideline when conducting and reviewing data from clinical trials conducted outside the United States of America (USA). As a result, there is limited protection for LMICs where USA-based companies conduct clinical trials [9]. The responsibility to uphold moral ethics thus shifts to the local investigators and review boards [9]. The limited protection referenced above pertains to the Good Clinical Practices of the Conference of International Harmonisation (ICH-GCP) being more flexible when choosing comparator drugs in clinical trials [10]. Article 33 in the DoH outlines stricter criteria for using placebo as an alternative to best proven intervention [7]. ICH-GCP, however, has no enforceable article guiding the choice of comparator leaving the decision to the study designer and review board’s discretion [10]. Consequentially, this avenue is open for exploitation in LMICs where scientific knowledge and ethics are comparatively weaker [8]. Together, the DoH and ICH-GCP should govern the impact clinical trials have in vulnerable communities, however, there is more nuance to the situation [1, 2, 3].

To ensure exploitation does not occur, participants must not be exposed to excessive risk and must understand the difference between clinical trials and clinical medicine [1, 5, 6, 7]. To participate in a trial, you willingly join an experimental process rather than have a therapy tailored to your medical needs [2, 3, 11, 12, 13, 14, 15, 16, 17]. We will discuss the aspects of trials as a whole and why LMICs are vulnerable to this exploitation, explore the concept of clinical equipoise, and discuss PCTs in the setting of COVID-19 vaccine trials during the pandemic.


2. What makes LMICs so vulnerable?

All manner of ethical research necessitates non-use of undue influence to garner research participant compliance [7, 8, 10]. However, what may seem negligible to cause undue influence in developed countries, could very well double or even be whole income for a household in LMICs that suffer from poverty, poor living conditions and no access to running water. For these reasons, it’s imperative to consider the medical benefits of clinical trials [9].

In LMICs, there is a prevailing lack of access to healthcare [11]. Clinical trials offer the opportunity for recruited participants to receive healthcare not otherwise available to them [1, 2, 3, 4, 8]. The DoH states: “medical research within a vulnerable group is only justified if the research is responsive to the health needs…” [7]. This highlights an obvious gap in the protection of these populations which is easily exploited if not appropriately safeguarded. The argument for choice of comparator weighs heavily on this point. Internationally, there is a call for using “best available standard” when designing clinical trials. However, in LMICs, there is no legal basis enforcing an international gold standard over a locally available comparator choice [1, 2, 3, 4, 5, 8, 9, 10, 11, 12]. Problems arise when conducting clinical trials in LMICs where there is no “locally available standard”. In vaccine trials, specifically where cold chain continuation is paramount, there’s advocation against use of the international gold standard should the target country have insufficient infrastructure to ensure preservation of drug.

Multiple publications reference the lack of ethics conducting clinical trials in LMICs [7, 18, 19, 20, 21]. Major challenges noted include: incomplete ethical regulations and guidance, limited knowledge of science, language barriers between researchers, sponsors and communities, and insufficient financial and material resources of local authorities to govern the conduct of clinical trials. Exploitation of LMICs is well documented throughout history. In 1994, the ACTG 076 trial involved in reviewing low-cost regimes of antiretroviral drugs to prevent mother to child transmission of human immunodeficiency virus (HIV), was rife with controversy. Placebo was administered despite having proven knowledge that zidovudine is effective in prevention of vertical transmission of HIV [8, 22]. Another example was a rotavirus vaccine trial conducted in India from 2011 to 2012. The use of placebo as comparator, despite availability of two internationally registered vaccines recommended by the World Health Organisation (WHO), and one locally registered vaccine. As a result, more than 3000 out of 7500 randomised children were exposed to rotavirus and associated risks [23]. Such use of placebo would be unacceptable in developed countries and the expectation that LMICs should carry this burden is unjust.


3. Principles of medical ethics and how they apply to LMICs

The cardinal pillars of medical ethics are autonomy, beneficence, non-maleficence, and justice. All manner of clinical research takes heed of these pillars and can be described and applied in a myriad of ways [24].

3.1 Social and clinical value

Risk exposure must be justified; any resulting scientific knowledge gains should be significant enough to warrant inconveniencing and risking the population of unknown health outcomes for the greater good [1, 8]. There are certain areas of research that are better conducted in LMICs based on the endemic nature of diseases such as HIV and tuberculosis (TB) [19]. Populations are thus able to benefit directly from the trial as participants. The common shortfall is post-trial access to the tested intervention. There is massive debate on the responsibility of stakeholders to provide post-trial access to drugs. Some cite reciprocal justice to participants, while others cite practicality of large-scale rollouts being the jurisdiction of government entities [19]. Clinical trials in LMICs need to account for these factors during study design to ensure value.

3.2 Scientific validity

Studies should be designed to answer specific questions, using research methods that are valid, and feasible [8]. Poor scientific reasoning and application of research trials damages the perception of clinical research. In the realm of LMICs it can be deleterious to future relationships in garnering support for clinical trials. Standards in LMICs may permit approval of fallacious studies by local authorities without better knowledge or insight. It is the responsibility of sponsors to ensure this avenue of exploitation is protected to the level of the country of origin [1, 2, 3, 4, 5, 18].

3.3 Favourable risk-benefit ratio

Uncertainty about the degree of risks and benefits associated with a treatment is implicit in clinical research [8, 13, 14, 15, 16, 17]. Clinical research is not conducted to provide health care though it is often a beneficial by-product [1, 2, 3, 4, 8]. When looking to conduct trials in LMICs and other vulnerable populations, there needs to be increased emphasis on these benefits [7]. Maintaining a favourable ratio requires the use of interim reviews during a study to timeously detect whether an intervention arm (active or control) is associated with increased risk. Should this occur, research should be stopped to allow the protection of participants [24].

3.4 Independent review

An independent review panel, with no vested interest in the outcome of the trial, should review proposal validity and ensure its integrity [8]. This is generally done by Institutional Review Boards (IRBs) and Research Ethics Committees (RECs). In high income countries, these committees comprise of highly qualified and experienced individuals who are well-suited to manage complex ethical issues. Their role serves to make sound, consistent and ethical decisions on matters related to patient safety. There is trepidation that IRBs and RECs in LMICs may not be adequately equipped to protect the human rights of clinical trial participants, due to lack of financial and material resources, inadequate training of members, lack of diversity of membership, lack of independence and inability to monitor approved protocols [21]. As a result, there may be inconsistencies in the review process outcomes thus compromising patient safety. Some countries intentionally weaken their regulatory framework to encourage foreign investment through externally sponsored research [24]. These shortcomings are historically exploited to conduct research in LMICs that would never pass the review process in the country of origin [24].

3.5 Informed consent

Participants must decide, independently and without duress, to take part in research [8, 24]. Subjects must be appropriately informed of the purpose, method, risks, benefit, and alternatives to research [24]. Furthermore, subjects must be made to understand these factors and how they apply to their situation. In LMICs, a common roadblock is language and minimum level of education [18, 21]. At times it is difficult to know the degree of participants understanding especially when translators are used [21]. Even in developed countries, the understanding of what a PCT is can be lacking.

3.6 Respect for subjects

Confidentiality and ensuring informed voluntary participation are the hallmarks of respecting autonomy of subjects [8]. Abiding by a subject’s wishes to withdraw consent and discontinue from a trial without consequence is important [24]. Sharing information that arises from interim review of previously unknown adverse events is the responsibility of research staff, even though it may change the subject’s opinion on the risks and benefits of participation [24]. In LMICs there is a role for Community Advisory Boards (CABs) to advocate for trial participants and promote the ethical conduct of clinical trials [20]. In South Africa, CABs are used to protect the interests of participants on HIV and TB drug trials. Their main roles have been preventing exploitation and building capacity for research in communities. By consisting of community members and encouraging interest in research by the individual in a community, CABs bring the value of research to the home country. Assisting in advancing research goals, their use has had positive benefit in information distribution and recruitment for trials [25].


4. Effects of Covid-19 on LMICs

The Covid-19 pandemic augmented the effects of resource deficiency in LMICs. In such countries, where healthcare access is limited under normal circumstances, the added burden of a pandemic will and has caused vast morbidity and mortality. In India alone, there was an estimated 30,000–50,000 ventilators available to service a projected 1 million people with severe disease requiring ventilation during the peak of their first COVID-19 wave [26]. Access to oxygen in LMICs has been a challenge, with many hospitals running out of oxygen amidst a massive surge in patients due to COVID-19. During these periods, many hospitals in LMICs had an additional shortage of beds and staff [26]. The development of life-saving vaccines against Covid-19 can mitigate this devastation, by preventing severe disease completely and limiting hospitalisation. With development and initial distribution of vaccines occurring predominantly in the western world’s high-income countries, a potentially faster way for LMICs to receive any form of Covid-19 vaccination is through clinical trials. While controversial, it cannot be overstated (especially given the critical nature of the pandemic), that there is a need for clinical trials to collaborate with communities in LMICs and involve them in research of novel and affordable versions of these vaccines. This will provide them all the benefits of early access and equip their governments with tools to advance a vaccine rollout plan, while the scientific world benefits from the data they provide.

Figure 1 [27] is from the United Nations Office for the Coordination of Humanitarian Affairs, showing countries with inter-agency humanitarian response plan (HRP). This graph depicts the vaccine coverage of population, provided by developed countries to HRP countries. This clearly depicts the health gap, the inequity of vaccine rollouts on a global scale.

Figure 1.

Estimated percent of population covered by delivered vaccines to HRP countries (based on two doses), as of 31 December 2021 [27] .


5. Ethics of trial design in Covid-19 vaccines

The genetic sequence of SARS-CoV-2 was published early in January of 2020. A global research and development effort followed to develop a safe and efficacious vaccine. Human clinical testing of the first vaccine candidate started in March 2020 [28]. At that time there was no doubt that PCTs were ethical and the preferred trial design to test potential Covid-19 vaccines.

A global pandemic is a highly dynamic situation and regular change in the clinical landscape can be expected. Ethical and moral considerations will also change as new developments unfold and new information becomes available. These considerations will be influenced by existing global inequality and a lack of resources in LMICs. The moment a safe and efficacious Covid-19 vaccine became available, it opened the ethical debate as to how long it will stay ethical to continue using PCTs.

5.1 Advantages of using PCTs in Covid-19 vaccines

Most of the arguments in favour of continuing the use of PCTs in Covid-19 vaccines stems from a document published in The New England Journal of Medicine by the WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation in January 2021 [29]. More than a year later, one could argue that this information is now outdated, but even though the global vaccine situation has changed dramatically, the WHO has not released any new guidelines.

The WHO Ad Hoc Expert Group stated that initial vaccine roll-out will be slow and in limited quantities. This would provide an opportunity to ethically obtain socially valuable data. Data could then be used to improve regulatory and public health decision making. Better data would lead to increasing public and professional confidence in vaccines [29].

Rapid vaccination of large numbers of people will inevitably cause the vaccine to seem temporarily associated with some uncommon side effects. A large, simple PCT could identify any rare short-term side-effects or show the absence of such side-effects. These probably unrelated events occurring by chance after vaccination, may incorrectly be attributed to the vaccine [29]. Groups opposed to vaccination may deliberately spread these anecdotes and cause vaccine hesitancy [29, 30].

Randomised, noninferiority trials can provide clinically relevant data but according to the WHO, “at considerable cost to efficiency”. PCTs would assist with earning broad public confidence required for widespread vaccine acceptance. A PCT is still the scientific gold standard for testing any new intervention and alternative designs could yield inferior data [29, 30, 31, 32, 33, 34, 35]. Even following the availability of the first vaccines, it is still crucial to further evaluate candidate vaccines to meet the global needs. Observational data obtained from non-randomised studies after vaccine deployment could yield inaccurate answers and suffer from substantial biases [29].

The obligations researchers have to participants are not the same as those clinicians have towards patients [32, 33]. Proper informed consent would allow participants to voluntarily enrol in a trial and accept some risks to collect socially valuable data. In this unparalleled global crisis, billions of individuals might benefit from finding a new safe and efficacious vaccine, and thus some participants might enrol in PCTs because of altruistic reasons [29].

Those in favour of continuing to use PCTs in Covid-19 vaccines, argue that research-ethics guidelines such as the DoH and the Council for International Organizations of Medical Science (CIOMS) Guidelines were not written with Emergency Use Designation (EUD) of vaccines in mind [29]. A vaccine approved under EUD does not render it “best proven intervention” or an “established effective intervention” [29].

In January 2020 the WHO stated verbatim that trial sponsors are not ethically obligated to unblind participants who desire to obtain a different investigational vaccine [29]. As with any clinical trial, participants would still have the option to withdraw from the trial and the WHO did not comment on this probability when engaging with participants who request unblinding.

5.2 Ethical shortcomings of using PCTs in Covid-19 vaccines

Several Covid-19 vaccines have been approved for emergency use, with some vaccines already receiving full approval from various regulatory authorities across the world. These vaccines have been proven to have high levels of efficacy and safety [36].

Once there is an available vaccine, with high level of safety and efficacy, new candidate vaccines should be tested against approved vaccines. Ongoing PCTs of Covid-19 vaccine candidates should be unblinded [37]. Continuation of PCTs of new vaccines in conditions where efficacious vaccines already exist, contravenes the bioethics principle of beneficence. It will be in direct conflict with the participants’ best interests. It puts them at a disadvantage compared to people who are not on the trial.

Researchers have a duty not to harm participants in clinical trials. In using placebo, researchers fail to provide protection against a deadly pandemic, as various Covid-19 vaccines have been proven to be safe, efficacious, and available [36]. The harm participants in the control group are exposed to is not minor [38]. There are limitations in current treatment options, thus it is in everyone’s own interest to take the first vaccine found to be safe, instead of participating in a PCT.

Ravinetto [39] stated that an ethical strategy cannot be built on an unethical premise. In this case it is the inequitable allocation of vaccines between countries which is in essence unethical. This is a prime example of so-called “ethics dumping”: undertaking research in LMIC settings, which would not be permitted in high income settings. This reverses the principle of benefit sharing in global research. The burden of the research is much higher for the most vulnerable communities, while the benefits are available only to the higher income countries.

In social justice terms, global health research should generate knowledge that improves the health and well-being of disadvantaged and marginalised communities [39, 40]. In the context of Covid-19 these communities are mostly in LMICs, those who lack access to vaccines due to unequal global distribution. Research involving this group should be based on health and social justice, rather than building on the existing structural injustice and exploitation of these groups.

Clinical equipoise can be defined as a state of uncertainty or true ambivalence toward the efficacy of a novel therapy in the medical or scientific community [41, 42, 43]. Based on the principle of beneficence if any novel therapy is believed, by consensus, to be efficacious, research subjects should not be denied access to that therapy. Similarly, if the novel therapy is found to cause harm, then it would go against the principle of nonmaleficence to continue that specific candidate as investigational product.

The ethical loophole that supporters of continuing PCTs in Covid-19 vaccine trials in LMICs are using, is based on the fact the so-called local “standard of care” in many LMICs would be no vaccine or very restricted access to a vaccine [40]. Arguing equipoise between placebo and local standard, in settings where vaccines are not yet available, due only to vaccines nationalism and lack of equity, would be unethical. One could argue that the ethical standards applied in the LMICs should be the same as if the research were carried out in the sponsoring country. People should be treated fairly, regardless of where they live.

The WHO states that if vaccines are not properly tested (with continuing PCTs), it might lead to public distrust [29]. However, in the authors’ opinion, using a different set of ethical standards for certain countries just because they are poor, disadvantaged and cannot afford vaccines, could lead to even more distrust and scepticism around how the WHO is dealing with global inequality during a deadly pandemic.

Although those who argue in favour of continuing to use PCTs in Covid-19 vaccines state that randomised control trial is the golden standard for modern clinical decision making [29, 30, 31, 32, 33, 34, 35], there are various other study designs that could yield good data without endangering or leaving any participants unprotected [37, 38, 39, 40, 44, 45, 46, 47, 48]. Non-inferiority blinded active control trials can be done to compare trial vaccines to an established vaccine, without leaving any participants unvaccinated [39]. If research can be conducted in several ways, the method that minimises morbidity and loss of human life should be prioritised above a method that supposedly gives scientific results more efficiently, but at a greater risk to the participants.

Various authors have commented on the WHO’s call to altruism aimed at communities in LMICs [39, 40, 44]. To quote the WHO document: “people who enrol in clinical trials would probably understand the value of gathering data that will further elucidate the safety and efficacy of these vaccines and their appropriate use” [29]. This seems to underestimate the complex nature of decision-making regarding participating in a clinical trial by people living in LMICs [49]. The WHO is expecting the people from poor, marginalised and disadvantaged communities to accept that their sacrifice will be for the greater good. Firstly, this sacrifice is per definition not expected from their counterparts in higher income countries. Secondly, the “value of gathering of data” will directly benefit the sponsor country long before it benefits the general population of the LMIC where the trial was conducted.

Ironically, Dr Ghebreyesus, the WHO Director-General, in relation to global vaccine inequity, stated “The world is on the brink of a catastrophic moral failure—and the price of this failure will be paid with lives and livelihoods in the world’s poorest countries” [50]. Now it is the WHO Ad Hoc Expert Group that is essentially giving researchers free reign to continue using PCTs in countries that are too poor to afford vaccines by misusing the clinical equipoise argument and thus further marginalising these vulnerable communities that they are meant to protect.

When conducting trials in LMICs there are certain specific considerations regarding informed consent [33, 34]. The level of literacy in LMICs is lower than in high income countries and thus it is more likely that a participant will have a diminished understanding of what a PCT entails [34]. The authors can reflect on several cases where despite extensive counselling and a thorough informed consent process, participants in various Covid-19 vaccine PCTs, when coming back for subsequent visits, could not recall that they were told of the possibility of having a salt-water injection. This caused great confusion for many participants and highlights the ethical challenges of conducting clinical trials in LMICs.

In many LMICs, some participants are more likely to trust a clinician blindly as it is seen as a sacred profession [40]. The clinician is supposed to act in the patient's best interest and the participants cannot be expected to always know the subtle difference between a clinician and an investigator. In some cultures, the clinician is seen as an authority figure and participants find it difficult to say no [40]. Medical care is often limited in LMICs and joining a clinical trial is a way for a participant to gain access to a scarce resource. In many LMICs there is still great uncertainty about the access to vaccines and the people are vulnerable and desperate for any type of help.

The Covid-19 pandemic has led to a massive socio-economic crisis with countless jobs lost. The exact economic effect of Covid-19 on LMICs, will not be discussed in this chapter, but in summary all can agree that the economic situation of many people living in LMICs is worse than ever. The monetary gain involved in being part of a clinical trial, when converted into the currency of the sponsor nation, is often seen as negligible and not considered a formal payment. For a participant in a LMIC, there is a higher probability that this payment might be a very strong motivator to join a clinical trial even if there are substantial risks. If the participant joins the trial as the only way to feed himself and his family, one could argue that it is not truly informed consent.

The WHO stated that sponsors are not ethically obliged to unblind subjects as soon as a different investigational vaccine becomes available [29, 31]. In South Africa, the vaccine roll-out for health care workers was via the Sisonke open label clinical trial. Outside of a clinical trial setting, there was no other way for a health care worker to get vaccinated. A small group of these health care workers were already participating in Covid-19 vaccine PCTs. This is another example of how participants in LMICs are motivated to participate in PCTs, because a 50% chance of getting the vaccine is still better than no chance at all. Even though, according to the WHO, sponsors were not obliged to unblind these participants, it would have caused a great ethical scandal if they were not given the option. In the author's experience, many participants made it clear that if they were denied unblinding, when they have a 100% chance of getting a vaccine elsewhere that is already authorised in several other countries, they would certainly withdraw from the PCT.

Ahmad and Dhrolia posed the following comparison. The question “Should we continue or permit placebo controlled vaccine trials for Covid-19 disease, when available vaccines have been found safe, efficacious and in use in many countries?” sounds very similar to “Should West African HIV-positive pregnant women receive placebo in HIV placebo-controlled trials when Zidovudine was found safe and efficacious for the prevention of vertical transmission of HIV infection elsewhere in the world?” or “Should African American men of Tuskegee, Alabama remain untreated even when penicillin was found safe and efficacious for the treatment of syphilis?” [40].

Any researcher who has attended training in Good Clinical Practice, should be familiar with these historical events, which serve as extreme examples of what should not happen during a clinical trial. They involve vulnerable, disadvantaged, poor populations with potentially life-threatening diseases. These populations do not have access to the standard of care that is available in higher income countries. They are trying to access interventions which the sponsors are able to provide, but deliberately chose not to do so.

Multiple Covid-19 vaccines have been found to be safe, efficacious and one of the only lifesaving interventions that would be able to end a pandemic. Over ten billion doses of vaccines have been administered globally [35]. The vaccine is freely available in high income countries, but only 9.5% of people in low-income countries have received at least one dose [51]. It could easily be argued that continuing to use PCTs in Covid-19 vaccines, and thus further exploiting the vulnerable pollution in LMICs, is no different to the West Africa or Tuskagee trials, and thus grossly unethical and a violation of human rights.


6. Conclusions

PCTs for a COVID-19 vaccine in vulnerable populations need to be reviewed with the above in mind. The onus of patient safety when looking to conduct clinical trials in vulnerable populations, which LMICs certainly are, should remain with the sponsor and country of origin that will benefit most from the data. Emphasis must be placed on autonomy; subjects need to understand what they are doing by participating. Cultural differences make this difficult and the need for community engagement is paramount. We have highlighted weakness in the ethical review process of LMICs, the lack of resources being a major factor. The COVID-19 pandemic has strained these resources further in all aspects, creating a need for investment in the health of LMICs by sponsors conducting clinical research. Necessary in these countries to bridge the health gap and provide healthcare access to the most impoverished of the world. We cannot however use this fact to exploit LMICs, the fact they are so desperate is more reason for sponsors to protect the communities, not less. The debate continues and each case will have its own nuance. The major points to take away are who benefits from the research, how will the local government use that research to generate national programs, are the communities adequately engaged throughout the process of clinical trials and what ethical frameworks, enforceable or otherwise, exist in the designated country where the trial will take place. Answering these questions will assist sponsors in maintaining ethical practice and protection of research participants in LMICs.


Conflict of interest

The authors declare no conflict of interest.


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Written By

Lesley Burgess, Jurie Johannes Jordaan and Matthew Wilson

Submitted: 10 February 2022 Reviewed: 01 April 2022 Published: 05 May 2022