Clinical Trials, Research, and Treatments

Overview

As COVID-19 spreads, scientists are developing pharmaceuticals and vaccines that might treat the disease. While everyone hopes for a rapid discovery, the quest to identify therapeutics and prove their efficacy raises important ethical considerations. Furthermore, the interests of patients, the scientific community, the general public, and government officials may conflict.

Thought questions:

  • What are the main ethical considerations in carrying out medical research on human populations?

  • How are these considerations challenged in times of crisis, and how does a society balance the needs of the population while maintaining core ethical principles that protect human study subjects?

To learn more about what makes a research trial design "ethical" according to the Belmont Report, please look at the supplemental material here.

Challenges to the Principle of Respect for Persons

Even under ordinary circumstances, ensuring proper informed consent can be difficult, as the term may be interpreted in different ways. In 1979, American philosophers Beauchamp and Childress offered one definition of informed consent that is still referenced: “an individual’s autonomous authorization of a medical intervention or of participation in research.” According to these philosophers, informed consent entails more than agreeing to a study. It must involve authorizing an act through the act of voluntary consent. In particular, Beauchamp and Childress stated that the following seven elements are thought to capture informed consent:

  1. Threshold Elements (Preconditions)

    1. Competence (to understand and decide)

    2. Voluntariness (in deciding)

  2. Information Elements

    1. Disclosure (of material information)

    2. Recommendation (of a plan)

    3. Understanding (of Disclosure and Recommendation)

  3. Consent Elements

    1. Decision (in favor of a plan)

    2. Authorization (of the chosen plan)

As we understand these elements that comprise informed consent, it begins to become clear how conditions of crisis may place constraints on these principles. In the context of the current COVID-19 pandemic, there are already a number of clinical trials underway, from testing antiviral drugs to vaccine trials to evaluating passive antibody transfer (see Modules 1 for more information regarding ongoing trials). Given the rapid spread of COVID-19, many of these trials do not have preliminary data on the risks of treatments for human subjects. While some therapeutics, such as the anti-malarial drug hydroxychloroquine, have been FDA-approved and are being tested on COVID-19 patients, these medications may have significant toxic side effects. Given the unknown risks of new or unproven treatments for COVID-19, how does a researcher ensure that a potential study participant has received appropriate disclosure, and how does a researcher assess a potential study participant’s understanding of the risks of participating?

Another ethical challenge that surrounds the issue of informed consent is determining whether severely ill COVID-19 patients may have the capacity to agree to clinical trials or experimental therapies. It has been reported that, after the initial onset of dyspnea, many COVID-19 patients rapidly deteriorate and develop Acute Respiratory Distress Syndrome (ARDS). Given the possible sudden decline in respiratory function in this subset of patients, many individuals may not have the opportunity to designate a health care proxy (if they had none prior). Thus for recent, expedited trials such as the convalescent plasma study, it may be difficult to determine whether patients who are severely sick would agree to be part of the research trial.

Challenges to the Principle of Beneficence

One of the key questions raised by COVID-19 research trials is the balance between risks to human subjects and potentially life-saving treatments that can help the rest of society? This is not the first disease in recent history for which this ethical question has been posed. During the AIDS crisis in the 1980s, as well as Ebola and Zika epidemics of the past decade, there were similar pressures to expedite research studies to find vaccines or therapeutics. Even in non-pandemic scenarios, experimental drugs developed for terminal illnesses may be fast-tracked to help critically ill patients. Here, we will discuss some of the adaptations in research guidelines that are made in situations where time is even more limited, as well as the risks and benefits of these different standards.

To learn more about the four phases of clinical trials, please read the supplemental materials here.

Approving off-label treatments

Even after a therapeutic is FDA-approved, the treatment cannot be used to treat any medical condition. According to the FDA, “off-label” refers to the unapproved use of a drug or treatment approved for a different use. During times of crisis, there is often an increased impetus to use medications approved for similar illnesses in the hopes that this previously FDA-approved therapeutic may be beneficial. In the context of the COVID-19 pandemic, the antimalarial agent hydroxychloroquine provides an example of an off-label drug being tested.

The FDA guidelines for “off-label” use of drugs approved for another purpose leave discretion to the individual treating physician, with oversight by local institutions, including its Institutional Review Boards (IRBs). The FDA explains, “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgement.” A physician’s responsibilities in using an approved product in such a way are three-fold:

1) awareness of the product and its effects 2) use based on “firm scientific rationale and sound medical evidence" 3) keeping a record of the drug’s usage and its effects.

While the off-label use of FDA-approved drugs and therapies is less stringently regulated, the testing of experimental drugs, therapies, and devices currently in the U.S. is bound by the Health and Human Service (HHS) Common Rule and FDA guidelines to ensure proper beneficence of any new drug or therapy. While a harmonized ruleset is currently expected, the expectation is that the more stringent and protective ruleset be followed by investigators.

To learn more about expedited FDA approval of treatments for experimental use, please read the supplemental materials here.

Ethics of vaccine development

We will now focus on ethical questions specific to vaccine development. Below is a comparison of traditional vaccine development timelines versus that in a pandemic. Some of the main differences involve the parallelization of the steps seen normally, which reduces time while increasing risk for developers (Lurie et al., 2020). Despite the condensed timelines, many of the recent vaccine development efforts for outbreaks such as Ebola, Zika, and MERS were not completed in a time frame relevant for intervention in their respective epidemics.

Difference between Traditional Vaccine Development and Development Using a Pandemic Paradigm

To achieve optimally time efficient vaccine development, intentional infectious inoculation of human subjects is one of many methods to obtain efficacy data. These studies, known as vaccine challenge experiments, are substantially more expedient compared to natural infection studies, making them useful during time-sensitive pandemics. However, given that these trials require deliberate inoculation of healthy volunteers, thorough and careful ethical consideration is warranted, particularly when exposing subjects to diseases with significant risk of morbidity and mortality, and in scenarios with no treatment options.

For these human challenge trials, an ethical review is deemed essential, particularly to assess the risks of exposure versus the benefit of data, as well as the robustness of informed consent. These trials are truly an arena in which the considerations of beneficence (risk versus benefit), respect for persons (informed consent and true understanding of potential risks by studied individuals), and justice (ensuring fair population recruitment for risk burden) must be carefully balanced. For this reason, human challenge trials are not acceptable in vulnerable populations, particularly those that cannot give clear informed consent (WHO, 2016). However, these trials have been performed in specific circumstances. For example, in a recent NIH malaria vaccine trial, the benefits of the study were determined acceptable relative to the risk of infection, particularly allowing for treatment and monitoring of the exposed group. As a counterexample, a human challenge study for a Zika vaccine was not conducted due to increased risk to potential non-consenting individuals (i.e., sexual partners of participants, fetuses) (Callaway, 2020).

Given that no treatments for COVID-19 exist, in addition to chance of morbidity and non-negligible chance of mortality, the discussion around a potential human challenge trial, which would expedite efficacy data collection, has only just begun to weigh the risks to the experimental population versus the benefits of the population as a whole (Callaway, 2020, Eyal et al., 2020). Further, even the fundamental design of a randomized clinical trial can be problematic in diseases with significant morbidity and mortality with regards to the placebo control arm. For example, during the Ebola vaccine efficacy trials, it was deemed unethical to employ placebo for control. Alternative methods were sought, including the use of early and delayed phase vaccination groups to determine efficacy. Design of efficacy trials for SARS-CoV-2 are currently being discussed (Lurie et al., 2020).

Challenges to the Principle of Justice

The principle of justice is to ensure that those who bear the risks of research benefit from it and, correspondingly, those who benefit from research should bear some risk. Vulnerable and stigmatized populations should be protected from exploitation, and privileged groups should not be favored. To learn some examples from U.S. history that illustrate threats to this ethical principle during wartime and in epidemics, please read the supplemental materials here.

It is crucial to ensure that vulnerable populations are not targeted at the expense of rapid scientific discoveries, as has occurred in the past. While many of these clinical trials are recruiting volunteers, this practice may not be as equitable as it sounds. For example, in passive antibody transfer studies, even though antibodies are being isolated from the plasma of patients who volunteer for the study, COVID-19 does not affect individuals equally. Patients from more vulnerable populations, such as the elderly living in crowded nursing homes or the homeless, are at greater risk of COVID-19 exposure and infection, and as such may represent a greater proportion of study participants. As the Atlantic pointed out in a recent article, there are no guidelines on who would own potentially therapeutic antibodies -- will the patients from whom these antibodies were obtained be able to choose to immunize loved ones, or might the rich be able to buy the plasma of the poor who were previously infected? If compensation is offered to increase the participation, particularly for vaccine trials, which typically require a large number of participants, this may bias for subjects of lower socio-economic background. People in the U.S. cannot receive financial compensation for donating blood or organs, but they can be compensated for plasma harvested eggs, and harvested sperm. When might compensation be considered coercive, limiting an individual’s ability to make a voluntary choice?