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Bioethics in a Pandemic: Vaccine Research and Clinical Trials

After exploring some of the ethical questions involved in allocating and distributing a potential COVID-19 vaccine and the basic tenets of bioethics, we continue by delving into the ethical issues relating to the vaccine development process, including clinical trials. As a first step, we provide a very brief introduction on how vaccines are developed and tested prior to approval and release.

The Vaccine Development Process

Vaccines work differently from most conventional drugs and biologics because vaccines induce the body’s immune system to build a long-lasting, prophylactic defense against an invading organism rather than directly treating an ongoing disease or condition. However, the development process for vaccines is quite similar to other regulated medical products. The process starts with identifying the substance that will induce a controlled immune response in the human body. Historically, whole virus (specifically, inactivated or attenuated live viruses to reduce pathogenicity) or pieces of the virus would be used so that the body’s immune system could recognize the molecular structure of the virus scaffold (specifically, the antigens protruding from the virus’s outer shell, or capsid) and generate antibodies to counter and prevent a future infection. Although many vaccine developers still use these tried-and-tested materials to make vaccines, new technological advances have introduced DNA-based and mRNA-based vaccines as possible contenders in the market. Vaccines based on these new technologies are more complex in terms of mechanism of action, but the result is the same: the immune system generates antibodies against the foreign matter to build a defense.

A vaccine developer tests various candidates in cultured cells (in vitro testing) and in animals (in vivo testing) to identify an active component that will work in humans. Once the active component of the vaccine is identified and has gone through the requisite pre-clinical testing, the developer starts the clinical development process, which includes phase 1, 2, and 3 clinical trials. Clinical trials are typically rigorous randomized double-blind studies in which one cohort of subjects receives the investigational treatment, a second cohort receives a placebo as a control, and neither the subjects nor the investigators know which substance each subject received. Clinical trials are set up this way in order to compare safety and effectiveness while minimizing bias.

Once the clinical development process is complete (meaning that the developer has sufficient evidence from adequate, well-controlled clinical trials that the vaccine is safe and effective for use as a prophylactic treatment), the developer submits a Biologics License Application (BLA) to FDA to obtain marketing authorization. Once FDA grants the BLA, the developer may promote, commercialize, and distribute the vaccine.

The Ethics of Vaccine Clinical Trials

Given the way that formal clinical trials are conducted with one set of subjects receiving a potentially effective treatment and another set receiving essentially no treatment at all, there is an inherent ethical quandary in asking individuals to take part in the trial. How can the trial sponsor and the investigators running the trial recruit individuals to participate when they could get nothing but a sugar pill or an injection of saline? The basic answer to this is that the investigational product is not yet proven to be effective, so in the absence of any other standard treatment (as is the case for COVID-19), there is no guarantee that the treatment arm of the trial will experience any greater benefit than the control arm.

In addition to that basic, practical answer, the U.S. government has put in place numerous laws and regulations to protect human research subjects and minimize the potential risks of participating in a clinical trial.

These protections were established  after troubling instances of injustices and abhorrent practices involving clinical trials in the U.S., including the Tuskegee Syphilis Study, a study at the Fernald School in which mentally disabled subjects were fed radioactive oatmeal, and a study at the Willowbrook State School in which mentally disabled subjects were intentionally infected with hepatitis so that researchers could monitor the disease’s progression. None of the subjects in these studies, nor any parent or guardian, were told about the research or given a chance to consent, and in many cases, subjects were deceived about the study’s intent. The horrific absence of patient protections in these studies led to the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which published the Belmont Report in 1979.  The Belmont Report outlines three key tenets of research ethics: respect for persons, beneficence, and justice. These principles led the U.S. government to develop various protections for human research subjects, including:

  • Informed consent – Requires researchers to present to each potential subject a written document clearly explaining the study and the potential risks involved, ensure the individual understands the content of the document, and obtain the individual’s signature indicating such understanding.
  • Institutional review boards (IRBs) – Ethics committees established at research institutions that serve as independent reviewers of research protocols involving human subjects and ensure that sufficient protections are in place to minimize potential harm to the subjects.
  • Specific protections for children participating in research – Regulations require (1) specific documentation showing that participating in the study is likely to benefit the child and justifying any anticipated risks and (2) special consideration of the child’s ability to consent.
  • Investigational product applications – Requires drug and biologic product developers to submit clinical development plans and protocols to FDA for review and comment before initiating clinical trials.

Vaccine trials apply these same protections, meaning that each subject should fully understand that they may not receive the experimental vaccine and that there may be certain risks to participating in the trial. And even though risks are involved, an IRB and the FDA reviewed those risks and found them to be acceptable in light of the potential benefit of bringing a vaccine to market that could prevent millions from getting a disease and prevent numerous deaths.

Some Ethical Considerations of the Current COVID-19 Vaccine Development

As described above, vaccine development is complex and involves many steps, and one of the most critical steps in development is the performance of adequate, well-controlled clinical trials to ensure that the ultimate vaccine will be safe and effective for public use. These trials, especially phase 3 trials, which provide the pivotal safety and effectiveness data, involve thousands of subjects and typically take months (and sometimes over a year) to complete, and this timeline does not include the time required for data analysis and generating the final report. It is conceivable that the clinical development timeline could be accelerated in the interest of getting the vaccine to market faster, but such acceleration introduces the possibility that subjects will not be monitored for a sufficient period of time.

The release of a vaccine for SARS-CoV-2 has enormous political and financial implications, and such factors only serve to muddy the ethics surrounding ongoing vaccine trials. An additional factor in the current race to develop a vaccine is that some of the potential SARS-CoV-2 vaccines are being developed from viral mRNA, a technology that has not been used before in a widely distributed vaccine. Any acceleration of the development or premarket review process for these vaccines could present potentially serious short-term or long-term risks for study subjects and those who receive the approved vaccine soon after release.

An additional factor to consider on the ethical side of the current situation is that SARS-CoV-2 vaccine developers will likely benefit from the protections afforded by the Public Readiness and Emergency Preparedness (PREP) Act, which shields developers of medical countermeasures and associated entities from liability relating to such products. In fact, the Department of Health and Human Services specifically extended PREP Act immunity over companies involved in the development, manufacture, testing, distribution, administration, and use of countermeasures relating to the COVID-19 pandemic. This means that SARS-CoV-2 vaccine developers need not fear a potential onslaught of product liability suits relating to their vaccines or other potential litigation, which usually serve as an additional incentive for manufacturers to ensure the safety and efficacy of their products.

In order to counter these potential ethical challenges, the CEOs of AstraZeneca, BioNTech, GlaxoSmithKline, Johnson & Johnson, Merck, Moderna, Novavax, Pfizer, and Sanofi, recently co-signed a pledge outlining a united commitment to uphold the integrity of the scientific process as they work towards potential regulatory filings and approvals of the first COVID-19 vaccines:

We, the undersigned biopharmaceutical companies, want to make clear our ongoing commitment to developing and testing potential vaccines for COVID-19 in accordance with high ethical standards and sound scientific principles….We believe this pledge will help ensure public confidence in the rigorous scientific and regulatory process by which COVID-19 vaccines are evaluated and may ultimately be approved.

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Authors

Bridgette A. Keller is a Mintz attorney who applies her experience in health system administration and ethics in health care to her health law practice. She advises health care providers, ACOs, health plans, PBMs, and laboratories on regulatory, fraud and abuse, and business planning matters.
Benjamin M. Zegarelli is a Mintz Associate who counsels clients on compliance and regulatory issues, with a focus on FDA regulations. Benjamin advises clients in the pharmaceutical, medical device, and biotech industries. He provides counsel on research approval, sales, and contract negotiations.