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The race is on to create and distribute a safe and effective vaccine against SARS-CoV-2 for the world. Historically, a vaccine’s efficacy against dangerous agents is tested by seeing whether vaccinated subjects in endemic areas have lower incidence of the disease than the surrounding population. Alternatively, if there’s a reasonable treatment for the condition, then those subjects might be exposed to the agent.  

A thought experiment. 

What if the FDA learns the best vaccine candidate was tested overseas using prisoners challenged with SARS-CoV-2 exposure? Assume the safety profile and evidence of efficacy are excellent. Should the FDA allow the compound to be marketed and distributed in the US? 

Now assume the submitted data package is unchanged but the trial investigators overseas made no mention of using prisoners. That fact is only learned from leaked documents exposing the details. What now? Should the vaccine, if approved, be withheld from the US market? 

The reason I bring this up is because of a position taken by virologists on a podcast I’ve been listening to: This Week in Virology. The panel’s consensus opinion seems to be challenging a patient with SARS-CoV-2 exposure after they’ve been vaccinated with a test vaccine would be unethical. They argue that a patient could get sick and die because there are no known highly efficacious treatments. That point is true. But, let’s step back a moment.  

First, there are thousands of people ready, willing, and able to participate in vaccine trials including being challenged with virus exposure.  

Next, Phase 1 preliminary safety studies are not without risk. Normally, such studies get the green light only after animal studies have demonstrated a reasonable safety profile. Nature does not always cooperate. Ever heard of BIA-2474 (sponsored by a company called Bial)? Most people have not. In 2016, that compound was tested in a Phase 1 safety trial. BIA-2474 was a FAAH inhibitor.  

To refresh

Drugs which enhance the activity of endocannabinoids such as cannabinoid receptor agonists, agents modifying cannabinoid transport or inhibiting their metabolism have the capacity to be used as analgesics, hypnotics, antiemetics, antihypertensive, antiasthmatics, antiepileptics, neuroprotectives, immunomodulatory, anti-inflammatory, alcohol withdrawal, and eating disorders.

One of the major advances in this field was the generation of fatty acid amide hydrolase (FAAH) inhibitors. FAAH hydrolyses the endocannabinoids with amide bonds including anandamide (AEA). Inhibition of FAAH would lead to extended endocannabinoid activity at its site of synthesis resulting in tissue selective activation of CB receptors. This enhanced endocannabinoid activity is suggested to be useful in the treatment of several clinical conditions. At present, a lot of research is being carried out to establish their role in the management of neuropathic pain. 

FAAH inhibitors are being researched extensively, but none of them has reached market yet. Other clinical trials that are conducted on FAAH inhibitors are Merck’s MK-4409, Pfizer’s PF-04457845, and Vernalis’ V158866. None of these trials had reported any adverse effect with this group of agents, and they were considered safe in humans. 

[Prior to human trials with BIA-2474], Bial performed studies on four animal species: rat, mice, dog, and monkey.

What happened? 

A total of 128 participants were enrolled in this trial, out of which ninety were dosed with compound, and the others were given placebo. Volunteers who were subjected to multiple doses of test drug were adversely affected, five of them were admitted to hospital, out of which one of the volunteers was declared brain dead and other four, were said to have irreversible brain damage. The magnetic resonance imaging (MRI) of the affected patients showed evidence of deep cerebral hemorrhage and necrosis.

In short, a disaster. With the benefit of hindsight, much was learned and recommendations were made to update future trial designs to enhance safety.  

Still, the point is that even Phase 1 safety trials pose risk. A Phase 1 safety trial for SARS-CoV-2 would similarly pose some risk. We just don’t know how to quantify that risk. 

Is there a reason to foreclose informed volunteers from participating in Phase 2 vaccine efficacy trials where the subject is challenged with exposure to SARS-CoV-2? Is it really unethical?  

Assume the test vaccine does nothing to protect. We have a reasonable idea of what the mortality and morbidity risk of COVID-19 is to various subjects. By selecting the right demographic, that risk can be controlled, but not eliminated.  

Assume the test vaccine makes the clinical course of SARS-CoV-2 worse than baseline. It’s possible. We don’t know how to quantify that risk. That risk is the same whether the patient is intentionally challenged with virus exposure or exposed to SARS-CoV-2 “in the wild” over time. The only difference is how soon we’ll know that vaccine is a dud.  

If subjects are informed of the risks, whether we can quantify them fully or not, and they volunteer to participate in a vaccine challenge trial, is it noble or unethical? I think the former. All sorts of people volunteer for risky activities that benefit society as a whole. Firefighters, policemen, Navy SEALs, ER and Critical Care Physicians, nurses, and many, many more. This list goes on and on.  

Further, we all accept some risk in our everyday life. We drive in cars. If we wanted to cut the risk of death from driving, we could mandate helmets and flame proof clothing. We could then cut the speed limit to 25 MPH. We don’t.  

We cannot eliminate all risk.

Back to SARS-CoV-2. If we adopt the traditional approach testing vaccinated subjects in endemic areas to learn whether they have a lower incidence of COVID-19 than the surrounding population, the rest of the world may not wait. Some societies may force those who cannot provide informed consent to be challenged with the virus. Then we’ll have a Faustian choice to make. 

Perhaps we’ll have better therapeutics available when Phase 2 and Phase 3 vaccine trials get started. If so, this discussion is academic.  

One statistic that is growing as fast, if not faster, than the US mortality rate from COVID-19. The list of people willing to test a vaccine and be challenged with exposure to SARS-CoV-2. 

What do you think? Let us know in the comments below.

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Dr. Jeffrey Segal, Chief Executive Officer and Founder of Medical Justice, is a board-certified neurosurgeon. Dr. Segal is a Fellow of the American College of Surgeons; the American College of Legal Medicine; and the American Association of Neurological Surgeons. He is also a member of the North American Spine Society. In the process of conceiving, funding, developing, and growing Medical Justice, Dr. Segal has established himself as one of the country’s leading authorities on medical malpractice issues, counterclaims, and internet-based assaults on reputation.

Dr. Segal was a practicing neurosurgeon for approximately ten years, during which time he also played an active role as a participant on various state-sanctioned medical review panels designed to decrease the incidence of meritless medical malpractice cases.

Dr. Segal holds a M.D. from Baylor College of Medicine, where he also completed a neurosurgical residency. Dr. Segal served as a Spinal Surgery Fellow at The University of South Florida Medical School. He is a member of Phi Beta Kappa as well as the AOA Medical Honor Society. Dr. Segal received his B.A. from the University of Texas and graduated with a J.D. from Concord Law School with highest honors.

In 2000, he co-founded and served as CEO of DarPharma, Inc, a biotechnology company in Chapel Hill, NC, focused on the discovery and development of first-of-class pharmaceuticals for neuropsychiatric disorders.

Dr. Segal is also a partner at Byrd Adatto, a national business and health care law firm. With over 50 combined years of experience in serving doctors, dentists, and other providers, Byrd Adatto has a national pedigree to address most legal issues that arise in the business and practice of medicine.