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.
When navigating unprecedented challenges, access to salient, seasoned experts is invaluable. Medical Justice has devised a collection of templates and guidelines that will see you through the emergent medico-legal challenges presented by COVID-19. These resources address obstacles related to informed consent, reopening your practice, and staff issues specific to COVID-19.
Members of Medical Justice: Access these resources by visiting your Members Only page. Need help? Call us: 1-877-633-5878.
Not a member? For a limited time, we are making these templates and protocols specific to COVID-19 available. Click here to learn how to access these resources.
Learn how Medical Justice can protect you from medico-legal mayhem…
Take Advantage of Our Review Monitoring Service
We provide qualified applicants with free review monitoring for 6 week. Reports delivered bi-weekly.
Request a Consultation with Our Founder
Medical Justice Founder and CEO, Jeff Segal, MD, JD, provides consultations to doctors in need of guidance.
Meet the Experts Driving Medical Justice
Our Executive Team walks with our member doctors until their medico-legal obstacles are resolved.
Jeffrey Segal, MD, JD
Chief Executive Officer and Founder
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.
What’s unethical are: 1) dictating the risks that people are allowed to take on their own and 2) forcing people to take real risks they’d rather not take.
If I want to go around without a mask or obsessive handwashing, it’s anti-liberty to try to force me to do those actions. In a close environment, like inside an aircraft, it’s reasonable to insist since others are involved; in a store, no one has to be close to me. If I choose to participate voluntarily in a vaccine trial, given that I will definitely be exposed to a pathogen, it’s my choice to do that. I would probably choose not to participate if there’s a placebo arm and I might be in it, but if assured that I wouldn’t be, I’d likely volunteer.
And that’s me: age 73, s/p angioplasty and stent placements in 1996, 3-vessel bypass in 2018, so: near-maximum risk category.
The only issue about whether the FDA should consider withdrawing approval for a vaccine tested on unwilling subjects is the fact that it’s not ethical to do that, and the data from any group that would be willing to do so would necessarily be suspect. Do I trust anything that I hear coming out of China? Not a chance. Might it be accurate and in good faith? Yes. Do I have a reasonable suspicion that it isn’t? Absolutely.
Bottom line: if the test subjects are treated unethically, so might the data thus generated. The Chinese haven’t shown any particular remorse about what’s happened in the past 6 months. They still see themselves as competing with the US, they act in ways that we see as unethical, they appear to lie and censor ruthlessly (think: expelling US and other western journalists–twice), and they have stated that they want to “assume their rightful position in the world.” Last times I heard those kinds of sentiments expressed was by Kim in NK, Hitler, and that ilk. I don’t trust the Chinese to be honest. No rational person would.
If a prisoner volunteers for testing, and given the testing regimen, develops antibodies, and then is exposed to the live virus, what is the harm? This is the same thing that would happen in the general prison or public populations.
The likelihood is that the prisoner so treated is going to be immune.
But what if he isn’t? The statement that there are no efficacious treatments is false. There is more and more evidence accumulating that hydroxycholorquine, and azithromycin in combination are very effective at treating the virus. Therefore the ethical risk to the prisoner even in the event of treatment failure is low. Are prisoners offered, or mandated to get the flu vaccine each year in order to provide herd immunity in the prison population? Is that unethical? The flu vaccine each year is at its finest a best guess about what flu viruses will be around that particular year. That is far less efficacious than the vaccine we are talking about in this case of Covid 19.
The raising of a particular drug in comparison to a vaccine is a false comparison. These are not equivalent circumstances at all. The drug is being used as a treatment for a condition. The vaccine is a preventative agent. The drug has to pass efficacy and safety concerns in humans. Vaccines for Covid 19 must pass efficacy and safety concerns, but the testing is being done concurrently instead of sequentially. That will shave many months off the testing process.
By the way, wearing masks that do nothing to contain or prevent inhalation of the Covid 19 virus, are useless window dressing designed to make people feel better. Why are physicians allowing politicians to prescribe ineffective useless masks that are a waste of money?
What happens if the prisoners did not volunteer? Is that any different than being mandated to take the flu vaccine, for the greater population good? The bottom line is that the work must be valid and corroborated in more than one test population, to make sure that the vaccine developed is efficacious and safe. We just need to get the bureaucracy out of the way so that this can be completed as rapidly as possible.
First, if the prisoners are not being given an option to volunteer for testing, it could be considered unethical. Most prisoners, however, would most likely volunteer, especially in exchange for a shortened sentence. And it would be, in the end, for the greater good. As far as the face mask issue is concerned, coming from one of the greatest at-risk populations (working 12 INCHES from a patient’s uncovered mouth) I assure you, I will be wearing a face mask and a shield. In public, my mask isn’t supposed to protect me from you. It is supposed to protect You from Me. It is supposed to capture the droplets loaded with virus that I exhale so that the droplets do NOT become airborne to be inhaled by you. And, no, Joe Horton, I can not always be a safe distance from you when walking by the way or passing you in a store. So, please sir, protect me. I am not ready to be exposed to this thing. And, yes, I get a yearly flu shot – and hope.