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Anna Taylor
 on July 15, 2020

Following the Thread of Risk through Vaccine Trials

A look into how clinical trials play a role in the identification, understanding, and prevention of medical risks. Understanding clinical research is key to comprehending vaccine decisions.

man on a highline

In the midst of a global pandemic, a working vaccine is an ambition for many scientists and a hope for many citizens. But dreams of immunity are tempered by the risks inherent to vaccines. In the context of COVID-19, both the risks and benefits may be amplified. Clinical trials play a major role in the identification, understanding, and prevention of medical risks. Understanding clinical research is key to comprehending vaccine decisions.

At every step in the vaccine development process, decision-makers weigh potential advantages and disadvantages, creating “benefit-risk” profiles. An obvious benefit of a successful vaccine is virus immunity for individuals and populations. With the high transmission rate of COVID-19, this potential benefit is enormous. But given this transmission rate, an ineffective vaccine leading to a false sense of security is an added risk. Additional risks include unexpected side effects, serious health concerns, and misuse of resources. From drug companies funding research, to patients consenting to clinical trials, to regulatory agencies evaluating safety, to consumers choosing to vaccinate: each party weighs benefits and risks, even if subconsciously.

The process of risk reduction begins well before human trials. Scientists work to isolate vaccines, investigating their designs with bench and animal testing. Preclinical risks are low, while theoretical benefits are vast. Yet at this vital stage, research outcomes are taken seriously. Scientists test for harmful reactions and an immune response in animals, after which few vaccine candidates move forward. This raises an important question: if thorough research occurs in the lab, why are clinical trials necessary?

The Purpose of Clinical Trials

Scientists cannot accurately predict the impact of a product on humans without first exposing humans. It’s not rocket science, but it is comparable. Before the Apollo 11 launch, aerospace engineers conducted extensive research on the moon’s surface, atmosphere, and orbit. They crash-landed crewless rockets, gathered soil samples, and pored over calculations until human safety was nearly guaranteed. A small, highly qualified, and tightly monitored group trained for takeoff. Still, the true risk for the first astronauts on the moon remained unknown.

Eagle Apollo module

Similarly, scientists model outcomes in the lab but cannot ensure vaccine safety without human testing. Phase 1 clinical trials act as “moon landings” for medical products. After thorough laboratory research, 20-100 healthy volunteers receive the vaccine in controlled environments. The purpose of these studies is to identify harmful reactions in humans. For Phase 1 volunteers, the benefit-risk profile has many unknowns in both categories. Participants risk unforeseen medical issues, but potential benefits include: early access to lifesaving vaccines, financial compensation, and the ability to contribute to scientific progress. Even when results flag safety issues and trials end, Phase 1 patients support large leaps for mankind.

When analyses indicate favorable results, clinical research expands. Phase 2 trials enroll several hundred people in hopes of establishing clear effectiveness. If vaccines display no benefit (i.e., do not create an immune response), no amount of further risk can be justified and the studies end. Phase 3 trials may enroll thousands of patients, splitting them into groups with different treatments. This way, a new vaccine can be directly compared with an available alternative or placebo. Larger sample sizes enable the collection of effectiveness data and common side effects (benefits and risks). Just as in space travel, the combination of variables possible in each new circumstance can be countless. Phase 3 studies collect mass data from different populations and environments so that experts can better predict individual outcomes.

Reducing Risk Through Clinical Trials

Clinical trials exist to decrease risk. Safeguards in study procedures protect patients in the trials themselves. Before subjects enroll, regulatory agencies review laboratory data and study plans. The risk allowance for healthy patients in vaccine trials is extremely low, because the benefit is wholly theoretical (patients are not already sick or without options). Less vulnerable populations are observed first (e.g., adults before children). Patients are also closely monitored, reducing the possibility that a side effect could go unnoticed. Regulatory agencies periodically review reports for unexpected safety concerns.

Even the best research cannot reduce the risk of individual side effects from a vaccine to zero. On the other hand, the risk of contracting COVID-19, for example, as an unvaccinated individual, is not zero either. There is risk in both action and inaction.

Anna Taylor

Investigational plans for clinical trials include several risk mitigations as well. Patients sign clear consent forms, which outline all expected procedures and risks. Stopping rules are generally set out beforehand, meaning certain results will immediately stop the study. This protects existing and potential patients, regardless of the study analysis.

While these features protect enrolled patients, the main goal of vaccine clinical trials is decreasing risk for the eventual intended population. Most importantly, vaccines that do not show a favorable benefit-risk profile do not move forward. Furthermore, study sites fill out case report forms for every patient, enabling retrospective correlation between risk factors and side effects. Adverse events are analyzed alongside population characteristics, environmental factors, and dosing amounts. Subsections of the population showing an increased risk for adverse events are noted. They may be investigated in later studies or excluded via vaccine labeling recommendations.

The Risk Ratio After Clinical Trials

As a consumer weighing benefits and risks of an available vaccine, the clinical trials process can be both reassuring and eye opening. The process is built to identify safety issues—both common and less common—but will never certainly catch them all. After clinical trials, regulatory authorities determine whether vaccine licensing is appropriate. Licensing, or approval, allows the vaccine to be publicly marketed and distributed. Regulatory agencies make decisions based on safety and effectiveness, independent of financial impact. In addition to the trial outcomes, they evaluate manufacturing to ensure a safe and consistent vaccine production.

Based on the widespread use of vaccines, some side effects may not be revealed until after a vaccine is on the market. Accordingly, vaccines are monitored after market approval using adverse event reporting systems. In the US, the Vaccine Adverse Event Reporting System (VAERS) is open to both public reporting and public review of side effects. The FDA notes that monitoring is necessary to catch events that may only happen in 1 in 100,000 people and to monitor groups who were not included in clinical trials. In the past, vaccines have been licensed and later withdrawn based on rare side effects discovered through monitoring.

FDA approval stamp stock photo

Even after a regulatory stamp of approval, consumers have the ability and duty to weigh their own benefits and risks when considering vaccination. Those at greater risk, such as pregnant women or people with chronic illness, should consider personalized discussions with a doctor they trust. Similar populations may have been studied in clinical trials or monitored afterwards. Unfortunately, even the best research cannot reduce the risk of individual side effects from a vaccine to zero. On the other hand, the risk of contracting COVID-19, for example, as an unvaccinated individual, is not zero either. There is risk in both action and inaction.

Risks Specific to the COVID-19 Clinical Trials

Typical vaccine development, involving preclinical, clinical, and manufacturing protocols, takes years. The expected compressed timeline of a COVID-19 vaccine is a fraction of the typical period, raising questions on safety standards for the desired vaccine. With building pressure from high infection rates and government requests, this concern is valid.

Fortunately, the cuts in timeline are mainly increasing financial risk, not safety-related risks. For example, one factor in the development timeline is the large-scale manufacturing of hundreds of millions of doses, which usually does not begin until after vaccine licensing. In the current environment, large-scale manufacturing of a promising product might begin (with funding) before Phase 3 trials end. If the vaccine is not licensed for widespread use, the manufacturing money is wasted, but safety is not compromised. Otherwise, the vaccine is available to more people much sooner. Similar shortcuts may occur between study phases, but safety information is ideally preserved.

In addition, the power of a global pandemic may drive certain inefficiencies out of the process naturally. Many of the current COVID-19 vaccine candidates are building on technology and research that has been shown to be safe in the past. A reduced timeline may also be an encouraging sign of alignment and cooperation towards a common goal. Information is shared; parallel research is performed; a safe and effective vaccine is found quickly, albeit not without risk.

Where is God in the Midst of Risk?

Passive decisions can carry great risk—particularly in the medical field—but inaction is tempting as a way of “leaving it up to God.” God can miraculously protect us from COVID-19, so why risk getting a vaccine?

The Bible shows us that God repeatedly calls his people to action, and often does so through miraculous but risk-prone paths. In Exodus 14:21, God works through a strong east wind: “Then Moses stretched out his hand over the sea, and the Lord drove the sea back by a strong east wind all night and made the sea dry land, and the waters were divided.” The Israelites could have seen the risk of the waters closing in on them as too great, even compared to the dangers of Egypt. They could have waited on the banks for God to work independent of nature and science. He could have made them fly or vanish before the army pursuing them. But Exodus tells us God employed the wind for a purpose: He wanted his people to move.

rendering of man (moses) parting the Red Sea

Today, we pray for miraculous healing and prevention of COVID-19. Can God supernaturally stop the virus? Yes. But just as God worked through the wind to miraculously save his people, he can work through vaccine development to eliminate COVID-19. Treatment options may not present a favorable benefit-risk ratio for everyone, but the mere existence of risk should not keep us from pursuing vaccination. When praying for deliverance, we must prepare for God to answer in unexpected ways, even through scientific means and those that carry some amount of risk.

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About the author

Anna Taylor

Anna Taylor

Anna Taylor is currently pursuing her MSc in Science and Religion at the University of Edinburgh. After studying biomedical engineering at Duke University, she is excited to combine science with a love of God's word. Prior to 2020, she lived in Washington, DC, working in medical device regulation and clinical trials at the FDA. Her research interests include disability theology, the embodiment of Christ, and medical ethics.