Real world evidence (RWE) is a pivotal tool in the battle against COVID-19. Real world data (RWD) are accumulating steadily from medical encounters, pharmacies, labs and other sources, awaiting exploration and evaluation. This information is critical to understanding how COVID-19 affects people, including what treatments they received, how well those treatments worked, etc. And as COVID-19 vaccines come to market, RWE will be used to monitor how well they work.
Some people may wonder why RWE would be of interest, since randomized clinical trials (RCT), not RWE, are the foundation of our regulatory process for approving new drugs and vaccines. But think ahead — any successful medication or vaccine will be used by a diverse population after approval, including people with complex medical histories, unstudied comorbidities, and other risk factors, all of which may affect the likelihood that they will benefit from that treatment or vaccine. Information is needed from real world settings to complement what is learned from studies in highly controlled settings.
Understanding Vaccine Surveillance
Hesitancy about using vaccines that were developed more quickly than typical vaccines stems, in part, from concern about their safety and effectiveness. A July survey conducted by Tufts found that only 57 percent of Americans say they are willing to receive a COVID-19 vaccine. A similar study from Gallup shows more than a third of Americans will decline such vaccines, even if approved by the FDA and available for free. This caution may spillover to other vaccines with strong records of proven effectiveness and safety.
To promote trust and understanding about vaccines, a variety of safety surveillance approaches can be implemented. Recalling the transverse myelitis that developed in a participant in AstraZeneca’s Phase 3 vaccine trial of 30,000 participants, forcing it to pause before restarting, it will be important to see if serious, unusual events occur once any vaccines are approved and, if so, whether the events are limited to a specific vaccine. It would also be useful to have a benchmark for how many such events should be expected if the vaccine were completely safe, which could be obtained from RWD for similar people who did not receive a COVID-19 vaccine.
Providing Early Information and Regular Updates from Reliable Sources
Larger, longer, and more inclusive trials can always be conducted, but waiting for those results could add years to this pandemic. Rather than wait and wonder, proactive reporting of RWE will help address the concerns of skeptics who are waiting for proof of vaccine safety. A regular flow of reliable information from trusted resources can be used to quantify the frequency of risks seen among newly vaccinated people as well as positive outcomes (no symptoms or only mild ones of short duration) and also provide benchmarks for these events among people who have not been vaccinated. Ideally, there will be a variety of surveillance programs studying various groups of interest like those with other health conditions that may put them at special risk. These surveillance activities may be sponsored by governments or the pharmaceutical industry or led by third parties that have no stake in the outcome.
Surveillance should not only monitor deaths and hospital admissions but also events that may not come to medical attention such as severe depression or neurological symptoms with slow onset. This will require a paradigm shift, since traditional safety surveillance systems depend on voluntary reporting of events that come to medical attention and provide counts of those events — a relatively haphazard approach compared to systematic collection of events of interest and reporting comparative information between vaccines and in comparison to those who were not vaccinated. A comparison of rates of events is a better metric than simply reporting the number of events, since knowing how many people were vaccinated and the proportion of those who had a bad experience is what we need to know.
No matter what events are studied, who sponsors the surveillance activities or where the RWD comes from, transparency about data acquisition and curation (like data reviews for clinical trials), privacy protection, and methods of analysis will continue to be important, as they are for any consequential use of RWE.
Real World Options
A core utility for RWD is to fill in evidence gaps remaining after RCT. For example, it would be useful to have information at hand that describes whether certain vulnerable populations, like the elderly, react differently to vaccines than their younger counterparts, and how children fare after vaccination. RWD is also useful for studying persistent conditions, like what has been referred to as “long COVID” in recognition of serious symptoms that may persist for many months. Rather than design a trial to study something that is not well characterized, it would make more sense to start with non-interventional real-world studies to collect information on people with conditions of interest, like long COVID, and monitor them over time to measure the duration and whether their symptoms improve.
The healthcare industry is already collecting millions of pieces of non-identified RWD via testing results, electronic health records, lab results, claims databases, hospital reports, and other clinical RWD. A substantial science is growing around the use of RWE, including its utility for regulatory submissions. Regulators started becoming interested in RWE way before COVID first appeared, as they were seeking means to assist in developing less expensive medications and to be more nimble in monitoring effectiveness and safety after market approval.
A strong set of RWE tools are available for vaccine surveillance including linked databases like ambulatory and hospital EMR and pharmacy records; self-reported symptoms and events; and clinical studies that closely follow people after they receive a particular vaccine. While most surveillance programs start with secondary data that can be analyzed for quick insights, these data sets are derived from encounters with the medical care system, and many have a substantial lag time before review, aggregation, and curation is completed.
More immediate results can be derived by adding the perspective of the “patient” to the data mix. Self-reported insights can be especially valuable when studying vaccines, which may be administered in pharmacies, grocery stores, or the workplace, generating only a billing record without information also being transmitted to the primary care physician. Registries can be created where volunteers contribute information about their health experience in hopes of benefitting themselves and others, and follow-up can be obtained through repeated contact. This methodology brings the patient perspective to the conversation, enabling pragmatic research that is meaningful to daily life.
FDA Real World Approach To COVID-19
In June, the FDA announced its participation in the COVID-19 Diagnostics Evidence Accelerator, reinforcing the message that regulators see RWD as a key weapon in fighting this virus. This multi-stakeholder collaborative project, organized by the Reagan-Udall Foundation with Friends of Cancer Research, leverages RWD to understand diagnostics and antibody testing. It will provide a central repository where data companies, researchers, and health systems can aggregate and analyze data to answer key questions about COVID-19. The output will inform the agency’s overall response to the virus, and help advance the development of diagnostics, treatments and vaccines.
This is one of many collaborations that are harnessing the benefits of RWD data to fill gaps in our knowledge about COVID-19 including any long term impacts, as well as providing information about the safety and efficacy of various treatments and vaccines, for which there is still limited data.