Establishing Safe and Effective COVID-19 Vaccines Through Accelerated Delivery, Use of Real-World Data and Real-World Evidence

Blog Posts  |  12 October 2020

Written by: John Farah, PhD and Geoff Caplea, MD, FAAFP, CPPS

Coronavirus Disease 2019 (COVID-19) has given rise to a global pandemic that is exacting an immense human toll, with over 37 million cases and more than one million fatalities recorded worldwide.1 Heading into fall, Americans are dying each day from COVID-19, even with better preparedness and improvements in medical care.2,3

The availability of safe and effective vaccines against SARS-CoV-2, the highly infectious virus responsible for COVID-19, is critical to reducing transmission and alleviating the ongoing public health crisis.

Accelerating Vaccine Delivery: Operation Warp Speed

Operation Warp Speed (OWS) is a public-private partnership between the US Department of Health and Human Services (HSS), the US Department of Defense (DOD), other federal departments and agencies, and private sector participants—pharmaceutical sponsors, manufacturers, and distributors.

OWS aims to control the spread of COVID-19 through accelerated testing, development, production, and distribution of medical countermeasures, including vaccines, therapeutics, and diagnostics.4

  • Expediting delivery of 300 million doses of COVID-19 vaccine(s), with the initial doses available in the United States by January 2021, is the goal of OWS.4

To lower innovation risk and facilitate vaccine delivery, OWS is supporting clinical development and subsidizing parallel, industrial-scale manufacture of candidate vaccines, while planning and implementing at a national level the logistics needed for distribution of one or more COVID 19 vaccines.5,6

Typical vs Accelerated Vaccine Development

Vaccine development has typically required up to ten years—and sometimes more—of discovery research, pre clinical studies, and three phases of clinical trials, including large-scale, randomized controlled studies, before successful candidates are approved, licensed, and manufactured.7,8 Vaccine development carries significant financial risk for vaccine sponsors, as failure rates are high (>90%).8

The accelerated time frames for COVID-19 vaccine initial availability—slated to occur within a year of the discovery of SARS-CoV-2—are predicated not only on the parallel execution of vaccine development, production, and distribution logistics offered by OWS but also on advances in vaccine platforms and design. Time-frame compression additionally leverages the notable similarities between the COVID-19 pathogen and a previously studied coronavirus.9,10

COVID-19 Pivotal Trials: Candidate Vaccines

To date, OWS is supporting at least six (and as many as eight) candidate vaccines; each has been judged according to pre-established criteria to be promising for stimulating neutralizing antibodies against SARS-CoV-2 as well as for eliciting other immunologic defenses.6 During the pandemic, some sponsors intend to provide vaccines without expectation of profit.11,12

Phase 3 clinical trials are underway for five of the candidates; trials for additional candidates are expected to launch later this year.6,10,13,14 First findings from in-progress clinical trials are expected in the coming weeks.

Speaking to the rigor of the clinical trial process are pauses placed on global trials of two vaccines, caused by single occurrences of undisclosed serious adverse events.11,15,16 As of early October, trials have resumed or are scheduled to resume for one candidate vaccine in the United Kingdom, South Africa, Brazil, India, and Japan.11,17,18

COVID-19 Pivotal Trials: The Importance of Diversity and Study Sample Size

The FDA considers inclusion of diverse populations (e.g., racial and ethnic minority groups, older individuals, and those with chronic conditions) in vaccine trials to be essential to informing clinical decisions. Vaccine developers are incorporating this requirement into their trial plans.

  • To ensure diversity, one sponsor has slowed enrollment at its phase 3 study sites. As of August 28, the study had enrolled over 17,000 participants and was more than halfway to the target sample size of 30,000.19
  • Another sponsor has submitted an amended protocol to increase the study sample size from 30,000 to 44,000 participants to further increase population diversity, as well as to provide additional safety and efficacy data.20

When safety endpoints are included among a pivotal study’s primary outcome measures, as in the vaccine trials, the required sample sizes are on the order of 30,000 or even higher to ensure study precision and power.21,22

Post-Market Monitoring: COVID-19 Vaccine Safety and Immunization Tracking in the Real World


Even with the inclusion of tens of thousands of study participants, rare (≥1 in 10,000 and <1 in 1,000) and very rare (<1 in 10,000) adverse events23 may not be detected during the conduct of clinical trials, making post-market safety surveillance of vaccines essential. Besides monitoring for rare or very rare adverse events, there is a need to track populations not adequately represented during phase 3 trials due to low enrollment and to assess vulnerable subpopulations.24

The FDA and Centers for Disease Control and Prevention (CDC) plan to use real-world data (RWD)—data sourced from outside of clinical research settings, including data from insurance claims and electronic health records (EHRs)25—to monitor the post-market safety of COVID-19 vaccines, as is done for established vaccines.24

For real-world safety surveillance of COVID-19 vaccines, regulatory authorities will consider how best to leverage new or existing pharmacovigilance infrastructure before vaccines are authorized or licensed.26 Existing passive or active surveillance platforms for monitoring the post-market safety of vaccines include

  • Vaccine Safety Datalink (VSD), CDC’s longstanding collaboration with participating healthcare systems. Using electronic health data from nearly twelve million individuals, the VSD prioritizes evaluation of new vaccines, searching for unusual health events post immunization and conducting studies on rare and serious adverse events.27,28,29 RWD collected in the VSD will be used to determine whether comorbidities such as diabetes and heart and lung conditions place individuals at increased risk of contracting COVID-19.29
  • Vaccine Adverse Events Reporting System (VAERS), a national vaccine safety surveillance program co-sponsored by the FDA and CDC that collects spontaneous safety reports from physicians and other healthcare providers, as well as from affected individuals, family members, or caregivers throughout the US.30 Adverse events surfaced in the VAERS program are reported to the VSD.27
  • Sentinel System, FDA’s active, medical product safety surveillance system. Launched in 2016, Sentinel collects electronic healthcare data and administrative claims, captured in billions of healthcare encounters, to support regulatory decision-making focused on protecting the public’s health.31 The FDA’s Sentinel System is modeled on the VSD.28

In addition to periodic safety reporting and expedited reporting of serious and unexpected adverse events, sponsors of COVID-19 vaccines may submit pharmacovigilance plans (PVPs) based on FDA recommendations. Depending on preclinical and pre-licensure safety data, pharmacoepidemiologic studies may be proposed to address identified and potential risks or to fill gaps in safety data.24 Safety studies that assess a known serious risk or an unexpected serious risk may also be required at the time of approval.24 A post-market safety study may become necessary in the event new safety information becomes available.24

Immunization Registries

Development of the Immunization Gateway (IZ Gateway), a network for sharing immunization data, has been an ongoing project of the CDC and the HHS Office of the Chief Technology Officer. When completed, the IZ Gateway will enable up-to-date exchange of immunization data for children and adults, linking immunization information systems (IIS) from multiple states and US territories to provide a more comprehensive view of patient immunization status and needs. These state and territorial registries currently capture vaccination data from the electronic EHRs of over two hundred thousand practices.32

The IZ Gateway is expected to facilitate coordination of COVID-19 vaccinations by streamlining and ensuring secure and timely communications among immunization registries and between registries and the CDC to support mass vaccinations, clinical workflows, and clinical decision-making.33

COVID-19 Vaccine Real-World Evidence Studies

Regulatory authorities have expressed an interest in leveraging RWD sourced from outside clinical research settings to generate real-world evidence (RWE)—clinical evidence of the use and of the benefits or risks of medical products34—to help fill information gaps for COVID-19 vaccines. Among other initiatives, the FDA is exploring how the COVID-19 Diagnostics Evidence Accelerator, a multi-stakeholder effort originally dedicated to advancing the development of SARS-CoV-2 diagnostic and antibody tests,35 may be expanded to include vaccines to provide supplemental insight into safety and effectiveness.36

Veradigm® is Contributing to Vaccine Safety Surveillance, Immunization Registries, Real-World Studies, and Other COVID-19 Initiatives

As a leading provider of data systems and advanced analytics, Veradigm, an Allscripts Company, is committed to advancing multiple COVID-19-related initiatives:

  • Veradigm is supporting vaccine and other medical product safety surveillance by helping to develop FDA’s Sentinel System with lead partner Harvard Pilgrim Healthcare Institute and other collaborating partners. Involvement focuses on helping to manage the Sentinel Operations Center and developing a new Sentinel Innovation Center.37
  • Veradigm and Allscripts are supporting immunization tracking efforts by providing integrated functionality to assist healthcare practitioners in connecting electronically with their state or local immunization registries through ambulatory care EHR systems.38,39
  • Veradigm is a founding member of a public-private consortium that has launched the COVID-19 Research Database, a secure repository of HIPAA-compliant, de identified, limited pandemic-related data. The repository, which includes RWD from EHRs and medical and pharmacy claims, is freely available to public health and policy researchers for generating RWE and insights into the COVID-19 pandemic.40
  • Veradigm is a member of the COVID-19 Healthcare Coalition, which is bringing together healthcare stakeholders “to preserve the healthcare delivery system and help protect US populations.” Among its objectives, the coalition is investigating “potential therapeutics to prevent and treat COVID-19, [creating] a de facto COVID-19 data standard to facilitate rapid sharing of outcomes and federated analytics on the effectiveness of treatments…as well as reinfection rates.”41,42

Veradigm is also collaborating with a pharmaceutical sponsor of influenza vaccines, using RWD sourced from ambulatory care EHR systems with linked transactional claims and advanced analytics to generate RWE for retrospective cohort studies evaluating relative vaccine effectiveness and medical encounters.43,44 These studies may be relevant to lessening the simultaneous impact of COVID-19 and influenza45 on hospitals and healthcare systems during the coming winter months.

As we eagerly anticipate the distribution of safe and effective vaccines, Veradigm is doing its part in the fight against COVID-19, in support of public health agencies, clinical researchers, healthcare professionals, and the patients they serve.


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