Clinical Trial Landscape and Phase 3 COVID-19 Vaccine Update Emily Coates, PhD Larisa Strom, Colorado School of Public Health Colorado Vaccine Equity Taskforce: Training on COVID-19 Vaccine Development November 20, 2020 Outline • Overview of U.S. federal health agencies • Clinical trial phases and regulations of vaccines • Vaccine safety and efficacy standards • U.S. government’s COVID-19 vaccine strategy • Phase 3 COVID-19 vaccine candidates in the U.S. • Strategies for vaccine distribution following FDA Emergency Use Authorization (EUA)/Biological License Application Approval Overview of the Department of Health and Human Services (HHS) • Founded in 1953 as a department within the Department of Health, Education, and Welfare; reorganized as single entity in 1980 • Mission statement: “to enhance the health and well-being of all Americans, by providing for effective health and human services and by fostering sound, sustained advances in the sciences underlying medicine, public health, and social services” • Comprised of 11 operating divisions, including the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) • HHS total budget authority for fiscal year 2020: 1,292,523 (in millions) • FDA: $5,900; CDC: $6,767; NIH: $41,680 • Workforce: 84,505 employees (2018) • Mission: “to protect the public health by ensuring the safety, efficacy, and security of human Food and Drug and veterinary drugs, biological Administration products, and medical devices” • Regulates vaccine clinical trials, (FDA) licenses vaccines, and monitors vaccine safety after licensure • Workforce: 18,555 employees • Mission: “to protect America from health, safety and security threats, Centers for Disease both foreign and in the U.S.” • Promotes immunization at the Control and country, regional, and global Prevention (CDC) levels by providing evidence-based strategies to control and eliminate vaccine-preventable diseases • Workforce: 10,796 employees • Mission: “to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability” National Institutes • Comprised of 27 institutes including the National of Health (NIH) Institute of Allergy and Infectious Diseases (NIAID) • Within NIAID, the Vaccine Research Center (VRC) “conducts research that facilitates the development of effective vaccines for human disease” • Workforce: 18,668 employees Other Divisions within HHS • Administration for Children and Families (ACF) • Administration for Community Living (ACL) • Agency for Healthcare Research and Quality (AHRQ) • Agency for Toxic Substances and Disease Registry (ATSDR) • Centers for Medicare & Medicaid Services (CMS) • Health Resources and Services Administration (HRSA) • Indian Health Service (IHS) • Substance Abuse and Mental Health Services Administration (SAMHSA) Outline • Overview of U.S. federal health agencies • Clinical trial phases and regulations of vaccines • Vaccine safety and efficacy standards • U.S. government’s COVID-19 vaccine strategy • Phase 3 COVID-19 vaccine candidates in the U.S. • Strategies for vaccine distribution following EUA Source: Centers for Disease Control and Prevention Clinical Trial Operations and Recruitment Questions How does NIH recruit for clinical trials? • Advertising in public places such as transit, radio, newspapers, bulletins • How are communities of color engaged/selected for VRC trials? • Advertisements on radio stations catering to urban or Spanish-speaking populations • Informed consent documents in Spanish to facilitate trial participation in that underrepresented ethnic group • Community outreach to college campuses, including community colleges Is there a minimum threshold of minority population inclusion that must be met in a clinical trial? • While there is no minimum threshold, the FDA strongly encourages that participants from diverse populations are included in all phases of vaccine development to ensure that vaccines are safe and effective in all affected populations • Vaccine safety and efficacy assessments, particularly in late phase clinical trials, should include an adequate representation of populations most impacted by COVID-19, specifically racial and ethnic minority groups Are community advisory boards a requirement for clinical trials? • Although not required, community advisory boards can be utilized to provide feedback or raise concerns during the protocol development stage • Institutional Review Boards (IRBs) are required and designated under FDA regulations to review and monitor biomedical research involving human subjects • Human subjects research: research that uses, studies, or analyzes information or biospecimens through intervention or interaction with subject; or research that uses, studies, analyzes, or generates identifiable private information or biospecimens • IRBs have authority to approve, require modifications to, or disapprove research FDA Emergency Use Authorizations (EUA) What is an FDA Emergency Use Authorization? • EUA allows the use of unapproved medical products to diagnose, treat, or prevent serious or life-threatening diseases in response to a declared public health emergency for which there are no adequate, approved, and available treatments • Introduced in 2004 as a measure against weapons of mass destruction • Criteria for issuing an EUA: • The known and potential benefits of the product outweigh the product’s known and potential risks • Sufficient data on product’s safety profile • Proof of worthwhile efficacy • Cannot be granted outside of a declared emergency • EUAs have previously been granted to products for anthrax, Ebola, Enterovirus, Zika, H1N1 influenza, MERS • EUA has only been granted for one vaccine, Anthrax Vaccine Adsorbed (AVA) in 2005, for individuals ages 18-65 at heightened risk of anthrax exposure Why now? FDA October 2020 Emergency Use Authorization for Vaccines to Prevent COVID-19: • FDA recommends EUA if data from phase 3 studies supports a positive benefit-risk assessment • Efficacy standard for approving EUA for COVID-19 vaccine: >=50% disease reduction in treatment vs placebo groups • A median of 2 months of safety follow-up data is required before companies can apply for EUA • Following Authorization: • Not subject to usual informed consent requirements, but recipients are provided a fact sheet detailing the product, its potential risks and benefits, and have the option to refuse the product • To minimize risk of EUA interfering with long-term safety and efficacy assessments, it is essential that data is still gathered on the vaccine even after the EUA Outline • Overview of U.S. federal health agencies • Clinical trial phases and regulations of vaccines • Vaccine safety and efficacy standards • U.S. government’s COVID-19 vaccine strategy • Phase 3 COVID-19 vaccine candidates in the U.S. • Strategies for vaccine distribution following EUA What criteria are used to deem a vaccine “safe”? • Pre-clinical studies to assess safety • In vitro and in vivo testing help define immunogenicity and safety profile • Animal models help identify vaccine-related safety risks and assist in selecting an appropriate dose, regimen, and administration route • Clinical trials • Safety is monitored for a 2-month median follow-up after full vaccination regimen to allow for detecting any potential AEs • FDA usually requires 6 or more months of safety follow-up for serious or other medically attended AEs before approving the licensure of a vaccine • Data and Safety Monitoring Boards (DSMBs) • Independent group of experts who oversee clinical trials and whose roles include: • Periodical review and evaluation of participant safety, study conduct and progress, and efficacy (if necessary) • Ability to make recommendations regarding trial continuation, modification, or termination When is a DSMB required? • A DSMB is required for: • All Phase 3 trials* • High-risk Phase 2 trials • Multi-site and randomized Phase 2 trials* • May be required for Phase 1 or 2 trials if trial is blinded, first-in-man, includes high-risk populations, or involves high-risk interventions • A DSMB is not generally required (but may still be recommended) for: • Single-center, open-label Phase 1 and 2 trials • Multi-site, high-risk Phase 1 trials with clear guidelines and criteria for halting the trial if unexpected side effects occur *Excludes certain low-risk nutritional or behavioral studies where participants should only experience mild side effects Assessing Long-term Safety after Licensure • As with all licensed vaccines, the vaccine’s safety profile will continue to be monitored post-licensure in order to facilitate detecting any rare AEs in the general population and populations underrepresented in pre-licensure trials • Phase IV trials may be conducted to continue assessing vaccine safety profile after licensure • Pharmacovigilance plan for COVID-19: 24-month post-licensure monitoring between CDC and FDA to determine vaccine’s performance in real-life scenarios to monitor efficacy and rare adverse events not found in pre-licensure trials • Post-licensure monitoring systems: • Vaccine Adverse Event Reporting System (VAERS) • Vaccine Safety Datalink (VSD) • Post-Licensure Rapid Immunization Safety Monitoring (PRISM) • Clinical Immunization Safety Assessment Project (CISA) Vaccine Adverse Event Reporting System (VAERS) • Co-managed by CDC and FDA • National early warning system that detects unexpected