Washington, DC, November 2, 2023
Overview
The ongoing COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in unprecedented morbidity and mortality and has overwhelmed health care systems throughout the world, with about 6.8 million deaths worldwide. Although the development and authorization of multiple COVID-19 vaccines and multiple therapeutics for treatment and prevention have helped to decrease the overall disease burden, the emergence of new variants that are immune-evasive have resulted in continued waves of severe disease and mortality. In addition, COVID-19 appears to be associated with post-COVID-19 syndrome (Long COVID), in a substantial proportion of individuals recovering from acute disease (1). All the previously authorized monoclonal antibodies used for COVID-19 treatment and prevention, particularly in immunocompromised and high-risk patients, are no longer active against the emerging, predominant variants, despite vaccination (2). Therefore, there remains populations with unmet medical need for broadly active therapeutics that can prevent and treat COVID-19.
Development of effective COVID-19 therapeutics is necessary; however, developing therapeutics for the treatment of COVID-19 in outpatients at higher risk of disease progression is particularly challenging. The primary goals of treatment in this group are to reduce mortality and prevent serious disease outcomes requiring significant medical intervention, such as hospitalization and intensive respiratory support (3). Presently, there are three antiviral treatments that are either authorized or approved for the treatment of outpatients at high risk of COVID-19 disease progression: remdesivir (approved), nirmatrelvir/ritonavir (authorized) and molnupiravir (authorized) (4). Several monoclonal Abs that were authorized for this purpose are no longer considered active against current circulating variants (5). Except for molnupiravir, other therapeutics showed reductions in hospitalization and death, approaching approximately 80-90% in high-risk outpatients (6). However, the remaining available antivirals have limitations, including intravenous administration (remdesivir); drug-drug interactions, making use difficult or impossible in up to 15-20% (nirmatrelvir/ritonavir); and suboptimal activity compared to other agents (molnupiravir) (6,7). To support the efficacy of the previously mentioned therapeutics, researchers conducted clinical trials primarily in unvaccinated individuals, during a time when viral strains had higher rates of severe disease. Given current high rates of natural and vaccine-mediated immunity, a trial endpoint relying only on hospitalization and/or death may no longer be practical.
In addition, placebo-controlled trials in high-risk patients are no longer considered ethical given the availability of active agents (8). Noninferiority trials are most likely not feasible due to the lack of constancy of outcome rates over time and across variants, making the calculation of a noninferiority margin nearly impossible (8). Treatment trials in low- or standard-risk outpatients may be more feasible because of the ability to use a placebo control, but may also present its own set of challenges. Challenges include choosing a primary endpoint to discern clinically relevant improvements in symptom relief in an illness that is self-resolving, but also with brief periods of relapse in a substantial proportion of individuals (9). As opposed to treatment trials in outpatients with COVID-19, both prevention and treatment trials of hospitalized patients are still feasible and somewhat less challenging. Prevention trials can still incorporate a placebo control in appropriate populations, and treatment trials in hospitalized patients can ethically assess superiority of a new agent added to standard of care options vs. standard of care alone (8, 9, 10). Although, endpoints in the treatment of hospitalized patients could still benefit from further refinement.
Thus far, clinical endpoints have been the regulatory recommendation rather than other surrogate endpoints. The use of novel endpoints such as antibody neutralization titers for the assessment of efficacy of new monoclonal antibodies has been discussed in a recent EMA/FDA workshop, but such endpoints would not apply to small molecules or other antivirals (10). Virologic endpoints, such as time to viral culture negativity and nasopharyngeal quantitative RT PCR, may be acceptable to consider for endpoints, if there were more conclusive data showing a correlation between virologic endpoints and clinical outcomes. Thus, it is advisable for investigators and industry sponsors to conduct analyses across drug development that can show the validity of the surrogate, to build consensus around establishing acceptable endpoints in future study designs. All stakeholders in the COVID-19 drug development field would benefit from guidance and clarity on acceptable primary and secondary virologic endpoints for the design of future trials (11).
Action Plan
A series of COVID-19 meetings will convene stakeholders across academia, industry, regulatory agencies, and patient advocacy to strategize on establishing acceptable trial designs, control arms, and clinical and/or surrogate virologic endpoints for future COVID-19 therapeutic drug development. These meetings will enable collaboration and discussion among these stakeholder groups to determine what data could be used and analyzed to support recommendations for new clinical trial designs and acceptable endpoints in both standard- and high-risk outpatients with COVID-19 that will ultimately increase the efficiency of drug development and regulatory science for future COVID-19 therapeutics.
The Forum invites researchers, industry sponsors, and patient advocates to present data and contribute to establishing acceptable SARS-CoV-2 endpoints that will accelerate drug development for future antiviral therapeutics. Regulators are invited to contribute to the regulatory perspective on possible virologic data needed in order to conclude safety and clinical benefit of future therapeutics.
Part One: Characterizing Risk Factors to Inform Patient Eligibility
The first meeting in this series will focus on characterizing risk factors for severe COVID-19 to inform participant eligibility criteria for outpatient clinical trials enrollment. The goal is to define patient populations based on risk of progression to severe COVID-19 (hospitalization and death), and further describe baseline risk factors, or underlying medical conditions associated with higher risk as described by the Centers for Disease Control and Prevention (CDC) (12), using the National Institutes of Health (NIH)’s COVID-19 Treatment Guidelines risk groups (Tiers 1-3 and low-risk) (13). This involves examining data evaluating patients in Tier 2 (unvaccinated individuals not included in Tier 1 who are at risk of severe disease [anyone ≥65 years or anyone aged <65 with clinical risk factors]) or Tier 3 (vaccinated individuals at risk of severe disease [anyone aged ≥65 or anyone aged <65 with clinical risk factors]) to determine current risk of hospitalization and death (13). The aim is to further differentiate NIH Tier 2 and 3 from those at low risk of progression to severe COVID-19, and to determine if some subsets of NIH Tier 2 or Tier 3 populations have risk similar to the low-risk population (13). For non-hospitalized patients with COVID-19, ethical considerations include determining an acceptable risk of developing severe COVID-19 (e.g., progression to hospitalization with oxygen requirement), as well as an acceptable risk of death, for enrollment into a placebo-controlled trial.
Thus, stakeholders are encouraged to share outcome information from their respective centers (clinical trial sites, etc.), detailing rates of hospitalization due to severe COVID-19 and/or death, for non-hospitalized patients based on baseline risk factors for progression to severe COVID-19. This includes information describing baseline risk factors based on NIH Tier 1-3 classification and low risk (13), and clinical risk factors based on CDC criteria (12), in addition to vaccination information through available databases. An important discussion topic is to determine whether a placebo-controlled trial with a symptom-based primary endpoint would be feasible and ethical, if the highest risk patients (e.g., >1% risk of severe COVID-19 or death) are excluded and use of approved or authorized antiviral therapies are prohibited.
About the Forum
The Forum for Collaborative Research (The Forum), founded in 1997, is a public/private partnership that addresses cutting edge science and policy issues through a process of stakeholder engagement. Its impetus was a request from Vice President Al Gore to convene all stakeholder groups to discuss and discover opportunities for cross-sector dialogue and collaboration. The Forum has and continues to address specific hurdles in drug development for human immunodeficiency virus (HIV), hepatitis B virus (HBV), transplantation-associated virus infections (TAVI), Primary Sclerosing Cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), and genetically based rare diseases. The Forum addressed a 7th disease area, HCV infection, through the HCV Forum, initiated in 2007 and completed in 2017.
The hallmark of the Forum is inclusion of all stakeholder groups, including patient and advocacy organizations, academia, federal agencies, industry, professional societies, and other relevant entities. The Forum works closely with the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), providing a trans-Atlantic regulatory scope and breadth to the deliberations. Collaborating experts are individuals with significant experience and expertise in understanding the science, disease process, clinical research from one of the stakeholder group’s perspectives and in senior positions within their organizations. They are committed to the goals of the Forum, able and willing to “leave the hat at the door” and engage in constructive and collaborative discussion. No one is asked to divulge confidential information.
The success of the Forum working in different disease areas has necessitated the restructuring of the organization into individual Forums (HIV Forum, HCV Forum, HBV Forum, TAVI Forum, Liver Forum, PSC Forum, and Rare Diseases Forum). Each of these reflects the basic Forum tenets of collaboration, objectivity and independence, contribution of each stakeholder’s voice to maximize efficiency in drug development without lowering the rigor and scientific level of evidence. For a list of relevant examples see Achievements.
References
1) Yong, S. J. (2021). Long Covid or post-covid-19 syndrome: Putative pathophysiology, risk factors, and treatments. Infectious Diseases, 53(10), 737–754. https://doi.org/10.1080/23744235.2021.19243972) UPMC. (2022). Evusheld™ update: What immunocompromised patients need to know. Retrieved January 30, 2023, from https://www.upmc.com/coronavirus/monoclonal-antibodies/immunocompromised-patients
3)Robinson, P. C., Liew, D. F., Tanner, H. L., Grainger, J. R., Dwek, R. A., Reisler, R. B., Steinman, L., Feldmann, M., Ho, L.-P., Hussell, T., Moss, P., Richards, D., & Zitzmann, N. (2022). Covid-19 therapeutics: Challenges and directions for the future. Proceedings of the National Academy of Sciences, 119(15). https://doi.org/10.1073/pnas.2119893119
4) U.S. Food and Drug Administration. FDA has approved two drugs and authorized others for emergency use. Retrieved January 30, 2023, from https://www.fda.gov/consumers/consumer-updates/know-your-treatment-options-covid-19
5) Corti, D., Purcell, L. A., Snell, G., & Veesler, D. (2021). Tackling covid-19 with neutralizing monoclonal antibodies. Cell, 184(12), 3086–3108. https://doi.org/10.1016/j.cell.2021.05.005
6) Dias, E., Aithal, A., & Shail, R. (2021). Recent pharmacological advances of drugs and vaccines used in COVID-19. Highlights on Medicine and Medical Science Vol. 6, 130–151. https://doi.org/10.9734/bpi/hmms/v6/2577f
7) Tiseo, G., Barbieri, C., Galfo, V. et al. (2023) Efficacy and Safety of Nirmatrelvir/Ritonavir, Molnupiravir, and Remdesivir in a Real-World Cohort of Outpatients with COVID-19 at High Risk of Progression: The PISA Outpatient Clinic Experience. Infect Dis Ther 12, 257–271. https://doi.org/10.1007/s40121-022-00729-2
8) Temple, R. (2000). Placebo-controlled trials and active-control trials in the evaluation of new treatments. part 1: Ethical and scientific issues. Annals of Internal Medicine, 133(6), 455. https://doi.org/10.7326/0003-4819-133-6-200009190-00014
9) Gavriatopoulou, M., Ntanasis-Stathopoulos, I., Korompoki, E. et al. (2021) Emerging treatment strategies for COVID-19 infection. Clin Exp Med 21, 167–179. https://doi.org/10.1007/s10238-020-00671-y
10) FDA-EMA. (2022, December 15th). Efficacy of monoclonal antibodies in the context of rapidly evolving SARS-CoV-2 variants [Joint EMA-FDA Workshop]. Virtual. Efficacy of Monoclonal Antibodies in the Context of Rapidly Evolving SARS-CoV-2 Variants - 12/15/2022 | FDA
11) FDA. February 2021. COVID-19: Developing Drugs and Biological Products for Treatment or Prevention. https://www.fda.gov/media/137926/download
12) Centers for Disease Control and Prevention (CDC). Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: Information for Healthcare Professionals. www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html.
13) National Institutes of Health (NIH). Prioritization of Therapeutics | COVID-19 Treatment Guidelines. COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/overview/prioritization-of-therapeutics/