The development of broad-spectrum antiviral medical countermeasures to treat viral hemorrhagic fevers caused by natural or weaponized virus infections.

The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir's clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule. The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA's established Animal Rule (21 CFR 314.600-650 for drugs; 21 CFR 601.90-95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.

Another Monoclonal Antibody Granted EUA to treat COVID-19.

The Food and Drug Administration has granted emergency use authorization to sotrovimab for the treatment of mild to moderate COVID-19 in patients at increased risk for progression to severe illness.Sotrovimab is a monoclonal antibody that works directly against the spike protein of SARS-CoV-2 to block its attachment and entry into a human cell.

Temporary Regulatory Deviations and the Coronavirus Disease 2019 (COVID-19) PCR Labeling Update Study Indicate What Laboratory-Developed Test Regulation by the US Food and Drug Administration (FDA) Could Look Like.

The coronavirus disease 2019 (COVID-19) response necessitated innovations and a series of regulatory deviations that also affected laboratory-developed tests (LDTs). To examine real-world consequences and specify regulatory paradigm shifts, legislative proposals were aligned on a common timeline with Emergency Use Authorization (EUA) of LDTs and the US Food and Drug Administration (FDA)-orchestrated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) labeling update study. The initial EUA adoption by LDT developers shows that the FDA can have oversight over LDTs. We used efficiency-corrected microcosting of our EUA PCR assay to estimate the national cost of the labeling update study to $0.3 to $1.4 million US dollars. Labeling update study performance data showed lower average detection limits in commercial in vitro diagnostic (IVD) assays versus LDTs (32,000 ± 75,000 versus 71,000 ± 147,000 nucleic acid amplification tests/mL; P = 0.04); however, comparison also shows that FDA review of IVD assays and LDTs did not prevent differences between initial and labeling update performance (IVD assay, P < 0.0001; LDT, P = 0.003). The regulatory shifts re-emphasized that both commercial tests and LDTs rely heavily on laboratory competence and procedures; however, lack of performance data on authorized tests, when clinically implemented, precludes assessment of the benefit related to regulatory review. Temporary regulatory deviations during the pandemic and regulatory science tools (ie, reference material) have generated valuable real-world evidence to inform pending legislation regarding LDT regulation.

Machine Learning: The Next Paradigm Shift in Medical Education.

Machine learning (ML) algorithms are powerful prediction tools with immense potential in the clinical setting. There are a number of existing clinical tools that use ML, and many more are in development. Physicians are important stakeholders in the health care system, but most are not equipped to make informed decisions regarding deployment and application of ML technologies in patient care. It is of paramount importance that ML concepts are integrated into medical curricula to position physicians to become informed consumers of the emerging tools employing ML. This paradigm shift is similar to the evidence-based medicine (EBM) movement of the 1990s. At that time, EBM was a novel concept; now, EBM is considered an essential component of medical curricula and critical to the provision of high-quality patient care. ML has the potential to have a similar, if not greater, impact on the practice of medicine. As this technology continues its inexorable march forward, educators must continue to evaluate medical curricula to ensure that physicians are trained to be informed stakeholders in the health care of tomorrow.

A COVID-19-ready public health surveillance system: The Food and Drug Administration's Sentinel System.

The US Food and Drug Administration's Sentinel System was established in 2009 to use routinely collected electronic health data for improving the national capability to assess post-market medical product safety. Over more than a decade, Sentinel has become an integral part of FDA's surveillance capabilities and has been used to conduct analyses that have contributed to regulatory decisions. FDA's role in the COVID-19 pandemic response has necessitated an expansion and enhancement of Sentinel. Here we describe how the Sentinel System has supported FDA's response to the COVID-19 pandemic. We highlight new capabilities developed, key data generated to date, and lessons learned, particularly with respect to working with inpatient electronic health record data. Early in the pandemic, Sentinel developed a multi-pronged approach to support FDA's anticipated data and analytic needs. It incorporated new data sources, created a rapidly refreshed database, developed protocols to assess the natural history of COVID-19, validated a diagnosis-code based algorithm for identifying patients with COVID-19 in administrative claims data, and coordinated with other national and international initiatives. Sentinel is poised to answer important questions about the natural history of COVID-19 and is positioned to use this information to study the use, safety, and potentially the effectiveness of medical products used for COVID-19 prevention and treatment.

The Pharmaceutical Industry in 2020. An Analysis of FDA Drug Approvals from the Perspective of Molecules.

Although the pharmaceutical industry will remember 2020 as the year of COVID-19, it is important to highlight that this year has been the second-best-together with 1996-in terms of the number of drugs accepted by the US Food and Drug Administration (FDA). Each of these two years witnessed the authorization of 53 drugs-a number surpassed only in 2018 with 59 pharmaceutical agents. The 53 approvals in 2020 are divided between 40 new chemical entities and 13 biologic drugs (biologics). Of note, ten monoclonal antibodies, two antibody-drug conjugates, three peptides, and two oligonucleotides have been approved in 2020. Close inspection of the so-called small molecules reveals the significant presence of fluorine atoms and/or nitrogen aromatic heterocycles. This report analyzes the 53 new drugs of the 2020 harvest from a strictly chemical perspective, as it did for those authorized in the previous four years. On the basis of chemical structure alone, the drugs that received approval in 2020 are classified as the following: biologics (antibodies, antibody-drug conjugates, and proteins); TIDES (peptide and oligonucleotides); natural products; fluorine-containing molecules; nitrogen aromatic heterocycles; and other small molecules.