FDA office of Clinical Pharmacology AND covid-19

“Since the COVID-19 National Public Health Emergency was declared in 2020, OCP drug evaluation activities have focused on ensuring the availability of treatments for patients fighting the devastating effects of SARS-CoV-2 infection.

The pathogenesis of COVID-19 is complex and multifaceted, and effective management targets the unique stages of the disease as it progresses, from asymptomatic to critical disease and beyond (i.e., post-COVID conditions).

Products developed for COVID-19 cover a wide range of mechanisms of action, including direct-acting antivirals, targeted monoclonal antibodies, anti-inflammatories, immunomodulators, and cardiovascular, pulmonary, and neurology agents. OCP teams in these therapeutic areas remain responsive to the constantly evolving pandemic treatment landscape.

In 2021, OCP contributions when evaluating products submitted for INDs, Emergency Use Authorization (EUA), and NDAs focused on translating pharmacokinetic, pharmacodynamic and exposure-response knowledge into sound dosing recommendations, expanding treatment options across diverse patient populations (e.g., pediatric patients), and formulating strategies to mitigate risk for patients with COVID-19 (See Figure 6). These contributions informed Fact Sheets for Healthcare Providers and Patients and Caregivers for authorized products, the principal mechanism for communicating clinical pharmacology aspects of COVID-19 treatments to the public.

Our benefit-risk assessments also considered multidisciplinary perspectives and learnings from real-time data sources and surveillance for safety and variants, the developing treatment landscape and understanding of the virus, and recurring international exchanges.

COVID-19

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Translate Knowledge Into Sound Dosing Recommendations

Expand Treatment Options For Diverse Populations

• Evaluated drug candidacy by comparing in vitro antiviral activity in relation to clinically achievable concentrations for repurposed drugs

• Explored relationships between drug exposure and disease severity to better understand effects of COVID-19 on pharmacokinetics to inform treatment regimens

• Integrated known pharmacokinetic and pharmacodynamic information, mechanism of action, in vitro activity, neutralization assays, viral dynamics, preclinical animal efficacy models, and prior clinical experience to predict safe and efficacious dosing regimens

• Used predictive modeling incorporating antiviral/neutralization activity against variants, duration of protection, and exposure targets to inform alternative routes of administration and dosing strategies for prevention Formulate Strategies To Mitigate Risk

• Applied knowledge of pharmacodynamic response (interleukin levels and receptor saturation) in COVID-19 pneumonia to evaluate proposed dosing regimens in pediatric patients

• Evaluated weight-based dosing strategies in adult patients to ensure adequate exposure to COVID-19 treatments

• Recommended pharmacokinetic sampling strategies and integrated mechanism of action, pharmacokinetic, and exposure/response information to inform dosing in patients with renal impairment

• Used pharmacokinetic/pharmcodynamic knowledge and supportive modeling to understand the effect of patient factors, such as acute lung injury and conditions of high-risk disease, on treatment selection and dosing

• Utilized data from clinical studies, extrapolation, and model-informed methods to derive dosing recommendations for pediatric patients for treatment and prevention of COVID-19

• Encouraged comprehensive drug-drug interaction (DDI) evaluation strategies, model-informed methods, and protocol modifications to lessen drug interaction liability

• Evaluated alternative routes of administration using pharmacokinetic data, viral load reductions in patients, safety findings, and simulated dosing scenarios to ensure adequate exposure and reduce treatment delays

• Identified cardiac toxicity signals related to active metabolite concentrations and accumulation

LL accumulation???

• Optimized sampling approaches to assess the relationship between maximum concentration and unintended immunosuppressive effects

• Provided advice on ex vivo cardiac studies and clinical protocol design to characterize proarrhythmic potential and cardiac risk

OCP's Pandemic Response

IMPACT AREAS

Figure 6.

Research trainees in 2021

2021 research budget

(approximate)

$18.7M

119

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OCP’s regulatory science research program is critical to advancing the science of clinical pharmacology and translational medicine and informs regulatory decision-making and contemporary policy development. OCP’s comprehensive research portfolio is designed to address immediate and emerging regulatory science issues that impact the development, evaluation, and utilization of therapeutic products. We conducted 76 research projects employing a variety of translational methods, including experimental and analytical approaches, mechanistic and model-based methodologies, data-based tools and mining, and clinical studies (See Figures 7 through 9). OCP conveyed research outcomes and regulatory application of findings with the broader scientific community through 183 publications in peer-reviewed journals (See Figures 10 and 11).

OCP’s dedicated research division, the Division of Applied Regulatory Science (DARS), specializes in the application of translational approaches such as in vitro and in vivo laboratory methods, experimental medicine, in silico computational modeling and informatics, and integrated clinical research to meet regulatory and public health challenges. OCP’s regulatory research activities are further enhanced by our robust research fellowship program offered unique development opportunities to 119 new scientists in 2021.

For more details on our dedicated research division, visit the DARS website (https://go.usa.gov/xAH6Z).

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“The work we do fills a gap that isn’t being done elsewhere. What we try to do is come up with new tools and models and approaches that can be applied across the drug development spectrum in multiple different types of drugs to better predict safety and effectiveness, and it’s really something that others aren’t doing quite like we are.” Average number of OCP publications per month in 2021”

Have you heard of the OCP as part of the FDA

reducing drug interaction liability? is that adverse event?

LOOK HERE