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Measuring Clinical and Virologic Outcomes in Different Age and Risk Groups

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Measuring Clinical and Virologic Outcomes in Different Age and Risk Groups Measuring Clinical and Virologic Outcomes in Different Age and Risk Groups Prabha Viswanathan, MD Senior Medical Officer Division of Antiviral Products Center for Drug Evaluation and Research, FDA ESCMID eLibrary © by author Overview • Common respiratory viruses and factors impacting the illness they cause • Endpoints in clinical trials – general concepts • Clinical and virologic outcomes in clinical trials of respiratory antivirals • Case Examples in antiviral drug development – Influenza – RSV ESCMID eLibrary 2 © by author Adenovirus (ADV) Coronavirus (CoV) Common Enterovirus (EV) Respiratory Human Metapneumovirus (hMPV) Viruses Influenza Parainfluenza (PIV) Respiratory Syncytial Virus (RSV) Rhinovirus (HRV) ESCMID eLibrary 3 © by author Virus + Host Factors = Clinical Disease ESCMID eLibrary 4 4 © by author Anatomy Environment Health Status Comorbidity Immune Function ESCMID eLibrary 5 5 © by author Impact of Host Factors • The same virus causes a different clinical illness in various population subgroups • The virus causes a similar disease across groups, but host factors affect the severity of the clinical illness ESCMID eLibrary 6 © by author Examples: Virus Causes Different Disease Manifestation RSV Bronchiolitis URI LRTI PIV Croup URI ESCMIDURI = Upper Respiratory Infection; LRTI = LowereLibrary Respiratory Tract Infection 7 © by author Example: Virus Causes Similar Disease Influenza Common signs and symptoms: fever, headache, myalgia, malaise, URI symptoms, cough Populations at risk for more severe disease – respiratory failure ESCMID eLibrary 8 © by author Relevance to Clinical Trials • Understanding when diseases are similar and different is important when designing trials for new antivirals, particularly for endpoint selection • Different endpoints may be needed for trials evaluating the same drug and same virus in different populations (e.g. RSV) • Similar endpoints could be utilized for different drugs and viruses that cause similar clinical illness (e.g. many respiratory viruses cause clinically indistinguishable URI symptoms in healthy adults) ESCMID eLibrary 9 © by author Purpose: to determine whether a drug provides clinical benefit to patients Clinical Trial - Clinical benefit: A positive, clinically meaningful effect on how an individual Endpoints: feels, functions, or survives Overview One of the most important aspects of drug development is how that benefit is measured ESCMID eLibrary 10 © by author Measuring “feels, functions, or survives” Clinical Outcome Assessments • Direct measures of clinical benefit (COAs) Surrogates • Measures that predict how a patient feels, functions, or survives *Biomarker: a physiologic, pathologic, or anatomic characteristic that is objectively measured and evaluated as an indicator of some normal or 11 ESCMIDabnormal biologic function, process or response to a therapeutic intervention eLibrary © by author Clinical Outcome vs Surrogate Clinical Outcomes (Examples) Surrogate Measures • Objective measures: • Laboratory studies, biomarkers, – Survival other measurements that predict – Changes in vital signs the direct clinical benefit – Disease exacerbation/progression • Examples: – Clinical event (e.g. hospitalization, – HIV: viral load used for HIV cardiovascular event) complications • Subjective measures: – Glaucoma: intraocular pressure – Symptom score (includes Patient used for loss of vision Reported Outcome [PRO], Observer Reported Outcome [ObsRO]*) – Diabetes Mellitus: blood glucose/ hemoglobin A1c used for – Quality of life metrics complications * http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071975.pdfESCMID eLibrary 12 © by author Endpoints for Trials of Respiratory Antivirals • Clinical Outcomes should be used to support approval of novel antiviral drugs – Treatment trials: endpoint measures how well the drug improves signs and symptoms of respiratory viral illness – Prevention trials: endpoint measures how well the drug prevents/mitigates respiratory viral illness • Objective or subjective measures can be used, or a combination of both – When COA instruments are used (e.g. PROs), validation is needed to ensure they are well-defined, reliable, interpretable, and able to detect changes • Optimal endpoints are still being established for many respiratory viruses ESCMID eLibrary 13 © by author Surrogate Endpoints: Virologic Measures • Clinical trials of direct acting antiviral drugs should assess the impact of the drug on the virus – However, changes in virologic measures alone are not sufficient to demonstrate clinical benefit • Virologic endpoints provide valuable information to guide development – Trends in viral load from dose-ranging studies can be used to optimize the dose and duration studied in pivotal trials – Reduction in viral load can help establish proof of concept, particularly when a correlation can be shown between virologic and clinical outcomes • No surrogate markers, including viral load, have been identified that consistently correlate with clinical benefit for respiratory viruses ESCMID eLibrary 14 © by author Endpoints that have supported Case marketing approval of antiviral Examples: products Influenza and RSV Trials that did not demonstrate clinical benefit ESCMID eLibrary 15 © by author Examples of FDA Approved Respiratory Antiviral Drugs Drug 1 Virus Indication Endpoint Benefit Oseltamivir Influenza Treatment of TTAS 2 Symptoms Zanamivir acute resolve ~ 1 day Peramivir uncomplicated sooner than Baloxavir Influenza control Palivizumab RSV Prevention of Hospitalization 45-55% severe RSV LRTI reduction in in high risk hospitalization infants compared to control 1 This table does not include all drugs approved for influenza and RSV 2 Time To Alleviation of Symptoms ESCMID eLibrary 16 © by author TTAS for Uncomplicated Influenza: Baloxavir • Uncomplicated Influenza: abrupt onset of constitutional and upper respiratory tract signs and symptoms (e.g., fever, chills, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis)* • In the registrational clinical trials, eligible subjects had: – Axillary temperature of at least 38˚C – At least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat) – At least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue) – Symptoms present for no more than 48 hours • TTAS defined as the time when all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been assessed by the subject as none or mild for a duration of at least 21.5 hours *Centers for Disease Control and Prevention: https://www.cdc.gov/flu/professionals/acip/clinical.htm ESCMID eLibrary 17 © by author Baloxavir vs Placebo: CAPSTONE-1 Time to Alleviation of Symptoms Change in Viral Titer Median TTAS was 26.5 hours shorter in the baloxavir Asterisks indicate a p value of < 0.05 as compared to group (53.7 hours; 95% CI, 49.5 to 58.5) vs. placebo placebo group (80.2 Hours; 95% CI, 72.6 to 87.1) (p<0.001). Source: Hayden FG, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med 2018; 379: 913- 923.ESCMID eLibrary 18 © by author Baloxavir vs Oseltamivir Time to Alleviation of Symptoms Change in Viral Titer Asterisks indicate a p value of < 0.05 as compared to placebo ESCMID eLibrary 19 © by author Severe Influenza – Going Beyond Acute Uncomplicated Population • Hospitalized patients Examples of • Continuous measures • Time to clinical resolution (TTCR) or stability Endpoints • Time to achievement of protocol-specified hospital discharge Used in Prior criteria Severe • Binary Influenza Trials • Incidence of influenza-related complications • Incidence of ICU admission ESCMID eLibrary 20 © by author Peramivir in Severe Influenza Median TTCR: 42.5 (34-57.9) vs. 49.5 (40- 61.9) hours peramivir vs. placebo (p=0.97) in ITTI non-NAI population Source:ESCMID de Jong et al., CID 2014; 59(12) eLibrary 21 © by author New Endpoints Needed for Severe Influenza? FDA does not have a single “best endpoint” for this indication -Unlike acute uncomplicated influenza, data are lacking to support any particular endpoint in this population Consider clinical signs & symptoms, hospital duration, time to normalization of vital signs and oxygenation, need for supplemental oxygen/assisted ventilation, mortality Sponsors are encouraged to submit development proposals in advance, providing evidence for the ability of their proposed endpoint to directly measure how a patient feels, functions, or survives ESCMID eLibrary 22 © by author Endpoints in Current Severe Influenza Trials Baloxavir marboxil1 Pimodivir2 • Randomized, double blind trial of • Randomized, double blind trial of baloxavir+SOC vs. placebo+SOC in 240 pimodivir+SOC vs. placebo+SOC in 600 hospitalized patients ages 12 and older hospitalized patients 13-85 years of age • Primary Endpoint: Time to Clinical • Primary Endpoint: Hospital Recovery Scale, Improvement up to day 35 Day 6 – Time to Hospital Discharge OR 1. Not hospitalized – Time to NEWS2* score ≤ 2 maintained 2. Non-ICU hospitalization, not requiring for 24 hours supplemental O2 3. Non-ICU hospitalization, requiring * Source: supplemental O2 https://www.rcplondon.ac.uk/projects/outputs/national-early- warning-score-news-2 4. ICU hospitalization, not requiring supplemental O2 5. Requiring invasive mechanical ventilation 6. Death 1. Clinical trials.gov identifier: NCT03684044 2. ClinicalESCMID trials.gov identifier: NCT03376321 eLibrary
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