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