A guide to respiratory endpoints in clinical trials

Understand respiratory endpoint types, data quality challenges, and best practices for clinical trials

• Collectively written by – the Clario Respiratory Science Team

Types of digital respiratory endpoints in clinical trials

Respiratory endpoints fall into several categories that serve different purposes in drug development. Understanding these categories clarifies what kind of evidence is being generated and how it supports drug discovery, drug development, and regulatory submissions.

Functional endpoints

Functional endpoints assess how well the lungs perform under specific conditions. This can measure airflow, inflammation, and more.

Spirometry parameters including FEV1, FVC, and PEF quantify airflow limitation, volume reduction, and remain foundational measures in asthma, COPD, ILD, and neuromuscular disease trials. These measurements are often used in respiratory clinical trials to assess general pulmonary function.

FeNO (Fractional Exhaled Nitric Oxide) measures airway inflammation and is often a key measure associated with asthma clinical trials but may also be used in other diseases (e.g., COPD) to characterize or rule out airway inflammation.

DLCO (Diffusing Capacity of the Lungs for Carbon Monoxide) provides valuable insights into lung disease severity and progression in diseases that affect gas exchange. In clinical trials, DLCO assessment is commonly used in trials focused on COPD, Cystic Fibrosis, Asthma, and Interstitial Lung Disease.

Cough, in the form of cough frequency and/or severity, can also be an important functional endpoint to measure. Cough can measure treatment effectiveness and overall lung health as well as quality of life for those with pulmonary disease.

Clinical event endpoints

Clinical event endpoints focus on episodes representing meaningful disease worsening: exacerbations, hospitalizations, urgent care visits, or treatment escalation. In COPD and severe asthma, reducing event burden often constitutes the primary therapeutic goal.

Events must be defined precisely and captured consistently. Poorly documented exacerbations damage evidence quality as much as missing data, particularly when event reduction is central to the study hypothesis. Clinical event endpoints, due to their inherent challenges for applying criteria consistently, are often adjudicated by a panel of independent experts during clinical study conduct, to ensure accuracy of endpoint characterization.

Patient-reported endpoints

Patient-reported endpoints capture what participants experience directly: breathlessness, cough burden, symptom fluctuation, sleep disruption, and treatment impact on daily life. These measures grow increasingly important because pulmonary disease is not identified and measured through spirometry alone.

Collection quality determines their value. Compliance, diary fatigue, translation quality, and timing all influence data integrity. Clario’s eCOA solutions address these challenges through flexible support for mobile devices and browser-based applications loaded with standardized respiratory questionnaires such as ACQ-7 and AQLQ, or customized instruments.

Imaging endpoints

Imaging endpoints bring structural and anatomical perspectives to respiratory trials. Quantitative analysis of functional and structural lung imaging plays an important role in understanding pathophysiology, diagnosis, monitoring, and treatment response.

Structural airway features can be quantified down to the seventh to tenth generation depending on indication. Functional imaging measures changes in lung parenchyma and regional ventilation distribution. Clario’s imaging solutions deliver high-quality and standardized support for clinical trials across sites and patients.

Integrated endpoint strategies strengthen regulatory submissions

Regulatory agencies increasingly support integrated, multimodal endpoint strategies that better reflect patient benefit and risk. This approach connects physiological changes to clinical relevance rather than relying on single measures.

Connecting biomarkers to patient outcomes

A therapy that improves test scores but introduces cardiovascular risks, mobility issues, or reduced independence cannot be considered a clear success. Integrated strategies address this by aligning multiple endpoint types.

Clario helps sponsors design studies connecting spirometry parameters with cardiac safety monitoring, imaging biomarkers, and patient-reported outcomes. This comprehensive view demonstrates not just biological activity but meaningful benefit.

Supporting composite endpoints

Composite endpoints combine multiple measures to capture the full spectrum of treatment effects. In respiratory trials, this might include FEV1 improvement, exacerbation reduction, and quality of life gains.

The technical challenge lies in collecting these diverse data types with consistent quality standards. Partners with deep expertise across respiratory, cardiac, imaging, and eCOA domains can maintain this consistency while simplifying sponsor workflows.

Common challenges in respiratory endpoint collection

Understanding common failure points helps sponsors anticipate and mitigate risks. Respiratory trials often fail not from dramatic protocol deviations but from small inconsistencies repeated across sites that accumulate over time.

Data quality

Respiratory data quality depends on a complex interplay of factors: proper technique, effective coaching, cooperative participants, and well-trained site staff. Subtle breakdowns at any point can introduce significant errors into measurements.

Even tests that meet ATS/ERS acceptability criteria may contain inaccuracies. Passing basic quality checks does not guarantee that captured values truly reflect lung function. Submaximal inspiration, poor blast effort, or implausible changes may go undetected without deeper review.

Unrecognized problems increase variability in study results, making it harder to detect true treatment effects. This added noise can dilute statistical power, mask meaningful changes in lung function, and complicate endpoint interpretation. The consequences extend to regulatory outcomes, trial timelines, and decisions about promising therapies.

Exacerbation documentation inconsistencies

Exacerbations carry clinical importance but present operational challenges. Some are treated at sites, others in urgent care, and others at home with rescue medication. Unless protocols define them clearly, and sites receive consistent training, endpoint reliability deteriorates.

Patient reporting compounds these challenges. Symptom diaries, event recall, and rescue medication tracking depend on sustained engagement that weakens during long studies without simple, well-supported systems.

Variability related to testing technique

Pulmonary assessments are highly sensitive to how they are performed. Spirometry quality, inhaler technique instruction, and relative timing of measurement all affect reliability.

In multi-center studies, measurement technique issues can cause high variability of the results not associated with a change in the patient’s condition. Standardization, retraining, and centralized review can help maintain the accuracy of measurements.

Site variability

Multi-site clinical trials amplify data quality risks through differences in equipment calibration, staff experience, and adherence to standardized procedures. A single protocol may be executed with subtle variations across dozens of sites, creating measurement inconsistencies that accumulate over time.

Spirometry performance is particularly sensitive to how tests are conducted. Coaching quality, timing of measurements, and calibration routines all affect reliability. When these variables drift across sites without centralized oversight, even valid endpoints lose discriminatory power.

Clario data demonstrates that centralized data collection and scientific spirometry quality review can reduce variability by up to 50%. This reduction directly translates to improved statistical power and clearer treatment effect signals.

Best practices for implementing respiratory endpoints

Successful implementation requires attention to practical considerations that determine whether digital technologies deliver their promised benefits.

Site selection and preparation

Select sites with respiratory expertise where possible but recognize that many trials include sites without specialized pulmonary experience. For these sites, comprehensive training becomes especially critical.

Use harmonized devices across all sites to reduce equipment variability. When existing site equipment must be utilized, implement paper-based solutions with centralized overread to maintain consistency.

Training program design

Design training programs that cover both proper technique and coaching skills. How site personnel instruct participants significantly affects data quality. Include proficiency testing that must be passed before enrollment begins.

Plan for ongoing training throughout the trial lifecycle. Skills erode over time, and staff turnover creates gaps. Regular proficiency monitoring identifies sites needing retraining before quality issues compound.

Quality monitoring protocols

Establish clear protocols for identifying and addressing quality issues. Define thresholds for intervention and processes for site remediation. Create feedback loops that enable continuous improvement rather than end-of-study discovery of problems.

Leverage endpoint data quality intelligence tools that focus oversight on critical data. Statistical analyses and variability assessments help teams move beyond surface compliance to identify hidden risks.

What to evaluate in a respiratory endpoints partner

Selecting the right partner for respiratory endpoint strategy requires evaluating capabilities across multiple dimensions. The goal is to identify an organization who understands the challenges of respiratory drug development and how variability in lung function data is generated. They should have in place approaches to rapidly detect highly variable and implausible data so that remedial action can be taken prior to critical damage occurring.

Data quality processes

Examine how prospective partners approach quality beyond basic compliance. Effective partners implement centralized data collection enabling routine cross-site reviews that identify anomalies, trends, and inconsistencies early.

Look for statistical analyses, variability assessments, and plausibility reviews that move beyond surface-level compliance. Partners should demonstrate methods for detecting submaximal inhalation error, medication washout failures, and biologically implausible results. The typical trial contains between 5% and 23% of study data which is considered implausible. Typically, highly variable data is not picked up by standard ATS/ERS compliance checks. Clario data indicates that around 85% of the most variable data within clinical trials are initially reported to have acceptable ATS/ERS compliance.

Clario’s Scientific Spirometry Quality Review services exemplify this approach by combining data monitoring tools, human validation, and clear reporting to identify potential quality issues as early as possible. Early intervention optimizes opportunities for successful mitigations before significant impact on study quality.

Compliance and regulatory framework

Regulatory compliance extends beyond meeting ATS/ERS technical standards. Evaluate whether partners maintain 21 CFR Part 11 and GDPR compliant platforms with verified data integrity and audit trails.

Partners should provide auditable documentation demonstrating that data collection, evaluation, and monitoring align with regulatory expectations. This documentation establishes that each maneuver underwent systematic review for acceptability, repeatability, and compliance with recognized criteria.

Clario’s electronic data capture platform maintains these standards while enabling seamless integration with sponsor, CRO, and third-party systems through API and data exchange.

Operational support capabilities

Assess the depth of training and site support programs. Effective partners recognize that training represents the single biggest lever for improving respiratory endpoint quality.

In-person, standardized, protocol-specific training can improve investigator proficiency, potentially improving data quality and creating efficiencies. Training benefits both sites and participants by reducing repeat visits and ensuring accurate data capture on the first attempt.

Clario has supported respiratory clinical trials for more than 50 years at more than 80,000 sites worldwide. This experience translates to practical knowledge about what works across different site environments, from established pulmonary facilities to remote oncology clinics with no prior spirometry experience. This breadth of experience allows you to benefit from cumulative lessons learned to reduce development risk.

Technology integration

Evaluate how respiratory endpoints integrate with other trial data. Siloed data systems create operational burden and complicated analysis. Partners offering a holistic endpoint technology platform combining imaging, cardiac safety, respiratory testing, and eCOA reduce this complexity.

Consider whether partners support both site-based and home-based data collection with consistent quality standards. This flexibility becomes increasingly important as sponsors adopt hybrid trial modalities.