Forced vital capacity (FVC) is key to understanding lung function in restrictive respiratory diseases. This metric, which quantifies the total volume of air exhaled after taking the deepest possible breath, is especially critical in evaluating the progression of idiopathic pulmonary fibrosis (IPF). Historically, FVC has been a primary endpoint for approving IPF treatments such as pirfenidone and nintedanib. However, generating reliable FVC data requires rigorous site training, testing standardization, and continuous quality control to ensure intra- and inter-subject reliability.
This blog explores the significance of FVC in IPF trials and how these measures ensure that the data meet regulatory standards while yielding meaningful insights into patient outcomes.
Understanding FVC as a Clinical Endpoint
FVC is a powerful indicator of lung health, and for patients with progressive respiratory disease, such as IPF, a decline in FVC over time can signal worsening lung function, which is a key factor in determining treatment efficacy. The significance of FVC as a clinical endpoint in restrictive lung diseases is well-documented, and it is now a standard measure for assessing novel IPF therapies. In the U.S., the FDA has acknowledged the importance of FVC, requiring its inclusion in all IPF trials. This recognition follows the successful use of FVC as a primary endpoint in the clinical trials of pirfenidone and nintedanib, which have fortified FVC’s place as a meaningful endpoint in clinical IPF research.
While FVC is an industry standard metric in clinical research, it’s an indirect measure of more critical outcomes, such as quality of life or survival. A change in FVC is commonly interpreted to assess the efficacy of treatments, but it is not a definitive measure of overall therapeutic success. Regulatory agencies’ stance on centralized spirometry, which mandates consistent technology and centralized interpretation, attempts to minimize variability within and between respiratory research studies. This standardization ensures that FVC data is uniform and thus more readily interpretable. However, successful FVC implementation across and within clinical sites still requires external support, such as training and monitoring, to ensure uniform data collection.
Start-Up Process & Training
Before discussing the specifics of FVC, it’s essential to address the foundational steps and emphasize the comprehensive training required to produce accurate and reliable data. Although spirometry is a standard assessment, it demands careful technique, and experts widely regard it as one of the most subjective tests in respiratory medicine. A significant portion of spirometry data is often of inadequate or questionable quality, which increases data variability and undermines trial validity. For example, a study by Mottram et al. identified that ~12% of test sessions across three asthma trials had a change to the original decision regarding maneuver acceptability, based on identification from the over-readers (i.e., quality reviewers).
- Sub-maximal inhalation or blast
- Cough during the first second
- Early termination
- Variable effort
- Extra breaths
- Equipment-related issues (e.g., leaks or calibration errors)
The test accuracy hinges on the participant’s effort and the technician’s ability to coach and guide the procedure effectively. This inherent subjectivity underscores the importance of robust and consistent training for FVC testing, which is critical to the success of any IPF trial.
The training programs for spirometry technicians are thorough and designed to address every facet of the process, from the proper use of the spirometer to the nuances of patient interaction. Specialists train technicians to position patients’ mouths appropriately, ensure a secure seal on the mouthpiece without obstruction from the tongue, and guide the patient through each phase of the maneuver with precision. These steps are vital to standardizing the procedure and minimizing variability across measurements. Yet, even with extensive initial instruction, regular practice and retraining are essential. Continuous sessions incorporating simulation and real-world scenarios help technicians sharpen their technique, build confidence, and troubleshoot common challenges.
The emphasis on standardization is especially critical in multicenter studies when collecting FVC measurements across multiple trial sites. Consistency in protocols and procedures is key to ensuring the reliability and comparability of the data generated. This standardization commences with rigorous initial training and extends through robust quality control measures. Regular refresher courses and ongoing education are essential for maintaining high testing standards. These courses keep technicians abreast of evolving techniques, guidelines, and best practices, ensuring consistent, high-quality data throughout the study lifecycle.
Ensuring Quality in Spirometry Data
Ensuring the quality of spirometry data requires a combination of careful technique, standardized protocols, and ongoing quality control. Poor-quality data can lead to incorrect conclusions, wasted resources, and failure to meet the trial’s endpoints. Regular spirometer calibration is also critical to ensure accurate FVC measurements. Calibration helps preserve the equipment’s precision, which is necessary for consistent and reliable data.
Additionally, respiratory trials must adhere to the ATS/ERS 2019 Guidelines, which provide a robust framework for conducting high-quality spirometry. These guidelines cover everything from initial setup and calibration of spirometers to the standardized techniques for performing and interpreting the tests. By following these guidelines, researchers can minimize variability in FVC test results, ensuring that the data are consistent and reliable. Adherence to these guidelines requires ongoing monitoring and review throughout the trial to catch and correct any protocol deviations.
One of the most challenging aspects of maintaining data quality is the lack of centralized oversight, which can compromise the reliability of quality control efforts. In such cases, generating data monitoring listings from electronic data capture systems is essential to analyze intra-patient and inter-site variability. These listings allow for the comparison of values between visits and the identification of outliers that may be indicative of user errors.
Taking a Deep Breath & Thinking Big Picture
The gold standard is using FVC in clinical care and as a clinical endpoint in IPF trials. When properly conducted, FVC assessments predict disease progression and mortality in patients with IPF. This critical measurement provides healthcare professionals with insight into the lung’s functional capacity and allows for more precise monitoring of respiratory disease and treatment effect. As the FVC values decrease, the risk of severe complications and death increases, underlining the importance of FVC as a tool for early intervention and proactive patient management.
Furthermore, FVC assists in tailoring treatment strategies by identifying patients at risk of rapid decline in lung function early. Patients with a steeper decline in FVC are at increased risk of additional respiratory complications and may benefit from more aggressive or alternative treatments. This early identification enables healthcare providers to personalize care plans, ensuring that each patient receives the most appropriate and effective intervention.
By adhering to the stringent requirements and standards, researchers can provide robust evidence to support the efficacy and safety of new therapies, ultimately leading to better treatment options for IPF patients.
Worldwide’s Commitment to High-Quality Spirometry Testing
Our partnership with the best spirometry overreading vendors allows us to have centralized reads, access to historic recruitment data during the feasibility process, and understand which sites produce the best quality spirometry data to help select the optimal sites to reduce variability in your endpoints. In addition, we also work closely with these teams to use real-time quality reporting, which our respiratory experts review to identify potential issues at sites and address them proactively to facilitate optimum data collection.
To support data integrity, we propose a minimum threshold of 91% of spirometry assessments meeting acceptable or borderline acceptable criteria, consistent with the respiratory trial ATS and ERS guidelines. Quality oversight may involve regular review of site-level data, identification of frequent technical errors (e.g., suboptimal effort, early test termination, or inconsistent flow-volume loops), and retraining of sites that fail to meet quality benchmarks. This approach ensures valid safety signal detection and reduces the risk of false-positive results. In our ongoing and finished trials, we have achieved over 91% of acceptable and borderline acceptable spirometry in more than 20,000 tests.
We are highly skilled in working with the sites to improve the spirometry quality. The process includes the following:
- Regular checking of the acceptability for each site and technician who performed spirometry
- Regularly monitoring for the most common errors at sites
- Retraining of the sites as needed
Contact us today to discuss how we can work together to ensure quality FVC data in your next respiratory investigation.
