Approximately 15% of the world‘s population suffer from Respiratory diseases such as Asthma, COPD or others. Most Respiratory Diseases are classified as either obstructive, which are an inflammatory condition of the airway, or restrictive, which are characterized by reduced total lung capacity (TLC), vital capacity, or resting lung volume. The therapies for two obstructive lung diseases, Asthma and COPD, provide one of the highest sources of revenue for the pharmaceutical industry, and the limited efficacy of many current products provides a strong incentive for continued research and development.
The central activity of drug development is measurement and documentation. In any respiratory trial, it is important to understand the measurement characteristics of pulmonary function testing (PFTs) to assess lung function. Unlike other laboratory tests, PFTs are affected by many variables such as diurnal fluctuations, environmental conditions, methodology, reference values, choice of instrumentation, technician training and patient/technician interaction. Critical endpoints may require multiple repeat measurements as well as a larger sample size to attenuate the variability. Variability can impair our ability to find important clinical signals in individuals and in populations in trials.1
Spirometry is one diagnostic test for pulmonary mechanics, which measures the inhalation and exhalation of air over time. It is also one of the most important clinical endpoints for any respiratory trial. These values are represented by spirograms (flow volume loop and volume time curve).
In a respiratory study, the parameters FEV1, FVC and Inspiratory Capacity (IC) are important spirometry values used to determine efficacy and safety of an experimental drug. The FVC is the volume delivered during maximal expiration starting from a deep inspiration and FEV1 is the volume delivered in the first second of the FVC maneuver. Like all other pulmonary function values, these parameters are subject to the great amount of variability inherent in the nature of the testing.
In 2005, the ATS/ERS released the updated Standardization of Spirometry document in an attempt to publish standards that can be applied globally.
The ATS/ERS Standardization of Spirometry for acceptability and repeatability are as follows:
- Steep rise to PEF
- Back extrapolation volume not greater than 150 mL or 5% of FVC
- Expiratory time at least 6 seconds
- Plateau for 1 sec.
- No artifacts
Repeatability (at least 3 acceptable efforts):
- FVC: best and 2nd best within 150 mL
- FEV1: best and 2nd best within 150 mL
- Inspiratory Capacity: the average of at least 3 maneuvers
At ERT there are three levels of data quality control (QC) to check for the overall quality of the spirometry test, repeatability, procedural correctness and compliance with the ATS/ERS Standards. The first level of QC is programmed within the Spirometry device, and the second level is the site technician’s judgment. The third level is where the flow volume loops are reviewed by a Respiratory OverReader, who then comments on the data quality based on ATS/ERS and sponsor specific criteria. If the data is considered unacceptable a notification will be sent back to the site indicating why. This level is also where the best test review of flow volume loops by the clinical specialist are performed. Clinical specialists analyze the spirograms for start of test criteria, flow dynamics, artifacts and coughs and end of test criteria. The elements of a good flow volume loop are a good start of test with maximum effort (FVC) and without hesitation, no coughing, no early termination of expiration or test unless necessary (stay on mouth piece), and the repeatability of efforts (must have at least 3 loops).
The best test review process is designed to remove unacceptable data and have the highest value reported from an acceptable effort represented. This will ensure the highest quality data, reduce the variability, decrease the sample size, reduce outliers and increase the probability of being able to observe a treatment effect. After the best test review, a grade indicating the data quality will be assigned. This grade can be used by the sponsor to determine if the data is usable for their analysis purposes.
As mentioned, the primary endpoint in phase II and III respiratory trials is determined by spirometry measurement. The validity of spirometry values are highly dependent on the cooperation of the subject, the interaction of the subject with the study coordinator, the influences of the surrounding environment and of course, the quality of the data overread. The term centralized spirometry includes both the standardization of equipment (each site receiving the exact same equipment with the same protocol specific software for a clinical trial), and the electronic transfer of the spirometry data to a centralized database, where the entire process of spirometry overread and quality control are performed and feedback to the sites regarding the quality of the data is given.
Standardizing the equipment, training of technicians, and the process of continuous monitoring can reduce interdevice and interlaboratory sources of variability, which is essential to a successful clinical trial.2 Centralized spirometry should be standard for a sponsor developing new compounds for the treatment of asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. A centralized method of clinical data collection and interpretation is known to yield much cleaner data and far fewer inaccuracies than the process of having multiple interpretations of the results, as in a decentralized approach. The analysis of any parameter without the professionally trained and consistent consideration of any and all of the variability factors could result in faulty or erroneous conclusions. Inconclusive results, as well as wasted time and money may ultimately prevent the release of a promising compound or, in the worst case, release a compound that is harmful to society.
1: MacIntyre 2007
2: Jensen et al, Instrument accuracy and reproducibility in measurements of pulmonary function. Chest 2007