EXACT
The EXAcerbations of Chronic pulmonary disease Tool (EXACT®) is a patient-reported outcome (PRO) measure for standardizing the symptomatic evaluation of acute exacerbations of chronic obstructive pulmonary disease (COPD) and chronic bronchitis (AECB) in natural history studies and clinical trials.
The EXACT was developed under the EXACT-PRO Initiative, a multi-year, multi-sponsor project involving experts in pulmonary medicine, instrument development, and drug development regulatory issues, dedicated to the development of a single, standardized instrument for evaluating the effects of treatment on acute exacerbations of COPD.
The Evaluating Respiratory Symptoms (E-RS):COPD scale is a derivative instrument used to measure the effect of treatment on the severity of respiratory symptoms in stable COPD.
The EXACT description
The EXACT is a 14-item PRO daily diary used to quantify and measure exacerbations of COPD.
This instrument provides a single, standardized approach for assessing the symptomatic manifestations of COPD exacerbations, with a development and validation history consistent with guidelines proposed by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) and well-known measurement principles.
Research benefits
Exacerbations are events characterized by an acute, sustained worsening in the patient’s COPD beyond normal day-to-day variability, including an increase in respiratory symptoms such as dyspnea, cough and sputum production that may require a change in treatment.
- The EXACT total score, computed daily over time, is designed to standardize the assessment of the patient’s condition in order to capture this dynamic process.
EXACT scores complement and extend information provided by traditional health care resource utilization (HCRU) data by:
- Standardizing the magnitude of symptomatic change around HCRU events (those seen in the clinic, emergency room or hospital)
- Quantifying frequency, severity and duration of reported and unreported symptom-defined events
The EXACT may be used in longitudinal, natural history studies or clinical trials, including:
- Maintenance and prevention trials testing the efficacy of therapies to modify or prevent COPD exacerbations
- Acute treatment trials evaluating therapies to treat exacerbations of COPD
Content of the EXACT and E-RSa
| Symptom construct | Item-level construct1 | Item number |
|---|---|---|
| Breathlessness | ||
| Breathless today2 | 7 | |
| Breathless with activity3 | 8 | |
| Short of breath – personal care3 | 9 | |
| Short of breath – indoor activity3 | 10 | |
| Short of breath – outdoor activity3 | 11 | |
| Cough and sputum | ||
| Cough frequency3 | 2 | |
| Mucus quantity3 | 3 | |
| Difficulty with mucus3 | 4 | |
| Chest symptoms | ||
| Congestion2 | 1 | |
| Discomfort2 | 5 | |
| Tightness2 | 6 | |
| Additional attributes | ||
| Tired or weak2 | 12 | |
| Sleep disturbance2 | 13 | |
| Scared or worried2 | 14 |
a All 14 items are administered as a daily diary; The EXACT total score uses all 14 items with logit scoring transformed to a 0 to 100 interval-level scale; E-RS scoring uses only the respiratory symptom items, with subscales for breathlessness, cough and sputum, and chest symptoms. E-RS scores are based on summation to yield ordinal-level scales.
1 Items are worded as simple questions. Recall: “Today”. Patients are asked to complete the diary every evening before they go to bed. The formatted instrument is available through CRGexactpro@thermofisher.com.
2 5-point scale, Not at all to Extremely
3 5-point scale – other
The EXACT development methods
The process involved more than 500 people, including 493 patients with COPD and 18 professionals from the U.S. and Europe with expertise in pulmonary medicine, clinical research, instrument development and drug development regulations.
Methods used to optimize content validity
Comprehensive literature review
A comprehensive literature review was performed to examine the clinical definition of COPD exacerbations and identify and evaluate existing PRO instruments used to evaluate exacerbation outcomes in clinical research, with specific interest in clinical trials. To ensure and document content validity through qualitative methods, 83 men and women with a diagnosis of COPD and history of exacerbations participated in elicitation focus groups or interviews.
- An iterative analytical process was used to identify themes and concepts to inform instrument content and structure.
- A draft instrument comprising 23 items was subjected to cognitive interviewing methodology in patients with COPD.
- During two advisory panel meetings, experts critiqued the research methods and results and assisted in the design of a prospective study to collect data for item reduction and to evaluate the performance characteristics of the final instrument in subjects with COPD.
- Methods and results are published in Leidy et al. 2010.
Quantitative data
Quantitative data were gathered through a prospective two-group observational validation study of 410 patients with COPD.
- Group one: 222 acute patients with a clinician-confirmed exacerbation completed the draft item pool and additional items via an electronic diary each evening before bedtime on days 1–28 of their exacerbation and again on days 60–67, with clinical assessments performed on multiple days throughout the assessment period.
- Group two: 188 stable patients completed baseline assessments and the diary over seven days.
Scoring
Item analyses and Rasch item-response theory were used to derive the final 14-item EXACT and Total score algorithm.
- The EXACT Total score is computed by using logit values and a simple look-up table to yield interval-level scores ranging from 0 to 100, where higher scores indicate a more severe condition.
- The EXACT Total score is used to determine the patient’s stable baseline, onset of an exacerbation event (threshold of sustained worsening), and recovery from the exacerbation (threshold of sustained improvement).
- Methods and results are published in Jones et al. 2011.
Tests of reliability, validity and responsiveness
Tests of the reliability, validity and responsiveness of EXACT scores were performed on data from the 410 subjects using an a priori statistical analysis plan and follow-up secondary analyses. Scores exhibited high levels of internal consistency and reproducibility.
Evidence of construct validity included:
- Ability to discriminate acute and stable groups
- Sensitivity to change over time in the acute group
Two expert panel meetings were held to discuss results and interpretation guidelines.
Further validation
EXACT scores were subjected to further tests of reliability and validity through secondary analyses of three clinical trial datasets, including one six-month trial in the U.S. and two three-month international trials.
Methods of administration
To facilitate standardized use, an EXACT-PRO User Manual was created, describing the instrument’s development, intended use, administration procedures and scoring. An eDiary certification program was developed to enhance consistency across eDiary vendors and platforms. Learn more about ePRO certification.
Qualifications
The history of the EXACT and E-RS are described in Leidy and Murray 2013 and Murray and Leidy 2018.
These documents specify that the EXACT and E-RS:COPD are qualified for use as exploratory endpoints in drug development trials evaluating the effect of treatment on exacerbations (EXACT) and respiratory symptoms (E-RS:COPD) of COPD.
This does not preclude their use as secondary, co-primary or primary endpoints. Sponsors should discuss their proposed use of the EXACT and/or E-RS with regulatory authorities prior to positioning in pivotal trials. Decisions related to positioning and potential for labeling claims are made on a case-by-case basis.
EXACT and E-RS translations
The EXACT has been translated into more than 55 languages.
Methods used to translate the EXACT followed the Principles of Good Translation and Cultural Adaptation Practice as suggested by ISPOR in 2005.
These methods include:
- Development of a definition document to guide all translations
- Dual forward translation; reconciliation; dual back translation; back translation review; and harmonization
- Cognitive testing with COPD patients in each target country
- Clinician review as needed to verify terminology
- Final proofing, including diacritics
This approach is designed to yield translated versions of the EXACT that are conceptually equivalent to the English source version and easily understood by the target population of patients with COPD.
Items comprising the E-RS:COPD are included in the EXACT and were therefore included in this translation process.
All EXACT translations are completed in partnership with FACIT Translation Services (FACITtrans). To ensure standardized translations, users are not permitted to translate the EXACT without prior, written consent.
How to acquire translations
We hold copyrights to the EXACT, E-RS and all derivative measures in English and all translations. Translations can be obtained through the EXACT licensing procedure.
Each translated version includes certification of the procedures used to assure conceptual equivalence. To ensure standardized translations, users are not permitted to translate the EXACT without prior, written consent.
Please contact CRGexactpro@thermofisher.com if you have questions related to developing a new EXACT translation.
Available EXACT/E-RS certified translations
Scroll the table to view the full list of translations of December 2024.
| Languages | Countries tested1 |
|---|---|
| Afrikaans | South Africa |
| Albanian | Albania |
| Arabic (Universal) | Egypt, Israel, Oman, Saudi Arabia, Tunisia, United Arab Emirates |
| Bengali | India |
| Bosnian | Bosnia |
| Bulgarian | Bulgaria |
| Catalan | Spain |
| Cebuano | Philippines |
| Chinese (Simplified) | China, Malaysia, Singapore |
| Chinese (Traditional) | Taiwan, Hong Kong |
| Croatian | Croatia |
| Czech | Czech Republic |
| Danish | Denmark |
| Dholuo | Kenya |
| Dutch (Universal) | Belgium, the Netherlands |
| English (Universal) | USa, Australia, Canada, Hong Kong, India, Ireland, Israel, New Zealand, Philippines, Singapore, South Africa, UK |
| Estonian | Estonia |
| Finnish | Finland |
| French (Universal) | Francea, Canada, Belgium, Switzerland, Tunisia |
| Georgian | Georgia |
| German | Germany, Austria, Belgium, Switzerland |
| Greek | Greece |
| Gujarati | India |
| Haitian Creole | Haiti |
| Hausa | Nigeria |
| Hiligaynon/Ilonggo | Philippines |
| Hindi | India |
| Hungarian | Hungary |
| Igbo | Nigeria |
| Ilocano | Philippines |
| Italian | Italy |
| Japanese | Japan |
| Kannada | India |
| Korean | Korea |
| Hebrew | Israel |
| Latvian | Latvia |
| Lithuanian | Lithuania |
| Macedonian | Macedonia |
| Malay | Malaysia, Singapore |
| Malayalam | India |
| Marathi | India |
| North Sesotho | South Africa |
| Norwegian | Norway |
| Odia | India |
| Polish | Poland |
| Portuguese (Universal) | Brazil, Portugal |
| Punjabi | India |
| Romanian | Romania |
| Russian | Russiaa, Ukraine, Latvia, Lithuania, Israel, Estonia |
| Serbian (Cyrillic) | Serbia |
| Serbian (Latin) | Serbia |
| Sesotho | South Africa |
| Setswana | South Africa |
| Slovak | Slovakia |
| Slovene | Slovenia |
| Spanish (Universal) | USa,b,, Spaina,b, Mexicob, Chilea,b, Argentinab, Peru, Colombia, Guatemala |
| Swahili | Kenya |
| Swedish | Sweden, Finland |
| Tagalog | Philippines |
| Tamil | India, Malaysia, Singapore |
| Telugu | India |
| Thai | Thailand |
| Turkish | Turkey |
| Ukrainian | Ukraine |
| Urdu | India |
| Vietnamese | Vietnam |
| Xhosa | South Africa |
| Yoruba | Nigeria |
| Zulu | South Africa |
1 Cognitive interviews
a Interviews included PDA usability assessment
b Three region-specific translations were initially developed and tested with patients. After further review of the Spanish translations by a team of linguists from each of the respective countries where Spanish versions were tested, it was determined that the three Spanish versions could be harmonized into one universal Spanish version. The Spanish (Universal) version was subsequently tested in Peru, Colombia and Guatemala.
Licensing
The EXACT and E-RS measures are available for licensing to use in research studies.
Resources
User Manual
An EXACT User Manual describing the instrument’s development, intended use, administration procedures and scoring is provided to all licensed users to facilitate standardized use.
FDA guidance documents
- Draft Guidance on the Qualification of the EXACT for the Measurement of Symptoms of Acute Bacterial Exacerbations of Chronic Bronchitis in Patients with Chronic Obstructive Pulmonary Disease
- Draft Guidance on Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease, a Patient-Reported Outcome, for the Measurement of Severity of Respiratory Symptoms in Stable Chronic Obstructive Pulmonary Disease: Qualification for Exploratory Use
- Guidance for Industry on Acute Bacterial Exacerbations of Chronic Bronchitis in Patients with Chronic Obstructive Pulmonary Disease
- Guidance for Industry on Qualification Process for Drug Development Tools
FAQs
- Get answers to frequently asked questions
ISPOR good research practices for outcomes research
- ISPOR PRO Task Force on Good Research Practices for Content Validity: Part 1
- ISPOR PRO Task Force on Good Research Practices for Content Validity: Part 2
- ISPOR PRO Task Force: Good Research Practices on Use of Existing Instruments and Their Modification
Trials using the EXACT® or E-RS™
Visit clinicaltrials.gov to obtain a list of trials using these measures.
Source: ClinicalTrials.gov
Publications
Access a resource list of publication references.
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