FDA Qualifies Second Patient Reported Outcome Tool for COPD; Five Years Coming, FDA Guidance Notes Further Work Needed

FDA’s second “qualified” Patient Reported Outcome questionnaire addresses overall respiratory symptom evaluation in COPD (Chronic Obstructive Pulmonary Disease).  The draft guidance  for “Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease” (E-RS: COPD) qualifies the tool for exploratory use.

The E-RS: COPD score is ultimately intended to be used as an exploratory endpoint to support labeling claims related to change in stable COPD respiratory symptoms. 

The qualification of the PRO instrument marks a second step in the process of validating drug development tools. Evidera has developed both of the first qualified PRO tools. In January 2014, Evidera became the first to receive FDA qualification for their EXACT-PRO instrument, designed to measure clinical outcomes in studies of COPD. (See our Jan. 15, 2014 note, “COPD Patient-Reported Outcome Questionnaire Is Early Example of FDA Drug Development Tool Qualification Process.)  The FDA qualification process for ER-S took just over five years. It was accepted into FDA’s Clinical Outcome Assessment Qualification program on March 3, 2011. 

According to Evidera’s EXACT-PRO Initiative webpage, the E-RS is a derivative of the previously qualified EXACT tool.  E-RS is specifically designed to address the patient need for a standardized daily diary for the assessment of respiratory symptoms in treatment/tracking of stable COPD.  Initially named the EXACT-Respiratory Symptoms Scale, Evidera explains that the tool has recently been renamed, at FDA’s urging, as the Evaluating Respiratory Symptoms (E-RS) measure.

Prominently displayed on the EXACT-PRO Initiative page is the announcement of the E-RS name change, reading the following:

…During the development of the Draft Qualification Statement for the E-RS, the FDA asked us to change the name of the instrument so the term “Exacerbation” would not appear in labeling related to symptoms of stable disease. In response to this request, we are pleased to announce the new name for the E-RS: Evaluating Respiratory Symptoms (E-RS™) measure…When referring to its use in COPD, the proposed context of use for qualification, the full name is: Evaluating Respiratory Symptoms in COPD (E-RS™: COPD).

In a section on “concept of use” in the FDA draft guidance, the agency suggests that the PRO is being initially qualified for a limited range of uses with further work expected on tying the PRO responses to clinically meaningful changes or to assess the effect of treatment on symptoms from baseline. “As further experience with the instrument is gained,” FDA says, “the qualification statement will be expanded to aid in interpretation of clinically meaningful change.” 

“Additional development work is needed to further assess measurement properties,” FDA says, “including the ability to detect clinically meaningful change with treatment or to assess the effect of treatment on reducing respiratory symptoms from baseline levels. We encourage additional research and analyses to evaluate the E-RS: COPD’s longitudinal measurement properties including the amount of change in an individual patient that can be considered meaningful for use in the interpretation of effectiveness.”

FDA also recommends that the proposed responder definitions associated with the E-RS tool be subject to further evaluation, and asks sponsors to discuss the use of the tool with the applicable Center for Drug Evaluation & Research review division when designing clinical trials.

E-RS Instrument Development Overview from Evidera’s EXACT-PRO Initiative

  • The 11 respiratory symptom items comprising the E-RS were selected from the 14-item EXACT diary.
  • Content validity was optimized and documented through information and data from
    • The literature;
    • Secondary analyses of qualitative data gathered during the development of the EXACT;
    • Results of an additional prospective qualitative study of patients with stable COPD and no history of exacerbation for at least 12 months.
  • Tests of the reliability, validity, and responsiveness of E-RS scores were performed with validation data from the parent instrument (EXACT) using an E-RS specific a priori SAP and follow-up post hoc analyses.
    • Exploratory factor analysis of the 11 E-RS respiratory items in patients with stable COPD showed the presence of 3 factors that can serve as symptom subscales:
      • RS-Breathlessness (5 items), RS-Cough and Sputum (3 items), and RS-Chest Symptoms (3 items).
  • Methods and results of the qualitative and initial quantitative work are published in Leidy et al. 2014.
  • Further validation
    • E-RS scores were subjected to further tests of reliability and validity through secondary analyses of 3 clinical trial datasets, including one 6-month trial in the United States and 2 3-month international trials.
    • Methods and results are published in Leidy et al. 2014.
  • Methods of administration
    • To facilitate standardized use, an E-RS User Manual was created, describing the instrument’s development, intended use, administration procedures, and scoring.
    • The eDiary certification program applies to the E-RS.
  • Translation
    • The EXACT, and therefore the E-RS, has been translated into over 50 languages. See more information about translations here.

The history of the EXACT and E-RS are described in Leidy & Murray 2013.