Clinical Outcome Assessment Qualification Program
Defining a clinical outcome assessment (COA): Clinical outcome assessments (COAs) measure a patient’s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions. COAs can be used to determine whether or not a drug has been demonstrated to provide treatment benefit. Treatment benefit can also be defined in terms of a safety benefit compared to other treatments. A conclusion of treatment benefit is described in labeling in terms of the concept of interest (COI), the thing measured by the COA.
COA qualification: COA qualification is based on a review of the evidence to support the conclusion that the COA is a well-defined and reliable assessment of a specified COI for use in adequate and well-controlled (A&WC) studies in a specified context of use (COU). COA qualification represents a conclusion that within the stated COU, results of assessment can be relied upon to measure a specific concept and have a specific interpretation and application in drug development and regulatory decision-making and labeling. For COAs that do not provide evidence of how patients feel, or function in daily life, qualification also includes a review of the evidence that the concept assessed is an adequate replacement for how patients feel or function in daily life.
There are four types of COA measures:
For those measures that do not measure how patients feel or function in daily life, CDER reviews evidence of how the outcome is linked to survival or how patients feel or function in daily life.
Roadmap to Patient-Focused Outcome Measurement in Clinical Trials
Before CDER reviews a COA for qualification, the submitter will need to identify the targeted COU and targeted COI to support labeling claims. The Roadmap diagram (above) describes the types of information to consider when understanding the disease or condition (column 1) and conceptualizing treatment benefit (column 2) resulting in identification of the targeted COU and COI for future clinical trial measurement. Once the COU and COI are established, then this information can be used to identify the proper type of outcome assessment. The process of selecting, modifying, or developing an outcome measure for CDER qualification (Column 3) depends on having adequately characterized the disease or condition and conceptualized a concept of interest that represents treatment benefit.
Choice of a COA type: Choosing a type of COA (PRO, ClinRO, ObsRO, or PerfO measure) depends on a determination of the most appropriate reporter for the concept of interest and the context of use. For example, if pain intensity is the concept of interest in a patient population that can respond themselves, a PRO is most appropriate. If clinical judgment is required to interpret an observation, a ClinRO is chosen. If the COI can only be adequately captured by observation in daily life (outside of a healthcare setting), and the patient cannot report for him or herself, then an ObsRO is chosen. When it would be useful to observe an actual demonstration of defined tasks demonstrating functional performance in the clinical setting, a PerfO may be appropriate.
Wheel and Spokes Diagram: Qualification of Clinical Outcome Assessments
The COA Wheel and Spokes diagram (above) identifies the key components of the documentation submitted to CDER to support COA qualification. The Wheel and Spokes diagram also represents the general iterative process used in developing a COA for qualification.
Spoke I corresponds with Columns 1 and 2 of the Roadmap diagram above and demonstrates that the COI and COU need to be identified before review of content validity (Spoke II) can begin. When review of content validity evidence is adequate, the final version of the instrument with its scoring rule can be tested for reliability in stable patients and cross-sectional evaluation of construct validity (Spoke III). At this point in time, submitters may consider the option of submitting Spoke I-III evidence for COA qualification. Qualification at this time will be for use in exploratory studies and for testing of other measurement properties. When all measurement properties are tested, Spokes I-IV evidence will be reviewed to support COA qualification for use in adequate and well-controlled studies as a primary or secondary endpoint measure of effectiveness.