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Table 4 Measurement Properties Reviewed for PRO Instruments Used in Clinical Trials
| Measurement Property | Test | What is Assessed | FDA Review Considerations |
|---|---|---|---|
| Reliability | Test-retest | Stability of scores over time when no change has occurred in the concept of interest | Does the PRO instrument reliably measure the concepts it was designed to measure? |
| Internal consistency | Whether the items in a domain are intercorrelated, as evidenced by an internal consistency statistic (e.g., coefficient alpha) | Were appropriate reliability tests conducted? | |
| Inter-interviewer reproducibility (for interviewer-administered PROs only) | Agreement between responses when the PRO is administered by two or more different interviewers | What was the quality of the evidence of reliability? | |
| Validity | Content-related | Whether items and response options are relevant and are comprehensive measures of the domain or concept | Do items in the verbatim copy of the PRO instrument appear to measure the concepts they are intended to measure in a useful way? |
| Have patients similar to those participating in the clinical trial confirmed the completeness and relevance of all items? | |||
| Ability to measure the concept (also known as construct-related validity; can include tests for discriminant, convergent, and known-groups validity) | Whether relationships among items, domains, and concepts conform to what is predicted by the conceptual framework for the PRO instrument itself and its validation hypotheses. | Do observed relationships between the items and domains confirm the hypotheses in the conceptual framework? Do results compare favorably with results from a similar but independent measure? | |
| Do results distinguish one group from another based on a prespecified variable that is relevant to the concept of interest? | |||
| Ability to predict future outcomes (also known as predictive validity) | Whether future events or status can be predicted by changes in the PRO scores | Do PRO scores predict subsequent events or outcomes accurately? | |
| Ability to detect change | Includes calculations of effect size and standard error of measurement among others | Whether PRO scores are stable when there is no change in the patient, and the scores change in the predicted direction when there has been a notable change in the patient as evidenced by some effect size statistic. Ability to detect change is always specific to a time interval. | Has ability to detect change been demonstrated in a comparative trial setting, comparing mean group scores or proportion of patients who experienced a response to the treatment? |
| Has ability to detect change been assessed for the time interval appropriate to study? | |||
| Interpretability | Smallest difference that is considered clinically important; this can be a specified difference (the minimum important difference (MID)) or, in some cases, any detectable difference. The MID is used as a benchmark to interpret mean score differences between treatment arms in a clinical trial | Difference in mean score between treatment groups that provides convincing evidence of a treatment benefit. Can be based on experience with the measure using a distribution-based approach, a clinical or nonclinical anchor, an empirical rule, or a combination of approaches. The definition of an MID using a clinical anchor is sometimes called an MCID. | The FDA is specifically requesting comment on appropriate review of derivation and application of an MID in the clinical trial setting. |
| Responder definition – used to identify responders in clinical trials for analyzing differences in the proportion of responders between treatment arms | Change in score that would be clear evidence that an individual patient experienced a treatment benefit. Can be based on experience with the measure using a distribution-based approach, a clinical or nonclinical anchor, an empirical rule, or a combination of approaches. | The FDA is specifically requesting comment on appropriate review of derivation and application of responder definitions when used in clinical trials. |
