Patient reported outcomes (PROs) are data obtained directly from patient self-reports, and their use in clinical trials is
increasingly common.1 The U.S. Food and Drug Administration (FDA) recently published for comment their "Patient Reported Outcome (PRO) Measures:
Use in Medical Product Development to Support Labeling Claims,"2 hereafter referred to as the PRO Guidance, to describe how they will evaluate PRO instruments. The PRO Guidance lays out
the type and quality of information that clinical researchers will need to provide to justify the use of a particular PRO
instrument in a trial and highlights the significance of PRO data in drug development.
By setting ground rules for use of PROs, the FDA has implicitly given credibility to PROs as the basis for evaluating drugs
and biologics. Further, such guidance will eventually make for more efficient, effective, and appropriate use of these tools.
Despite the enthusiasm and promise of the PRO Guidance, some researchers perceive a few challenges. First, some conclude that
the FDA will maintain higher regulatory standards for PRO measurement than for clinician-based measures. Second, the PRO Guidance
relies on technical language in its specification and may come across as daunting to some researchers. The cumulative effect
of these challenges could be to discourage the use of PROs altogether.
However, our interpretation of the Guidance is that the recommendations are manageable. Further, we anticipate that the FDA
will begin to apply appropriate rigor to other, similar clinical endpoints (e.g., clinician reported outcomes). The goal of this article is to give an overview of the PRO Guidance for clinical researchers implementing PROs. While not
exhaustive, we spotlight two important activities that clinical researchers must undertake to meet regulatory requirements
for PROs. First, clinical researchers will have to document the history and psychometric properties (i.e., reliability and
validity) of their PRO instruments. Second, investigators who modify an existing PRO instrument must define the degree of
modification, decide how much revalidation, if any, might be necessary in light of these changes, and defend these decisions
to the FDA.
Documentation and instruments
PRO Instrument Selection Factors
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The PRO Guidance discusses a variety of factors that, if appropriately documented, can justify use of a given PRO instrument.
These factors are based on a large literature on psychometrics—the science of PRO assessment—which is too extensive to recap
here. We believe, however, that these factors can be summarized under four categories of information: the conceptual framework,
administration, performance characteristics, and study design issues that characterize the instrument as used in the trial3 (see Table 1).
Conceptual framework: A conceptual framework ensures that a researcher identifies and defines: what he or she intends to measure (i.e., the PRO
concept); how he or she will measure it (i.e., the PRO instrument); and why he or she is measuring it (i.e., what is the label
claim to be supported by the PRO data).
The importance of a thoroughly specified conceptual framework cannot be understated, since it is the basis of all the other
evaluations of the instrument and for evaluating its relevance to product labeling. In other words, stating clearly what the
researcher intends to measure and relating it clearly to the proposed claim, to the condition being treated, and to the product's
mechanism of action sets the stage for justifying why Questionnaire A is well-suited or better suited for the task than Questionnaire
B.
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