FDA Finalizes Guidance on the Use of Patient-Reported Outcomes to Support Labeling Claims

By Nisha P. Shah –

On December 8, 2009, the Food and Drug Administration ("FDA") issued its final, non-binding guidance for industry on “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.”  A draft guidance was published in February 2006.  The final guidance explains how FDA evaluates patient-reported outcomes ("PRO") instruments used in measuring endpoints in clinical trial studies.  The guidance also sets forth standards of how sponsors can generate and use PRO instruments to improve the probability of supporting claims in the product labeling.

The guidance defines PRO as a measurement “coming directly from the patient about the status of a patient’s health condition” without interpretation of the response by a health care professional or anyone else. PRO endpoints can serve as either primary, secondary, or exploratory endpoints. PRO instruments can be useful tools to evaluate the effect of treatment on one or more “concepts,” or how a person functions or feels about a health condition or its treatment. The instruments can capture significant clinical information that traditional evaluations by health care professionals cannot, such as a patient’s perception of improvement in pain and mobility.

In determining whether to use existing PRO instruments or to develop a new one, sponsors should consider “their labeling goals, a PRO instrument conceptual framework, and the relationship of the PRO endpoints to other clinical trial endpoints in preliminary endpoint models for the planned confirmatory trials.” If existing PRO instruments do not adequately support the sponsor’s goals, the guidance describes procedures for sponsors to generate their own PRO instrument.

Regardless of whether an existing or new instrument is used, the guidance cautions against measuring “general concepts”, such as overall physical health, because the instrument may not distinguish adverse events of treatment that may affect the general concept but were unknown at the time the clinical trial study was designed.  The measurement of more specific concepts, such as improvement in pain, may be more useful in supporting labeling claims.

In developing a new instrument, sponsors should conduct patient interviews, focus groups, and additional assessments to ensure comprehension and completeness of the items contained in the PRO instrument, as well as to demonstrate content validity and reliability. Sponsors are advised to maintain appropriate documentation through the evolution of developing and testing the instrument because the agency will examine the final version of the instrument “in light of its development history,” including “the complete list of items generated and the reasons for deleting or modifying items.” The guidance states that FDA will review this documentation along with clinical trial results to determine whether a labeling claim is substantiated.

The guidance also spells out FDA’s specific concerns when using electronic PRO instruments.  FDA expressed concerns particularly over the principal investigator’s ability to maintain control and to have access to the records that serve as the electronic source documentation for the purpose of an FDA inspection. Additional measures the sponsor should address in the protocol when using an electronic PRO instrument include database security and measures to prevent loss of adverse event data. 

Much like capturing the more traditional clinical endpoints, sponsors should consider measures to optimize the quality of the PRO instrument, minimize inconsistencies in conducting the trial, and develop a statistical analysis plan to analyze the PRO endpoints and handle incomplete data. To interpret the clinical trial results, FDA maintains that “it [is] informative to examine the cumulative distribution function ("CDF") of responses between treatment groups to characterize the treatment effect and examine the possibility that the mean improvement reflects different responses in patient subsets,” rather than focusing on the statistical significance of the PRO measures alone.

The guidance encourages sponsors to solicit feedback early in the process of instrument and protocol development and engage the FDA in a discussion about a new PRO instrument before clinical trial protocols are finalized, and includes a checklist of background information to provide when submitting a PRO instrument to FDA for review.