PROs: Defining Clinical Benefit From the Patient's Perspective

Drugs approved by the US Food and Drug Administration (FDA) must demonstrate substantial evidence of efficacy from adequate and well-controlled trials and be safe for their intended use. A 1962 amendment to that Act codifies the efficacy requirement. Guidance promulgated in the 1980s indicated that efficacy should represent a "clinical benefit" demonstrated by prolongation of life, better life, or effect on an established surrogate for at least one of these. Direct clinical benefit assessments have included improvements in survival, physical functioning, or tumor-related symptoms.

Clinical trials evaluating an anticancer product's treatment benefits have increasingly incorporated patient self-reported measures (patient-reported outcomes, or PRO measures). These direct assessments of clinical benefit are elicited without clinical interpretation. PRO instruments assess treatment benefits or risks by capturing concepts related to a product's impact on how a patient feels or functions with respect to his or her health or condition.

Results of such trials are submitted to FDA in support of efficacy claims. In February 2006 the FDA published a draft guidance, "Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims." This guidance provides the Agency's current thinking on the use of PRO instruments intended to support claims in approved product labeling.[1]

PRO instruments in drug development provide unique opportunities to assess a drug's clinical benefit. These instruments may either be primary indicators of effectiveness or be used as supportive efficacy evidence. PRO measurements may be useful when treatment effects are known only to the patient, when patients provide a unique perspective on a drug's effectiveness, or when formal assessments using these instruments are more reliable than informal interviews.

PRO instruments range from measurements of a single concept to measurements of multiple domains (eg, health-related quality of life.) Over the past decade, PROs have been used to support the approval of a number ofcancer drugs, including porfimer sodium (Photofrin), gemcitabine (Gemzar), mitoxantrone (Novantrone), topotecan (Hycamtin), amifostine (Ethyol), and palifermin (Kepivance).[2]

Similar to other efficacy claims, such as survival improvements, marketing claims based on PRO instruments must be evidence-based, statistically robust, and clinically meaningful. The PRO measures must match the concepts of the claims. The results of the PRO instrument must be reliable, valid, and supportive of treatment benefit.

The FDA encourages industry to specify early in the drug's development what claims they intend to seek, determine what concepts underlie those claims, and subsequently develop an adequate PRO instrument to assess and measure those concepts.

Adequate conceptual development of a PRO instrument is optimally accomplished with patient input early in the drug's development. A PRO instrument is only valuable if it assesses treatment aspects or events important to patients. The validation of a PRO instrument can be accomplished through many methods that yield estimates of the measurement properties of the instrument in the populations in which it is tested. Extensions of PRO instruments to new claims or populations may make repeated validation necessary to confirm measurement properties in the new application.

Interpreting clinical study results using PRO measures depends on documentation of instrument development, modification, and validation. Reported outcomes must be congruent with what is purported to be measured to support a labeling claim, and the same rigorous standards still apply. In summary, PRO measures must be subject to the same level of regulatory evidence and scrutiny used for other conventional end points in drug approval.

References:

1. Available at www.fda.gov/cder/guidance/5460dft.pdf. Accessed April 25, 2006.

2. Williams G, Pazdur R, Temple R: Assessing tumor-related signs and symptoms to support cancer drug approval. J Biopharm Stat 14:5-21, 2004.