A Review of FDA Warning Letters and Notices of Violation Issued for Patient-Reported Outcomes Promotional Claims between 2006 and 2012

Objective: To ascertain the frequency and types of patient-reported outcome (PRO) violations made in US pharmaceutical promotional materials between 2006 and 2012 and determine whether there were increases in violation warnings after issuance of the Food and Drug Administration (FDA) draft and final PRO Guidance. Methods: All warning letters (WLs) or notices of violation (NOVs) issued by the FDA's Office of Prescription Drug Promotion were reviewed for PRO violations (n = 213). Each letter containing a PRO violation was reviewed to determine the type of violation: 1) PRO measure not fit for purpose, 2) study design/interpretation of results, 3) statistical analysis, and 4) no treatment benefit Results: Forty-one (19%) letters contained information about PRO infringements. Noticeable spikes in letters were shown in 2007 (37%) and 2010 (31%) after the issuance of the draft and final PRO Guidance, respectively. The most common violation was PRO measure not fit for purpose (54%), specifically: use of individual items (45%), insufficient evidence of content validity (36%), and broadening of the claim beyond what the PRO measures (27%). Issues with study design/interpretation of results were also high (49%), particularly broadening of claim beyond what was measured in the trial (55%) and no PRO measure used (50%). Conclusions: A fifth of the letters issued to companies contained PRO violations, with most related to poor selection of the PRO measure used or trying to broaden the claim. More guidance from the Office of Prescription Drug Promotion about what is considered "substantial evidence" in this area could help reduce the number of letters issued.