An Updated Review of Food and Drug Administration Warning and Untitled Letters for Clinical Outcome Assessment Claims...

We aimed to ascertain the frequency and types of Food and Drug Administration (FDA)-identified clinical outcome assessment (COA) violations in US pharmaceutical promotional materials from 2013 to 2021 by updating the review by Symonds et al (covering the period 2006-2012 for patient-reported outcomes [PRO] measures), expanding to infringements across all types of COAs, and grouping by efficacy or overall patient experience.

Warning letters (WLs) and untitled letters (ULs) issued by the FDA's Office of Prescription Drug Promotion were reviewed for COA violations and classified by their type: (1) COA measure not fit for purpose, (2) issue with study design or interpretation of results, and (3) inadequate statistical analysis.

From 2013 to 2021, the FDA issued 22 WLs and 65 ULs. Year 2013 showed the highest number of letters issued (n = 24). Of the total 87 letters reviewed, 22 (25%) contained a COA violation, consisting of 6 WLs (27%) and 16 ULs (25%), including 20 (23%) with a PRO-related violation. The most common violations cited "study design or interpretation of results" (21 of 22 [95%]).

Overall, the absolute number of WLs and ULs issued declined when comparing 2006 to 2012 with 2013 to 2021. Despite the overall reduction, this review still identified 25% of letters citing COA infringements (23% with PRO issues), which was similar to the prior review (19% PRO infringements). This may be due to increased FDA attention to patient-focused drug development.