Adherence to risk evaluation and mitigation strategies (REMS) requirements for monthly testing of liver function

Abstract

Background:Risk evaluation and mitigation strategies (REMS), as mandated by the US Food and Drug Administration (FDA) for medications with the potential for harm, are increasingly incorporating rigid protocols for patient evaluation, but little is known about compliance with these programs. Despite the inherent limitations, data on administrative claims may provide an opportunity to investigate adherence to these programs.Methods:We assessed adherence to liver function test (LFT) requirements included in the REMS program for bosentan through use of administrative claims. Patients observed in the Optum Research Database who were initiators of bosentan from November 20, 2001 to March 31, 2013 were included. Adherence to LFTs was calculated using pharmacy claims for bosentan dispensation and medical claims for laboratory services, and was assessed at the time of drug initiation and within specified time intervals throughout follow-up.Results:Of 742 patients, 523 (70.5%) had ≥1 qualifying LFT. Among patients with ≥12 dispensations, claims for LFTs at individual dispensations were 53.2–64.0%. Median proportion of dispensations with ≥1 LFT was 0.8 among patients with ≥6 (interquartile range, 0.7–1.0) or ≥12 (0.7–0.9) dispensations. Adherence was 90–100% for 33.3% of all initiators, whereas 29.3% of initiators were non-adherent (defined as <50% of on-therapy LFTs).Conclusions:Analyses of administrative claims suggest that the REMS program for bosentan may not have adequately guaranteed adherence to the program’s monthly monitoring of LFTs. Such investigations of existing REMS programs may provide insight on how to accomplish more successful evaluation of REMS.

New and incremental FDA black box warnings from 2008 to 2015

“…Additionally, since the vast majority of new and incremental BBWs were not associated with ETASU REMS, FDA is rarely monitoring distribution of drugs with these BBWs. While ETASU REMS have been associated with changes in prescribing [19,20], the evidence for the impact of BBWs on formulary coverage and prescribing is not consistent. This limited regulatory monitoring further underscores the importance of implementing tools to support clinician awareness of BBWs.…”

The RIMES Statement: A Checklist to Assess the Quality of Studies Evaluating Risk Minimization Programs for Medicinal Products

“…The purpose of restricting the timeframe was to focus the search on more recent studies that were expected to have higher reporting quality, given that they had been requested by a regulatory authority and had been published in the wake of European Union (EU) pharmacovigilance legislation that provided guidance on how sponsors were to evaluate formal risk minimization commitments. For the inter-rater reliability testing, we selected a convenience sample of the first 10 articles that met all the inclusion criteria (Table 1 ) [ 4 , 5 , 45 – 52 ].…”

Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review

“…Even when a REMS program mandates ALT monitoring, as is the case with bosentan,[174] results have been less than optimal. [175] Addressing the inconvenience of testing, a new home point-of-care ALT test similar to glucose fingerstick testing is in the process of being developed,[176] and may offer a cost-effective alternative across all liver diseases, including DILI.…”

“…To that end, the discovery of accurate predictive biomarkers that can be measured prior to the onset of DILI in its earliest form remains the quest of numerous researchers. [1, 8, 13, 14, 175] ALT measures injury that has already occurred, and while useful in defining stopping rules, it is neither sensitive nor specific when it comes to predicting the severity of hepatotoxicity. [3, 14]…”