Liver safety biomarkers gain regulatory support

The Innovative Medicines Initiative SAFE-T Consortium and Critical Path Institute Predictive Safety Testing Consortium announced the FDA and EMA each issued a Biomarker Letter of Support for multiple liver safety biomarkers for potential use against drug-induced liver injury.

The letters of support indicate biomarkers cytokeratin 18 (CK-18), high mobility group protein B1 (HMGB1), osteopontin and macrophage colony-stimulating factor 1 receptor (MCSFR1, or CSF1R) hold potential to be used in humans, per a press release. The letters aim to encourage scientists to collect additional data from nonclinical and exploratory clinical studies, and enable more research to gain qualification of the biomarkers for use in clinical trials on top of standard safety tests.

“Many current obstacles in drug development pose substantial scientific and logistical challenges to industry and public health that are impossible to tackle by individual companies or research organizations alone,” Pierre Meulien, PhD, Innovative Medicine Initiative executive director, said in the release. “Large scale public–private partnerships are an indispensable prerequisite to solve complex tasks such as development and qualification of new safety biomarkers, as exemplified by [Innovative Medicines Initiative] SAFE-T and [Critical Path Institute Predictive Safety Testing Consortium].”

In the FDA letter of support to the SAFE-T consortium — submitted in July — Janet Woodcock, MD, director of the CDER, praised the collaboration between the two consortiums.

Janet Woodcock

“We support the collaborative initiative of both the SAFE-T consortium and PSTC to encourage the voluntary and complementary use of these biomarkers to better understand their potential role as monitoring biomarkers in the context of clinical trials where [drug-induced liver injury] has been diagnosed by the standard methods….”

Woodcock wrote that the FDA encourages further development of the four biomarkers alone or in combination to assess risk for progression of DILI in patients who have received diagnosis based on biomarkers alanine aminotransferase alone or in combination with total bilirubin, noting that greater experience in the nonclinical and clinical setting are needed to better understand the applicability of each for DILI.

The EMA support is indicative of promising results for serum biomarkers total HMGB1, total and caspase-cleaved keratin 18, miR-122, and GLDH for potential improvement in early prediction of liver injury in other clinical trials, per the release.

In the EMA letter of support — submitted in September — Guido Rasi, executive director, wrote that further research is encouraged to validate the markers and that the consortium is expected to make all data available for review in a transparent and comprehensive way to facilitate future investigations and validation of these markers.

References:

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM514812.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/09/WC500213479.pdf

Disclosure: Meulien is employed by the Innovative Medicines Initiative. Rasi is employed by the EMA. Woodcock is employed by the FDA.