FDA and EMA Letters of Support Pave the Way for Clinical Qualification. The Innovative Medicines Initiative (IMI) SAFE-T (Safer and Faster Evidence Based Translation) Consortium and The Critical Path Institute (C-Path) announced today that the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) each issued a Biomarker Letter of Support for new liver safety biomarkers investigated by the SAFE-T Drug-Induced Liver Injury Work Package, and the Predictive Safety Testing Consortium’s (PSTC) Hepatotoxicity Working Group.

Research work was supported by the Drug-Induced Liver Injury Network (DILIN) in the US, an expert network established by The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

The liver safety biomarkers, cytokeratin 18 (CK-18), high mobility group protein Bl (HMGBI), osteopontin, and macrophage colony-stimulating factor I receptor (MCSFR1, or CSFIR), are proteins that can be measured in human serum. Both FDA and EMA acknowledged that higher levels of these biomarkers in patients diagnosed with Drug-Induced Liver Injury (DILI) could indicate a risk for progression towards liver failure, which may result in death or the need for liver transplantation. DILI is an adverse drug reaction that has for decades been an important cause of late stage failures in drug development and post-marketing withdrawals.

Micrograph of an intrahepatic cholangiocarcinoma (right of image) adjacent to benign hepatocytes (left of image). H&E stain.Micrograph of an intrahepatic cholangiocarcinoma (right of image) adjacent to benign hepatocytes (left of image). H&E stain.
In addition, EMA considered results promising for serum biomarkers total HMGB1, total and caspase-cleaved keratin 18, miR-122, and GLDH in terms of possibly improving early prediction of liver injury in clinical trials with compounds having the potential to cause intrinsic liver toxicity, similar to e.g. paracetamol.

The Letters of Support indicate that the new biomarkers have potential for use in humans, warranting additional exploration and data generation, and intend to encourage scientists to collect additional data from nonclinical and exploratory clinical studies. With this milestone, in-depth research can continue on the qualification of the new markers 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. 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 IMI’s SAFE-T and C-Path’s PSTC,” said Pierre Meulien, IMI Executive Director.

“The collaboration demonstrated by these specific IMI and C-Path programs has enabled this significant advance which encourages utilization of these novel liver biomarkers by sponsors.
Acquiring more experience and data with these biomarkers will provide greater confidence and refinement in their utility, thereby assisting decision making within drug development programs and by regulatory authorities.” Martha A. Brumfield, PhD, President & CEO, Critical Path
Institute

”The success of the SAFE-T/PSTC collaboration nicely demonstrates the benefits of working together across public private partnerships on a global scale. Shared scientific enthusiasm, persistence, and team-spirit were the key foundation for this achievement”. Michael Merz, MD, Novartis Institutes for BioMedical Research, IMI SAFE-T project coordinator.

“The SAFE-T/PSTC collaboration represents the best collaborative science, bringing together experts from Europe and North America around the common goal of qualifying safety biomarkers. This relationship demonstrates how two public private partnerships can work together in support of their members’ goals and vision.” John-Michael Sauer, PhD, Critical Path Institute, PSTC Executive Director.

The FDA Letter of Support is posted on the FDA website, the EMA Letter of Support on the EMA website. Both documents can also be accessed via the SAFE-T website, as well as via the C-Path PSTC website under the Regulatory Successes tab, along with a summary data package describing the studies that support the use of these liver safety biomarkers.

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115003, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.

About the Innovative Medicines Initiative

The Innovative Medicines Initiative (IMI) is working to improve health by speeding up the development of, and patient access to, the next generation of medicines, particularly in areas where there is an unmet medical or social need. It does this by facilitating collaboration between the key players involved in healthcare research, including universities, pharmaceutical companies, other companies active in healthcare research, small and medium-sized enterprises (SMEs), patient organisations, and medicines regulators. This approach has proven highly successful, and IMI
projects are delivering exciting results that are helping to advance the development of urgentlyneeded new treatments in diverse areas.

IMI is a partnership between the European Union and the European pharmaceutical industry, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA). Through the IMI 2 programme, IMI has a budget of €3.3 billion for the period 2014-2024. Half of this comes from the EU’s research and innovation programme, Horizon 2020. The other half comes from large companies, mostly from the pharmaceutical sector; these do not receive any EU funding, but contribute to the projects ‘in kind’, for example by donating their researchers’ time or providing access to research facilities or resources.

For more information, visit www.imi.europa.eu.

About the Critical Path Institute

C-Path (Critical Path Institute) is an independent, nonprofit organization established in 2005 with public and private philanthropic support from the Arizona community, Science Foundation Arizona, and the US Food and Drug Administration (FDA). C-Path’s mission is to catalyze the development of new approaches that advance medical innovation and regulatory science, accelerating the path to a healthier world. An international leader in forming collaborations, CPath has established 12 global, public-private partnerships that currently include over 1,300
scientists from government and regulatory agencies, academia, patient advocacy organizations, and dozens of major pharmaceutical companies. C-Path is headquartered in Tucson, Arizona.

For more information, visit www.c-path.org.

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