Background

Non-alcoholic fatty liver disease (NAFLD) comprising both non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), has emerged as a leading cause of chronic liver disease. NAFLD affects approximately 25% of adults and 10% of children in the U.S. [1,2], and is associated with obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension [3].

Patients with NASH may progress to cirrhosis, increasing the risk of liver-related morbidity and mortality, including hepatocellular carcinoma [4]. In addition to liver-related outcomes, patients with NASH also have an increased risk of cardiovascular disease [5], chronic kidney disease [6], and non-liver cancers [7]. NASH is now the leading indication for liver transplantation in women, and the second leading cause in men [8].

With the growing burden of end stage liver disease, and the inherent limitations of transplantation (access, cost, and availability), it is critical to increase the pace of development of safe and effective therapies to prevent and treat NASH, fibrosis and cirrhosis to reduce morbidity and mortality.

Interest in the development of therapeutic options to prevent and treat NASH is high; however, the drug development field is challenged by the complexity of the disease etiology and pathophysiology, natural course of disease and the resulting divergent strategies for therapeutic approaches.

Read more about The Forum for Collaborative Research's history, achievements, operating procedures and working process.

Aims

Our aim is to advance the regulatory sciences for the treatment of NAFLD/NASH and liver fibrosis by providing an independent and neutral venue for ongoing multi-stakeholder dialogue. Our work will facilitate making the best science-based decisions on how to study efficacy and safety in real time, as our collective knowledge and experience with therapies for liver diseases advances.

Once new drug candidates and therapeutic strategies are identified, their rapid, safe development is in the best interest of all stakeholders, most of all, the patients[9]. Careful deliberation on issues of common interest and concern by an independent body whose neutrality and objectivity is ensured through representation and active engagement of scientific experts from all stakeholder groups, including academia, industry, patient community and regulatory agencies, in a non-competitive and safe environment, breaks down inefficiencies by increasing clarity and standardization and decreasing uncertainty, and allows the whole field to benefit from valuable lessons learned. The Liver Forum provides a platform for such a process.

Context

Traditional FDA approval mechanisms require demonstration of benefit based on hard clinical endpoints. For conditions with a long asymptomatic natural history such as NASH, the time to reach hard endpoints such as cirrhosis, hepatocellular carcinoma and death can be a significant barrier for clinical trials. The potential for accelerated approval, requiring identification and validation of surrogate markers, is hampered by the heterogeneity of disease presentation, underlying disease mechanisms, and progression. The field also lacks ideal standards for assessing and staging fibrosis, NAFLD, NASH, and cirrhosis. Effective therapeutic strategies will likely require combination therapies, personalized according to patient characteristics. The regulatory pathway for combination therapies can be complex, full of uncertainties and burdensome for patients, clinical researchers, regulators and industry.

The Trial Designs and Endpoints for Liver Disease Secondary to Nonalcoholic Fatty Liver Disease [10] meeting sponsored by the U.S. Food and Drug Administration (FDA) and the American Association for the Study of Liver Disease (AASLD) highlighted these concerns and issues. Consensus emerged that the field of hepatology would benefit from continuing the multi-stakeholder dialogue initiated at that meeting, as this rapidly moving and dynamic field will require collaborative bridges and coordinated effort between many parties. Thus the Liver Forum was established in 2014.

Action Plan

The Liver Forum operates in accordance with The Forum's guiding principles, which include neutrality and independence; transparency and accessibility; inclusiveness; collaboration; and efficiency and productivity.

The Liver Forum is led by a Steering Committee which provides overall scientific leadership and guidance, and is managed by Forum staff. Throughout the year, the Liver Forum convenes working group conference calls, email/web-based communication, in-person meetings, webinars, and workshops as needed. Presentations and materials from previous meetings are posted, with permission, on our website.

The Liver Forum agenda is informed by member feedback and determined by the Steering Committee. Focus areas and topics for discussion include:

• Identification and validation of biomarkers and endpoints.
• Identification and characterization of patient populations that need intervention (according to mechanism of disease and mechanism of action of the drug).
• Identification and characterization of factors that drive disease and phenotype in NAFLD and its progression to cirrhosis.
• Collaborative efforts to generate data to support the "reasonably likely to predict clinical benefit" standard of surrogate endpoints.
• Collaborative efforts to address the lack of natural history data for NASH and liver fibrosis.

Working groups have been developed to carry out the work of the Liver Forum by addressing priority areas identified by both the Steering Committee and Liver Forum members. Expected outcomes of the working groups include recommendations, position papers, reports, manuscripts for submission to peer-reviewed journals, and presentations at conferences.

Membership

Liver Forum membership is by invitation only. Project members are recruited from academia, regulatory agencies, professional societies, patient organizations, and industry. Industry membership is open to scientific experts from pharmaceutical, biotech, and diagnostic organizations committed to and actively engaged in research and development in NAFLD/NASH.

Participation from industry is conditional on an annual sponsorship contribution.  Industry members will be acknowledged as Liver Forum sponsors. Sponsorship includes participation in-person meetings, working groups, webinars, remote attendance, and project updates. Non-sponsoring industry will have access to information published on the Liver Forum’s website. Annual contributions from non-industry organizations are encouraged. Members from pharmaceutical, biotech, device, and diagnostic industry organizations must be scientific or regulatory experts actively engaged in research and development in the field of NAFLD/NASH. Industry members join as an organization. Commercial, marketing, and investment experts are not permitted to attend closed Liver Forum members meetings, but will be allowed to participate in any public meetings the Forum sponsors.

The Forum does not cover any honoraria or provide items of value (gifts) to any speakers or attendees. Membership cannot be combined/ divided for participation in different disease specific projects at the Forum.

References