The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Seeks Industry Partners for Clinical Research Collaborations on Therapeutics, Diagnostics or Devices for the Liver Cirrhosis Network The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) of the Department of Health and Human Services (DHHS) has released Requests for Applications RFA-DK-20-003 and RFA-DK-20-004 for the establishment of the Liver Cirrhosis Network; and seeks industry collaborators to provide novel or repurposed therapeutic agents, diagnostic markers, biomarkers, devices, or services for use in NIH-sponsored multi-center clinical trials and ancillary studies in adult patients with advanced liver disease and cirrhosis; and the hepatic and extrahepatic related complications emanating from cirrhosis. BACKGROUND : The NIDDK is proposing the establishment of the Liver Cirrhosis Network through Funding Opportunity Announcements RFA-DK-20-003 seeking Clinical Centers; and in conjunction with RFA-DK-20-004 seeking a single Scientific Data Coordination Center, in order to promote clinical and translational research on cirrhosis of the liver and related complications in adults. Cirrhosis represents not a single disease but is rather the consequence and major serious outcome of many chronic liver diseases, caused by a wide range of conditions. The etiologies of cirrhosis in the United States include infectious causes such as chronic hepatitis B, C and D; genetic causes such as Wilson disease, hemochromatosis and alpha-1-antitrypsin deficiency; metabolic causes such as nonalcoholic steatohepatitis; autoimmunity such as autoimmune hepatitis, primary biliary cholangitis and sclerosing cholangitis; and toxic causes such as alcohol-associated liver disease and chronic liver injury from medications such as methotrexate and amiodarone. Cirrhosis from these diseases is almost always the result of chronic injury with persistent inflammation and cell damage that results in faulty healing and fibrosis. As fibrosis accumulates it causes distortion of the architecture of liver, portal hypertension and compromise of liver function. Clinical complications of cirrhosis include symptoms of fatigue, weakness, weight loss, itching and jaundice; gastrointestinal bleeding from varices or portal hypertensive gastropathy, coagulopathy, ascites and disturbance of fluid and electrolyte balance, renal dysfunction and hepatic encephalopathy. The most dreaded complication of cirrhosis is hepatocellular carcinoma, a highly fatal cancer that arises in 1 to 3% of persons with cirrhosis yearly. Once cirrhosis is present, treatment of the underlying liver disease can lessen further progression and deterioration, but does not eliminate all risk of complications, particularly hepatocellular carcinoma. Mortality due to liver disease remains a significant public health burden in the United States, currently ranked 11th overall and ranking 6th in persons below the age of 65 years. Cirrhosis appears to be rising in some populations such as persons living with HIV infection, nonalcoholic fatty liver disease and cystic fibrosis. Hepatocellular carcinoma incidence is also rising in the United States and is a surrogate for the prevalence of cirrhosis. Treatment of underlying causes of chronic liver disease such as antivirals for chronic hepatitis B and C; therapeutic phlebotomy for genetic hemochromatosis; ursodiol for primary biliary cirrhosis; weight loss for nonalcoholic steatohepatitis (NASH), and cessation of alcohol consumption for alcohol-associated liver disease, all underpin the overarching clinical approach to prevent the development of cirrhosis by early abrogation of ongoing injury to the still noncirrhotic liver. Neutralization of the liver disease etiology may allow the injured liver to invoke endogenous mechanisms to reverse the consequences of chronic inflammation and the accumulation of mild or even modest amounts of liver fibrosis. However, once advanced fibrosis or cirrhosis has been established, neutralization of the causes of liver disease generally will not reverse fibrosis or cirrhosis completely. While the residual risk of complications may be decrease, this may be off-set by the improvement in survival, so that patients with cirrhosis and advanced fibrosis will live and be at risk for the complications longer. Liver transplantation is currently the only medically viable avenue for patients with end-stage liver disease that will extend their longevity. On an annual basis, despite treatment success rates for chronic hepatitis C and other liver diseases, the national wait list for liver transplantation in the United States remains essentially unchanged at approximately 13,000 patients. Only 8000 liver transplantations are performed annually. However, far, far more patients with end-stage liver disease are not even placed on liver transplantation lists for a variety of co-morbid or psychosocial issues. Given the discrepancy between the need and the availability of liver organs for patients on liver transplant waiting lists and the even more numerous patients who are unable to be considered for listing for liver transplantation, there is a significant need to improve our understanding of clinical and translational scientific aspects of liver fibrosis and cirrhosis. In addition, there is a need for furthering fundamental understanding of both the underlying pro- and anti-fibrotic mechanisms as well as risk factors and mechanisms that accentuate pro- and anti-fibrotic processes. STUDY GOALS : The overall goal of The Liver Cirrhosis Network is to promote clinical and translational research that will advance the understanding of liver fibrosis and cirrhosis pathophysiology; improve clinical management of liver cirrhosis and complications of advanced fibrosis; and to conduct clinical trials to alter cirrhosis liver disease trajectory and the related complications. While specific details of the protocols for the Liver Cirrhosis Network are yet to be defined and will be made by consensus by the future Steering Committee of the Network, it is expected that sufficient numbers of subjects will be enrolled with either stable, Child Class A, cirrhosis or evidence of advanced fibrosis (such as bridging fibrosis on liver biopsy or evidence of advanced disease as assessed by validated non-invasive markers) to operationalize the eventual Network studies. An attempt will be considered to enroll subjects with all forms of cirrhosis (viral, autoimmune, genetic, toxic, alcohol-associated and “cryptogenic”) and with a diverse range of demographics as typifies chronic liver disease in the United States. The Liver Cirrhosis Network is interested in conducting research that will lead to improved clinical outcomes in adults with cirrhosis and advanced liver disease with industry collaborators to: • Evaluate the natural history, pathogenesis, diagnosis, genetic factors, genomics, proteomics, metabolomics, lipidomics, epigenomics, imaging studies, and determinants of progression and severity of advanced liver disease and cirrhosis-related complications • Explore use of serum markers for fibrosis and serum markers for disease activity to predict hepatic histology or function either by themselves or in combination with other clinical, laboratory, genomic, proteomic, metabolomic, and lipidomic variables • Explore the utility of these serum markers as surrogate markers of therapeutic response in study subjects participating in treatment trials • Investigate proprietary or repurposed drugs (such as statins, anti-fibrogenic agents, autophagy inducers, chemo-preventive agents, nonsteroidal anti-inflammatory agents, etc.), reagents, or devices in controlled randomized clinical trials as potential diagnostics or therapies for advanced liver disease, cirrhosis and cirrhosis related complications • Evaluate noninvasive imaging methods for assessing fibrosis, portal vein hypertension, hepatic function, screening for or diagnosis of liver cancer, and parenchymal pathology in cirrhosis liver disease including but not limited to the use of elastography, nuclear magnetic resonance imaging, and molecular imaging. • Evaluate the use of cytokine assays for analyses of serum/plasma cytokine levels as markers of disease activity and as surrogate markers of histologic or clinical improvement in therapeutic trials CAPABILITY STATEMENT : Commercial organizations interested in pursuing clinical collaborations with NIDDK for cirrhosis liver disease are required to submit a Capability Statement to the NIDDK. The Capability Statements submitted in response to this announcement will be used to evaluate and select industry collaborators. The Capability Statement should not exceed 10 (ten) pages of narrative (not including appendices) and should include the following information: 1. A description of the therapeutic, diagnostic or device proposed to be used in the clinical research study. (Note: The proposed therapeutic or device must have been tested already in a Phase I trial in humans.) 2. The specific details of the methods to be utilized in the investigation of the pharmacologic, surgical or device intervention in patients with cirrhosis liver disease, and a clear description of the important issues surrounding the evaluation of disease progression in these patients. 3. A detailed plan demonstrating the ability to provide sufficient quantities of the therapeutic, diagnostic or device either in total prior to study initiation (preferred if possible) or in a timely manner for the duration of the study. 4. A description of all laboratory tests that are needed and proficiency in conducting these laboratory tests, including assays and required amount of specimens, to determine specific biomarker(s) levels and list potential biomarkers, along with appropriate methods for performing such tests. 5. A description of other core facilities and interactions with core facilities that are needed for the study. 6. Dosing, pharmacodynamic, and pharmacokinetic data from human studies for any novel therapeutics. 7. Adverse event profile for the proposed therapeutic or device. 8. A description of the practices and procedures that would be used to assure patient privacy and maintain confidentiality of data obtained from the study. 9. (Optional) Outcome measures of interest to the organization. The specifics of the proposed outcome measures should include but not be limited to treatment and evaluation of cirrhosis liver disease or cirrhosis related complications. 10. Any other resources the organization proposes to commit to the collaboration (in addition to the proposed therapeutic, diagnostic or device), which may include any of the following: equipment, reagents, supplies, access to facilities, personnel or services, and, if appropriate, funding (pursuant to a Cooperative Research and Development Agreement (CRADA) authorized under 15 U.S.C. § 3710a), to help support the conduct of the clinical study. 11. Affirmative statements that the organization: a. agrees to provide a Letter of Cross Reference to the Drug, Biologic or Device Master File for the proposed therapeutic or device, which will be included with any US FDA filing by the IND or IDE Sponsor of the Liver Cirrhosis Network study; b. agrees to have the proposed therapeutic, diagnostic or device used in the Liver Cirrhosis Network-developed protocols which will be conducted by the Liver Cirrhosis Network research network for which the study data collection and analysis will be performed by the Liver Cirrhosis Network Scientific and Data Coordinating Center; c. agrees to assure patient privacy and will maintain confidentiality of data obtained from the study; d. agrees to share all safety data from other studies involving the proposed therapeutic or device as well as relevant efficacy data from other studies (updated Investigator Brochure, etc) with the Liver Cirrhosis Network; e. understands that because the Liver Cirrhosis Network is supported by NIDDK funding, the study results will be published and therefore agrees to the prompt publication of research results from the clinical study using the organization's proposed therapeutic, diagnostic or device; f. has intellectual property rights to provide laboratory test/biomarker(s), therapeutic or device to NIDDK for testing and has no current agreements or arrangements that could impede this right; and f. understands that the clinical study will be conducted under an agreement with NIDDK which must adhere to PHS intellectual property policies (see: http://www.ott.nih.gov/policy/phspat_policy.aspx). SUBMISSION : Capability Statements received by NIDDK will be considered. Prospective collaborators may be invited to attend, at their own expense, a Liver Cirrhosis Network Steering Committee meeting to be held in the Baltimore-Washington, DC area to discuss the information in their Capability Statement with the Steering Committee members. NOTE:NO FUNDS WILL BE PROVIDED BY NIDDK TO ANY ORGANIZATION SELECTED FOR THIS CLINICAL RESEARCH COLLABORATION OPPORTUNITY. SUBMISION AND INQUIRIES : Submit Capability Statements to: NOO Coordinator, National Institute of Diabetes and Digestive and Kidney Diseases e-mail:
[email protected] For Scientific Inquiries contact: Edward Doo, MD, Director, Liver Diseases Research Program Division of Digestive Diseases and Nutrition, NIDDK 6707 Democracy Blvd., Room 6149 Bethesda, MD 20892-5450 Telephone: (301) 451-4524 FAX: (301) 480-8300 e-mail:
[email protected] For Inquiries Regarding Partnering with NIDDK (Intellectual Property Matters and Collaboration Agreements) contact: Agnes Rooke, JD Technology Advancement Office NIDDK, NIH, HHS Telephone: 301-451-6072 e-mail:
[email protected] This Notice of Opportunity is also posted at: http://techdev.niddk.nih.gov/collabs.shtml.