The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Seeks Industry Partners for Clinical Research Collaborations on Therapeutics, Diagnostics or Devices for Childhood Cholestatic Liver Diseases

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Seeks Industry Partners for Clinical Research Collaborations on Therapeutics, Diagnostics or Devices for Childhood Cholestatic Liver Diseases

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) seeks industry collaborators to provide novel therapeutic agents, diagnostic markers, biomarkers and devices for use in NIH-sponsored multi-center clinical trials and ancillary studies in patients with childhood cholestatic liver diseases, including biliary atresia, alpha-one antitrypsin deficiency, cystic fibrosis liver disease, Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis defects, mitochondrial respiratory chain and fatty acid oxidation defects, primary sclerosing cholangitis, and idiopathic neonatal hepatitis; and the liver disease related complications emanating from these diseases.

BACKGROUND: The Childhood Liver Disease Research and Education Network (ChiLDReN) is a multi-center consortium of 10 clinical sites in the United States plus a scientific data coordinating center funded by NIDDK to study rare childhood liver diseases that result in cholestasis, including primary sclerosing cholangitis, biliary atresia, alpha-one antitrypsin deficiency, cystic fibrosis liver disease, Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis defects, mitochondrial respiratory chain and fatty acid oxidation defects, and idiopathic neonatal hepatitis. Five ongoing studies being conducted by ChiLDReN include: 1) A Prospective Database of Infants with Cholestasis (PROBE), a longitudinal observational study starting in infancy which has enrolled 890 infants with biliary atresia and 621 with intrahepatic cholestasis; 2) Biliary Atresia Study in Infants and Children (BASIC), a longitudinal study of children with biliary atresia both before and after liver transplant, which has enrolled over 1768 children with biliary atresia 3) Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC), a longitudinal study of intrahepatic cholestasis diseases, which has enrolled 474 subjects with Alagille syndrome, 572 with alpha-1 antitrypsin deficiency liver disease, 355 with PFIC and 36 with bile acid defects; 4) Longitudinal study of Mitochondrial Hepatopathies (MITOHEP) with 73 participants; and 5) Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in Cystic Fibrosis (PUSH), a study of the prognostic value of hepatic ultrasound on the development of liver fibrosis in CF, which has enrolled over 770 subjects. In addition, ChiLDReN completed a placebo-controlled clinical trial to determine if post-operative corticosteroid therapy improves serum bilirubin and survival without liver transplantation in 140 infants with biliary atresia who have undergone the Kasai surgery ("START"). Ancillary studies to evaluate the natural history, clinical outcomes and quality of life, pathogenesis, genetics and genomics, proteomics, metabolomics, lipidomics, imaging studies, and determinants of progression and severity of these cholestatic liver diseases present a variety of research collaboration opportunities. ChilDReN is also interested in conducting clinical trials of promising therapies to improve clinical outcomes for these cholestatic liver diseases. Finally, improved diagnostics or screening procedures for biliary atresia and cholestasis in infants are of great interest to ChiLDReN.

STUDY GOALS: The overall goal of ChiLDReN is to determine the etiology, genetics, pathogenesis, natural history, clinical outcomes, complications, predictors of outcomes and optimal therapy of the cholestatic liver diseases. ChiLDReN studies have enrolled and are following a relatively large and well characterized population of children and young adults with these rare disorders. ChiLDReN is interested in conducting research that will lead to improved clinical outcomes in children and young adults with these cholestatic liver diseases 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 biliary atresia, alpha-one antitrypsin deficiency, cystic fibrosis liver disease, Alagille syndrome, PFIC, bile acid synthesis defects, mitochondrial respiratory chain and fatty acid oxidation defects, primary sclerosing cholangitis, or idiopathic neonatal hepatitis.

• Explore use of serum markers for fibrosis and serum markers for disease activity to predict hepatic histology 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 (e.g., START study for biliary atresia)

• Investigate proprietary drugs (such as novel choleretic agents, anti-fibrogenic agents, autophagy inducers, chloride channel inducers, fat-soluble vitamin supplements, bone mineral density agents, etc.), reagents, or devices in controlled randomized clinical trials as potential diagnostics or therapies for biliary atresia, alpha-one antitrypsin deficiency, cystic fibrosis liver disease, Alagille syndrome, PFIC, bile acid synthesis defects, mitochondrial respiratory chain and fatty acid oxidation defects, primary sclerosing cholangitis, or idiopathic neonatal hepatitis

• Evaluate novel newborn or infant screening techniques or devices for biliary atresia or cholestasis.

• Evaluate noninvasive imaging methods for assessing fibrosis, biliary disease, and parenchymal pathology in these diseases 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 childhood cholestatic liver diseases are required to submit a Capability Statement to 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 biliary atresia, alpha-one antitrypsin deficiency, cystic fibrosis liver disease, Alagille syndrome, PFIC, bile acid synthesis defects, mitochondrial respiratory chain and fatty acid oxidation defects, primary sclerosing cholangitis, or idiopathic neonatal hepatitis, and a clear description of all 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 in a timely manner for the duration of the study.

4. A description of all laboratory tests that are needed, including assays and required amount of specimens, to determine specific biomarker levels 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 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 biliary atresia, alpha-one antitrypsin deficiency, cystic fibrosis liver disease, Alagille syndrome, PFIC, bile acid synthesis defects, mitochondrial respiratory chain and fatty acid oxidation defects, primary sclerosing cholangitis, or idiopathic neonatal hepatitis.

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 ChiLDReN study;

b. agrees to have the proposed therapeutic, diagnostic or device used in ChiLDReN-developed protocols which will be conducted by the ChiLDReN research network for which the study data collection and analysis will be performed by the ChiLDReN 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 ChiLDReN;

e. understands that because the ChiLDReN 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; 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 ChiLDReN 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: contact@example.gov

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: +1 (555) 000-0000

FAX: +1 (555) 000-0000

e-mail: contact@example.gov

Katrina Loh, MD

Director, Pediatric Gastrointestinal and Liver Diseases

Division of Digestive Diseases and Nutrition, NIDDK

6707 Democracy Blvd., Room 6148

Bethesda, MD 20892-5450

Telephone: +1 (555) 000-0000

FAX: +1 (555) 000-0000

e-mail: contact@example.gov

For Inquiries Regarding Partnering with NIDDK (Intellectual Property Matters and Collaboration Agreements) contact:

Agnes Rooke, JD

Technology Advancement Office

NIDDK, NIH, HHS

Telephone: +1 (555) 000-0000

e-mail: contact@example.gov

This Notice of Opportunity is also posted at: http://techdev.niddk.nih.gov/collabs.shtml.