SOW_71805.docx

PERFORMANCE WORK STATEMENT

Title of Project: Identification of Hepatotoxic Agents and Novel biomarkers in Herbal and Dietary Supplement Induced Liver Injury

C.1 Background and Need

Herbal and Dietary Supplements (HDS) used for weight loss are among the most common supplements implicated in liver injury and represent a threat to food safety and public health. The etiology of HDS-associated liver injury is poorly understood because of limitations of toxicology testing capacity to identify exposure substances found in HDS and the absence of specific clinically useful biomarker(s) in persons who develop liver dysfunction. This project will identify hepatotoxic agents found in case-patient associated HDS samples reported to the Drug Induced Liver Injury Network (DILIN) and attempt to identify novel biomarkers for a select list of implicated hepatotoxins to assist in diagnosis of HDS-induced liver injury.

Liver injury due to HDS is an emerging food safety and public health issue. Many recent and past incidents exist in the medical and lay press in which readily available and ostensibly ‘safe’ products have been implicated in hepatotoxicity. For example, CDC and FDA have been involved in an investigation of OxyElite Pro, which was associated with over 60 cases of liver injury nationwide and internationally. The Drug Induced Liver Injury Network (DILIN) is a consortium of academic centers funded by NIH that investigates and maintains a national registry of patients with hepatotoxicity due to medications and HDS. Implicated products thought to be responsible have been used for various purposes, but in the experience of the Drug Induced Liver Injury Network (DILIN), those marketed for weight loss are among the most common. The current regulatory framework for HDS in the US does not require pre-market safety and efficacy testing. This is in contrast to other drugs such as prescription pharmaceuticals, which have to undergo rigorous safety and efficacy testing prior to being sold in the US. A better understanding of why certain HDS cause hepatotoxicity is of increasing concern to the CDC, NIH, FDA and other governmental agencies, as well as to the American public.

Establishing a causal relationship between HDS and liver injury is confounded by several factors, including the large number of ingredients in these products, the possibility of undeclared ingredients or contaminants, and the lack of readily available toxicology testing capacity and clinically useful biomarkers for patient diagnosis and management. The first step in understanding the mechanism of HDS induced liver injury is the specific identification of substances or agents that can potentially acts as hepatotoxins, as well as the precise quantification of these substances found in HDS preparations. Secondly, a laboratory biomarker that can confirm exposure in people will aid in the diagnosis and management of affected patients. Currently, such sophisticated laboratory testing does not exist.

C.2 Project Objective

The objectives are the following:

1. Development of a standard laboratory panel for chemical mass spectroscopic laboratory analyses to look for known hepatotoxins in HDS induced liver injury patients

2. Evaluate unique biomarkers in the corresponding serum from HDS induced liver injury patients

C.3 Scope of Work

A pilot study of 10 to 20 cases of severe HDS induced liver injury associated with hospitalization, liver transplant and/or death will be conducted using existing preserved or biobanked specimens in the DILIN repository. No additional data collection or contact with original participants recruited into the DILIN study will be performed. All HDS marketed for weight loss that were implicated as the cause for liver injury and contained within the DILIN repository for HDS will be available for analysis, and a subset selected. HDS samples will be analyzed and quantified for targeted ingredients including polyphenols, pharmaceuticals, pesticides and herbicides, and heavy metals by a variety of analytical methods, including liquid chromatography-tandem mass spectrometry (LC-MS/MS), IR spectra, and atomic absorption spectroscopy. Based upon the initial chemical analyses, protein [especially serum albumin] adducts of selected major components of HDS in stored participant serum samples that, upon the analytical and clinical work and upon prior knowledge base, are the most feasible candidates for novel biomarkers of hepatotoxicity due to HDS will be identified.

C.4 Technical Requirements: The contractor shall provide the reagents and supplies necessary to carry out the work. This will include the purchase of selected standards such as catechins, amphetamines, etc. and columns, solvents, and equipment needed for mass spectroscopy and ICP-MS.

a) Sample analysis Up to 20 samples will be analyzed (no less than 10).

C.5 Reporting Schedule: The contractor shall provide the following reports:

Progress report and Final reports and documents described in the Deliverables in C.9.

C.6 Special Considerations:

The laboratory testing protocols developed from this project will be proposed as a standard laboratory panel for product testing of future instances of HDS induced liver injury reported to DILIN and will be published in the scientific literature. The contractor will not share any identifiable data with CDC based on a mutually signed agreement. The contractor must submit proof of approval from the Institutional Review Board at their institution prior to carrying out any pertinent research activities.

Technical Considerations Contractor performance and resulting deliverables must adhere to all federal, HHS, and CDC IT security and privacy policies, standards and procedures.

The following HHS FAR IT security clauses may apply based on the Contractor’s technical proposal to support the stated requirements. The clauses may be found at: http://www.hhs.gov/policies/hhsar/subpart352-30s.html.

· 352.239-70 Standard for security configurations.

· 352.239-71 Standard for encryption language. Note per OMB and CDC requirements, any/all portable media (CD, DVD, USB drives, etc.) and mobile devices (laptops, tablets, etc.) used for administration and data collection/transfer must be encrypted. (this applies even if the information is not sensitive or otherwise protected)

· 352.239-72 Security requirements for federal information technology resources. Note contractor must support security authorization process as required by CDC in accordance with this HHS FAR Section.

Use of any third-party / social media sites must be approved, and compliant with HHS and CDC policies, procedures and best practices (including security and privacy) such as those found at: http://www.hhs.gov/web/socialmedia/ and http://www.cdc.gov/SocialMedia/Tools/guidelines/.

The contractor must protect the confidentiality of proprietary, sensitive, and Personally Identifiable Information (PII). Section 508 of the Rehabilitation Act (29 USC 794d)

Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794d) requires Federal agencies to purchase electronic and information technologies (EIT) that meet specific accessibility standards. All final deliverables must comply with applicable Section 508 accessibility standards, and CDC reserves the right to reject deliverables that fail to meet the standards. Remediation of any materials that do not comply with the applicable provisions of 36 CFR Part 1194 as set forth in the SOW or PWS, shall be the responsibility of the contractor or consultant retained to produce the Web- suitable content or communications material. Regardless of format, all electronic documents - including text, audio or video - must conform to applicable Section 508 standards to allow federal employees and members of the public with disabilities to access information that is comparable to information provided to persons without disabilities.

The following Section 508 provisions apply to the content or communications material identified in this SOW or PWS:

36 CFR 1194.22, .31, and .41 Documents must be in unlocked form. Acceptance checklists for various file formats are available at http://www.hhs.gov/web/508/index.html.

C.8 References:

Drug Induced Liver Injury

· Navarro VJ, Bonkovsky HL, Hwang SI, Vega M, Barnhart H, Serrano J. Catechins in dietary supplements and hepatotoxicity. Dig Dis Sci. 2013 Sep;58(9):2682-90.

· Bell LN, Vuppalanchi R, Watkins PB, Bonkovsky HL, Serrano J, Fontana RJ, Wang M, Rochon J, Chalasani N; US Drug-Induced Liver Injury Network (DILIN) Research Group. Serum proteomic profiling in patients with drug-induced liver injury. Aliment Pharmacol Ther. 2012 Mar; 35(5):600-12.

· Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008 Dec; 135(6):1924-34, 1934.e1-4.

Governing Laws, Guidelines or Requirements: Federal laws and guidelines that may have major impact on the requirements of this SOW include:

· Federal Section 508 Laws and Guideline http://www.access-board.gov/508.htm

· Federal Information Security Management Act of 2002 (FISMA). http://csrc.nist.gov/groups/SMA/fisma/index.html

· The Privacy Act of 1974 - adequate administrative, operational, and technical security controls must be implemented to prevent unauthorized access to or disclosure of any personally identifiable information (PII) that will be accessed by the contractor http://www.hhs.gov/foia/privacy/index.html

· Paperwork Reduction Act (PRA) http://www.hhs.gov/ocio/policy/collection/index.html

· E-Government Act of 2002 http://www.archives.gov/about/laws/egov-act-section-207.html

· CDC Information Technology Guidelines (May be made available upon request after execution of a CDC/HHS Non-disclosure Agreement)

· CDC Web Template Guidelines http://www.cdc.gov/healthcommunication/ToolsTemplates

· CDC Social Media Guidelines http://www.cdc.gov/SocialMedia/Tools/guidelines/index.html

· Other guidelines as produced and sanctioned by the CDC.gov web Council and the CDC Social Media Council http://www.cdc.gov/healthcommunication/index.html

· Office of Management and Budget (OMB), National Institute of Standards and Technology (NIST), and General Accounting Office (GAO) policies that can be primarily found at or through the Federal CIO Council website at http://cio.gov

· NCEH/ATSDR Information Resources Governance Board See CDC/HHS Enterprise Performance Life Cycle {EPLC} http://www2a.cdc.gov/cdcup/library/other/eplc.htm

C.9 Deliverables: The contractor will submit the following deliverables in accordance with the schedule below:

7/17/2014