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Drug –induced Liver Injury (DILI)

Solicitation Number: FDA-RFQ-1048351-2
Agency: Department of Health and Human Services
Office: Food and Drug Administration
Location: Office of Acquisitions and Grants Services - Rockville
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Combined Synopsis/Solicitation
Added: Aug 23, 2008 1:31 pm
Solicitation Number:


Title: Drug –induced Liver Injury (DILI)

Notice Type:

Combined Synopsis/Solicitation


This is a combined synopsis/solicitation for commercial items prepared in accordance with the format in FAR 12.6, simplified acquisition procedures and the resultant purchase order will include all applicable provisions and clauses in effect through the Federal Acquisition Circular 05-26.

This announcement constitutes the only solicitation and a written solicitation will not be issued. This synopsis, NAICS code 541690, is to notify contractors that the government intends to issue a Purchase Order in accordance with FAR Part 13.106 for the following statement of work, under the simplified acquisition procedures. Prospective offerors are responsible for downloading the solicitation and any amendments. It is the offeror's responsibility to monitor the FedBizOpps website for the release of any amendments to this solicitation. The Government reserves the right to award a contract without discussions if the Contracting Officer determines that the initial offer(s) is/are providing the Best Value and discussions are not necessary.

This solicitation is issued as a Request for Quote (RFQ)

The Food and Drug Administration (FDA) intends to award a purchase order for professional services as described in the following Statement of Work:

1.0 Background. Drug-induced liver injury (DILI), the most frequent cause of liver failure in the U.S., is the single most common cause of regulatory action for new drugs, including failure to approve, withdrawal from the market, restrictions on use and warnings to physicians. DILI can be either pharmacological (dose- and time-dependent; related more directly to drug) or idiosyncratic (rare; hypothesized to be related more to the individual characteristics of susceptible patients).

The early detection, mechanistic understanding and mitigation of potential drug safety problems are key objectives of the Food and Drug Administration (FDA)’s Critical Path Initiative, a national effort to find innovative ways to modernize drug development. As part of this effort, FDA seeks to develop an in silico (computer) model of liver homeostasis and DILI. The model would be designed to improve current risk assessment approaches for DILI.

Current preclinical approaches aimed at predicting and mitigating the impact of pharmacological DILI can be significantly improved. Although a consortium of multinational pharmaceutical companies, academics and regulators reports that the “true positive” concordance rate between preclinical studies and human clinical outcome is approximately 70% if toxicity is observed in one or more preclinical species, the concordance rate is only 55% for liver toxicity . Moreover, these figures have not appreciably improved in nearly 50 years , .

To mitigate the potential for idiosyncratic DILI, sponsors of late-stage clinical trails typically screen patient databases for any evidence of impaired liver function (e.g., elevated circulating liver enzymes and bilirubin) that could indicate a high mortality risk in the absence of other causes (“Hy’s Law”). Although this method is indicative of drugs that can cause idiosyncratic DILI, Hy’s Law is not a robust predictive tool. For example, some drugs associated with idiosyncratic DILI do not cause a striking elevation in liver enzymes. Furthermore, data show that most individuals can tolerate or adapt to hepatotoxic compounds, and only rare individuals display a severe reaction. When suspected cases of idiosyncratic DILI do appear after a drug has been approved, it can be difficult for the sponsor/manufacturer and the FDA to clearly separate drug-specific effects from all other possible causes, such as patient-specific risk factors. Analysis tools that can quickly bring regulators and manufacturers to a clarity of understanding are needed to best inform critical decisions that can affect the availability of otherwise beneficial medicines.

1.1 Project objectives. FDA would like to bring the benefits of biosimulation methodologies to the field of DILI. The knowledge gained from doing so is expected to advance the understanding of the inherent toxicity of drug compounds and the variability in the severity of liver injury observed in the clinic. To comprehend the underlying causes of DILI, one must develop a systematic model of liver function that describes and explores the processes that lead to liver injury. The proposed modeling and simulation platform will quantitatively integrate multiple, disparate sets of data into a unified, dynamic, mathematical model of the liver. This model will capture the complex interactions and relative contributions of multiple systems to the onset and progression of DILI. The platform will also enable researchers to propose and develop mathematically explicit hypotheses that link virtual patient phenotypes to a well-defined set of biological processes. Insights from the model may allow researchers to derive useful preclinical models, develop predictive functional bioassays, useful preclinical models, and candidate biomarkers.

Current challenge Anticipated model applications

Improve the concordance between animal models and human clinical response • Optimize first-in-human trial protocols by predicting starting doses that allow clinical goals to be achieved in less time, with fewer subjects and at lower cost

• Identify and prioritize assays that build confidence in a compound’s likely mechanism of action and off target effects

Advance the understanding of liver toxicity in susceptible humans, especially idiosyncratic responses • Inform ongoing genomic/genetic screening studies designed to reveal the etiology of DILI

• Identify candidate biomarkers more predictive of patients at risk

1.2 References.

• Olsen et al, Reg Toxicol Pharmacol 32: 56-67 (2000)

• Litchfield JT Jr., Ann N Y Acad Sci. 123: 268-72 (1965).

• Litchfield JT Jr., Clin Pharmaco Ther 3: 665-72 (1962).

1.3 Acronyms and Definitions.

DILI – Drug-Induced Liver Injury

2.0 Scope of Work or Scope.

• To support these applications, FDA is interested in developing a detailed model of liver homeostatsis and drug injury in both preclinical animal species (i.e., rat) and humans, as defined in Table 1. The model would be expected to advance our understanding of the underlying mechanisms of drug toxicity, the variability in the severity and susceptibility of liver injury observed in the clinic, and the quantitative translation of animal model responses to human subjects. This knowledge may guide the development of more predictive assays and clinical biomarkers.

• The model should reproduce the responses of tolerator, adaptor and susceptible phenotypes observed in the clinic, consistent with available validation data for benchmark compounds (especially time course data).

• Specifically, the work to be funded under this SOW is for the contractor to evaluate the current state of computer modeling and scientific data related to DILI to develop a set of requirements for the eventual computer models in rat and human. The contractor should provide specific information on the following four aspects of the requirements specifications:

1. Biological phenomena of interest. The contractor should provide a review of the DILI literature to determine which clinical or preclinical outcomes the model should be capable of reproducing.

2. Pertinent physiological mechanisms. The contractor should review available scientific literature to identify all relevant mechanisms for DILI

3. Model architecture. The contractor should examine the scientific literature to develop requirements for the overall architecture of the model relating to how biological phenomena are linked to form a cohesive metabolic system. This system should contain as many known physiological pathways for DILI as possible to allow for the exploration of multiple hypotheses.

4. Based on the above project scoping, the contractor will present a detailed model development and tool development strategy, beta testing plan for predictive accuracy, and implementation plan including a budget and timeline for each phase.

Table 1. Overview of Proposed DILI Model

Rat Human

Phenomena Scope • Reference rat phenotype

• Data sources for model calibration and validation:

o Published studies

o Sponsor proprietary databases, if available • Reference human phenotypes

o Responses of 3 observed clinical phenotypes (tolerators, adaptors and susceptibles) to benchmark compounds as assessed by standard circulatory markers of liver toxicity (e.g., liver enzymes, bilirubin, albumin, bile salts, coagulation factors)

• Data sources for model calibration and validation

o Published studies

o Drug responses (especially time sequence data for DILI onset and progression) detailed in human clinical trials to be requested from the Drug-Induced Liver Injury Network (DILIN) database managed by the U.S. National Institutes of Health (NIH).

o Any available retrospective data from proprietary databases, if available


Scope • Healthy liver physiology.

• Interactions between liver-specific and whole-body support systems (i.e., liver-resident nonparenchymal cells, the innate immune system, blood circulation, urine).

• Five known modalities of liver injury: hepatocellular necrosis, hepatocellular apoptosis, cholestasis, steatosis and mitochondrial dysfunction.

3.0 Contractor Requirements/Expertise

• Demonstrated capabilities in liver function and metabolism (CHO, lipid processing, substrate utilization)

• Ability to explore mechanistic variability and heterogeneity across a virtual population of patients

• Demonstrated capabilities in acute and chronic inflammation, including innate immune response in multiple tissue types

• Ability to reverse-engineer underlying mechanisms from clinical phenotypes, including the underlying pathophysiology derivation from individual patient data, off-target mechanism derivation, and evaluation of compound- and class-effect hypotheses

• Demonstrated capabilities in toxicogenomics

• Ability to conduct cross-species analyses, for example human/rat and human/mouse

• Expertise in preclinical safety assessment (Skin Sensitization Induction – LLNA replacement)

• Ability to explore patient variability and safety assessment, including patient stratification and biomarker pattern identification

4.0 Contractor Personnel:

The contractor selected for performance of this SOW must have specific expertise in computer modeling of complex, multivariate biological systems. The contractor must also demonstrate a specific, in-depth understanding of DILI and its impact on regulation of drugs by FDA. The contractor’s project leader must have achieved technical training equivalent to an M.D., Ph.D., or both. The contractor must demonstrate their ability to read and understand scientific literature, and translate that literature into a computer model that can be used for further scientific research. The contractor must have prior experience in creating mechanism based (i.e., systems biology) computer models that solve disease or adverse event issues in drug discovery and development.

5.0 General Information.

5.1 Place of Performance. Except for one one-day trip to FDA at the end of the contract period, The contractor shall perform all work under this SOW at their location, and shall furnish all necessary space, computers, supplies, etc.

5.2 Period of Performance.

6 months from the date of award

5.3 Travel. The contractor shall make one one-day trip to FDA at White Oak, MD to present their final report at the end of the contract period. It is anticipated that four people would travel to meet with the project staff at FDA.

5.4 Post Award Conference. The contractor shall schedule a teleconference with FDA within 15 days of contract award to discuss any remaining details regarding the SOW and deliverables.

5.5 Task Order Transition. Include any transition/task closeout requirements.

6.0 Deliverables.

At the close of this contract, the Contractor shall provide the following to FDA:

• Final Report: The Contractor shall submit a final report of the work performed under the contract. The final report shall contain detailed descriptions of: (1) a summary of all work conducted; (2) a description of the scientific background, hypotheses/objectives, methods used, description and discussion of results, and conclusions from the review of the scientific literature for each of the three steps detailed in section 2.0 of this SOW. The length of the final report shall be no more than 25 pages, not including references. The final report shall be submitted within thirty (30) days after completion of contracted tasks as specified above, not to exceed 3 months after contract award. FDA will review the draft and will meet with the Contractor to provide feedback or changes within 15 days of receipt. No later then 15 business days after this meeting, the Contractor shall provide the final version of this report, as described above. All work under this contract shall be completed within 4 months after contract award

• Software Requirements Specification. The Contractor shall submit a completed Software Requirements Specification document, to FDA, along with the Final Report. This document shall be sufficient to specify the scientific aspects of the eventual computer model as expressed in section 2.0 of this SOW. The contractor shall not be required to present detailed requirements as to the internal design of the computer model algorithm.

It is expected that the work performed by the Contractor will be the first phase of a more extensive development and research collaboration. A two-year period will see the development of a validated matrix of patient vs. compound profiles that can be used by pharmaceutical sponsors and FDA to rapidly conduct risk assessments of suspected cases of DILI, based on case report forms from the event and existing preclinical and clinical data on the compound (or combination therapy). Based on these analyses, pharmaceutical manufacturers and the FDA will be able to develop the best rationale to support the decision to continue either marketing a drug (or combination therapy) with a specific black box warning, or withdrawing from the market entirely.

7.0 Performance Requirements Summary.

The contractor shall provide a final report as detailed above in section 8.0 within the contracting period. The contractor shall also supply a specific software requirements specification document derived from the work performed under this SOW.

RESPONSES TO THIS RFQ shall include a technical and a firm fixed price cost proposal:

The technical proposal shall not exceed 20 pages in length, not including resumes. The Font shall be not be smaller than 12 point. Proposals shall be singled-sided, doubled spaced pages.

The firm fixed price cost proposal shall provide a breakdown of the labor costs, material costs and any other costs such as travel.


Basis for Award:

a. Proposals received will first be evaluated from a technical standpoint without regard to proposed cost. Those proposals considered to be technically acceptable will then be evaluated from a financial and management standpoint.

b. Technical factors are significantly more important than cost or price. It is pointed out, however, that should technical competence between offerors be considered approximately the same, then cost or price could become primary.

c. FDA will base its award decision using a best value analysis that results in the most advantageous acquisition for the government. FDA’s acquisition strategy used to obtain best value may result in an award to other than the lowest priced, technically rated offeror. Best value analysis spans a continuum from the lowest priced, technically acceptable proposal to those proposals in which tradeoffs between price, past performance, and each offeror’s technical solution is evaluated. This tradeoff process (see FAR 15.101-1) depends on the government’s assessment of quality factors, including but not limited to past performance, compliance with solicitation requirements, technical excellence, management capability, personnel qualifications and prior experience, and price.


Evaluation Criteria WEIGHT

1. Technical Approach 45 Points

The government will evaluate the offeror's technical approach to meet the needs, technical difficulties, challenges, and objectives of the Statement of Work(SOW). The government will consider the completeness, thoroughness, and soundness of the response to all functions and elements of the SOW.

2. Staffing/Management Approach (sub-criteria of equal importance) 25 Points

• Evaluation of the offerors capabilities for development of computer models of complex biological systems, and expertise in the field of Drug Induced Liver Injury (DILI).

• Evaluation of the individuals proposed as key personnel who will be responsible for fulfilling the requirements of this RFP will be based on their qualifications, education, background and previous experience in similar requirements.

• Documented availability, qualifications, experience, education and competence of professional, technical and other personnel who will be assigned to work on this contract.

• Managerial ability to achieve delivery or performance requirements as demonstrated by the proposed use of management and other personnel resources, and to successfully manage the project.

• Evaluation of the project staffing strategy, a plan for the selection and use of expert consultants, estimated hours and labor mix, the experience, skills and qualifications of the proposed personnel to adequately minimize risk and successfully complete the requirements of this Contract.

3. Organizational & Personnel Experience and Resources 30 Points

Experience is the opportunity to learn by doing similar work under similar contracts. The Contractor will be evaluated on the quality, applicability, and significance of relevant experience as it relates to the requirements of this SOW. Evaluation of the individuals proposed as key personnel who will be responsible for fulfilling the requirements of this RFP will be based on their education, background and previous experience in similar requirements. Additionally, the Contractor will be evaluated on the documented availability of adequate physical facilities, equipment, and other resources necessary to meet the requirements of this project.

TOTAL: 100 Points


Payment will be made as follows:

Delivery and acceptance of Draft Final Report – 25% of total award price

Delivery and acceptance of Software Specification Requirements - 25% of total award price

Delivery and acceptance of Final Report – 50% of total award price

CCR: Vendors must be registered in the Central Contractor Register (CCR) prior to the award of a contract. You may register by going to You will need your Dun & Bradstreet number and banking information.

QUESTIONS DEADLINE: All questions are to be submitted via email to no later than Friday August 29, 2008, 2:00pm EST.

QUOTATIONS DUE: All quotations are due, via email to: Lee.Cohen , no later than 12:00pm, EST on Monday, September 8, 2008.

PROVISIONS and CLAUSES: The provision at FAR 52.212-1, Instructions to Offerors Commercial Items applies to this solicitation. The following agenda has been attached to this provision: None. Offerors shall include a completed copy of the provision at FAR 52.212-3, Offeror Representations and Certifications Commercial Items. The clause at FAR 52.212-4, Contract Terms and Conditions, Commercial Items applies to this acquisition. The following agenda has been attached to the clause: None. The clause at FAR 52.212-5 Contract Terms and Conditions Required to Implement Statues or Executive Orders, Commercial Items applies to this acquisition. The following FAR clauses cited are applicable: FAR 52.217-8, FAR 52.222-26, FAR 52.222-35, FAR 52.222-36, and FAR 52.232-33. Clauses and provisions are incorporated by reference and apply to this acquisition.

Responses to this notice must be sent via email to Lee.Cohen .

Contracting Office Address:

5630 Fishers Lane, Room 2100

Rockville, Maryland 20852

Place of Performance: Contractor’s facility

Primary Point of Contact.:

Lee F. Cohen


Phone: 301-827-7046

Fax: 301-827-7106

Added: Sep 04, 2008 1:37 pm
This amendment is to notify all potential offerors that no questions were received in response to the solicitation.

Offerors are notified of the following information:

The maximum firm, fixed price award for this requirement will be $100,000. Offerors should included all costs in their price proposal as that will be a firm, fixed price amount.

It is noted that any resultant award will be a firm, fixed price purchase order under Federal Acquisition Regulations. This is not a grant.

5630 Fishers Lane, Room 2129
Rockville, Maryland 20857-0001
Lee Cohen,
Associate Director, OAGS
Phone: 3018277046