StatementofWork.pdf

RFP/N02-CM-07007-39

Attachment 2

January 2010

ATTACHMENT 2

STATEMENT OF WORK

“Pathology and Veterinary Support for Preclinical Toxicology Studies”

GENERAL REQUIREMENTS

Typical tasks to be performed will include, but not be limited to, the following:

• Pathology peer review of toxicology studies conducted by another contractor

• Necropsy and pathology support for in vivo studies (TRAVEL WILL BE REQUIRED)

• Immunohistochemical localization and semi-quantitation of molecular targets/biomarkers of interest from in vivo and in vitro studies

• Human (and animal, if applicable) tissue binding specificity studies of therapeutic antibodies per FDA guidelines (contractor prepares a study protocol)

• Processing of human biopsies/samples into slides, stain (routine, immunohistochemical or specialty), histologic evaluation and interpretation of results (no diagnosis)

• Storage of pathology materials from pharmacology and toxicology studies including slides, blocks, fixed tissues and frozen specimens

• Storage of pathology materials from other sources such as studies at an outside investigator’s lab

• Establishing a repository database that has a format compatible with seamless migration of data to a variety of other databases

• Maintaining and promptly updating the repository database

MANDATORY REQUIREMENTS

Mandatory Qualification Criteria are described in detail in Attachment 11. Mandatory criteria include the following: 1) the offeror must comply with the FDA's current Good Laboratory Practice Regulations (GLPs) and provide a copy of their most recent FDA GLP inspection report as documentation; and 2) the offeror shall provide documentation of board certification by the American College of Veterinary Pathologists for ‘contributing pathologists’ who generate the pathology reports for this contract.

SPECIFIC WORK REQUIREMENTS

Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment and facilities, not otherwise provided by the Government on an as needed basis under the terms of this contract.

Work assignments will be utilized on this contract. Tasks will be assigned when the Contracting Officer Technical Representative (COTR) (formerly known as “Project Officer”) sends a Work Assignment (WA) to the contractor that delineates the work to be conducted, the period of performance, the deliverable(s) and the due date for the deliverable(s). Most often, WA deliverables are a draft report (Word or WordPerfect document) and a final report (pdf file).

The contractor shall respond to a Work Assignment by having an authorized individual sign the WA and submit the signed WA along with a cost proposal to the COTR. Work starts after the WA is signed by the TPB COTR and the NCI Contracting Officer. For some WAs, the contractor will prepare a study protocol which is reviewed by the COTR. Once there is a mutually agreed upon signed study protocol, a study is initiated. The contractor will also be required to track the number of labor hours for each WA even though this is not a level-of-effort contract. If there is an abundance of work, the COTR will determine the order of priority.

I. Diagnostic Pathology Support

A. An assigned peer review pathologist from the contractor shall:

1. Compare the gross description at time of necropsy (Study Pathologist) with the microscopic evaluation and bring any discrepancies to the attention of the COTR and the Study Pathologist. Review the Study Pathologist’s diagnoses of all tissues to determine the appropriateness of drug-related lesion designations (primary vs secondary) and verify that no lesions have been missed or incorrectly diagnosed by the Study Pathologist. Address vehicle and treatment related lesions and effects.

Pathology peer reviews shall follow the recommendations in the article Best Practices for Reporting Pathology Interpretations within GLP Toxicology Studies (Appendix 22). A draft report shall be submitted to the COTR describing the findings approximately 20 business days after the contractor receives tissue slides and relevant sections of the study report.

2. Compare diagnostic interpretation across studies and species on the same compound to make certain of consistency of interpretation. Notify the COTR of any discrepancies.

3. Correlate histopathologic findings to observed toxicity as noted in the study report.

4. Evaluate the histotechnique quality. Activities include review of all slides for the presence of protocol required tissues and evaluation of a representative number of slides for histotechnique quality using ASCP (American Society of Clinical Pathologists) criteria. This evaluation shall be included in all pathology reports.

5. Peer review reports shall include the following: an introduction detailing the study design, type of lesions found, nature and significance of the lesions and a general evaluation of the quality of the slides and original pathology review. All lesions shall be categorized either as drug-related or non-drug related. Each lesion shall be listed and coded by the most specific topographic and morphologic diagnoses, severity and distribution using the International Harmonization of Nomenclature and Diagnostic criteria (http://www.goreni.org/), Standardized System of Nomenclature and Diagnostic Criteria (SSNDC) Guides and the International Harmonization of Rat Nomenclature (http://www.toxpath.org/nomen/). Pathology code tables found at the National Toxicology Program website http://ntp.niehs.nih.gov/?objectid=72016020- BDB7-CEBA-F3E5A7965617C1C1, may also be used.

B. The contractor shall conduct the following pathology support services as requested by the COTR:

1. Perform, on an as needed basis, histology operations such as processing fixed and frozen tissues into slides; routine staining (ie. H&E); process tissues into slides and stain as appropriate for specialized applications such as neuropathology or immunopathology; and immunohistochemical staining (ie. protein of interest).

2. Provide personnel to conduct full necropsies at the DTP contract laboratories, government facilities, or collaborators’ facilities, on an as needed basis (travel required). The pathology contractor shall provide a veterinary pathologist and prosector(s). Necropsy technique may include whole body or organ perfusion for ultrastructural analysis. Euthanasia will NOT be administered by the pathology contractor.

3. Perform histopathologic evaluation of all study protocol required organs or target organs only and address vehicle and treatment related lesions and effects. Tissue slides will come from pharmacology and toxicology studies, NCI in-house studies and studies from outside investigators. Alternatively, the pathology contractor may be required to prepare the tissue slides from these studies. The contractor will receive the draft study report (at least the relevant sections) prior to the initiation of their work. The contractor shall record the findings, prepare summary tables of histomorphologic data, and write a narrative that summarizes the diagnoses and an interpretation of the results. Each lesion shall be listed and coded by the most specific topographic and morphologic diagnoses, severity and distribution using the International Harmonization of Nomenclature and Diagnostic criteria (http://www.goreni.org/), Standardized System of Nomenclature and Diagnostic Criteria (SSNDC) Guides and the International Harmonization of Rat Nomenclature (http://www.toxpath.org/nomen/). Pathology code tables found at the National Toxicology Program website http://ntp.niehs.nih.gov/?objectid=72016020-BDB7- CEBA-F3E5A7965617C1C1, may also be used. The contractor shall define drug-related effects. In addition, the contractor shall address the correlation of clinical signs/organ weights/clinical pathology results and morphologic lesions, and, when applicable, discuss the pathogenesis, whether primary or secondary effect and reversibility of the induced injury. In addition, the contractor shall follow the recommendations in the article Society of Toxicologic Pathology Position on Histopathology Data Collection and Audit Trail: Compliance with 21 CFR Parts 58 and 11(Appendix 22). A draft report describing all findings with select photomicrographs shall be submitted to the COTR within the time frame specified in the Work Assignment or study protocol, 15 - 30 business days following receipt of the slides and study report.

4. Evaluate specificity of binding of a therapeutic antibody in human tissues and animal tissues (if appropriate). Initially, pilot studies will be conducted in a limited number of human tissues to optimize the conditions for antibody binding and minimize non-specific background. Appropriate controls shall be used to assess the quality of the assay. In the definitive study, the therapeutic antibody will be used at two concentrations. The lowest antibody concentration that provides a maximum signal shall be the low concentration in the study. A ten-fold higher concentration of therapeutic antibody shall be used for the high concentration in order to detect potential cross-reactivity outside of the intended target organ sites. The study shall be conducted in compliance with FDA regulations. The study report shall include all findings in the definitive study and information from the pilot studies as it pertains to the optimal conditions for antibody specific binding. A draft study report including select photomicrographs shall be submitted to the COTR in the time frame stated in the study protocol or Work Assignment. It is expected the initial pilot studies will not require more than one month and the definitive study another 20 – 30 business days.

5. For other biologic agents, the contractor may be required to determine tissue distribution of the test article by using PCR amplification or by expression and detection of marker genes such as $-galactosidase or luciferase.

6. Provide pathology support for in vitro studies such as processing cultured tissues

(which have been frozen or fixed) into slides, stain (H&E, other stains, immunohistochemistry) and histology evaluation. Pathology support may also involve cultured cells which are stained and evaluated histologically.

C. The contractor shall provide pathology support for clinical & preclinical studies as requested by the COTR

1. Fixed or frozen human biopsy samples shall require pathology support services on an as needed basis. The contractor shall provide tissue trimming; tissue embedding;

microtomy; H&E slide preparation; immunohistochemical staining for specific molecular targets/biomarkers; and possibly specialized staining for specific cell type or subcompartment.

2. In addition to histopathology evaluation of human biopsy samples, the contractor shall be required to determine localization and semi-quantitation of a molecular target/biomarker following immunohistochemistry. Based on the molecular target being stained and all other results obtained, the pathologist (contractor) shall include in the study report an interpretation of the findings such as mechanism of action or molecular pathway affected. A clinical diagnosis will not be required. In addition, the contractor shall follow the recommendations in the article Society of Toxicologic Pathology Position on Histopathology Data Collection and Audit Trail: Compliance with 21 CFR Parts 58 and 11(Appendix 22). The draft study report shall be submitted to the COTR within the time frame specified in the Work Assignment or study protocol, typically 15 - 30 business days following receipt of the biopsy tissues and relevant government-provided information.

NOTE: See section H of the RFP for provisions applicable to the use of human materials. The contractor shall closely monitor activities being conducted in performance of the contract which may lead to or result in additional regulatory and/or policy requirements.

3. For select preclinical studies, the contractor shall be required to determine localization and semi-quantitation of a molecular target/biomarker following immunohistochemistry. Based on the molecular target being stained and all other results obtained, the pathologist (contractor) shall include in the study report an interpretation of the findings such as mechanism of action or molecular pathway affected. The report shall be submitted to the COTR within the time frame specified in the Work Assignment or study protocol, typically 15 - 30 business days following receipt of the tissues and relevant government-provided information.

D. Facilities

The contractor’s facility will be the location for contract performance. The contractor must have an adequate (see II.A.1 below) and secure (see II.A.5 below) facility (repository) to store thousands of pathology materials. The contractor must also have facilities and equipment for histology-related functions including the fixation of tissues and processing into slides, staining slides using routine H&E (or specialty stains and immunohistochemistry) and equipment for high quality histology evaluations. In addition, the contractor may also prepare frozen tissue sections and appropriate equipment for this task is desired. Lastly, the contractor shall have equipment and software to capture data acquired in their facility, collate results, create images, and present data in a suitable format.

II. Repository and database support for stored pathology materials

A. The contractor shall provide a repository for the safe storage of pathology materials as described below.

1. The contractor shall provide a secure repository (storage facility) for pathology materials including microscopic slides, tissue blocks, fixed tissues, and frozen tissues/samples. The contractor shall be required to provide sufficient space (~500,000 slides, ~300,000 blocks, ~1000 cu. ft. of fixed tissues, ~40 cu. ft. of frozen samples) to store these materials for the duration of the contract. The contractor shall ensure the formalin fixed tissues are stored appropriately, (ie, double bagged in cartons) and re-bag as needed. Frozen tissues shall be stored at ≤70ºC.

2. Within 45 calendar days the contract is awarded, all pathology materials stored at the present contractor repository shall be transferred to the new contractor’s facility (if applicable).

In addition, TPB’s toxicology and pharmacology contractors will ship pathology materials with an inventory list to the repository when their contracts end.

3. Periodically, TPB contractors may ship pathology materials or frozen samples to the repository (contractor) for storage. However, the toxicology or pharmacology contractor must first notify the COTR and obtain get approval prior to shipping pathology materials to the repository.

4. Periodically, the COTR will request the pathology contractor to ship select pathology materials (or study samples) to another facility.

SHIPMENT OF MATERIALS TO AND FROM THE REPOSITORY SHALL BE PAID

FROM THE PATHOLOGY CONTRACT.

5. In order to ensure the protection of the repository and its contents, the contractor shall have security procedures in place. At a minimum, this shall include: 1) a security system to prevent unauthorized entry into the repository (ie, card key entry and limited personnel access), 2) a formal system or procedure to prevent unauthorized removal of material from the repository, 3) a formal procedure in place to prevent loss or misplacement of repository materials, 4) a formal procedure to record and retain the name, affiliation, date, entry and exit time of visit, and reason for the visit, of all visitors to the repository, and 5) adequate training of all repository staff to understand and utilize the security system and procedures appropriately.

B. The contractor shall generate and maintain a detailed inventory of the stored pathology materials as described below.

1. The contractor shall use software to maintain an inventory of all stored pathology materials using a format compatible with seamless migration of data to a variety of government databases. At the start of the contract, the inventory at the present contractor shall be transferred to the new contractor (if applicable). It may be necessary to manually input the inventory information into the new contractor’s database if the two inventory databases are not compatible.

2. The new contractor shall conduct an inventory of the received pathology materials at the same time the pathology materials are transferred into the repository and assigned a storage location. The contractor’s repository database will be updated with the new information.

3. Once all pathology materials are transferred and inventoried, the new contractor shall maintain the inventory and update within 7 calendar days following the receipt of new materials for storage.

4. The contractor shall send electronically (via mutually agreeable format) the updated inventory to the COTR on a semi-annual basis.

5. At a minimum, information to be included in the pathology inventory database is compound NSC number and name, entire study title, study number, contractor name or facility, species, sex, what type of pathology materials (slides, paraffin blocks, formalin-fixed tissues, frozen tissues, etc.) and a list of individual items from the study.

6. If pathology materials are shipped from the repository to another location, the repository database shall be updated to clearly identify the pathology materials that are shipped (see 5. above), the date of shipment, the name and address of the destination, and the name of the recipient (scientist, not shipping personnel). In addition, a brief description of the purpose for the shipment (ie, assay or evaluation) shall also be included as a field in the database. The pathology contractor shall ship materials only when requested by the COTR.

7. The repository database shall be safeguarded with security software and have a means to limit contractor personnel access to the database. Lastly, TPB’s inventory shall be backed up at other locations or formats (ie, DVD). Since the COTR will receive a copy of the pathology inventory semi-annually, this will serve as an additional backup.

III. Additional Requirements

A. Disposition of Data

Data derived from this contract will be considered the property of the Government and delivered on an established schedule to the COTR. Contractors will be permitted to patent any process or use developed under the agreement. Information made available to the Contractor for performance of the contract (except information in the public domain) and information generated by studies conducted under the contract shall NOT be released to the public without the prior written permission of the COTR and Contracting Officer. A confidentiality clause will be required in the contract. These restrictions are necessary since contract studies may involve proprietary compounds and/or data provided to DCTD/NCI by third party suppliers. Agreements established between DCTD/NCI and such parties may require strict confidentiality of information in order to protect suppliers’ patent rights or licensing opportunities. Information/data produced under these contracts may be sent to suppliers of test agents, and provided to other DCTD staff and contractors to facilitate the preclinical and clinical development of antitumor and other therapeutic agents. Towards these ends, such information may be presented at various NCI committee meetings and included in IND applications to the

FDA.

B. Travel Periodically, an in vivo study will require necropsy and pathology support. In these instances, the pathology contractor will supply a pathologist and prosector(s) for the necropsy at the study site. Travel to the facility will be required and paid for under the contract. The fixed tissues will subsequently be shipped to the contractor’s facility for processing, etc.

C. Transition/Phase-In Plan Except for the incumbent, all offerors shall submit a phase-in plan (in the event the incumbent is not awarded the contract) describing how they plan to take over the activities/performance of the contract including the transfer of the repository pathology materials and frozen samples.

Commitments for a proposed facility shall be in place at the time of proposal submission which meets the requirements as stated in the Statement of Work and Technical Proposal Instructions. Those commitments must demonstrate and support an operational facility at the time of contract award. The move of ALL materials must be accomplished within 45 calendar days after the effective date of the contract. The offeror shall address how all pathology materials, frozen samples, associated documentation (electronic and hard copy files) and equipment will be transported and re-located from their current location at Frederick, MD to the new contractor’s site.

A Pre-Award Site Visit may be conducted to verify the offeror’s ability to meet the Government’s requirements for the repository. Offerors shall provide in a separately tabbed section of the technical proposal, labeled Phase-in plan, a detailed plan for moving the repository contents from its present location to the proposed new location.

(see Technical Proposal Instructions for further details)