AdditionalTechnicalProposalInstructions.pdf

RFP/N02-CM-07007-39

ADDITIONAL TECHNICAL PROPOSAL INSTRUCTIONS

“Pathology and Veterinary Support for Preclinical Toxicology Studies”

A detailed work plan must be submitted indicating how each aspect of the work as described in the Statement of Work and Technical Evaluation Criteria (TEC) is to be accomplished. The technical approach should contain as much detail as you consider necessary to fully explain your proposed approach. The technical proposal should reflect a clear understanding of the nature of the work being undertaken. The technical proposal must include information on organization, staffing and management of the project. Information should be provided which will demonstrate understanding and management of important tasks.

I. Staff Qualifications and Capabilities

Describe the experience and qualifications of all personnel who will be assigned for direct work on the proposed contract. Information is required which will show the composition of the task or work group, its general qualifications, and recent experience with similar equipment or programs. Special mention shall be made of direct technical supervisors and key technical personnel, and the approximate percentage of total time each will be available for this program. Organizational and staffing charts, including the Quality Assurance Unit, shall be provided.

Resumes of all proposed personnel must be provided and include the education, background, recent relevant experience, present responsibilities and specific scientific or technical accomplishments. Unrelated information and resumes of persons not assigned or involved with the proposed work group are neither necessary nor desired and will be considered as detracting from the proposal. A complete bibliographic listing for all proposed key personnel should also be provided.

Offerors shall provide assurance that the Principal Investigator, and all other personnel proposed, will not be committed on federal grants and contracts or non-government work for more than a total of 100% of their time. If the situation arises that a proposed employee is committed for more than 100% of their time, the government will require action on the part of the offeror to correct the time commitment.

A. PRINCIPAL INVESTIGATOR

An individual must be identified who will be responsible for overseeing the project. This individual is responsible for the overall implementation of the proposed contract. This individual should be knowledgeable in all aspects of the contract requirements and have demonstrated the ability to direct a program of similar complexity. The individual proposed for this position must have a minimum of 5 years of relevant experience and must be a full time employee of the offeror (not a consultant). The principal investigator is considered a key personnel on this contract.

B. CONTRIBUTING PATHOLOGIST(S)

Contributing pathologist(s) will be considered key personnel on this contract. Any pathologist who generates and/or interprets anatomic and/or clinical pathology data is considered a “contributing pathologist” and must have the education, qualifications and experience to perform these tasks. These individuals should have greater than five years experience in toxicologic pathology in multiple species, especially rodents, dogs and non-human primates. Pathologists for two broad types of activity will be required for this contract.

1) Peer review – A mutually agreed upon pathologist will be identified following contract award. A single pathologist is preferred, however, other pathologists may be involved on a case-by-case basis.

2) Primary reviewer – A pathologist who provides a single source of review for a study (study pathologist). Other types of pathology support are also required as described below, under II. Technical Approach.

C. ADDITIONAL PERSONNEL

1. Quality Assurance Officer

This individual shall be responsible for determining whether the contractor is in compliance with the FDA guidelines ‘Good Laboratory Practices for Non-Clinical Laboratory Studies’.

2. Laboratory Manager A qualified and experienced laboratory manager shall supervise the histology operations conducted for this contract.

3. Repository Manager This individual shall keep track of all pathology materials by ensuring all repository procedures and security measures are followed and the location of all materials is promptly updated in the database. In addition, the manager shall ensure pathology materials are shipped as requested by the COTR and the COTR receives the repository inventory on a semi-annual basis.

4. Data Manager (computer specialist) This individual shall be responsible for maintaining the repository database (detailed inventory) and ensure repository staff are trained in how to use the software and capture the required information.

D. CONSULTANTS or SUBCONTRACTORS

The technical areas, character, and extent of consultant or subcontractor activity must be indicated and the anticipated sources specified. A resume and letter of commitment or other evidence of availability is required for all proposed personnel who are not current employees of the offeror. A resume alone will not meet this requirement. Letters of commitment from consultants and other personnel to be hired must include:

a. Specific areas of expertise relevant to the contract

b. Availability and amount of anticipated time for work on the contract

c. Willingness to be a consultant for the offeror

d. Arrangement for how publications and patents will be handled

II. Technical Approach

A. PATHOLOGY SUPPORT AS PRESENTED IN THE SOW & TEC

1. Pathology Peer Review

The offeror shall detail all procedures and time requirements to conduct a pathology peer review. (See the entire section I.A. of the SOW for a description of the minimum information to be collected during a peer review of the study pathologist’s findings and the requirements for reporting.) The tissue slides will come from toxicology studies of potential drugs conducted in rodents, dogs and non-human primates. Most of the studies will be GLP compliant. It is estimated that 8 pathology peer reviews (5 rodent, 3 dog and <1 NHP) will be conducted annually.

Approximately 100 rats, 30 dogs and 16 NHPs will be used in the studies. Typically, peer review is conducted on all the slides from large species. For rodent studies, slides are evaluated from ~20% of the animals plus the target tissues from all the animals. At present, 45 tissues per dog and 38 tissues per rodent are routinely evaluated for microscopic lesions. Pathology peer review shall be conducted following the recommendations in the article Best Practices for Reporting Pathology Interpretations within GLP Toxicology Studies (Appendix 22).

2. Necropsy

The offeror shall detail all procedures and time requirements to conduct a necropsy.

The necropsy will occur at the study site (DTP contract laboratory, government facility or collaborator’s facility) and travel will be required. Euthanasia will be conducted by staff employed at the facility, not the pathology contractor. The study site will supply the basic materials required for the necropsy and preservation of collected tissues. (It is impractical for the pathology contractor to bring all needed materials.) The contractor shall have a veterinary pathologist present during the necropsy and a prosector(s). The collected tissues will be shipped to the pathology contractor and all subsequent histology work will be conducted at the contractor’s facility.

3. Histotechnical Services The offeror shall detail all procedures and time requirements to conduct histotechnical services for the following applications: 1) routine processing and H&E staining, 2) processing tissues into slides and staining as appropriate for specialized applications such as neuropathology and immunopathology, and 3) immunohistochemical staining for a protein (biomarker or molecular target) of interest. In describing these services, provide information such as controls for the staining (positive and negative), and procedures used to minimize background and maximize visualization of stained tissues.

In addition, the offeror may provide pathology support for in vitro studies such as processing cultured tissues (which have been frozen or fixed) or cultured cells into slides, stain (H&E, other stains, immunohistochemistry) and histology evaluation.

The offeror should provide details for conducting these services.

4. Diagnostic Pathology

The offeror shall detail all procedures and time requirements to conduct histopathologic evaluation of all study protocol required organs or target organs only.

Treatment related lesions and vehicle effects shall be addressed. In addition, the offeror shall describe their procedure to address the correlation of clinical signs/organ weights/clinical pathology results and morphologic lesions. The offeror shall discuss their approach to determining the pathogenesis, whether primary or secondary effect, and reversibility of the induced injury.

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. 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).

5. Therapeutic Antibody Binding Studies

The offeror is expected to have the capability and experience to evaluate specificity of binding of a therapeutic antibody in human tissues and animal tissues (if appropriate) following FDA’s GLP regulations (21 CFR Part 58). Pilot studies will be conducted in a limited number of human (and animal) 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. Using the defined optimal conditions 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 offeror shall detail the procedures used to assess tissue binding specificity of a therapeutic antibody. In addition, the offeror will explain how the results will be interpreted, such as, a situation in which tissue binding is negative at the low concentration and positive at the high concentration, or binding occurs at sites not expected but can be explained scientifically.

6. Other Biologic Agents

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. If the offeror has experience with either of these approaches, provide details on the procedures used and controls to verify results.

7. Pathology Support for Human Biopsy Samples The offeror shall supply detailed information regarding the processing of human biopsy samples into slides, staining and validation procedures (specificity of stain), semi-quantitation of results and interpretation of findings. In responding, the offeror should keep in mind that the size of a biopsy sample is a few milligrams.

Fixed or frozen human biopsy samples shall require pathology support services on an as needed basis (typically 2 – 4 biopsy samples at a time). The contractor shall provide tissue trimming, tissue embedding, microtomy, H&E slide preparation, immunohistochemical staining for a specific molecular target/biomarker; and possibly specialized staining for a specific cell type or subcompartment. The contractor will be required to determine localization and semi-quantitation of the molecular target/biomarker being stained. Based on those results, information provided by the government, and scientific literature search, 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).

NOTE: The Dept. of Health and Human Services/ Office for Human Research Protection (OHRP) considers private information or specimens not to be individually identifiable when they cannot be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. For example, OHRP does not consider research involving only coded private information or specimens to involve human subjects as defined under 45 CFR 46.102(f) if the following conditions are both met:

(1) the private information or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals; and

(2) the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example:

(b) there are IRB-approved written policies and operating procedures for a repository or data management center that prohibit the release of the key to the investigators under any circumstances

With regard to condition (1), the contractor will not have any interaction or intervention with living individuals. Moreover, the pathology materials will be collected and archived in a central repository. Human specimens used by the contractor will come from a central repository, never directly from a clinical trial. This distinction is important because the above-mentioned guidance is not applicable to archived human specimens. With regard to condition (2)(b), the human specimens will be collected during IRB-approved clinical trials and archived in a central repository(s) in compliance with an IRB-approved protocol. The clinical trial site(s) and central repository(s) will label the human specimens with identifiers and those sites will have the key for their respective identifiers. The IRB-approved protocols prohibit the release of the key under any circumstances. Neither the NCI Project Officer nor the contractor will have the key for those identifiers. Therefore, it will be impossible to identify the source of the human specimens.

8. Database and Repository Management & Receipt and Shipment of Materials

The contractor shall describe in full detail their database to inventory and track pathology materials and study samples stored in the repository. The database shall be in a format that allows for compatibility with other commonly used software. At a minimum, the database shall capture the following information: compound NSC number and name, entire study title, study number, contractor name or facility, species, gender, type of pathology materials (slides, paraffin blocks, formalin-fixed tissues, frozen tissues, etc.) and a list of individual items from the study. As new materials arrive, they shall be stored promptly and the database updated at the same time. The database must provide information on the specific storage site for each item.

The offeror shall describe their experience with special handling procedures necessitated by shipment and receipt of pathology materials and frozen study samples. Related to this, the offeror shall provide information regarding their database’s ability to track materials if they are moved (ie, sent to an investigator), or modified (ie, sections prepared from blocks) in order to maintain an accounting of all materials. If pathology materials are shipped from the repository to another location, the repository database shall be immediately updated to clearly identify the pathology materials that are shipped (offeror provide details), the date of shipment, the name and address of the destination, and the name of the recipient (identify the scientist, not shipping personnel). In addition, the contractor should include additional description of their database if it captures information not mentioned here.

The offeror shall provide information regarding the experience and training of the staff using the software, and IT support to troubleshoot problems. The contractor shall include information regarding the initial setup of a repository database which will be in a format that allows seamless migration of data to a variety of other databases.

B. FACILITIES and EQUIPMENT

1. Facilities and Equipment The offeror shall describe in detail the space and equipment available, and the adequacy and conformance of the facilities to conduct the work as described in the Statement of Work. It is desirable that a floor plan be provided for the repository and laboratory space, identifying areas where different facets of work will be conducted.

Special emphasis should be placed on describing the equipment available for histologic processing (fixed and frozen), staining, immunohistochemistry, imaging and quantitation of results.

2. Repository for Pathology Materials and Study Samples The repository must provide adequate space, maintenance, back-up systems and security measures to safely archive pathology materials and frozen study samples.

Presently there are ~500,000 slides, ~300,000 blocks, ~1000 cu. ft. of fixed tissues and ~40 cu. ft. of frozen samples being archived. Moreover, the amount of these materials will increase during the 7 year period of the contract. In the description of the repository, the following considerations must be taken into account:

a. The repository must be protected by an automatic halon fire suppressive system and fire doors and walls.

b. The facility must be equipped with temperature and humidity controls, smoke and thermal detection systems and alarms.

c. The repository must have an emergency back-up power source.

The offeror shall provide information regarding transportation of materials to and from the repository. In the event the contract is not awarded to the incumbent, the new contractor shall provide transportation and personnel support for the immediate, safe transfer of all government-owned materials and property in the present repository at Frederick, Maryland, to the contractor’s site.

The offeror shall describe the security measures in place to protect the contents of the repository. 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 in place in case of fire,

5) a formal procedure to record and retain the name, affiliation, date, entry and exit time of each visit, and reason for the visit, of all visitors to the repository, and 6) adequate training of all repository staff to understand and utilize the security system and procedures appropriately. Standard operating procedures for these internal control measures must be in place at the start of the contract. Removal or receipt of any materials at the repository must first be approved by the COTR.

III. Organizational Support and Experience

Organizational experience is defined as the accomplishment of work, either past or on-going, which is comparable or related to the effort required by this RFP. This includes overall offeror or corporate experience, but not the experience and/or past performance of individuals who are proposed as personnel involved with the Statement of Work in this RFP.

The offeror shall describe in detail any recent pertinent organizational experience in conducting work as described in the State of Work, such as pathology peer reviews, various histotechniques and pathology evaluations, and the operations of a repository. In detailing this experience, indicate specific government and commercial contracts for similar projects and provide a synopsis of the work involved.

Since this will be a Work Assignment (WA) managed contract, the offeror shall explain its process to respond to a WA and initiate work in a timely manner. Describe possible interfering commitments which might cause delays in completion of the effort required. The WAs to be expected will represent the range of activities described in the Statement of Work. Indicate the priority to be placed on this work as compared to existing commitments.

The offeror shall detail how the group will be organized, both technically and administratively. Indicate by chart and/or in narrative form how the various activities will be coordinated so as to demonstrate an awareness of organization influences on project implementation and control. Include a clear description of relevant lines of authority and responsibility. Describe a management plan for implementing the project including provisions for backup technical support for the project team.

The offeror must provide evidence of compliance with FDA Good Laboratory Practice guidelines and the most recent FDA Form 483 inspection reports (if the facility was inspected).

For this contract, the contractor is not expected to directly handle toxic agents from NCI.

However, the tissues (and downstream materials) to be handled and analyzed will originate from animals treated with potentially hazardous substances. Moreover, the contractor will be working with formalin and possibly other harmful chemicals. Therefore, all necessary precautions must be taken to protect personnel and the environment against possible exposure to the agents being tested and toxic reagents being used. The contractor shall perform all work associated with this contract in accordance with all applicable federal, state and local regulations for occupational exposure to hazardous chemicals in laboratories. [e.g.

Regulations (Standards - 29 CFR) 1910.1450] and follow regulations governing the transportation and disposal of hazardous waste. In addition, the offeror shall describe laboratory safety controls and procedures for handling and disposing of potentially toxic materials (ie, formalin), and slides, blocks, fixed tissues and frozen specimens. Describe procedures for the prevention of contamination during laboratory operations.

IV. 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 secure 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 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. The transfer of ALL materials must be accomplished within 45 calendar days after the effective date of the contract.

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.

1. A time line to establish a fully functional repository to archive thousands of pathology materials and frozen samples within 45 calendar days. The time line shall be divided into the following minimum functions: establishment of a database framework that captures detailed inventory information as described in the Technical Proposal Instructions; safe and suitable transportation of materials from the present repository to the offeror’s repository;

inventory items received from the present repository; inventory in the new database and assignment of storage location; and transfer items to designated storage location. Offerors shall demonstrate in their transition plan a timely, efficient and effective transition with particular importance on tracking all materials and safe relocation.

2. A thorough discussion of safeguards for prevention of loss, protection of temperature sensitive materials and fragile materials, handling of damaged items and insurance coverage. The transition plan must address the safe packaging, the use of multiple shipments, and any other considerations that the offeror determines to be critical.

3. A discussion of all required federal, state and local approvals for the transport and in-transit storage of pathology materials, study samples and other hazardous materials. A summary of the required approvals should also be provided in table form along with copies of available documentation.

4. A discussion of all required federal, state and local approvals, licenses, certificates, permits and other legal requirements necessary for the repository and its contents, at the proposed location and for the proposed use. These shall be in place at the time of the proposal submission. A summary of the required approvals should also be provided in table form along with copies of available documentation.

5. The cost for the Phase-In transition plan/activities shall be included as a separate line item in the business proposal.