Attach_10-Additional_Technical_Proposal_Instructions_01132021.pdf

Attachment 10, Dated- 01/13/2021 75N91021R00003

ADDITIONAL TECHNICAL PROPOSAL INSTRUCTIONS

Preclinical Toxicology of Small Molecule Drugs Developed for Cancer and Other Indications

It is strongly recommended that Offerors use the following template as the Table of Contents for the Technical Proposal. All information presented in the Technical Proposal should be presented in the order specified below.

1. Technical Discussion

These additional Technical Proposal instructions reflect the requirements of the RFP and provide specific instructions and formatting for the Technical Proposal. While Section L.2.b.

of the RFP provides a generic set of Technical Proposal instructions applicable to all NIH Research & Development (R&D) solicitations, these additional Technical Proposal instructions are tailored to the specific requirements of the RFP. The information requested in these instructions should be used, along with Section L to format and prepare the Technical Proposal, and should be used as a Table of Contents for your Technical Proposal.

Offerors are advised to give careful consideration to the Statement of Work (SOW) and attachments, Sample Protocols, Mandatory Qualification Criteria and Technical Evaluation Criteria in Section M, and the RFP as a whole in the development of their Technical Proposals.

Offerors should submit a proposal that addresses the Mandatory Qualification Criteria, the Task Areas in the Statement of Work, and the Sample Protocols. If the proposed approach will involve a subcontracting arrangement, then the Offeror shall include a letter of commitment from the subcontractor(s), plus documentation of subcontractor's expertise, qualifications and prior performance, as well as a narrative describing how the Offeror will manage the subcontractor.

A detailed work plan should be submitted indicating how each aspect of the Statement of Work and Sample Protocols are to be accomplished. Your technical proposal should be in as much detail as you consider necessary to explain fully your proposed methods and rationale for their selection and should reflect a clear understanding of the nature of the work being undertaken. The technical proposal must also include information on how the project is to be organized, staffed, and managed. Information should be provided which will demonstrate your understanding of management of timeframes for planning and accomplishing the work to be performed.

Record and discuss specific factors not included elsewhere which support your proposal.

Using specifically titled subparagraphs, items may include: Unique arrangements, equipment, etc., which none or very few organizations are likely to have which is advantageous for effective implementation of this project.

The Offeror must adhere to a 150-page limit. Pages in excess of this limitation will be removed from the proposal and will not be provided to the reviewers to be read or evaluated. The 150-page limit excludes the cover sheet, resumes, and all appendices or attachments. The 150-page limit also excludes the 15 pages for each Sample Protocol response. Please refer to the Sample Protocol for specific proposal submission instructions.

Pages shall be of standard size (8.5x11) with a font size of 10 points or larger. Proposal pages shall be numbered "Page 1 of 150", "Page 2 of 150" and so on.

TECHNICAL PROPOSAL - TABLE OF CONTENTS

General Instructions:

SECTION 1

A. PROPOSAL TITLE PAGE. Include RFP title and number, name of organization, DUNS number, proposal part, and identify if the proposal is an original or a copy.

B. PROJECT OBJECTIVES (NIH FORM 1688-1)

C. GOVERNMENT NOTICE FOR HANDLING PROPOSALS

D. PROPOSAL SUMMARY AND DATA RECORD (NIH-2043)

E. TABLE OF CONTENTS

SECTION 2: MANDATORY QUALIFICATION CRITERIA

The offeror should include all information which documents and/or support the mandatory qualification criteria in one clearly marked section of its technical proposal. At minimum, proposals shall include the following:

GLP Compliance: The most recent FDA Establishment Inspection Report demonstrating that the facility is currently in compliance with FDA GLP regulations, i.e. not currently disqualified.

Animal Care and Use: 1) A copy of your organization’s most recent letter from NIH’s Office of Laboratory Animal Welfare (OLAW) documenting approval of a valid Animal Welfare Assurance, and 2) a copy of your organization’s most recent USDA Animal Welfare Act registration certificate.

SECTION 3: TECHNICAL DISCUSSIONS

A. PERSONNEL

Describe the experience, qualifications and training of personnel who will be assigned for direct work on this program. 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 the total time each will be available for this program.

CVs for all personnel shall be submitted. Each shall indicate educational background, recent experience, specific or technical accomplishments, and a listing of relevant publications and technical reports. Limit CVs to 2-3 pages and provide selected references for publications relevant to the scope of the RFP, and include experience with projects of similar scope, size and complexity carried out over the past five (5) years.

1. Principal Investigator/Project Director

Describe the education, training, expertise, qualifications, experience, and accomplishments of the Principal Investigator. The Principal Investigator should have a Ph.D., D.V.M., or M.D. degree or equivalent experience. The Principal Investigator should have experience in managing an interdisciplinary team in the conduct of toxicological and pharmacological assessments to qualify potential small molecules for cancer and other indications for further testing and clinical development according to Food and Drug Administration (FDA) requirements; and adherence to FDA and International Conference on Harmonization (ICH) guidelines for toxicity and safety studies of compounds. State the percentage of effort for the Principal Investigator to be spent on the project.

2. Other Scientific and Technical Personnel

The Offeror should list all other investigators/professional personnel who will be participating in the project. Describe the education, training, experience, expertise, qualifications, role in the project, and percentage of effort for all proposed key scientific and technical personnel of the Offeror and all proposed subcontractors. Document relevant qualifications for: pathology (specifically necropsy of animals and microscopic evaluation of blood and tissues), clinical pathology, statistics, veterinary medicine, laboratory animal care, analytical chemistry, pharmacokinetics and quality assurances.

3. Additional Personnel

• Offerors staff should include an experienced DVM pathologist with an American College of Veterinary Pathology (ACVP) diplomate to be present at and oversee all scheduled necropsies and conduct histopathological evaluations. If the offeror does not have a DVM pathologist with the above credentials, the Offeror may propose a subcontractor or consultant.

• Offerors staff should include a participating ACLAM certified veterinarian, or a veterinarian with the equivalent certification, to oversee the animal medicine and animal husbandry operations. Alternatively, a contractual relationship with an on-call consultant ACLAM veterinarian should be established. Provide documentation of your ACLAM, or equivalent, certified participating veterinarian.

• Offerors staff should include a Toxicologist who has documented experience and background in animal toxicity testing and who is certified by the American Board of Toxicology.

• The Offeror shall list names, titles, and proposed duties of additional personnel, if any, who will be required for full-time employment, or on a subcontract or consultant basis. For all proposed personnel who are not currently members of the Offeror's staff, a letter of commitment or other evidence of availability should be included.

Commitment letters for use of consultants and other personnel to be hired should include:

• The specific items or expertise they will provide.

• Their availability to the project and the amount of time anticipated.

• Willingness to act as a consultant.

B. TECHNICAL APPROACH AND AWARENESS

Offerors shall submit a proposal that addresses all areas specified in the Statement of Work.

If the proposed approach will involve a subcontracting arrangement, then the offeror shall include a letter(s) of commitment from the subcontractor(s), plus documentation of subcontractor's expertise, qualifications and prior performance, as well as a narrative describing how the Offeror will manage the subcontractor.

1. Describe the procedures to be used for carrying out the types of preclinical toxicology studies indicated in the Statement of Work, including criteria for moribund sacrifice, method and equipment to be used for euthanasia, collection, handling and storage of blood samples for clinical pathology and plasma drug analysis, necropsy and histopathology procedures, and analytical chemistry procedures. Also describe how the carcasses of animals that die overnight will be stored until necropsy can be performed the next (calendar) day.

2. Describe approach to regulatory issues and study design.

3. Describe the approach to the development of analytical procedures for the assay of a drug in plasma, urine, and tissues.

4. Describe the features and capabilities of data management, including software programs currently in use. Describe proposed plans for oversight of data management functions, including protection of intellectual property and confidentiality of data.

5. The Offeror shall discuss the handling and format of acquired data and plans for providing raw and derived data to the NCI COR at the end of studies. The data needs to be compatible with NCI/DCTD's data management system (currently Excel), and, if specified in the project, also be submitted in SEND-compliant format. Specifications for compatibility will be given in each project. The report will be formatted as per FDA guidance in the electronic Common Technical Document (eCTD) format for IND filing.

6. Describe the operation of the Quality Assurance Unit within your organization concerning auditing of critical study events, raw data and study reports. Indicate when these audits take place in relation to the generation of data and reports.

7. Provide a copy of Standard Operating Procedures (SOPs) relating to the conduct of the type of tasks found in the Statement of Work, including laboratory SOPs.

8. Safety and Health for Personnel - Provide a Safety and Health Plan. Offerors' Safety and Health Plan shall include recent and ongoing organizational background and experience in all areas specified in the Statement of Work (SOW), especially where data has been utilized for Investigational New Drug/New Drug Application (IND/NDA) submissions and/or publications in peer-reviewed journals. Offerors shall also submit their Safety Manual.

9. Offerors should describe procedures and controls to be employed during tests included in the SOW to ensure that the work is conducted in a safe and healthful manner. All pertinent chemical and or biological hazards shall be addressed in the Plan, from receipt of test agents to ultimate disposal of contaminated waste. Details of appropriate administrative and emergency controls, personnel, protective equipment and work practices shall be addressed.

All work shall comply with applicable local, state and federal statutes relating to occupational safety and health, transportation and handling, and environmental protection.

Discuss equipment and unusual operating procedures established to protect personnel from hazards associated with this project and other factors you feel are important and support your proposed approach.

10. Statistics - Methods of statistical analysis (parametric versus nonparametric) shall be described by the Offeror for data and underlying distributions being compared. Specifications of the in-house historical database for each species shall be described. In the dog study the statistical analyses shall include change with treatment over time, i.e. differences or percent changes for an analyte between testing intervals for each dog, which are then averaged within the group and compared across groups.

11. Offerors should discuss, as appropriate, the management of collaborations with subcontractors. Discuss how the technical and scientific planning and implementation of task orders will be managed by the Principal Investigator (Pl). Discuss how the PI will manage the proposed team(s) both within and across collaborating and subcontracting institutions.

12. Letters of commitment from and qualifications of all subcontractors shall be included in the proposal.

C. SAMPLE PROTOCOLS

Offerors must respond to all Sample Protocols separately and clearly label each proposal.

The responses to the Sample Protocols should be included as a separate section (appropriately marked) in the Technical Proposal. The page limit for each Sample Protocol proposal is 15 pages. The Sample Protocol 15-page limit excludes the cover sheet, resumes, and all appendices or attachments. The responses to the Sample Protocols do not count towards the technical proposal 150-page limit. The Offeror's responses to the Sample Protocols should include discussion of technical approach, personnel proposed, facilities and equipment.

See Section J- Attachment 4- Sample Protocols

D. ORGANIZATIONAL BACKGROUND AND EXPERIENCE

Discuss prior experience with similar tasks and provide documentation of completed studies.

1. Provide a list of study reports that have been submitted to the FDA as part of an Investigational New Drug (IND) application. This listing should not include any proprietary information, but should list type of agent, study, route and species. Offerors should limit this information to the past five (5) years.

2. Quality Assurance - The Offeror shall discuss the organization, operation, and responsibilities of the Quality Assurance Unit in similar studies. FDA inspections, data audits, and outcomes should be presented. Validation studies undertaken to assure the accuracy of transmitted data for the version(s) of software shall be described.

3. Subcontracts - The Offeror shall describe any previous working relationship with proposed subcontractors. Furthermore, the Offeror shall address how they will handle privity of contract issues, i.e., the Offeror should explain how information will flow between the NCI, the prime contractor (Offeror), and any subcontractors since the prime contractor's presence is required for any discussions. The Offeror shall describe the subcontracting process - timelines and oversight.

4. The Offeror shall provide documentation of current AAALAC accreditation.

5. The Offeror shall provide documentation of a current established IACUC.

6. The Offeror should include an organizational chart that describes the reporting structure of the organization.

7. Provide a statement noting the prioritization of this project in relation to other ongoing projects. Provide a list /description of resources committed to the project. Provide a five

(5) year history of recruitment and retention on similar projects.

E. COMPLIANCE WITH FEDERAL REGULATION 21 CFR PART 58

Provide documentation of current compliance with 21 CFR PART 58. A strong proposal shall include no inspectional observations that have not been adequately addressed. To demonstrate adequate compliance with FDA GLP, Offers shall submit the following:

• The most recent FDA Establishment Inspection Report from the last 10 years.

• Any Discussion Items or Inspectional Observations documented on a FDA Form 483 that were flagged during that inspection.

• Any warning letters from the FDA because of inadequate responses/actions to resolve any Inspectional Observations.

• Your written responses to the Inspectional Observations or warning letters.

• Any FDA letters in response to your written responses or to your assurances of the corrective actions that have been taken or will be taken. These documents shall be provided before or at the time of submission of the Final Proposal Revision.

F. FACILITIES AND EQUIPMENT

1. Facilities - The proposal must document that the facilities meet the requirements and are available to the project. The offeror shall have an operating laboratory which is suitable for cell culture and laboratory animal studies using hazardous and/or carcinogenic test materials. The laboratory shall be capable of handling hazardous chemicals safely and must be able to provide appropriate facilities for housing animals required in the study. The laboratory and animal care must be sanitary and properly maintained. The laboratory and animal facility must be compliant with all federal, state and local regulations and statutes (see Section M 4. of the Solicitation, Mandatory Qualifications Criteria).

Discuss operation, procedures, and administration of the cell culture and animal facility and provide floor plans drawn to scale with the scale indicated clearly on the diagram. Indicate your capability to perform several studies of the same type at the same time (i.e., concurrently), in particular, with large animals (dogs). In addition, indicate the location (with distance) for any facilities which are not contiguous. The Offeror should describe the facilities and equipment that belong to subcontractors. Where facilities of the Offeror are not contiguous and for any no-co-localized subcontractors, the Offeror must describe logistical plans for the transfer of materials and/or data.

Discussion shall include, as appropriate, but not be limited to:

• available room capacities

• temperature controlled C02 incubators, sterile laminar flow hoods

• sterile tissue culture materials and techniques

• cryopreservation capability, microscopy capability

• climate controls and alarm systems

• caging and exercise

• diet and compound storage and preparation areas

• water systems

• cage washing areas

• data collection and computer systems

• animal treatment laboratories (cardiology, ophthalmology, phlebotomy, necropsy)

• clinical and anatomic pathology laboratories and established quality control practices

• electrical and environmental back up provisions for critical components e.g. animal rooms, chemical test article and biological samples, etc.

• data back-up systems

2. Equipment - The offeror shall have all the equipment necessary to accomplish the studies including but not limited to, incubators, microscopes, centrifuges, animal racks and caging, hazardous chemical storage cabinets and refrigerators, pathology equipment, such as microtomes, laboratory and analytical chemistry equipment. The laboratory shall have or have access to appropriate terminal and computer facilities and equipment for data collection and storage.