AdditionalTechnicalProposalInstructions.pdf

RFP/N01-CM-07014-39

Attachment 15

Additional Technical Proposal Instructions

“Preclinical Pharmacokinetic and Pharmacological Studies of Anticancer and Other Therapeutic Agents”

A detailed proposal must be submitted indicating how each aspect of the statement of work is to be accomplished. Your narrative should be in as much detail as you consider necessary to fully explain your proposed technical approach or methods. The technical proposal 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 and management of tasks related to analytical methods development and preclinical pharmacokinetics.

1. Mandatory Qualification Criteria

Offerors must include as a separate section of the Technical Proposal a discussion of how they meet the Mandatory Qualification Criteria required by the Mandatory Qualification Criteria. Specifically,

a. The offeror may not be a pharmaceutical or chemical firm because agents of a commercially confidential nature (discreet) may be evaluated.

b. The offeror must possess a valid Nuclear Regulatory Commission (or foreign equivalent) license permitting the purchase, storage, and use of radioisotopes (e.g., 3H, 14C, 35S) likely to be used in the proposed pharmacological research. It is expected that cumulative permissible inventory amounts of each nuclide will be similar to the default quotas shown at:

http://drs.ors.od.nih.gov/forms/activitylimits.pdf

2. Technical Discussions

The technical discussions included in the technical proposal should respond to the items set forth below:

A. Personnel

OFFERORS SHOULD ASSURE THAT THE PRINCIPAL INVESTIGATOR AND ALL

OTHER PERSONNEL PROPOSED SHALL NOT BE COMMITTED ON FEDERAL

GRANTS AND CONTRACTS FOR MORE THAN A TOTAL OF 100 PERCENT OF

THEIR TIME. IF THE SITUATION ARISES WHERE IT IS DETERMINED THAT A

PROPOSED EMPLOYEE IS COMMITTED FOR MORE THAN 100 PERCENT OF

HIS OR HER TIME, THE GOVERNMENT WILL REQUIRE ACTION ON THE PART

OF THE OFFEROR TO CORRECT THE TIME COMMITMENT.

(1) Principal Investigator

A Principal Investigator responsible for overseeing the Project should be named.

This individual should possess at least 5 years of diverse experience in the pharmacologic and pharmacokinetic investigation of therapeutic agents (particularly antitumor agents) and have demonstrated an ability to lead a multi-disciplinary team of scientists, which shall include individuals with analytical methods and pharmacokinetic expertise. He or she should have attained doctorate level (or equivalent) educational status in pharmacology or a closely related discipline. A resume for the proposed Principal Investigator should be provided which indicates his/her education, background, recent experience, and specific scientific accomplishments. A complete bibliographic listing of published or accepted papers as well as any unpublished technical study reports should also be provided (proprietary compound names may be censored). Study reports that have been submitted to the FDA as part of an IND or NDA is considered of equal importance with peer-reviewed publications in demonstrating experience. The Principal Investigator should devote no less than 25% of his or her time to this project.

(2) Other Professional Personnel

All other investigators/professional personnel should be named, indicating their present responsibilities and availabilities to the project. Current resumes of all proposed personnel, which indicate education, scientific background, recent experience, and specific scientific or technical accomplishments, should be provided. Unrelated information or resumes of individuals not assigned to, or involved with, the proposed project are neither necessary nor desired, and will be considered as detracting from the proposal. A bibliography listing publications (including any study reports) relevant to this project should be included for each individual proposed. The percent effort/annual hours to be provided by each individual should be indicated

Particular emphasis should be placed on the senior professional staff who will oversee and manage the specific technical tasks described in the Statement of Work [e.g., high pressure liquid chromatography (HPLC), mass spectrometry (MS), enzyme-linked immunosorbant assay (ELISA), bioassays, animal dosing and sample collection, pharmacokinetic analyses, metabolite quantitation and identification, in vitro ADME, etc.]..

Knowledge and experience in the area of drug metabolism shall also be required.

Techniques will include: (1) isolation and identification of metabolites from plasma, urine, and tissues following administration of test compounds to animals and; (2) performance of in vitro metabolism studies utilizing, for example, tissue S9 fractions, microsomes, cloned P450 isoforms, hepatocytes, liver slices, and mice with genetically-engineered human drug-metabolizing enzymes.

Experience with one or more of the following techniques is considered desirable, but will not be an absolute requirement for award: (1) the use of in vitro methodologies (such as permeability through cell monolayers or other specialized cell lines) to predict the bioavailability of new compounds; (2) the ability to perform pharmacokinetic studies in large animals such as dogs and non-human primates; (3) expertise in specialized animal procedures (e.g., bile duct cannulation, surgical techniques to perform site specific absorption or hepatic clearance studies.); (4) the identification and quantitation of biological therapeutic agents (e.g., immunotoxins, antibodies, gene therapy constructs) using techniques such as ELISA, PCR, immunoblots, and mass spectroscopy;

(5) the use of microdialysis techniques to monitor blood and/or tissue levels of test agents and metabolites in real time.

(3) Additional Personnel

List names, titles, level of effort, and proposed duties of any additional personnel, including technical and support staff, proposed on the contract. Current resumes of the proposed personnel, which indicate education, training, and recent experience and accomplishments relevant to their proposed roles should be provided as appropriate.

Since technical expertise will be an important consideration in the work to be performed, particular emphasis should be placed on the overall technical capabilities of the group, identifying those individuals who will be responsible for specific technical tasks, [e.g., high pressure liquid chromatography (HPLC), mass spectrometry (MS), enzyme-linked immunosorbant assay (ELISA), bioassays, animal dosing and sample collection, pharmacokinetic analyses, metabolite quantitation and identification, in vitro ADME, etc.]. The percent effort/annual hours to be provided by each individual should be indicated.

(4) Subcontractors and Consultants

List names, titles, level of effort, and proposed duties of any personnel who are proposed on a subcontract or consultant basis. The technical areas, character, and extent of subcontract or consultant activity should be indicated and the anticipated sources should be specified and described. For all proposed personnel who are not currently members of the offeror's staff, a letter of commitment or other evidence of availability is required. A resume or CV for each proposed subcontractor or consultant should be provided, but this does not meet the requirement for evidence of availability. Commitment letters for use of consultants must 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.

• How rights to publications and patents will be handled.

B. Technical Approach and Awareness of the Problem

Describe in detail how the group will be organized, both scientifically and administratively. The proposal should include a detailed description of at least one recent example from the group's own experience with the development of a method for the analysis of a drug in biological fluids such as plasma or urine. Also include a description of a pharmacokinetic study in the mouse, rat, dog or other species recently performed by the proposed group of investigators and the approach used to model the data. Discuss in detail previous work experiences and approaches that will be used in conducting the proposed pharmacological studies, encompassing the items listed in the Statement of Work. This discussion should detail the breadth of experience of the proposed research team with analyses of diverse chemical structures and the conduct of in vivo and in vitro pharmacokinetic studies.

Additional discussions should include approaches to developing sensitive analytical methods for highly potent compounds, available techniques for collecting single or multiple blood samples from rodents, the potential advantages/disadvantages (and availability) of conducting pharmacokinetic studies in tumor-bearing animals, and the procedures to be used for small animal necropsy, including collection, processing, and storage of selected tissue samples.

Successful contractors shall be expected to apply state-of-the-art instrumental analysis techniques to the development and validation of quantitative assays for test compounds in plasma, tissues, and/or other biological fluids. Core techniques expected to be available include HPLC, LC-MS, and/or LC-MS/MS. Additional desirable techniques may include (but are not limited to) gas chromatography, capillary electrophoresis, and immunoassays.

The current role of mass spectroscopic techniques for rapid and sensitive quantification of therapeutic agents should be discussed. Include approaches to the development and validation of these methods, including “generic” platforms that may allow rapid method implementation with limited validation for early-stage pilot/screening applications.

C. Facilities and Equipment

Describe in detail the laboratory space and equipment available for the performance of the studies proposed. A floor plan to scale, indicating relevant dimensions should be provided for all laboratory space available to this project, identifying the areas where different facets of the work are conducted. In situations where more than one building or institution is involved, a clear description should be given of the locations of all sites, the distances and travel time between them, and (if proposed) the procedures for transport of animals and/or biological samples from one site to the other.

A complete description of animal facilities to be used on the project should be provided, along with relevant floor plans to scale. Accreditation of the facility by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International), the Canadian Council on Animal Care (CCAC) or the UK Animals Scientific Procedures Inspectorate (ASPI) is highly desirable. A copy of the latest review, if applicable, should be included. Offerors should have appropriate facilities and equipment to perform pharmacokinetic studies in rodents (and optionally in larger species) using various routes of administration (e.g., intravenous, oral, subcutaneous, and intraperitoneal injections and/or infusions).

A description of all major equipment available for the work should be provided and its location noted. Particular attention should be given to the analytical instrumentation available for this project. The ability to use mass spectrometric instrumentation in conjunction with liquid chromatography for routine quantitative analysis of samples from pharmacokinetic studies is expected, and if this equipment is NOT under the direct control of the Principal Investigator, an alternative approach should be proposed and justified. Availability of appropriate mass spectrometric instrumentation for elucidation of chemical structures is also required.

Information should be provided on institutional procedures for equipment maintenance, calibration, and validation. While it is expected that most equipment will be under the direct control of the PI and project team members, special mention should be made when this is not the case. When equipment is only available on a shared basis, some evidence should be provided as to who is responsible for controlling access and how the determination of priority of usage will be made (letter of commitment from Department Head, etc).

A description of computer hardware and software available for the project should be provided. Particular emphasis should be given to the pharmacokinetic modeling software to be used. A description of available electronic information and or library resources should be provided; if not completely in-house, a description should be given of outside facilities within easy traveling distance of the institution that are available for use.

D. Organizational Experience and Support

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, not necessarily the experience and/or past performance of individuals who are offered as personnel in your proposal.

The established existence of an organizational environment which fosters pharmacological investigations of therapeutic agents should be demonstrated, especially for the recent past. Examples of institutional accomplishments in these areas should be provided. An organizational chart(s) that shows lines of authority within the organization and the research team should be included Assurance should be provided that the organization is capable and willing to provide appropriate personnel and resources to accomplish the stated work over the period of performance of any contract awarded.

How your institution would handle simultaneous Work Assignments or possible periods with no active Work Assignments (other than the Administrative Work Assignment) should be discussed from a technical and administrative perspective.

E. Safety and Security

Each test agent will be considered potentially hazardous. Therefore, all necessary precautions must be taken to protect personnel and the environment against possible exposure to the agents being tested. 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. 29 CFR 1910.1450) and follow regulations governing transportation and disposal of hazardous waste.

Describe fully the proposing organization’s policy on safety and security. Describe laboratory safety controls and procedures for handling and disposing of carcinogens and toxic waste materials proposed to be used for this project. Describe procedures for the prevention of contamination during laboratory operations. Indicate your awareness of OSHA regulations, etc., and provide documentation of any recent OSHA inspections and compliance. Please supply a copy of the organization’s current Health and Safety Manual. Describe current security procedures for protection of animal and other facilities.

3. Technical Evaluation

Proposals will be technically evaluated in accordance with the factors, weights, and order of relative importance as described in the Technical Evaluation Criteria.

4. Work Assignments

Work Assignments will be issued under cost-reimbursement, completion-type contracts resulting from this solicitation. Work Assignments will be initiated by the Project Officer, who will forward a request to the Principal Investigator stating the period of performance, the specific work to be performed, and the deliverables. Within the specified period, the Contractor will submit to the Project Officer a detailed description of the technical approach to be used in carrying out the Work Assignment, and an estimate of the required effort and cost. The cost of a Work Assignment shall not exceed the funds remaining in a funding period. With the concurrence of the Project Officer, the Contracting Officer will then execute the Work Assignment. No later than three months after completion of the Work Assignment, the Contractor shall forward to the Project Officer a Work Assignment Completion report providing a listing of the actual labor and cost for the Work Assignment and the stated deliverables. Upon the recommendation of the Project Officer, the Contracting Officer will then approve the Work Assignment for completion. For further information see Attachment 22 - Sample Work Assignments for Offerors’ Information and Cost Estimates

At the time of award of a contract, an Administrative Work Assignment shall be initiated for the first year of performance. This Work Assignment will cover the effort and expenditures necessary for administration of the contract (other than the conduct of specific pharmacology studies). As shown in Attachment 22 the tasks specifically applicable to this Administrative Work Assignment will consist of and be limited to: (1) preparation of responses to subsequent Work Assignments; (2) preparation of monthly status reports; (3) preparation of final Work Assignment Reports, Annual Reports, and the Final Contract Report; and (4) allowable travel expenditures as detailed in Section C.

5. Additional Technical Proposal Information

A. Proposals which merely offer to conduct a program in accordance with the requirements of the Government's scope of work will not be eligible for award. The offeror must submit an explanation of the proposed technical approach in conjunction with the tasks to be performed in accomplishing the project objectives.

B. Separate technical and cost/business evaluations will be performed. Inter-relationships of the two will be assessed consistent with DHHS regulations concerning the consideration of cost and other factors in making awards.

C. The technical evaluation is conducted in accordance with the weighted technical evaluation criteria by an initial review panel. This evaluation produces a numerical score which is based solely upon the information in the offeror's proposal.

D. Travel Requirements

(1) The offeror should plan for the Principal Investigator and/or a staff scientist to attend one national scientific meeting per year. This travel must be approved, in advance, by the Project Officer and the Contracting Officer. For budget purposes, assume per diem, lodging, and air fare for one four-day meeting at a distance of a thousand miles.

(2) The offeror should plan for the Principal Investigator to visit Rockville, MD once per year to discuss technical matters with Program staff. For budget purposes, assume all allowable travel expenses for a single one-day meeting per year.

6. Other Considerations

A. Confidentiality. All data provided to the Contractor and developed by the Contractor under this contract must be treated confidentially. The data to be treated confidentially are associated not only with the certain “discreet” compounds which are not available to the public, but with all agents that are under development by the National Cancer Institute (NCI). When compounds are assigned to the Contractor, “discreet” compounds will be identified by the letter “D” as a prefix to the compound’s NSC number, and in those cases the compound shall be referred to by the NSC number only and not by name. Under no circumstances are chemicals or drugs or any information associated with these chemicals or drugs, including the data generated under this contract, to be released or divulged to the public without prior written approval of the NCI Project Officer.

The Government requires that all data accumulated under the projected contracts be immediately available for its review and that provisions be made to maintain confidentiality of all data. Authority to release data may be granted only by the Contracting Officer together with the Project Officer and must be in writing.

B. Record and discuss specific factors not included elsewhere which support your proposal. Using specifically titled subparagraphs, items may include:

(1) Unique arrangements, equipment, etc., which none or very few organizations are likely to have which are advantageous for effective implementation of this program.

(2) Equipment and unusual operating procedures established to protect personnel from hazards associated with this project.

C. Each institution should establish and provide resources for an animal care and use program that is managed in compliance with applicable federal, state, and local laws and regulations, such as the federal Animal Welfare Regulations, or AWRs (CFR 1985), and Public Health Service Policy on Humane Care and Use of Laboratory Animals, or PHS Policy (PHS 2002). To implement the recommendations in this Guide effectively, an institutional animal care and use committee (IACUC) must be established to oversee and evaluate the program.

The Contractor must also provide an animal welfare assurance indicating compliance with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals, information for which is available on:

http://grants.nih.gov/grants/olaw/references/phspol.htm#USGovPrinciples and the OLAW website at http://grants.nih.gov/grants/olaw/olaw.htm.

The National Institutes of Health (NIH) requires that prior to awarding of funds for contracts involving the use or intended use of animals in research, an acceptable assurance statement must be on file with the Office for Protection from Research Risks (OPRR).

D. Human Subjects

It is hereby understood and agreed that research involving human subjects shall not be conducted under this contract, and that no material developed, modified, or delivered by or to the Government under this contract, or any subsequent modification of such material, will be used by the Contractor or made available by the Contractor for use by anyone other than the Government, for experimental or therapeutic use involving humans without the prior written approval of the Contracting Officer. However, refuse human materials such as blood, serum, plasma, bone marrow, liver, kidney, etc., may be necessary for use on this contract.

E. Government-Furnished Supplies and Information

(1) Animals, particularly mice and rats, may be supplied by the Government when available; otherwise they shall be purchased by the contractor under this contract from a suitable commercial vendor as authorized by the Project Officer. All dogs, rabbits, non-human primates and specialty animals such as catheterized mice or rats shall be purchased by the contractor under this contract from a suitable commercial vendor as authorized by the Project Officer.

(2) All test agents, including radiolabeled test agents, will be supplied by the

Government. Radiolabeled compounds shall routinely be assessed for radiopurity by the Contractor.

(3) Individual Work Assignments will be accompanied by all pertinent information available to the Government concerning the compound under investigation.

Such information will include, for example, chemical properties and purity, analytical methodology, stability and storage information, safety and other toxicity data, pharmaceutical and formulation information, effective doses and/or concentrations, and other pertinent biological data.

F. Estimate of Effort

It is expected that up to seven (7) cost-reimbursement, completion-type contracts will be awarded as a result of this RFP for a period of five (5) years. Only one award will be made to an institution.

To assist you in the preparation of your proposal, the Government considers the effort required to be approximately 5000 labor hours per year, exclusive of vacation, sick leave, and holidays, for the period of the contract. This information is furnished for the offeror's information only and is not to be considered restrictive for proposal purposes. A breakdown of the Government’s estimated effort per year is as follows:

Labor Category Estimated Hours Per Year Principal Investigator 350 hours Other Professional 375 hours Technical Support 3,625 hours Other 650 hours Total Hours Per Year 5,000 hours

In order for offerors to establish a basis for their cost estimates, the series of sample Work Assignments (#1-4) provided in Attachment 22 comprise a representative one year of work on any contract(s) to be awarded from this solicitation. Assume that WA 1 will run continuously for the 1-year period, that WAs 2 and 3 will run sequentially for a total of 9 months and that WA 4 will run for a 5-month period that partially overlaps with WA 3.

Actual assignments each year will vary but will comprise up to an equivalent amount of effort. In addition to using this information to prepare an overall cost estimate for your proposal, offerors should also submit cost estimates for each Work Assignment in the format shown in the attached spreadsheet.

G. PAST PERFORMANCE FACTOR

The offeror’s past performance will be evaluated after determination of the competitive range. Only those offerors included in the competitive range will be evaluated.

The Government will evaluate the quality of the offeror’s past performance based on information obtained from references provided by the offeror, as well as other relevant past performance information obtained from other sources known to the Government.

Evaluation of past performance will be a subjective assessment based on a consideration of all relevant facts and circumstances. It will not be based on absolute standards of acceptable performance. The Government is seeking to determine whether the offeror has consistently demonstrated a commitment to customer satisfaction and timely delivery of services at fair and reasonable prices.

The assessment of the offeror’s past performance will be used as a means of evaluating the relative capability of the offeror and the other competitors. Thus, an offeror with an exceptional record of past performance may receive a more favorable evaluation than another whose record is acceptable, even though both may have acceptable technical proposals.

Past performance will not be scored, but the Government’s conclusions about overall quality of the offeror’s past performance will be highly influential in determining the relative merits of the offeror’s proposal and in selecting the offeror whose proposal is considered most advantageous to the Government.

By past performance, the Government means the offeror’s record of conforming to specifications and to standards of good workmanship; the contractor’s record of forecasting and controlling costs; the offeror’s adherence to contract schedules, including the administrative aspects of performance; the offeror’s reputation for reasonable and cooperative behavior and commitment to customer satisfaction; and generally, the offeror’s business-like concern for the interest of the customer.

The Government will consider the number or severity of an offeror’s problems, the effectiveness of corrective actions taken, the offeror’s overall work record, and the age and relevance of past performance information.

The lack of a performance record may result in an unknown performance risk assessment, which will neither be used to the advantage nor disadvantage of the offeror.