Task order 1-Attachment 3.pdf

Request for Task Order Proposal – Task Order 1

TASK ORDER 1 -Attachment 3

RTOP No: FDA-23-RTOP-11751

Study Title: Are reductions in BOE, BOPH, and other health risk markers proportional to reductions in cigarette smoking upon switching to ENDS?

BRIEF DESCRIPTION OF SERVICES

The primary function of the Food and Drug Administration (FDA) is to promote public health associated with the use of foods, dietary supplements, cosmetics, drugs, tobacco, and other products under its jurisdiction. FDA's Center for Tobacco Products (CTP) implements PL 111-31 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act), which was signed into law on June 22, 2009. The Tobacco Control Act granted FDA important authority to regulate the manufacture, marketing, and distribution of tobacco products to protect public health. Currently, data evaluating the relationship of cigarette reduction to resultant reductions in biomarkers and negative health effects are limited to associations. No published studies quantify the cause-effect relationship of controlled cigarette reduction to reduction in individual health risk. This study proposes controlled cigarette reduction while supplementing participants’ nicotine intake through ad libitum Electronic Nicotine Delivery System (ENDS) use as a model of switching and dual use of ENDS and combusted cigarettes. The aims of this study are to 1) examine whether reductions in biomarkers of exposure (BOE), biomarkers of potential harm (BOPH), and other health risk markers (i.e., vital statistics, adverse events (AEs), serious adverse events (SAEs)) are proportional to reductions in combusted cigarette smoking; identify the magnitude of cigarette reduction needed to produce changes in BOE and BOPH that translate into clinically meaningful impacts on human health outcomes, and 2) compare changes in BOE, BOPH, and other health risk markers across proportion of cigarette reduction (e.g., 25%, 50%, 75%, 100% reduction in cigarettes per day [CPD]).

TASK ORDER TYPE

The Government anticipates the award of a hybrid contract, with a mix of firm-fixed price and time and materials deliverables, as a result of this RTOP.

The Government recommends the following tasks are fixed price deliverables:

• Task 1: Kick off meeting

• Task 2: Non-disclosure of private information (NPI) forms

• Task 3: Biweekly meetings

• Task 4: Monthly progress reports

• Task 7: Final laboratory study protocol

• Task 8: Final clinical study protocol

• Task 10: Obtain clearances for the study

• Task 12: Participant recruitment updates

• Task 13: Draft clinical study report

• Task 14: Final clinical study report

• Task 15: Draft laboratory study report

• Task 16: Final laboratory study report

The Government recommends the following tasks are time and material deliverables:

• Task 5: Draft laboratory study protocol

• Task 6: Draft clinical study protocol

• Task 9: Perform laboratory study

• Task 11: Perform clinical study

SCOPE OF WORK

The primary aims of this task order are to examine whether reductions in BOE, BOPH, and other health risk markers (i.e., vital statistics, Adverse Events [AE], Serious AEs [SAE]) are proportional to reductions in combusted cigarette smoking supplemented by ENDS use; identify the magnitude of cigarette reduction needed to produce changes in BOE and BOPH that translate into clinically meaningful impacts on human health outcomes for those who become dual users (i.e., concurrent use of combusted cigarettes and ENDS) or switch completely to ENDS use; and compare changes in BOE, BOPH, and other health risk markers across proportions of cigarette reduction (e.g., 25%, 50%, 75%, 100% reduction in CPD) in dual users and those who switch to exclusive ENDS use. The Contractor shall recommend an ENDS and e-liquid that represents the current ENDS marketplace and fits within the parameters set forth by the FDA.

The Contractor shall conduct a randomized, parallel cohort switching study conducted under in-patient conditions. Current cigarette smokers will be recruited and randomized to complete one of five experimental conditions: continue cigarette smoking, or switch to ENDS while concurrently reducing combusted cigarette smoking by either 25%, 50%, 75%, or 100% of their baseline CPD. Prior to entering the in-patient clinic, participants will be asked to continue their normal cigarette smoking behavior to allow for baseline assessment of BOE/BOPH and other study outcomes at intake. Eligible participants will then be admitted into an in-patient clinic where they will stay for seven days. In the period between intake and randomization (e.g., 1-2 days), participants will be able to use combusted cigarettes ad libitum to establish baseline consumption. The contractor shall recommend an appropriate timeline for intake, baseline assessment, and the experimental portion of the inpatient study. Following randomization, participants in the continue-cigarette-smoking condition will have ad libitum access to combusted cigarettes throughout their in-patient stay. Participants randomized to switch to ENDS and concurrently reduce cigarette smoking will have ad libitum access to ENDS and will receive a designated number of combusted cigarettes to use per day, depending on condition (i.e., 25%, 50%, 75%, 100% reduction of their baseline CPD). Serial blood, urine, and saliva samples will be collected at intake and throughout the in-patient stay to assess changes in BOE (e.g., nicotine, carboxyhemoglobin, metabolites of TSNAs, PAHs, VOCs) and BOPH (e.g., HDL-cholesterol to assess cardiovascular function, IL-6 and IL-8 to assess inflammation, 8-isoprostane (8-isoPGF2α) to assess oxidative stress, 2,3-dinor thromboxane B2 (2,3-d-TXB2), leukotriene E4 (LTE4) to assess pulmonary and cardiovascular function (e.g., systolic and diastolic blood pressures, heart rate)). AEs and SAEs, although largely unexpected, will be recorded throughout the in-patient stay and reported in predetermined timeframes.

The contractor shall perform chemical characterization of the e-liquid (including nicotine, PG:VG ratio, pH; consider NNN, NNK) and machine-generated aerosol (including nicotine, PG:VG ratio, particle size; consider other HPHCs such as formaldehyde, acetaldehyde, crotonaldehyde, acrolein, acetone) from the study e-liquid.

The Contractor shall perform all data analyses, provide FDA all raw data, and write study reports. All results and source documents shall be submitted to the Contracting Officer’s Representative (COR) and Study Project Lead(s).

PRICING TABLE

Task Deliverable Quantity Price 1 Kick-off Meeting 1 $ 2 NPI Forms 1 for each staff member involved in clinical study

3 Biweekly Meetings 1 meeting every 2 weeks $ 4 Monthly Progress Reports 1 electronic version per month

5 Draft Laboratory Study Protocol

1 electronic version;

preliminary drafts may be needed

6 Draft Clinical Study Protocol 1 electronic version;

preliminary drafts may be needed

7 Final Laboratory Study Protocol

1 electronic version $

8 Final Clinical Study Protocol 1 electronic version $ 9 Perform Laboratory Study 1 $ 10 Obtain Clearances for the

Study (OMB and IRB) 1 electronic version each $

11 Perform Clinical Study 1 $ 12 Participant Recruitment

Updates 1 electronic version per week

13 Draft Clinical Study Report 1 electronic version;

additional drafts may be needed

14 Final Clinical Study Report 1 electronic version $ 15 Draft Laboratory Study Report 1 electronic version of final draft; additional drafts may be needed

16 Final Laboratory Study Report 1 electronic version $ Total $

SPECIFIC TASKS

Task 1 – Kick-off Meeting Within 10 business days of award, the Contractor shall set up and host a kick-off teleconference with the Study Project Lead(s), COR, and other FDA personnel to discuss roles, expectations, and deliverables associated with the task order requirements. During the kick-off meeting, the Contractor shall propose several commercially available ENDS and e-liquids to be used in the clinical study.

Task 2 – NPI Forms All Contractor staff shall sign NPI forms prior to commencing work. All signed forms shall be submitted electronically to the COR. If additional staff are added to this contract after contract award, Contractor staff shall sign the NPI form immediately, and the COR shall be notified.

Task 3 – Biweekly Meetings The Contractor shall set up biweekly teleconferences, for the duration of the contract, with the Study Project Lead(s), COR, and other FDA personnel to discuss study progress, challenges, and other study details every two weeks and as needed. Within 5 business days following each teleconference, the Contractor shall submit teleconference meeting minutes to FDA that include a detailed summary of the discussion as well as the contract progress status.

At the first biweekly teleconference, approximately 20 business days after contract award, the Contractor shall recommend 1-2 ENDS and e-liquids to be used in the clinical study. The Contractors recommendation shall be made with consideration of marketplace popularity, availability, and FDA marketing authorization (for a list of authorized ENDS, see: Premarket Tobacco Product Marketing Granted Orders | FDA). The Contractor’s recommendation shall include proposed brands and nicotine strengths of e-liquid(s), how the proposed products meet the criteria outlined in the SOW, relevant published data on nicotine PK, abuse liability, HPHC analysis, or chemical characterization of the proposed products, and any potential risks, drawbacks, and benefits to using each product in the clinical study.

Task 4 – Monthly Progress Reports The Contractor shall submit monthly progress reports on the 10th day of each month, for the duration of the contract, to the Study Project Lead(s), COR, and Contract Specialist detailing study progress, challenges (and solutions to those challenges), contract budget status, recruitment status, study deviations, adverse events, and other study details pertaining to the prior months progress. Progress reports shall indicate which deliverables or percentages of deliverables were completed during the month and overall progress of the contract and budget.

Task 5 – Draft Laboratory Study Protocol The Contractor shall develop a Draft Laboratory Study Protocol for the study titled “Are reductions in BOE, BOPH, and other health risk markers proportional to reductions in cigarette https://www.fda.gov/tobacco-products/premarket-tobacco-product-applications/premarket-tobacco-product-marketing-granted-orders https://www.fda.gov/tobacco-products/premarket-tobacco-product-applications/premarket-tobacco-product-marketing-granted-orders smoking upon switching to ENDS?” based on the following study objectives and protocol requirements:

Laboratory Study Objectives:

1. The Contractor shall recommend and, upon FDA approval, obtain an ENDS and e-liquid to be used in the clinical and laboratory studies. The ENDS type (e.g., pod-style, cartridge-based, tank) and e-liquid (e.g., nicotine concentration, formulation, PG:VG ratio) shall be representative of FDA-authorized ENDS and e-liquids in the current marketplace.

2. The Contractor shall conduct chemical characterization of study e-liquid, which may need to be removed from a closed-system ENDS, to measure analytes in the e-liquid (including nicotine, PG:VG ratio, pH; consider NNN, NNK) and aerosol (including nicotine, PG:VG ratio, particle size; consider other HPHCs such as formaldehyde, acetaldehyde, crotonaldehyde, acrolein, acetone). The Contractor shall select the laboratory and research facilities which are equipped to perform the study.

Protocol Requirements:

The Draft Laboratory Study Protocol shall include:

1. A description of the methods used by the Contractor to select an FDA-authorized study ENDS and e-liquid that are representative of the current marketplace.

2. A protocol detailing the storage conditions and how the samples are prepared and pulled for testing and use.

3. Analytical methods used to generate aerosol (i.e., puffing regimens) and yields from the

ENDS.

4. The Contractor shall provide a detailed step-by-step description of the analytical methods and procedures used to generate yield data. Information on the analytical procedure shall include (but not be limited to):

a. Analytical instrument

b. Apparatus

c. Laboratory consumables

d. Reagents

e. Test standards

f. Qualified personnel

g. Method calibration range, limit of detection (LOD), and limit of quantitation

(LOQ)

h. Sample preparation for the tobacco products and standards with any other pertinent protocol(s) including but not limited to extraction protocol

i. System suitability criteria

j. Data analysis (calculation applied to process data) and criteria in handling the outliers

k. Management systems

5. Verification of analytical methods to demonstrate that the methods are acceptable and suitable for their intended use. (If the test methods are standard or international standards, identify any deviation from those standards and provide scientific justification.) This includes, but is not limited to, the evaluation of the following parameters:

a. Accuracy

b. Precision

c. Specificity

d. Matrix effects

6. Validation of analytical methods if the methods are developed by the Contractor, detailing testing plans for the following parameters, if applicable:

a. Sample preparation (derivatization, extraction, concentration, etc.)

b. Reference sample

c. Accuracy

d. Precision (repeatability, intermediate precision and/or reproducibility)

e. Linearity

f. LOD

g. LOQ

h. Range

i. Specificity

7. The Draft Laboratory Study Protocol shall also include: study procedures; data handling and record keeping, data analysis; quality assurance plan; publication plan (if applicable); and administrative information.

It is required that the chosen e-liquid has documentation of PG/VG purity, USP grade nicotine, diethylene glycol levels below 0.10%, and ethylene glycol levels below 0.10% (e.g., Certificate of Analysis) and has received FDA marketing authorization.

Task 6 – Draft Clinical Study Protocol The Contractor shall develop a Draft Clinical Study Protocol for the study titled “Are reductions in BOE, BOPH, and other health risk markers proportional to reductions in cigarette smoking upon switching to ENDS?” based on the following study objectives and protocol requirements:

Study Objectives:

1. Examine whether reductions in BOE, BOPH, and other health risk markers (i.e., vital statistics, AEs, SAEs) are proportional to reductions in combusted cigarette smoking;

identify the magnitude of cigarette reduction needed to produce changes in BOE and BOPH that translate into clinically meaningful impacts on human health outcomes.

2. Compare changes in BOE, BOPH, and other health risk markers across proportion of cigarette reduction (e.g., 25%, 50%, 75%, 100% reduction in CPD).

Protocol Requirements:

1. The study shall be a single-site, randomized, parallel cohort switching study conducted over the course of seven days in an in-patient facility. The Contractor shall provide statistical considerations for sample size (e.g., a power analysis). Participants shall be adult, current combustible cigarette (CC) smokers. Full eligibility criteria shall be proposed by the Contractor. The study shall consist of a screening visit, intake, and a seven-day in-patient stay. The contractor shall recommend an appropriate timeline for intake, baseline assessment, and the experimental portion of the inpatient study.

Following intake, but before randomization, eligible participants will smoke their usual brand (UB) cigarettes ad libitum to establish baseline CPD. Prior to randomization, baseline urine, saliva, blood samples and vitals will be collected for baseline biomarker analysis and assessment of other baseline health effects. Participants will then be randomized into one of five cohorts and admitted to an in-patient clinic where they will remain for seven days. The five possible cohorts include: 1) 0% CC reduction (i.e., continued CC ad libitum use), 2) 25% CC reduction supplemented by ad libitum study ENDS use, 3) 50% CC reduction supplemented by ad libitum study ENDS use, 4) 75% CC reduction supplemented by ad libitum study ENDS use, and 5) 100% CC reduction supplemented by ad libitum study ENDS use (i.e., complete switching to study ENDS).

Participants randomized to reduce cigarette smoking and supplement with study ENDS will have ad libitum access to study ENDS and will receive a designated number of UB CC to use per day, based on cohort assignment.

2. The experimental study visit, including establishment of baseline combusted cigarette use, shall last seven days in an in-patient facility. Participants will be given a controlled number of UB cigarettes per day as determined by randomization cohort, and a study ENDS for ad libitum use. At designated times throughout the in-patient stay, the following steps should be taken:

a. Serial blood and saliva samples shall be collected at baseline and multiple days throughout the randomization period (e.g., first, third, final day) to assess BOE (e.g., carboxyhemoglobin, other BOEs) and BOPH (e.g., HDL-cholesterol, IL-6, IL- 8, other BOPHs) as proposed by the Contractor. Time of saliva collection and blood draws shall be recommended by the Contractor (e.g., morning, afternoon, evening). Maximum blood draw volume shall not exceed 100 mL per participant per study day.

b. Urine shall be collected for each participant at baseline and pooled on multiple days throughout the randomization period (e.g., first, third, final day) to assess BOE (e.g., metabolites of nicotine, TSNAs, PAH, VOCs, other BOEs) and BOPH (e.g., 8-isoprostane; 2,3-d-TXB2, LTE4, other BOPHs), as proposed by the Contractor.

c. Vital signs (e.g., heart rate, systolic blood pressure, diastolic blood pressure) shall be collected throughout the visit, as proposed by the Contractor.

d. Subjective measures of abuse liability (e.g., craving, withdrawal, sensory effects) shall be measured with existing scales and assessments as proposed by the Contractor. Sampling timing and frequency shall be recommended by the Contractor.

e. Daily product use behavior (e.g., e-liquid consumption, cigarette consumption) shall be evaluated throughout the experimental stay. Additional use behavior measures may be recommended by the Contractor.

f. Participants shall be monitored for all adverse events and serious adverse events throughout the study.

3. The Draft Clinical Study Protocol shall include: study procedures, human subjects’ protection documentation (e.g., consent form, adverse event reporting, etc.), statistical analysis plan, data handling and record keeping, publication plan (if applicable), quality assurance plan, and administrative information.

4. A Proposed Statistical Analysis Plan document which shall include:

a. Details regarding data collection, organization, analysis, and interpretation as well as information on the personnel who shall conduct the statistical analyses and their credentials (e.g., training and courses completed).

b. The statistical model(s) and software program(s) that shall be used to analyze the data.

c. Methods and criteria for outlier detection and removal, where applicable.

d. Information on the selection of the significance level and post- hoc analysis, when applicable.

SGE and FDA Internal Review Once the Contractor submits the first version of the draft protocol, FDA and the Contractor shall not exceed 3 rounds of edits. Following these edits, the clinical study protocol will undergo Special Government Employee (SGE) review. The Project Lead(s) and Contractor will edit the protocol based on SGE feedback and then the clinical study protocol will undergo an FDA internal review process. The Project Lead(s) and Contractor may need to edit the protocol based on this internal FDA review process as well. Together, these two review processes will take up to 2-3 months.

Data Monitoring A preliminary clinical study data monitoring plan shall be submitted as part of the Contractor’s study proposal (i.e., bid proposal).

The draft and final clinical study protocols shall include a section describing the proposed plan for interim data monitoring. This section shall explain who is to be responsible for interim monitoring, what data will be monitored (e.g., performance, risk assessment), the timing of the first data review, and the frequency of interim reviews (which will depend on such factors as the study design, interventions, and anticipated recruitment rate). The plan shall specify "stopping guidelines" and other criteria, if appropriate, for the monitors/auditors to follow in their review of the interim data. Guidance on these topics is available at:

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf.

In addition to the study data monitoring plan described above, CTP has a supplemental separate monitoring program in which the Study Project Lead(s) and CTP Study Monitoring http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf

Point of Contact will provide additional oversight of data and human subject protection monitoring, ensuring that monitoring systems are in place, that the quality of the monitoring activity is appropriate, and that the Principal Investigator (PI) or designee and COR are informed of recommendations and actions resulting from monitoring activities. All study data may be reviewed, and data sources verified, on site or remotely.

CTP monitoring will be in place for each research study, to safeguard the well-being of study participants and to ensure scientific integrity. CTP monitoring may include the reports of adverse events, unexpected events, non-compliance, protocol deviations, recruitment issues, other reported human subjects’ protection (HSP)/data integrity issues. CTP monitoring may be performed throughout subject accrual, while study procedures are being conducted, and during follow-up periods. Information regarding data and safety monitoring shall be included in the clinical study protocol.

The specific approach to CTP monitoring will depend on features of the research study to be conducted. CTP monitoring activities will be appropriate to the study, study population, research environment, and degree of risk involved.

In addition to CTP Study Monitoring, FDA/CTP/OCE has the authority to audit this study at any time, with appropriate notification. Federal or state laws may require FDA to show information to university or government officials (or sponsors), who are responsible for monitoring the safety of this study. To the extent possible, directly identifying information (e.g., names, addresses) will be safeguarded and maintained under controlled conditions as appropriate.

Task 7 – Final Laboratory Study Protocol The Contractor shall incorporate FDA feedback from the Draft Laboratory Study Protocol development phase to deliver a Final Laboratory Study Protocol for FDA approval.

The Final Laboratory Study Protocol shall include: study procedures; data handling and record keeping, a statistical analysis plan; quality assurance plan, publication plan (if applicable), and administrative information.

Task 8 – Final Clinical Study Protocol The Contractor shall incorporate FDA feedback (including SGE and FDA Internal Review feedback) from the Draft Clinical Study Protocol development phase to deliver a Final Clinical Study Protocol for FDA approval. This version of the clinical study protocol will then be submitted for internal CTP HSP and IRB review and approval and may require additional edits after all human subjects’ protections reviews have concluded in Task 10.

Task 9 – Perform Laboratory Study The Laboratory Study shall begin after FDA approval of the Final Laboratory Study Protocol. The Contractor shall perform the Laboratory Study according to the procedures in the Final Laboratory Study Protocol developed in Task 7. The Contractor shall submit any relevant source documents to the Study Project Lead(s).

The Contractor shall direct laboratory technicians and other staff to perform the laboratory tests as required.

Task 10 – Obtain Required Human Subjects Clearances for the Study The Contractor shall work with the FDA to submit proper human subjects’ clearance documents and obtain necessary human subjects’ clearances to perform the study, including:

1. Office of Management and Budget (OMB) approval, if applicable o Approval from the OMB, consistent with the Paperwork Reduction Act, is necessary for data collection from ten (10) or more individuals. Some studies may be granted exemption from OMB based on study procedures. The Contractor shall be responsible for providing the COR and Study Project Lead (s) with the necessary information about the Contractor’s procedures for data collection.

2. Institutional Review Board (IRB) approval o For research exempt from the requirements of 45 CFR Part 46:

The Contractor will submit to FDA a letter from their IRB or human subjects protection entity that the proposed research is exempt (see 45

CFR 46.104).

In accordance with SMG 9001.4, FDA will follow its procedures for exempt research determination. Data collection from human subjects cannot commence under this contract until the FDA COR provides the Contractor with the outcome of the FDA determination.

o For nonexempt human subjects research:

The Contractor agrees to protect the rights and welfare of human subjects involved in research under this contract by complying with 45 CFR Part 46 and the clause at HHSAR 352.270-4b.

Initial proof of compliance with 45 CFR Part 46 shall consist of:

• A copy of a current Federal-wide Assurance on file with the Office of Human Research Protections (https://www.hhs.gov/ohrp/federalwide-assurances-fwas.html).

The copy of a current Federal–wide Assurance shall be included with the Contractor’s proposal.

• A letter from the Contractor’s local IRB (the IRB specified in the Offeror’s Assurance of Compliance) stating that it has reviewed and approved the proposed research protocol. The letter from the local IRB shall be submitted to the COR.

• In accordance with SMG 9001.4, the FDA will determine if FDA is considered engaged in the research for purposes of 45 CFR part

46. Data collection from human subjects cannot commence under this contract until the FDA COR provides the Contractor with the outcome of the FDA determination. When that determination is made, the FDA will confirm the extent to which the terms of “352.270-11 Protection of Human Subjects— https://www.hhs.gov/ohrp/federalwide-assurances-fwas.html

Research In Human Subjects Committee Approval of Research Protocols Required” apply.

The Contractor shall obtain all necessary internal approvals, such as determination from its own IRB prior to any human subject data collection. All staff working with human subjects or having access to human subjects’ data must complete human subjects training appropriate for this type of clinical study.

In addition, internal CTP human subjects protection reviews may be required prior to IRB review for packages including the initial protocol package, amendments, adverse event reporting and study closure. The Project Lead(s) and Contractor may need to edit the protocol based on this internal CTP review process. For each review, the process can take up to 20 business days.

Task 11 – Perform Clinical Study Clinical study recruitment shall begin within five (5) business days of IRB approval. The Contractor shall perform the clinical study using the Final Clinical Study Protocol developed in Task 8 and the Final Laboratory Study Protocol developed in Task 7. The Contractor shall submit any relevant source documents to the Study Project Lead(s) upon request.

The Contractor shall select the laboratory and clinical research facilities which are equipped to perform the study. The Contractor shall provide nurses, laboratory technicians, and other clinical staff to perform the screening, behavioral assessments, and laboratory tests, to collect specimen samples, and to assay the biologic samples.

The Contractor shall recruit healthy, volunteer, adult male and female current and experienced combusted cigarette users for the study and assess their inclusion and exclusion criteria to satisfy the Final Clinical Study Protocol. The Contractor is responsible for proactively ensuring recruitment can be achieved and for identifying measures to increase recruitment, if needed.

The Contractor shall inform the FDA for the measures taken to ensure the confidentiality of data.

The Contractor will be compensated incrementally for this task as participants complete the clinical study (i.e., after reaching 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 100% of the participant completion goal agreed upon by both parties).

Task 12 – Clinical Recruitment Updates The Contractor shall deliver informal weekly updates via email to the COR and Study Project Lead(s) on the status of recruitment and progress of research for the duration of recruitment.

Recruitment updates shall begin one week after the start of recruitment and shall be delivered on the same day of the week throughout the duration of the study.

Recruitment updates shall include the number of participants scheduled/completed for the prior week’s duration, the number of participants scheduled/completed from the start of recruitment, the number of participants who are deemed ineligible during pre-screening and screening, and reasons for ineligibility.

Task 13 – Draft Clinical Study Report Within two (2) months of completing the final study participant, the Contractor shall deliver a Draft Study Report to the COR and Study Project Lead(s) containing: the background and purpose of the project, summary of recruiting, biological sampling frame, data collection techniques and procedures, BOE analyses (e.g., metabolites of nicotine, TSNAs, PAHs, VOCs;

carboxyhemoglobin), BOPH analyses (e.g., HDL-cholesterol, IL-6 and IL-8, 8-isoprostane, 2,3-d- TXB2 and LTE4), vital statistics analyses (systolic blood pressure, diastolic blood pressure, heart rate), health effects analysis, subjective effects analyses, AEs and SAEs, any significant problems encountered during the study and their solutions, data preparation and processing, any information necessary to reproduce statistical results and reanalyze datasets (e.g., coding procedures, statistical/analytic code), and any common themes or problems encountered during execution of the study.

All raw data and data analysis files will be submitted in SAS transport format and Microsoft Excel. The Contractor shall submit all documents relating to study monitoring to the COR. The Contractor shall write up the results of the study in the form of an expanded American Psychological Association (APA; http://www.apastyle.org) format introduction section. The Contractor shall write these documents in MS Word (Office 2019 or newer) compatible software.

Data files shall be prepared and delivered according to the following specifications:

1. Each record shall be uniquely identified and shall correspond to one respondent's data.

2. All data values shall be numeric rather than character.

3. Adverse events shall be described with the time in the event table.

4. One (1) electronic copy of a finalized, complete, and correct Coding Book shall be included.

5. One (1) electronic copy of the data analyses report, including files, tables and figures, and appropriate statistical analyses of the results shall be included.

The Contractor should estimate FDA review of the data and draft clinical study report will take 3 months.

Task 14– Final Clinical Study Report The Contractor shall address all feedback and deliver a Final Study Report to the COR and Study Project Lead(s) within two (2) months after receiving comments from the FDA on the Draft Study Report. All biospecimens should be properly stored until FDA confirms receipt and approval of the final clinical study report.

Should the FDA have any additional comments on the Final Study Report, the Contractor shall respond to any comments from the FDA in a revised report to be submitted within one (1) month after receipt of FDA comments.

Task 15 – Draft Laboratory Study Report Within two (2) months of the completion of the laboratory study, the Contractor shall deliver a draft laboratory study report to the COR and Study Project Lead(s) containing: the background and purpose of the project, analytical methods, validation protocols and reports, if applicable, verification protocols and reports, if applicable, deviation protocols for any or all analytical methods used, data preparation and processing, any information necessary to reproduce statistical results and reanalyze datasets (e.g., coding procedures, statistical/analytic code), and any significant problems encountered during the laboratory study and their solutions, conclusions.

All raw data and data analysis files shall be submitted in SAS transport format and Microsoft Excel. The Contractor shall write up the results of the study in the form of an expanded American Psychological Association (APA; http://www.apastyle.org) format introduction section. The Contractor shall write these documents in MS Word (Office 2010 or later) compatible software.

Data files shall be prepared and delivered according to the following specifications:

1. All data values shall be numeric rather than character.

2. One (1) electronic copy of a finalized, complete, and correct Coding Book shall be included.

3. One (1) electronic copy of the data analyses report, including files, tables and figures, and appropriate statistical analyses of the results shall be included.

The Contractor should estimate FDA review of the data and draft laboratory study report will take 3 months.

Task 16 – Final Laboratory Study Report The Contractor shall address all feedback and deliver a Final Laboratory Study Report to the COR and Study Project Lead(s) within one month after receiving comments from the FDA on the Draft Study Report. All laboratory products/samples should be properly stored until FDA confirms receipt and approval of the final laboratory study report.

Should the FDA have any additional comments on the Final Study Report, the Contractor shall respond to any comments from the FDA in a revised report to be submitted within one (1) month after receipt of FDA comments.

PERIOD OF PERFORMANCE

Thirty months from date of task order award.

DELIVERABLE SCHEDULE

Task Number

Deliverable Quantity Delivery Date after Task Award

1 Kick-off Meeting 1 Within 10 business days of task order award.

2 NPI forms 1 per staff member

Within 30 business days of task order award.

3 Biweekly Meetings Biweekly for contract duration

Biweekly. Start within 10 business days of Kick-off Meeting.

4 Monthly Progress Reports 1 electronic version per month for contract duration

Electronically submit to the COR by the 10th of each month for each thirty-day period prior to the report due date.

5 Draft Laboratory Study Protocol

1 electronic version

Initial draft within 30 business days of task order kick-off meeting. Multiple iterations (no more than 3) may be necessary to address feedback from all FDA review processes.

6 Draft Clinical Study Protocol 1 electronic version

Initial draft within 30 business days of task order kick-off meeting. Multiple iterations (no more than 3) may be necessary to address feedback from all FDA review processes.

7 Final Laboratory Study Protocol

1 electronic version

Within 10 business days of receiving final Government comments on Draft Laboratory Study protocol.

8 Final Clinical Study Protocol 1 electronic version

Within 10 business days of receiving final Government comments on Draft Clinical Study Protocol.

9 Perform Laboratory Study 1 Within 5 days of FDA approval of the Final Laboratory Study Protocol.

10 Obtain Clearances for the Study (OMB and IRB)

1 each Variable, approximately 4 months is anticipated.

Clearance must be obtained prior to any data collection.

11 Perform Clinical Study 1 Within 5 business days of final IRB approval.

12 Participant Recruitment Updates

1 electronic version per week

Weekly for the duration of the clinical study.

13 Draft Clinical Study Report 1 electronic version

Within 2 months of completing the final study participant.

14 Final Clinical Study Report 1 electronic version.

Within 1 month after receiving FDA comments on the Draft Clinical Study Report.

15 Draft Laboratory Study Report 1 electronic version

Within 2 months after completion of the laboratory portion of the study.

16 Final Laboratory Study Report 1 electronic version

Within 1 month after receiving FDA comments on the Draft Laboratory Study Report.

INSPECTION AND ACCEPTANCE

The COR shall review and inspect all deliverables furnished under this task order in accordance with the deliverables cited herein.

CONFLICT OF INTEREST

The Contractor warrants that it is in compliance with Section C.17 -Organizational Conflicts of the base award.

OTHER REQUIREMENTS

FDA considers the sharing of FDA-funded research, including digital data, an important means to enhance its value and support future research. When the findings associated with research developed with FDA funds are published, they are required to be made readily available to the public. In addition, investigators seeking FDA funding, in whole or in part, via a contract, grant, or assistance agreement must have an FDA-approved Data Management Plan – a plan for digital data management and sharing – prior to commencing any related services or work.

Upon acceptance for publication, researchers are also responsible for submitting the author’s final manuscript of any peer-reviewed scientific publication resulting from research supported, in whole or in part, with FDA funds to the NIH National Library of Medicine's (NLM) PubMed Central (PMC). FDA defines the author's final manuscript as the final version accepted for journal publication, which includes all modifications resulting from the publishing peer review process. The PMC archive is the designated repository for these manuscripts for use by the public, health care providers, educators, scientists, and FDA. FDA expects timely release and sharing of final research data from FDA-funded studies for the research community’s use in accordance with the submitted Data Management Plan. Please see the FDA Public Access Policy (provided as Attachment/Exhibit XXYY; or, available at http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/staffmanualguides/ucm47926 8.pdf).

INSTRUCTIONS TO CONTRACTORS

The Contractor shall include a project timeline to accompany the technical proposal. The timeline shall depict how all contract milestones will be accomplished during the period of performance including, but not limited to: protocol development and review (FDA and Contractor review timelines), human subject protections review (FDA and External), purchase of study product(s), laboratory study, clinical study, data analysis and reporting. Specifically, the Contractor shall provide in weeks or months, how long they anticipate each deliverable will take to complete as well as a visual timeline.

EVALUATION CRITERIA

For overall evaluation purposes, technical and all other non-price factors are considered more important than price. As technical scores become more equal, price may become the determining factor.

EVALUATION FACTORS

Factor 1: TECHNICAL APPROACH

a. The Contractor shall provide a narrative description of the approach to performing the work described in the task order. The narrative should describe the Contractor's understanding of the project (both from a business and technical standpoint) and its relevance to CTP regulatory activities, how the Contractor intends to satisfy the technical requirements, any risks it foresees in carrying out its approach, along with mitigation strategies for those risks. This shall also include a project timeline for the life of the contract. The timeline will be evaluated on reasonableness and the Contractors ability to complete the project within the specific period of performance. The Contractor shall demonstrate when each deliverable will be completed and all target milestones.

b. STAFFING PLAN

1. The Contractor shall provide a narrative description of the approach to staffing the project. This should include discussion of how it shall ensure that the project is adequately staffed. Representative resumes of proposed personnel for the contract.

2. The Contractor shall provide a Staffing Plan that shows the positions to be used to support this effort. The plan should conform to the following requirements:

• Shows all proposed positions by labor category.

http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/staffmanualguides/ucm479268.pdf http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/staffmanualguides/ucm479268.pdf

• Indicate with a “Yes” or “No”, whether it is a key position.

• Lists the number of hours for each proposed position.

• Calculates subtotals, segregated by the CLINs delineated

• Calculates total hours.

• Describes the functional/technical role corresponding to each position.

c. KEY PERSONNEL

1. The Contractor shall provide a narrative in which the Contractor identifies key personnel. The narrative should describe the roles of key personnel and expected contributions of each individual identified. The following labor categories are considered key personnel: Senior Scientist, Project Manager, Subject Matter Expert, Pharmacokineticist/Scientist.

2. The Contractor shall submit a resume for each proposed key personnel describing experience, education, work history, professional certifications, and any other relevant information regarding their qualifications. Each resume shall be limited to three (3) 8.5 x 11 inch pages (anything over this limit shall be ignored).

3. The Contractor shall submit a letter of commitment on company letterhead for each key person proposed who is not already an employee of the proposed prime or subcontractor. This includes any key person that is a 1099/consultant/or subcontractor employee. Date the letter, list the named individual and position, show dates of committed employ, and have the letter signed by both parties. Any salary amounts shall be redacted from the letter.

Factor 2: PRICE

The Contractor shall include a price per deliverable and a detailed price breakdown to demonstrate how each price was developed. The Contractor shall include their methodology for how they determined the price for each deliverable.

AWARD DECISION

Award will be made based on a best value tradeoff. When combined, all non-price factors are considered significantly more important than price.

CLAUSES

All clauses included in your master contract flow down to this task order and remain in effect.