Solicitation 75F40125R00096.pdf

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4. ORDER NUMBER3. AWARD/ 6. SOLICITATION

75F40125R00096

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67 2 of

Solicitation No. 75F40125R00096

Offeror Name UEI

Study Title: Do laboratory prescribed, and ad libitum use sessions represent real-world ENDS use?

SECTION 1 – COMBINED SYNOPSIS SOLICITATION

SECTION 2 – LINE ITEMS

SECTION 3 – STATEMENT OF WORK/DESCRIPTION

• 3.1 Background

• 3.2 Scope of Work

• 3.3 Objectives

• 3.4 Task

• 3.5 List of Deliverable

SECTION 4: CONTRACT REQUIREMENTS

• 4.1 Conflict of Interest

• 4.2 Government-Furnished Property, Material, Equipment, or Information (GFP, GFM, GFE, OR GFI)

• 4.3 Security

• 4.4 Travel

• 4.5 Special Material Requirements

• 4.6 Other Unique Requirements

• 4.7 Place of Performance

• 4.8 Period of Performance

• 4.9 Contract Type

SECTION 5: GENERAL EVALATUATION INFORMATION EVALUATION AND

AWARD

SECTION 6: ADDEDUM / CONTRACT CLAUSES AND PROVISIONS / ADDITIONAL

TERMS AND CONDITIONS

• 6.1 52.212-5 CONTRACT TERMS AND CONDITIONS REQUIRED TO

IMPLEMENT STATUTES OR EXECUTIVE ORDERS (JAN 2025)

• 6.2 FAR 52.204-27 PROHIBITION ON A BYTEDANCE COVERED APPLICATION

(JUN 2023)

• 6.3 FAR 52.252-2 CLAUSES INCORPORATED BY REFERENCE (FEB 1998)

• 6.4 INVOICE INSTRUCTIONS

• 6.5 DEPARTMENT OF HEALTH AND HUMAN SERVICES ACQUISITION

REGULATION (HHSAR) (48 CFR CHAPTER 3) CONTRACT CLAUSES

• 6.6 FAR 52.212-1 INSTRUCTIONS TO OFFERORS—COMMERCIAL

PRODUCTS AND COMMERCIAL SERVICES (SEP 2023)

• 6.7 52.212-2 Evaluation - Commercial Products and Commercial Services.

(NOV 2021)

• 6.8 52.212-3 OFFEROR REPRESENTATIONS AND CERTIFICATIONS-

COMMERCIAL PRODUCTS AND COMMERCIAL SERVICES. (MAY

2024)

• 6.9 RFP INQUIRIES AND QUESTIONS DUE DATE

• 6.10 PROPOSAL SUBMISSION

SECTION 7: PROPOSAL INSTRUCTIONS

• 7.1 Evaluation Factors

SECTION 8: BASIS FOR AWARD

SECTION 1 – COMBINED SYNOPSIS SOLICITATION

This is a combined synopsis/solicitation for commercial products or commercial services prepared in accordance with the format in subpart 12.6, as supplemented with additional information included in this notice. This announcement constitutes the only solicitation;

proposals are being requested and a written solicitation will not be issued. The solicitation number is 75F40125R00096 and is issued as an RFP. This solicitation and incorporated provisions and clauses are those in effect through Federal Acquisition Circular 2025-04, effective June 11, 2025. The North American Industry Classification Systems (NAICS) Code 541715 - Research and Development in the Physical, Engineering, and Life Sciences.

SECTION 2 – LINE ITEMS

The Government intends to issue a hybrid contract, with a mix of firm-fixed price and time and material deliverables. Offerors are requested to provide a proposal in accordance with the Statement of Work.

SECTION 3 - STATEMENT OF WORK (SOW)

3.1 Background

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 the FDA authority to regulate the manufacture, marketing, and distribution of tobacco products to protect public health. The Behavioral and Clinical Pharmacology branch of CTP is tasked with evaluating the abuse liability of tobacco products in product marketing applications, to assess whether the new product is appropriate for the protection of public health.

Typically, the abuse liability of new Electronic Nicotine Delivery Systems (ENDS) is characterized using laboratory studies of prescribed puffing and ad libitum use. However, to our knowledge, no clinical studies have systematically compared ENDS use behaviors and nicotine pharmacokinetics (PK) between ambulatory and laboratory environments or examined how these outcomes are affected by a product’s nicotine concentration and/or the experience levels of the study participants.

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 5: Selections of ENDS, e-Liquid, and Topography Monitoring System

• Task 6: Draft laboratory study protocol

• Task 7: Draft clinical study protocol

• Task 8: External and Internal Review

• Task 9: Final laboratory study protocol

• Task 10: Final Clinical Study Protocol

• Task 12: Obtain clearances for the study

• Task 13: Perform clinical study

• Task 15: Draft laboratory study report

• Task 16: Draft clinical study report

• Task 17: Final laboratory study report

• Task 18: Final clinical study report

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

• Task 3: Biweekly meetings

• Task 4: Monthly progress reports

• Task 11: Perform laboratory study

• Task 14: Clinical study recruitment updates

3.2 SCOPE OF WORK

There are two Primary Aims of this study: 1) to determine if current prescribed puffing regimens that assess nicotine PK in the laboratory reflect nicotine exposure from ambulatory (at-home) use patterns; and 2) to determine if laboratory assessments of ad libitum use patterns (e.g., puff topography) reflect ambulatory use patterns. There are also two Secondary Aims: 1) to determine if e-liquid nicotine concentration affects nicotine PK and puff topographies during ambulatory and laboratory use sessions; and 2) to determine if participant experience with ENDS affects nicotine PK and puff topographies during ambulatory and laboratory use sessions. Lastly, there is one Exploratory Aim: to determine if use behaviors escalate during the first 7 days of at-home use and if these outcomes depend on e-liquid nicotine concentration and participant ENDS experience.

3.3 OBJECTIVES

The Contractor shall recommend an ENDS topography monitoring device and a closed-ENDS that can be purchased with two different nicotine concentrations (high and low). If necessary, the Contractor shall fabricate adapters to connect the topography monitor with the study ENDS, and conduct a laboratory study to validate adapter fit and e-liquid contents. The Contractor shall conduct a randomized multi-stage clinical study. First, all participants will undergo a 14-day in-home session with the assigned ENDS and single nicotine concentration, with ambulatory use topographies assessed by the topography monitoring device. Next, participants will complete a within-subject study requiring two laboratory visits. During the first laboratory visit, participants will complete a prescribed puffing regimen derived from the participants’ own pattern of use during the last 7 days of the Ambulatory Stage. During the second laboratory visit, participants will complete a prescribed puffing regimen commonly used in clinical studies, followed by an ad libitum use period. Laboratory prescribed and ad libitum use sessions will be conducted with the same ENDS and nicotine concentration used during the Ambulatory Stage. Blood draws for nicotine PK evaluation and detailed puff topography data will be collected throughout both laboratory visits.

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 Non-disclosure of Private

Information (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 Selection of ENDS, e-Liquid, and Topography Monitoring System

1 Monitor, 1 ENDS, 2 e-liquids

6 Draft Laboratory Study Protocol

1 electronic version;

preliminary drafts may be needed

7 Draft Clinical Study Protocol 1 electronic version;

preliminary drafts may be needed

8 External and Internal Clinical Study Protocol Review

1 electronic version $

9 Final Laboratory Study Protocol

1 electronic version $

10 Final Clinical Study Protocol 1 electronic version $ 11 Perform Laboratory Study 1 $ 12 Obtain Human Subjects

Clearances for Clinical Study 1 electronic version each $

13 Perform Clinical Study 1 $ 14 Clinical Study Recruitment

Updates 1 electronic version weekly during clinical study

15 Draft Laboratory Study Report 1 electronic version;

additional drafts may be needed

16 Draft Clinical Study Report 1 electronic version;

additional drafts may be needed

17 Final Laboratory Study Report 1 electronic version $ 18 Final Clinical Study Report 1 electronic version $

OPTION – FDA Audit Costs $ Total $

3.4 TASKS

Task 1 – Kick-off Meeting Within ten (10) business days of award, the Contractor shall set up and host a kick-off teleconference with the Study Project Lead(s), COR, Study Monitor, and other FDA personnel to discuss roles, expectations, and deliverables associated with the contract requirements. During the kick-off meeting, the Contractor shall propose potential topography monitoring systems, ENDS, and e-liquids to be used in the clinical study. Side-by-side comparisons of product characteristics for each considered product shall be provided by the Contractor. Considerations for various topography monitors shall minimally include data logging and retrieval, battery life, usability, cost, availability, and considerations regarding fit with potential ENDS. Considerations for ENDS and e-liquids shall minimally include available tobacco-flavored e-liquids, nicotine concentrations, nicotine form (freebase vs salt), device power, cost, availability, and considerations regarding fit with potential topography monitors.

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/Contract Specialist. 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, any action items, and the contract progress status.

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. 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 – Selection of Study ENDS, e-Liquid, and Topography Monitoring System

Study ENDS The Contractor shall recommend and (upon FDA approval) obtain a commercially available closed-ENDS (e.g., Vuse Alto) after consideration of marketplace popularity, available CTP-authorized tobacco flavors and nicotine concentrations, nicotine form (freebase vs salt), device power, cost, availability, and considerations regarding fit with potential topography monitors.

Study e-Liquid The Contractor shall recommend and (upon FDA approval) obtain commercially available low and high nicotine concentration tobacco-flavored e-liquids. Selection of high and low nicotine concentration shall be made with consideration to the study ENDS product, nicotine concentrations available, cost, marketplace popularity, and availability. Non-nicotine characteristics of the e-liquid, (e.g., PG:VG ratio, flavor ingredients, pH) should be held constant across e-liquids used in the study and verified in the Laboratory Study.

Study Topography Monitor The Contractor shall recommend a puff topography data collection instrument (e.g., CReSS, Sodim, RIT-wPUM) capable of monitoring puff topographies in ambulatory (at-home) environments. This system must record the start/end times and flow rate for each puff of the study ENDS for 14 days. Additionally, this system must have a battery life that exceeds 14 days or is easily user rechargeable.

Task 6 – Draft Laboratory Study Protocol The Contractor shall develop a Draft Laboratory Study Protocol for the study titled “Validation of ENDS topography monitor and characterization of study e-liquid” based on the following study objectives and protocol requirements:

Laboratory Study Objectives:

1. As needed, the contractor shall design and fabricate adapters for pairing the selected topography monitor, as determined in Task 5, with the study ENDS.

2. As needed, the Contractor shall provide data on validation of the topography monitor based on manufacturer data and data collected during calibration/validation in the laboratory with the study ENDS. The validation of the following outcomes are recommended: puff number, puff duration, puff volume, flow rate, and draw resistance.

The Contractor may recommend additional validation approaches. Using the study ENDS, the Contractor shall validate puff parameters (e.g., puff volume) at very low and very high flow rates (e.g., 2-23 mL/s, increasing in 5 mL/s increments) to ensure accurate measurements of puff parameters at low flow rates and ensure compatibility between study ENDS and topography monitor adapter. As needed, the Contractor shall ensure a proper fit (no leakage of aerosol) of the study ENDS with the topography monitor prior to study data collection.

3. The contractor shall provide pictures of the device (alone and with ENDS attached) including labels of the parts.

4. Conduct chemical characterization of study e-liquids, including nicotine concentration, PG:VG ratio, and pH.

5. 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, at minimum, methods for the characterization of study e-liquids, but may also include methods for validating the topography monitor and adapter. Specifically, the protocol should minimally include:

1. A protocol detailing the storage conditions and methods for how e-liquid samples and topography monitors are prepared and pulled for testing and use.

2. The Contractor shall provide a detailed step-by-step description of the analytical methods and procedures used to generate data characterizing the study e-liquids and validating the topography device and adapter as needed. Information on the analytical procedures shall include (but not be limited to1):

• Analytical instrument

• Apparatus

• Laboratory consumables

• Reagents

• Test standards

• Qualified personnel

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

(LOQ)

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

• System suitability criteria

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

• Management systems

3. Verification of analytical methods to demonstrate that the methods are acceptable and suitable for their intended use. If the test methods are appropriate U.S. 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:

• Accuracy

• Precision

• Specificity

• Matrix effects

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

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

• Reference sample(s)

• Accuracy

• Precision (repeatability, intermediate precision and/or reproducibility)

• Linearity

• LOD

• LOQ

• Range

• Specificity

5. The Draft Laboratory Study Protocol shall also include: study procedures, data handling and record keeping, data analysis, quality assurance plan, and administrative information.

6. A Proposed Statistical Analysis Plan document, which shall include:

• 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).

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

1For further guidance on analytical procedures please see: U.S. Department of Health and Human Services.

Validation and Verification of Analytical Testing Methods Used for Tobacco Products, Rockville, MD: US Dept of Health and Human Services, Food and Drug Administration, Center for Tobacco Products; 2021.

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

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

• Multiple iterations of the protocol draft may be necessary to address feedback from all FDA review processes, but this process shall not exceed 3 protocol iterations.

Task 7 – Draft Clinical Study Protocol The Contractor shall develop a Draft Clinical Study Protocol for the study titled “Do laboratory prescribed and ad libitum use sessions represent real-world ENDS use?” based on the following study objectives and protocol requirements:

Clinical Study Objectives:

Primary Study Aims:

• To determine if current prescribed puffing regimens that assess nicotine PK in the laboratory reflect nicotine exposure from ambulatory (at-home) use patterns.

• To determine if laboratory assessments of ad libitum use patterns (e.g., puff topography) reflect ambulatory use patterns.

Secondary Study Aims:

• To determine if e-liquid nicotine concentration or ENDS use experience affect nicotine

PK during ambulatory and prescribed use sessions.

• To determine if e-liquid nicotine concentration or ENDS use experience affect ad libitum and ambulatory puff topographies.

Exploratory Study Aim:

• To determine if use behaviors escalate during the initial 7 days of at-home (ambulatory) use, and if this depends on e-liquid nicotine concentration and/or ENDS use history.

Protocol Requirements:

1. The study shall consist of a randomized, multi-stage, between- and within-subject design.

The study shall consist of a screening visit, a baseline visit in which participants are provided with study products and instructed on the use of the topography monitoring device, a 14-day ambulatory (at-home) use session, and two laboratory sessions.

Participants shall be instructed to abstain from using any nicotine containing products for 12 hours prior to the start of both laboratory sessions. The Contractor shall confirm nicotine abstinence via biochemical analyses.

2. Participants shall be adult (21+ years old) males and females who currently smoke combusted cigarettes and are experienced ENDS users or inexperienced ENDS users.

There shall be two cohorts of participants: 1) ENDS experienced cohort (e.g., daily use or use for most days of the week for at least 2-3 months) and 2) ENDS inexperienced cohort (e.g., ≤ 5 lifetime uses of ENDS). Full eligibility criteria will be proposed by the Contractor and may include restrictions on the type of ENDS used by participants (e.g., use of an ENDS type and nicotine concentrations similar to those used in the study).

3. The Contractor shall provide statistical considerations for sample size based on study objectives.

4. Participants shall be provided the Study ENDS (selected in Task 5), assigned to one of the two e-liquid nicotine concentration groups (low and high, selected in Task 5), and provided with a 14-day supply of their assigned e-liquid.

5. During the Ambulatory (at-home) stage of the experiment, participants shall exclusively use their assigned ENDS ad libitum, at home, equipped with the puff topography monitoring device. The total duration of the Ambulatory Stage shall be 14 days. The Contractor shall propose a strategy for ensuring adequate participant training on the use of the topography monitor and participant compliance with study directives.

6. The Contractor shall propose a statistical approach to generate a prescribed puffing topography based on each individual participant’s Ambulatory behavior, for use during the first laboratory session. This prescribed topography shall be determined from the first daily bout of ENDS use on each of the last 7 days of the Ambulatory Stage and shall include the start and end times for each puff, as well as puff intensity. For an example of how to develop puff topographies based on Ambulatory use, the Contractor should refer to (Hensel et al., 2022).

7. During the first Laboratory visit, study participants shall conduct a prescribed puffing experiment over a 2-hour period. The following steps should be taken:

• Each participant shall be trained to follow the prescribed topography instructions, and then perform the prescribed puffing topography developed by the Contractor, based on that individual participant’s own Ambulatory behavior.

8. Blood samples shall be collected for nicotine PK assessment at baseline (prior to product use), and 3, 5, 7, 10, 15, 30, 45, 60, 90, and 120 minutes after regimen start.

• E-liquid weight shall be assessed prior to beginning and after completing the laboratory session.

• ENDS use topography shall be measured during the prescribed puffing, using the same topography monitor identified in Task 5. Data from the topography monitor shall be used to ensure adherence to the prescribed puffing regimen and determine if total product use could be predicted from the prescribed topography.

9. The Contractor shall identify a second prescribed puffing regimen, based on commonly used clinical study protocols, such as 10 puffs with 5 sec puff duration and 30 sec inter-puff interval. This topography shall be used during the second laboratory visit.

10. During the second laboratory visit, participants shall be instructed to complete a prescribed puffing regimen followed by an ad libitum use period. During the study, the following steps shall be taken:

• Each participant shall be trained to follow the prescribed topography instructions, and then perform the prescribed puffing topography identified by the Contractor, based on prior clinical study protocols.

• Blood samples shall be collected for nicotine PK assessment at baseline (prior to product use), and 3, 5, 7, 10, 15, 30, 45, 60, 90, and 120 minutes after prescribed puffing regimen start.

• After completing the prescribed puffing regimen, participants shall be allowed to use the study products ad libitum for 3 hours. During the ad libitum period, blood samples will be collected 5, 10, 15, and 30 minutes after start, and then continue every 30 minutes until the end of the period (180 minutes).

• E-liquid weight shall be assessed prior to beginning and after completing the prescribed puffing and ad libitum phases of the laboratory session.

• ENDS use topography shall be measured during the prescribed puffing and ad libitum phases, using the same topography monitor identified in Task 5. Data from the topography monitor shall be used to ensure adherence to the prescribed puffing regimen and determine if total product use could be predicted from the prescribed topography.

11. Urine samples and exhaled carbon monoxide (eCO) shall be collected from every enrolled participant at screening and before and after each experimental visit. Additional biological samples may be recommended by the Contractor. Urine samples shall be analyzed to determine urinary cotinine levels.

12. The contractor shall conduct a safety analysis that may include assessments of eCO, carboxyhemoglobin (COHb), and adverse experiences during the screening visit and at the beginning and end of each experimental visit. In addition, participants shall be monitored for adverse events throughout the study.

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

14. A Proposed Statistical Analysis Plan, including:

• Details regarding data 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).

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

• Plans for comparing the pattern of product use during the ambulatory phase to the pattern of use during the ad libitum phase of the laboratory visit, including factors for nicotine concentration and user experience level.

• Plans for comparing the nicotine concentration across the two prescribed puffing regimens, including factors for nicotine concentration and user experience level.

• Plans for characterizing changes in the pattern of product use during the ambulatory phase, including factors for nicotine concentration and user experience level.

• The methods to be used for any other statistical comparison needed to address the aims put forth in the study protocol.

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

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

15. Multiple iterations of the protocol draft may be necessary to address feedback from all

FDA review processes, but this process shall not exceed 3 protocol iterations.

Data Monitoring 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.

With appropriate notification, FDA/CTP/Office of Compliance and Enforcement Quality Assurance and Quality Improvement (QA/QI) Human Subjects Protection Program has the authority to audit this study at any time in order to ensure research activities comply with the study protocol, standard operating procedures, Good Clinical Practice standards and Federal Regulation HHS 45 CFR § 46, as well as any additional applicable agency regulatory http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf requirements. 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. If this study is selected for audit, the Contractor may bill for costs incurred as determined in the optional line item.

Task 8 – External and Internal Clinical Study Protocol Review In order to ensure a robust study design, the clinical protocol will need be reviewed by experts in the field. These experts may be external to FDA or may be internal depending on the subject.

Once the Contractor submits the first draft protocol, FDA and the Contractor shall not exceed 3 rounds of edits. Following these edits, the clinical study protocol will undergo external review by Special Government Employees (SGEs) and/or Regular Government Employees (RGEs). The Project leads and Contractor will edit the protocol based on SGE/RGE feedback and then the clinical study protocol will undergo an FDA internal review process. The Project leads and Contractor may need to edit the protocol based on this internal review process. Together, these two review processes will take up to 2-3 months.

Task 9 – Final Laboratory Study Protocol The Contractor shall incorporate FDA feedback from the Draft Laboratory Study Protocol development phase and 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.

Once the final laboratory study protocol is approved by FDA, work shall begin to validate the topography device and characterize the study e-liquids, which shall be completed before the start of the Clinical Study.

Task 10 – Final Clinical Study Protocol The Contractor shall incorporate FDA feedback (including SGE/RGE and FDA Internal Review feedback) from the Draft Clinical Study Protocol development phase and deliver a Final Clinical Study Protocol for FDA approval. This version of the clinical study protocol will then be submitted for human subjects protections review and approvals (Task 12).

Task 11 – 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 9. The Contractor shall submit any relevant source documents to the Study Project Lead(s).

The Contractor shall provide laboratory technicians and other staff to perform the laboratory testing as required in the protocol.

Task 12 – Obtain Required Human Subjects Clearances for the Clinical Study The Contractor shall work with the FDA to submit proper human subjects’ clearance documents and obtain necessary human subjects’ clearances to perform the clinical study, including:

1. Institutional Review Board (IRB) approval, as applicable

2. Office of Management and Budget (OMB) approval, if applicable

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.

For research exempt from the requirements of 45 CFR Part 46:

(a) 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).

(b) 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.

For nonexempt human subjects research:

(a) 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.

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

(1) A copy of a current Federal-wide Assurance on file with OHRP (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;

(2) A letter from the Contractor’s local IRB (the Institutional Review Board (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 Contracting Officer Representative (COR).

(3) 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—Research Involving Human Subjects Committee (RIHSC) Approval of Research Protocols Required” apply.

In addition, the Contractor shall obtain all necessary internal approvals, including a 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.

Task 13 – Perform Clinical Study Clinical study recruitment should begin within five (5) business days of IRB approval. The Contractor shall perform the clinical study using the Final Laboratory Study Protocol developed in Task 9 and the Final Clinical Study Protocol developed in Task 10. The Contractor shall submit any relevant source documents to the Study Project Lead(s) upon request. Within five (5) business days of IRB approval, the Contractor shall begin recruitment activities such as posting advertisements, contacting participants in their database, and preparing staff/materials at the clinical site.

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 https://www.hhs.gov/ohrp/federalwide-assurances-fwas.html 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 males and females who currently smoke combusted cigarettes and are experienced ENDS users or inexperienced ENDS 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 efforts, if needed.

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

Task 14 – Clinical Study Recruitment Updates The Contractor shall deliver informal weekly updates via email to the CTP Study Monitor, 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 15 – Draft Laboratory Study Report Within two (2) months of completing the final study participant, 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, data collection techniques and procedures, e-liquid analyses, puff topography monitor validation, 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 conclusions.

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

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

Task 16 – Draft Clinical Study Report Within two (2) months of completing the final study participant, the Contractor shall deliver a Draft Clinical Study Report to the COR and Study Project Lead(s) containing: the background and purpose of the project, summary of recruiting, data collection techniques and procedures, puff topography analyses, PK analyses, eCO and urinary cotinine analyses, adverse experiences, 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 conclusions.

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 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 description with the time in the event table.

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

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

Task 17 – 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 two (2) months after receiving comments from the FDA on the Draft Study Report.

Should the FDA have any additional comments on the Final Clinical 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 18 – 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.

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.

NOTE:

All study data will be collected, processed, analyzed, and submitted according to the latest applicable versions of the Clinical Data Interchange Standards Consortium (CDISC) data standards, including the specifications outlined in the latest version of the CDISC Tobacco Implementation Guide (TIG) (See Attachment 1 – TIG)

3.5 List of Deliverables

DELIVERABLE SCHEDULE

Task Number Deliverable Quantity

Delivery Date after Task Award

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

2 NPI forms 1 per staff member

Within 30 business days of contract award.

3 Biweekly Meetings Biweekly for contract duration

Meetings to 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 Selection of ENDS, e-Liquid, and Topography Monitoring System

1 Monitor, 1 ENDS, 2 e-liquids

Prior to submission of the draft protocols.

6 Draft Laboratory Study Protocol

1 electronic version

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

7 Draft Clinical Study Protocol 1 electronic version

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

8 External and Internal Clinical Study Protocol Review

1 electronic version

Within 10 business days of receiving final SGE/RGE comments on Draft Protocol.

9 Final Laboratory Study Protocol

1 electronic version

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

10 Final Clinical Study Protocol 1 electronic version

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

11 Perform Laboratory Study 1 Upon FDA approval of the Final Laboratory Study Protocol.

12 Obtain Human Subjects Clearances for Clinical Study

1 each Variable, approximately 4 months is anticipated.

Clearance must be obtained prior to any data collection.

13 Perform Clinical Study 1 Within 5 business days of final IRB approval, or after FDA has reviewed and accepted the required topography monitor validation and e-liquid characterization data, whichever occurs last.

14 Clinical Study Recruitment Updates

1 electronic version per week

Weekly for the duration of the clinical study.

15 Draft Laboratory Study Report 1 electronic version

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

16 Draft Clinical Study Report 1 electronic version

Within 3 months after completion of the last participant.

17 Final Laboratory Study Report 1 electronic version

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

18 Final Clinical Study Report 1 electronic version.

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

INSPECTION AND ACCEPTANCE

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

SECTION 4 CONTRACT REQUIREMENTS

4.1 CONFLICTS OF INTEREST

The purpose of this section is to ensure that the contractor and its subcontractors:

(1) Are not biased because of their financial, contractual, organizational, or other interests which relate to the work under this contract, and

(2) Do not obtain any unfair competitive advantage over other parties by virtue of their performance of this contract.

(b) Scope. The language of section VII applies to performance or participation by the contractor, its parents, affiliates, divisions and subsidiaries, and successors in interest (hereinafter collectively referred to as “contractor”) in the performance of this contract as a prime contractor, subcontractor, co- sponsor, joint venture, consultant, or in any similar capacity.

(c) Definition of Conflict of Interest Conflict of interest means that because of other activities or relationships with other persons or organizations, a person is unable or potentially unable to render impartial assistance or advice to the Government, that the person's objectivity in performing the contract is or might be otherwise impaired, or that the person has or might acquire an unfair competitive advantage (see FAR 9.501).

(d) Contractor’s Conflict of Interest Responsibilities The individual contractor must be free of interest prior to performing under this contract. Any time prior to or during the performance of the contract the individual contractor believes that a potential or actual conflict exists, the individual should notify the contract officer and project officer. The contract officer will determine whether or not a conflict of interest exists and how to resolve or mitigate it. The contractor should not commence or continue working on the contract until directed by the contract officer.

(e) Warrant and Disclosure. The warrant and disclosure requirements apply to both the contractor and all subcontractors. The contractor warrants that, to the best of the contractor's knowledge and belief, there are no relevant facts or circumstances which would give rise to an organizational conflict of interest, as defined in FAR Subpart 9.5, and that the contractor has disclosed all relevant information regarding any actual or potential conflict. The contractor agrees it shall make an immediate and full disclosure, in writing, to the Contracting Officer of any potential or actual organizational conflict of interest or the existence of any facts that may cause a reasonably prudent person to question the contractor's impartiality because of the appearance or existence of bias or an unfair competitive advantage. Such disclosure shall include a description of the actions the contractor has taken or proposes to take in order to avoid, neutralize, or mitigate any resulting conflict of interest.

Prior to award, contractors that disclose potential or actual conflicts of interest shall submit a mitigation of conflicts of interest plan along with their technical proposals.

(f) Remedies. The Contracting Officer may terminate this contract for convenience, in whole or in part, if the Contracting Officer deems such termination necessary to avoid, neutralize or mitigate an actual or apparent organizational conflict of interest. If the contractor fails to disclose facts pertaining to the existence of a potential or actual organizational conflict of interest or misrepresents relevant information to the Contracting Officer, the Government may terminate the contract for default, suspend or debar the contractor from Government contracting, or pursue such other remedies as may be permitted by law or this contract.

(g) Subcontracts. The contractor shall include a clause substantially similar to this clause, including paragraphs (f) and (g), in any subcontract or consultant agreement.

(h) Prime Contractor Responsibilities– The contractor shall identify and avoid, neutralize, or mitigate any subcontractor organizational conflict prior to award of the contract to the satisfaction of the Contracting Officer.