75F40124R00126.docx

GENERAL INFORMATION

This is a combined synopsis/solicitation for commercial items prepared in accordance with the format in Federal Acquisition Regulation (FAR) Subparts 12.6 AND Part 13, as supplemented with additional information included in this notice. Offerors are being requested and this announcement constitutes the only solicitation. The solicitation document and incorporated provisions and clauses are those in effect through Federal Acquisition Circular (FAC) 2024-05 dated May 22, 2024.

THIS ANNOUCEMENT CONSTITUTES THE ONLY SOLICITATION AND A SEPARATE SOLICITATION WILL NOT BE ISSUED. The solicitation number for this acquisition is 75F40124R00126 and is being issued as a Request for Proposals (RFP). The NAICS Code for this solicitation is 541690, Description: OTHER SCIENTIFIC AND TECHNICAL CONSULTING SERVICES, and the Small Business Size Standard is $19.0 Million in millions of dollars. This will be awarded as a hybrid contract type with a mix of Firm-Fixed Prices and Time & Material (T&M) deliverables. Prospective Offerors are responsible for downloading the solicitation and any amendments. The Government reserves the right to award without discussions if the Contracting Officer determines that the initial offer is providing the Best Value and discussions are not necessary.

SECTION 1 - SUPPLIES OR SERVICES/PRICES

1.0 LINE ITEMS AND PRICES

The Government contemplates awarding a hybrid contract, with a mix of firm-fixed price and time and materials deliverables resulting from this solicitation. Offerors are requested to provide a fixed price proposal (including time and material deliverables, when applicable).

PRICING TABLE

OPTION – FDA Audit costs

Contract Type The Government anticipates the award of a hybrid contract, with a mix of firm-fixed price and time and materials deliverables.

Travel Travel is not required and will not be paid/reimbursed.

Government Furnished Equipment/Information No Government-furnished property will be provided to the Contractor.

Period of Performance The anticipated period of performance for this order is September 1, 2024 – August 31, 2027.

Place of Performance All tasks will be performed at the Contractor’s facilities or as specified by the Contractor.

Section 2 – Statement of Work

Study Title: Investigating the Impact of Non-tobacco Nicotine Enantiomeric Ratio on ENDS Abuse Liability

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. The Tobacco Control Act initially limited CTP’s regulatory scope to products featuring tobacco-derived nicotine (TDN), which, combined with the declining costs associated with manufacturing non-tobacco nicotine (NTN), prompted some tobacco companies to change their product formulations to feature unregulated NTN. Consequently, tobacco products featuring NTN have become fixtures of the tobacco marketplace in recent years, and the limited data to inform the biobehavioral effects of NTN poses unique challenges for CTP review of many premarket tobacco product applications (PMTAs). Although legislation that passed in April 2022 placed NTN under CTP regulatory authority and closed this loophole, marketing of products featuring NTN continues, and this research will add to the scientific basis informing the scientific review of products containing NTN.

CONTRACT TYPE

This is a hybrid contract, with a mix of firm-fixed price and time and materials deliverables.

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 5: Draft laboratory study protocol

· Task 6: Draft clinical study protocol

· Task 7: Internal and External Review

· Task 8: Final laboratory study protocol

· Task 9: Final Clinical Study Protocol

· Task 11: Investigational tobacco product (ITP) submission and clearance

· Task 12: Obtain clearances for the study

· Task 13: Perform clinical study

· Task 14: Participant recruitment updates

· Task 15: Draft clinical study report

· Task 16: Final clinical study report

· Task 17: Draft laboratory study report

· Task 18: Final laboratory study report The Government recommends the following tasks are time and material deliverables:

· Task 10: Perform laboratory study

SCOPE OF WORK

The primary aims of this contract are to determine whether abuse liability, as measured by nicotine exposure, subjective measures, and product use behavior, differs between e-liquids formulated with TDN and NTN, and to determine whether the enantiomeric ratio of S-: R-nicotine (e.g., >99:<1, 75:25, 50:50) impacts abuse liability of e-liquids formulated with NTN.

The Contractor will identify an electronic nicotine delivery system (ENDS) device and manufacture or otherwise obtain four investigational tobacco product (ITP) e-liquids for use in the study. The four ITP e-liquids will have identical total nicotine concentration, nicotine formulation (i.e., freebase, salt), pH, and PG:VG ratio, but will differ by nicotine source (i.e., TDN, NTN) and ratio of S- to R-nicotine. One ITP e-liquid will contain TDN (i.e., >99% S-nicotine), and three e-liquids will contain varying enantiomeric ratios of NTN (e.g., S-: R-nicotine 99:1, 75:25, 50:50). The Contractor shall perform chemical characterization of the ITP e-liquids (including S- and R-nicotine, PG:VG ratio, pH). The Contractor shall conduct a randomized, double-blinded, within-subjects, crossover clinical laboratory study in which adult current users of ENDS (exclusive or dual users of ENDS and combusted cigarettes) will be recruited to complete five laboratory visits where they will use their own brand e-liquid, e-liquid containing TDN, and three e-liquids with NTN varying by enantiomeric ratio. At each laboratory visit, participants will use the assigned product under prescribed use conditions (e.g., 5 minutes with directed puff duration and frequency), then, following an abstinence period (e.g., 120 minutes), participants will use the assigned product under ad libitum conditions (e.g., 180 minutes). During ad libitum use, participants will be allowed to use the products as they please to assess their naturalistic use behavior and corresponding nicotine exposure. Serial blood samples will be collected during both prescribed and ad libitum use conditions to assess S- and R-nicotine pharmacokinetic parameters (AUC, Cmax, Tmax, nicotine boost). Pharmacodynamics (e.g., blood pressure, heart rate) and subjective effects (e.g., liking, withdrawal, sensory effects) will be assessed at designated times throughout each session. Use topography measures (e.g., time to first use, puff count, puff duration) will be determined during the ad libitum phase. Additional abuse liability outcomes, such as hypothetical purchasing tasks, will be collected at the end of each session.

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).

SPECIFIC 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, and other FDA personnel to discuss roles, expectations, and deliverables associated with the contract requirements. During the kick-off meeting, the Contractor shall recommend three (3) ENDS to be used in the clinical study. The Contractor’s 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, how the proposed products meet the criteria outlined in the statement of work (SOW), relevant published data on nicotine pharmacokinetics (PK), abuse liability, harmful and potentially harmful constituent (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 2 – Non-disclosure of Private Information (NPI) Forms All Contractor staff shall sign NPI forms prior to commencing work. All signed forms shall be submitted electronically to the COR within thirty (30) business days of contract award. 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 (as necessary) to discuss study progress, challenges, and other study details every two (2) weeks and as needed. Within five (5) business days following each teleconference, the Contractor shall submit teleconference meeting minutes to FDA that include a detailed summary of the discussion, the contract progress status, and any discussed action items.

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 “Investigating the Impact of Non-tobacco Nicotine Enantiomeric Ratio on ENDS Abuse Liability” based on the following study objectives and protocol requirements:

Laboratory Study Objectives:

1. The Contractor shall recommend and, upon FDA approval, obtain an ENDS to be used in the clinical and laboratory studies (see details below).

2. The Contractor shall recommend and, upon FDA approval, manufacture or otherwise obtain four ITP e-liquids in sufficient quantities to perform the clinical and laboratory studies.

3. The Contractor shall conduct chemical characterization of the four ITP e-liquids, to measure analytes in the e-liquids (including S- and R-nicotine, PG:VG ratio, pH; consider N-nitrosonornicotine (NNN); 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); 1,3-Dichloro-2-propanol; ethyl nicotinate; 1-methyl-2-pyrrolidinone; methylene chloride; myosmine; beta-nicotyrine; cotinine; anatabine). The Contractor shall select the laboratory and research facilities which are equipped to perform the study.

Selection of ENDS The selection of ENDS to be used in this study will involve input from multiple Divisions within CTP’s Office of Science. The Contractor shall recommend an ENDS with consideration of marketplace popularity, availability, and FDA marketing authorization.

Study E-liquids The Contractor shall recommend, and upon FDA approval, manufacture or otherwise obtain the ITP e-liquids to be used in the clinical and laboratory studies. The Contractor shall provide information regarding chemistry controls, analytical methods, and relevant data for ITP submission and laboratory methodology/study reporting with respect to the ITP e-liquids. The Contractor will develop and provide chemical characterization (e.g., nicotine, PG:VG ratio, pH, S/R nicotine ratio, radiocarbon analysis on nicotine, and other characteristics recommended by the Contractor) for four investigational tobacco product (ITP) e-liquids for use in the study. Characteristics of the ITP e-liquids (e.g., PG:VG ratio, flavor ingredients, pH) not including the source of nicotine (i.e., TDN or NTN) should be held constant across the e-liquids used in the study. The four ITP e-liquids shall have identical total nicotine concentration, nicotine formulation (i.e., freebase, salt), pH, and PG:VG ratio, but will differ by nicotine source (i.e., TDN, NTN) and ratio of S- to R-nicotine. One ITP e-liquid will contain TDN (i.e., >99% S-nicotine), and three e-liquids will contain varying enantiomeric ratios of NTN (e.g., S-: R-nicotine 99:1, 75:25, 50:50).

The Contractor shall be responsible for working with the FDA Study Project Lead(s) to obtain ITP clearance to perform the study. Up to two (2) months of stability testing data shall be required before the ITP submission can be submitted for clearance. Based on ITP e-liquid contents, stability testing may include nicotine concentration and formulation, pH, NNN, NNK, and other characteristics as recommended by FDA or the Contractor. In addition, it is recommended that the e-liquids have 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).

The Contractor shall conduct additional stability testing of the ITP e-liquids prior to their use in the Clinical Study; FDA will review and approve stability data. Stability testing shall be conducted throughout the study, as needed. If an ITP e-liquid sample or batch is not within stability specifications, then it shall be remanufactured and/or require additional testing, and the FDA shall be consulted as soon as possible before remanufacture and/or continuance of the study.

Topography The Contractor shall recommend a laboratory-based puff topography data collection instrument (e.g., CReSS, Sodim). Software accompanying the topography data collection instrument shall be used to configure, initialize, and download data. The Contractor shall provide data on validation of the topography instrument based on manufacturer data and data collected during calibration/validation in the laboratory with the study ENDS. The following validation is recommended (but not required): using individual data points, averages, standard deviation, and target specifications, the validate puff parameters including, but not limited to, puff number, puff duration, puff volume, flow rate, 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 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 any attachments with the topography device. The Contractor shall also ensure a proper fit of the study ENDS with the topography data collection instrument prior to study data collection. The Contractor shall provide pictures of the device (alone and with ENDS attached) including labels of the parts.

Protocol Requirements:

1. A description of the methods used by the Contractor to select an ENDS that is representative of the current marketplace and appropriate for the study.

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

3. The Contractor shall provide a detailed step-by-step description of the synthesis and analytical methods and procedures used to produce the ITP e-liquids. Information on the 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 ITP e-liquids and standards with any other pertinent protocol(s) including but not limited to extraction protocol

i. ITP e-liquid samples storage conditions

j. System suitability criteria

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

l. Management systems

4. Verification of synthesis and 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

5. Validation of synthesis and analytical methods, detailing testing plans for the following parameters, if applicable:

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

b. Calibration curves

c. Reference sample

d. Accuracy

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

f. Linearity

g. LOD

h. LOQ

i. Range

j. Specificity

6. In this study, puff topography during participant use of ENDS will be measured using a commercial smoking topography instrument. For every individual smoking topography data collection instrument to be used in this study, the Contractor shall:

a. Validate all puff parameters produced by each puff topography instrument to be used in the study to ensure acceptable instrument performance.

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.

Multiple iterations of the protocol draft may be necessary to address feedback from all FDA review processes, but this process shall not exceed three (3) protocol iterations. Methods and results from the laboratory study shall be submitted for ITP clearances (See Task 10).

Task 6 – Draft Clinical Study Protocol The Contractor shall develop a Draft Clinical Study Protocol for the study titled “Investigating the Impact of Non-tobacco Nicotine Enantiomeric Ratio on ENDS Abuse Liability” based on the following study objectives and protocol requirements:

Clinical Study Objectives:

1. Evaluate and compare nicotine pharmacokinetics, pharmacodynamics, subjective effects, relative reinforcement, and product use behavior of ENDS containing a TDN ITP e-liquid to ENDS containing an NTN ITP e-liquid.

a. Plasma samples: nicotine to determine Cmax, Tmax, and AUC

b. Pharmacodynamic measures (i.e., vital signs)

c. Validated behavioral and subjective measures of abuse liability, which may include self-report scales of craving, withdrawal, sensory effects, satisfaction, liking, and actual or hypothetical demand (e.g., purchase tasks).

d. Use behavior, including puff frequency, puff duration, and puff latency.

2. Evaluate and compare nicotine pharmacokinetics and pharmacodynamics, subjective effects, relative reinforcement, and product use behavior of ENDS containing NTN ITP e-liquids of varying enantiomeric ratios of NTN (e.g., S-: R-nicotine 99:1, 75:25, 50:50).

a. Plasma samples: nicotine to determine Cmax, Tmax, and AUC

b. Pharmacodynamic measures (i.e., vital signs)

c. Validated behavioral and subjective measures of abuse liability, which may include self-report scales of craving, withdrawal, sensory effects, satisfaction, liking, and actual or hypothetical demand (e.g., purchase tasks).

d. Use behavior, including puff frequency, puff duration, and puff latency.

Protocol Requirements:

1. The study shall be a single-site, double-blinded, within-subjects, crossover study design. The contractors will identify an ENDS device and manufacture or otherwise obtain four investigational tobacco product (ITP) e-liquids for use in the study. The Contractor shall provide statistical considerations for sample size (e.g., a power analysis). Participants shall be adult, experienced, current users of ENDS (exclusive or dual users of ENDS and combusted cigarettes). Full eligibility criteria shall be proposed by the Contractor. The study shall consist of a screening day and five test days.

2. Experimental study visits shall last approximately 6-8 hours. At each visit, inclusion and exclusion criteria shall be reviewed to ensure participants remain qualified for the study. Participants shall be randomized into groups to determine the order of experimental conditions. Participants will use, across the 5 separate test days, own-brand e-liquid, e-liquid containing TDN, and three e-liquids with NTN varying by enantiomeric ratio. At each laboratory visit, participants will use the assigned product under prescribed use conditions (e.g., 5 minutes with directed puff duration and frequency), then, following an abstinence period (e.g., 120 minutes), participants will use the assigned product under ad libitum conditions (e.g., 180 minutes). During ad libitum use, participants will be allowed to use the products as they please to assess their naturalistic use behavior and corresponding nicotine exposure. At designated times throughout each experimental visit, the following steps should be taken:

a. Serial blood samples will be collected during both prescribed and ad libitum use conditions to assess S- and R-nicotine pharmacokinetic parameters (AUC, Cmax, Tmax, nicotine boost) before, during, and after product use. Time of blood draws shall be recommended by the Contractor. Maximum blood draw volume shall not exceed 100 mL per participant per study day.

b. Pharmacodynamic endpoints (e.g., heart rate, systolic blood pressure, diastolic blood pressure) shall be collected throughout the visit, as proposed by the Contractor.

c. Subjective measures of abuse liability (e.g., liking, craving, withdrawal, sensory effects) shall be measured during both the prescribed and ad libitum phases of each visit with existing scales and assessments as proposed by the Contractor. Sampling timing and frequency shall be recommended by the Contractor.

d. Use topography (e.g., time to first use, e-liquid consumption, puff count, puff duration) shall be evaluated throughout the ad libitum use period. Additional use behavior and topography measures may be recommended by the Contractor.

e. Participants will complete validated measures of product reinforcement (e.g., hypothetical purchasing tasks, hypothetical substitution tasks) for the study product.

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

3. The Draft Clinical Study Protocol shall include: descriptions of each study visit, study procedures, including the procedures used to administer e-liquids in ENDS to participants, 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. Study procedures include, but are not limited to, procedures used to control the puffing regimen during ENDS use, procedures used to collect subjective responses from exposures to e-liquids in ENDS, and procedures used to measure reinforcement from e-liquids in ENDS. The Draft Clinical Study Protocol shall also include copies of questionnaires addressing participants’ urge to smoke, mood (e.g., Positive and Negative Affect Scale (PANAS)), symptoms of nicotine withdrawal (e.g., Minnesota Nicotine Withdrawal Scale (MNWS)), reward from e-liquids in ENDS, and sensory effects from e-liquids in ENDS (e.g., Duke Sensory Questionnaire (DSQ)). The Draft Clinical Study Protocol shall also describe procedures to be used to collect and analyze blood samples and vital signs. The Contractor shall provide recommendations and rationale for any additional subjective measures which the Contractor believes should be administered before and after nicotine exposure, and about the frequency and amount of collection of biological samples.

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 rationale for determination of the size of the study sample.

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

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

Study 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, efficiency data), 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 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 7 – Internal and External 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 (as described above). 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 8 – 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 descriptions of the methods used to chemically and physically characterize the ITP e-liquids and the ENDS to be used by participants in this study, including measurements of S- and R-nicotine. The Final Laboratory Study Protocol shall also include methods for testing and validating the topography data collection device. The Contractor may recommend additional product characteristics to test.

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), data analysis, and administrative information.

Task 9 – 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. The Final Clinical Study Protocol will include: study design, study procedures, study population, and recruitment details including inclusion, exclusion, and discontinuation criteria, human subjects’ protection documentation (e.g., consent form), statistical analysis plan, data handling and record keeping, quality assurance plan, adverse event plan, publication plan, and administrative information. This version of the clinical study protocol will then be submitted for internal CTP HSP and institutional review board (IRB) review and approval and may require additional edits after all human subjects’ protections reviews have concluded in Task 11.

Task 10 – Perform Laboratory Study The Laboratory Study shall begin within five (5) business days of receiving 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 select the laboratory and research facilities which are equipped to perform the laboratory study. The Contractor shall direct laboratory technicians and other staff to perform the laboratory tests as described in the laboratory protocol.

Task 11 – ITP Submission The Contractor shall be responsible for working with the FDA Study Project Lead(s) to obtain ITP clearance to perform the study. This requires approval of the Human Subjects Protection-ITP checklist by CTP leadership and the CTP-ITP Subject Matter Expert. Time to ITP clearance is variable, is subject to regulations, and can take 1-2 months.

Regarding ITP submission, Section 910(g) of the FD&C Act states, “The Secretary may exempt tobacco products intended for investigational use from the provisions of this chapter under such conditions as the Secretary may by regulation prescribe.” FDA intends to propose regulations establishing conditions for exempting ITPs from certain FD&C Act requirements. Until then, ITPs are not exempt from applicable FD&C Act requirements, including premarket submission requirements and tobacco product standards.

Researchers may seek to study tobacco products that do not have marketing authorization or that do not comply with an applicable tobacco product standard. Until regulations governing the use of ITPs are issued and finalized, FDA intends to evaluate specific uses of ITPs according to potential public health concerns or other impacts on public health. In making enforcement decisions, FDA generally intends to consider:

1. Whether there are controls on how and to whom the tobacco products intended for investigational use are distributed.

2. Whether the protocol for the clinical investigation or the procedures used during the clinical investigation adequately provide for the protection of human subjects.

3. Whether the study is designed to ensure the quality and integrity of the study data and permit other investigators to replicate the findings.

4. Whether there are adequate procedures in place to ensure that ITPs are not commercialized.

The Contractor may reference the ITP Draft Guidance for further recommendations on the types of information to include in the ITP submission. For any questions, please contact CTP-OS-ITP@fda.hhs.gov.

The Contractor shall discuss ITP elements with the Study Project Lead(s) prior to internal ITP submission. The Contractor shall submit all information relevant to the ITP process in electronic format to the Study Project Lead(s).

Task 12 – 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

a. 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 (e.g., collection of blood and urine samples). 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

a. 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.

b. 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—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 will 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 twenty (20) business days.

Task 13 – Perform Clinical Study Clinical study recruitment shall begin within five (5) business days of IRB approval or after FDA has reviewed and accepted the required ITP stability data, whichever occurs last. 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 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, experienced ENDS users (exclusive or dual users of ENDS and combusted cigarettes) for the study and assess their inclusion and exclusion criteria to satisfy the Final Clinical Study Protocol. The Contractor will continually and closely monitor throughout the duration of recruitment, to validate that the inclusion and exclusion criteria chosen are appropriate to ensure an adequate number of participants, based on sample size calculations from the Statistical Analysis Plan. The Contractor is responsible for proactively ensuring recruitment can be achieved and for identifying measures to increase recruitment, if needed.

All biospecimen samples collected during the clinical study shall be properly stored until the end of the contract period of performance.

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

The Contractor will be compensated for this task as recruitment milestones are reached (i.e., after reaching 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 100% of the recruitment goal agreed upon by both parties).

Task 14 – 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 15 – Draft Laboratory Study Report Within two (2) months of the completion of the laboratory study (i.e., the collection and analysis of the final sample), 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 including methods used to conduct chemical and physical characterization of the study ITP e-liquids, study ITP vapor, final disposition of samples, methods used to validate each smoking topography device used, 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), any significant or common problems encountered during the laboratory study and their solutions, and conclusions.

All raw data and data analysis files shall be submitted in Statistical Analysis System (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. Delivered electronically in SAS transport format and Microsoft Excel.

2. 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.

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; biological sampling frame; data collection techniques and procedures for pharmacokinetic, pharmacodynamic, puff topography, physiological effects, subjective effects, and reinforcement data; all analyses of pharmacokinetic, pharmacodynamic, puff topography, physiological effects, subjective effects, and reinforcement data; final disposition of samples; adverse events (AEs) and serious adverse events (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. Delivered electronically in SAS transport format and Microsoft Excel.

2. 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.

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 one (1) month after receiving comments from FDA on the Draft Laboratory Study Report.

Should the FDA have any additional comments on the Final Laboratory Study Report, the Contractor shall respond to any comments from FDA in a revised report to be submitted within two (2) weeks after receipt of FDA comments.

Task 18– Final Clinical Study Report The Contractor shall address all feedback and deliver a Final Clinical Study Report to the COR and Study Project Lead(s) within one (1) month after receiving comments from FDA on the Draft Clinical Study Report.

Should FDA have any additional comments on the Final Clinical Study Report, the Contractor shall respond to any comments from FDA in a revised report to be submitted within two (2) weeks after receipt of FDA comments.

PERIOD OF PERFORMANCE

The period of performance shall be three years from the date of award.

DELIVERABLE SCHEDULE

INSPECTION AND ACCEPTANCE

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

CONFLICT OF INTEREST

a) 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 and business 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.