Amendment 3 RFP Nicotine Dose Discrimination.docx

Amendment 3 FDA -20-RFP-1223088 Assessment of Nicotine Dose Discrimination in Marketed Cigarettes

PART 1: DESCRIPTION

This is a combined synopsis/solicitation for commercial items prepared in accordance with the format in Subpart 12.6, as supplemented with additional information. This announcement constitutes the only solicitation; proposals are being requested and a written solicitation will not be issued. FAR Provisions and Clauses set forth herein are current through Federal Acquisition Circular (FAC). The resultant award will include all applicable provisions and clauses in effect through the Federal Acquisition Circular 2020-04 effective January 15, 2019. The North American Industrial Classification System (NAICS) code for this procurement is 541720 and the size standard is $22.0 million. The Government contemplates a firm fixed price contract. This solicitation is for Full and Open competition. All responsible small business under the applicable NAICS code may respond.

PART 2: SUPPLIES /SERVICES AND PRICES

2.1 Brief Description of Supplies or Services

The U.S. Food and Drug Administration (FDA) acquires an assessment of Nicotine Dose Discrimination in Marketed Cigarettes.

2.2 Pricing Schedule

PART 3: STATEMENT OF WORK

3.1 Background

The primary function of the 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 new authority to regulate the manufacture, marketing, and distribution of tobacco products to protect the public health. In 2016, FDA has deemed products that meet the statutory definition of “tobacco product” (i.e., any product made or derived from tobacco that is intended for human consumption) to be subject to the FD&C Act, including Electronic Nicotine Delivery Systems (ENDS) or e-cigarettes. The aim of this study is to use established laboratory methods to assess whether smokers can discriminate between different nicotine doses in two marketed cigarettes, and to compare smokers’ ability to discriminate those cigarettes with their ability to discriminate two similar doses of nicotine delivered intravenously.

3.2 Scope of Work

This project will use established laboratory methods to assess whether smokers are able to discriminate between two modestly different nicotine doses delivered from two different marketed cigarettes, and to compare smokers’ ability to discriminate nicotine doses in those cigarettes with their ability to discriminate two similar doses of nicotine delivered intravenously. Smokers’ success in discriminating nicotine doses from two marketed cigarettes and discriminating two doses of intravenous nicotine will be measured. The Contractor shall implement a double-blind, within-subject cross-over study in which current dependent, non-menthol cigarette smokers will complete three experimental study visits. During these visits, each participant will puff two Spectrum brand research cigarettes which differ in nicotine yield, puff two marketed, brand cigarettes which differ in nicotine yield, and will receive intravenous (IV) infusions containing two different doses of nicotine. Visit 1 will serve as a training/screening visit during which eligible participants will receive instructions to puff two Spectrum brand research cigarettes over multiple trials using a prescribed puff regimen. Participants who meet specific requirements after Visit 1 will continue participation on Visits 2 and 3. On Visits 2 and 3, participants will take part in test trials during which they will each puff two marketed cigarettes chosen for their difference in nicotine yield on one visit, and will receive two doses of nicotine delivered intravenously on the other visit. The order of Visits 2 and 3 will be randomized. The Contractor shall use methods recommended by the Study Sponsor to measure success of nicotine dose discrimination after participants puff the Spectrum cigarettes, after participants puff the marketed cigarettes, and after participants receive the IV infusions. The Contractor shall recommend a puff topography data collection device to control puff volumes/smoke exposure during cigarette use. After each nicotine exposure from cigarettes or infusions, the Contractor shall measure subjective effects (e.g., self-reported urge to smoke, nicotine withdrawal, mood, sensory effects, product reward, product reinforcement). Biological samples (e.g., blood plasma nicotine) shall be collected after each cigarette/IV nicotine exposure to measure pharmacokinetic nicotine exposure, and pharmacodynamic measures (e.g., heart rate, blood pressure) will also be collected. The Study Sponsor shall provide validated subjective and objective measures to collect these data, but the Contractor may make additional recommendations.

During development of the draft laboratory and clinical protocols, the Study Sponsor shall select non-menthol marketed cigarette products which differ in nicotine yield. Two cigarettes with different nicotine yields will be administered to each participant. Cigarette flavor, full or “light” flavor, will be matched to the flavor of participants’ usual brand. The Contractor shall perform chemical analyses on the two study marketed cigarettes to assess characteristics such as, but not limited to, nicotine yield, tar, pH, and Carbon Monoxide (CO) in the smoke, verified by the International Organization for Standardization (ISO) and Canadian Intense (CI) smoking regimens, as well as nicotine content, ventilation data, and physical characteristics (e.g. ventilation percentage, rod length, rod weight, rod diameter, filter length, draw resistance, and tobacco filler weight) of the products.

3.3 Tasks

Task 1 – Kick-off Meeting The Contractor shall set up and host a kick-off teleconference with the Study Sponsor(s), COR, Study Monitor and other FDA personnel to discuss roles, expectations, and deliverables associated with the task order requirements.

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 provided to the COR/Contracting Officer. In the event that 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 with the Study Sponsor(s), COR, Study Monitor, and other FDA personnel to discuss study progress, challenges, and other study details every two weeks or as needed. Within 5 business days of each teleconference, the Contractor shall submit teleconference meeting minutes to the 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 to the Study Sponsor(s), COR, and Contract Specialist detailing study progress, challenges (and solutions to those challenges), 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 – Draft Clinical Study Protocol The Contractor shall develop a Draft Clinical Study Protocol for the study titled “An Assessment of Nicotine Dose Discrimination in Marketed Cigarettes” based on the following study objectives and protocol requirements:

1. Determine if current dependent, non-menthol smokers can discriminate between two marketed cigarettes with different nicotine yields. (see “Nicotine Dose Discrimination Methods Proposed by the Study Sponsor” below)

a. Use self-report questions to measure successful nicotine dose discrimination between two marketed cigarettes, across multiple trials, in individual participants.

b. Use self-report questions to measure successful nicotine dose discrimination between two marketed cigarettes in the overall study sample.

2. Compare smokers’ ability to discriminate between two marketed cigarettes with different nicotine yields with their ability to discriminate between two intravenous infusions containing different doses of nicotine.

a. With the same self-report questions used to measure successful nicotine dose discrimination between two different marketed cigarettes, measure successful nicotine dose discrimination between two IV nicotine infusions.

b. Compare measures of successful nicotine dose discrimination between two doses of IV nicotine infusions with measures of successful nicotine dose discrimination in the marketed cigarettes to estimate whether the cigarette discrimination findings might be attributed to nicotine alone, or to a combination of nicotine and non-nicotine factors (i.e., sensory stimuli) typically associated with cigarette use.

3. Compare smokers’ reinforcement from marketed cigarettes with their reinforcement from intravenous nicotine.

a. Use a choice procedure to measure reinforcement from each marketed cigarette/nicotine infusion.

b. Use the modified Cigarette Evaluation Scale to measure overall reward from each marketed cigarette/nicotine infusion.

4. Compare smokers’ subjective responses to marketed cigarettes with their subjective responses to intravenous nicotine by using questionnaires to measure:

a. Change in urge to smoke

b. Change in mood

c. Change in symptoms of withdrawal

d. Perceptions and liking of the study cigarettes/nicotine infusions

e. Sensory effects from the study cigarettes/nicotine infusions

The study shall be a single-site, double-blind, within-subject, cross-over design. Participants shall be current, dependent, smokers of non-menthol cigarettes. Participants shall complete three experimental visits; the order of Visits 2 and 3 shall be randomized and all visits shall be separated by a washout period. The Study Sponsors propose seven trials of cigarette puffs or IV nicotine infusions during each of Visits 2 and 3. The Contractor may provide additional recommendations about the number of trials during Visits 2 and 3, including justifications for those recommendations. The Contractor shall provide statistical considerations for study sample size.

Experimental study visits shall range in length from approximately five to eight hours per visit. Exhaled carbon monoxide (CO) shall be measured at the start of each visit to confirm smoking abstinence. In addition to exhaled CO, the Contractor may recommend additional measures to confirm abstinence from other tobacco products, such as cotinine in urine or saliva, along with rationale for the use of each recommended measure. Serial blood samples shall be collected to assess nicotine pharmacokinetics during each visit Specific duration and sampling frequency of the blood samples shall be recommended by the Contractor. Vital signs (heart rate (ECG) and blood pressure) shall be collected throughout each visit. Subjective effects shall be measured with existing behavioral scales and assessments. Using visual analogue scales (VAS), questionnaires addressing participants’ change in urge to smoke, mood (Positive and Negative Affect Scale, PANAS), and symptoms of nicotine withdrawal (Minnesota Nicotine Withdrawal Scale, MNWS), shall be administered before and after each cigarette and IV nicotine infusion. Reward from the study cigarettes and nicotine infusions (12-item modified Cigarette Evaluation Scale, mCES), and sensory effects from the study cigarettes and nicotine infusions (Duke Sensory Questionnaire, DSQ) shall be administered after each cigarette and IV nicotine infusion exposure. The Contractor shall recommend methods to prepare and administer intravenous nicotine infusions. Timing of the collection of biological samples and vital signs shall be recommended by the Contractor. Participants will be monitored for adverse events (AEs) throughout the study.

Nicotine Dose Discrimination Methods Proposed by the Study Sponsor Study Visit 1 shall serve as a screening visit, and shall determine which participants are eligible to move on to Visits 2 and 3. The screening procedures used in Study Visit 1 shall be based on a protocol designed by Perkins and colleagues (2016)1 such that smokers who cannot successfully discriminate between the 0.03 and 0.8 mg nicotine doses in Spectrum cigarettes during Study Visit 1 shall be excluded from continuing to the study test trials (Study Visits 2 and 3). During Visit 1, demographics, baseline subjective measures (dependence, urge to smoke, mood, and withdrawal), and exhaled breath carbon monoxide (CO) shall be collected. During this visit, participants shall be trained to follow the procedures involved in discriminating between two Spectrum cigarettes that differ from each other only in nicotine dose. There shall be seven training trials in which participants shall be presented with two Spectrum cigarettes (0.03 mg vs. 0.8 mg nicotine yield, equivalent to 0.4 mg/g vs. 16 mg/g nicotine content). Using a prescribed puff regimen of four puffs per cigarette, participants shall puff each cigarette, one at a time. Puff volumes shall be controlled using a puff topography device, with pre-defined time periods between cigarettes and between trials (cigarette pairs) to be recommended by the Contractor. After puffing each cigarette, participants shall use a VAS ranging from 0 (no nicotine) to 100 to rate “How much nicotine do you believe this cigarette delivered?” To measure nicotine dose discrimination after each trial (cigarette pair), they shall be asked “Do you think these two cigarettes were the same or different in the amount of nicotine they delivered?” Those who correctly discriminate a difference in nicotine doses in 80% or more of the training trials shall move on to the test trials in Visits 2 and 3. As an additional measure of each participant’s ability to correctly identify which dose of nicotine was higher in each pair, those who respond “different” shall be asked “Which cigarette do you believe delivered more nicotine?”

Marketed cigarette discrimination (study visit 2 or 3) shall involve seven cigarette discrimination test trials, including five active trials (pairs) of different marketed cigarettes (selection of these cigarettes is explained in detail in the ‘Draft Laboratory Study Protocol’) and two control trials of identical marketed cigarettes. Participants shall puff two study cigarettes (full-flavored marketed products that differ from each other in nicotine content) per trial using the same prescribed puff regimen as in Study Visit 1. The order in which the two study cigarettes are presented within each trial shall be randomized. After four puffs of each cigarette, participants shall use a VAS ranging from 0 (no nicotine) to 100 to rate “How much nicotine do you believe this cigarette delivered?” After each trial (cigarette pair), they shall be asked “Do you think these two cigarettes were the same or different in the amount of nicotine they delivered?” Those who respond “different” shall be asked “Which cigarette do you believe delivered more nicotine?”

IV nicotine discrimination (Study Visit 2 or 3) shall involve seven IV nicotine discrimination test trials, including five trials (pairs) of different IV nicotine dose infusions (the dose will be equivalent to the pre-measured nicotine yields of cigarettes used during Study Visit 2) and two control trials of identical IV nicotine dose infusions. Participants shall receive two IV nicotine doses using a prescribed infusion procedure that shall be recommended by the Contractor. Participants shall receive infusions (IV catheter) using a dosing schedule comparable to Study Visit 2, with pre-defined time periods between infusions and between trials; the duration of both of these washout periods shall be recommended by the Contractor. The order of the two study infusion doses shall be randomized. After each infusion, participants shall be asked to use a VAS ranging from 0 (no nicotine) to 100 to rate “How much nicotine do you believe this infusion delivered?” After each trial (infusion pair), they shall be asked “Do you think these two infusions were the same or different in the amount of nicotine they delivered?” Those who respond “different” shall be asked “Which infusion do you believe delivered more nicotine?”.

The order of Visits 2 and 3 shall be randomized so that half of the participants shall experience the cigarette trials on Study Visit 2, and the other half shall experience the IV nicotine trials on Study Visit 2. The exact number of of discrimination test trials during Study Visits 2 and 3 shall be finalized during the study protocol development stage.

In addition to measures of discrimination, subjective questionnaire data and subjective and behavioral measures of reinforcement shall be collected.

To supplement the subjective measure of reinforcement in Study Visits 2 and 3, a behavioral measure of reinforcement shall be administered after the last cigarette trial (Trial 7, Study Visit 2 or 3) and the last nicotine infusion trial (Trial 7, Study Visit 2 or 3). The behavioral measure of reinforcement shall involve participants taking part in a choice procedure in which they identify which cigarette of the pair and which IV nicotine infusion of the pair is more reinforcing than its counterpart.

1Perkins, K. A., Kunkle, N., Michael, V. C., Karelitz, J. L., & Donny, E. C. (2016). Assessing discrimination of nicotine in humans via cigarette smoking. Nicotine & Tobacco Research, 18(9), 1830-1836.

SGE and SRG Review Multiple iterations of the Draft Clinical Study Protocol may be necessary to address feedback from all FDA review processes. Once the contractor submits the first draft protocol, FDA and the contractor shall not exceed 4 rounds of edits. After a maximum of 4 rounds of edits, the protocol will undergo Special Government Employee (SGE) review. The Sponsor and Contractor will edit the protocol based on SGE feedback. The Clinical Study Protocol will then undergo an FDA internal review process with an Office of Science Scientific Review Group (SRG) before the protocol is finalized. Together, these review and editing processes may take a total of 5 months.

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

The draft and final clinical study protocols shall include a section describing the proposed plan for interim data monitoring. This section shall explain who is to be responsible for interim monitoring, what data shall be monitored (e.g., performance, risk assessment, efficacy 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.

In addition to the study data monitoring plan described above, CTP has a separate monitoring program in which the Study Sponsor and CTP Study Monitoring Point of Contact will provide additional oversight of data and human subject protection monitoring, ensuring that monitoring systems are in place, that the quality of the monitoring activity is appropriate, and that the Principal Investigator (PI) or designee and COR are informed of recommendations and actions resulting from monitoring activities. All study data may be reviewed, and data sources verified, on site or remotely.

CTP monitoring will be in place for each research study, to safeguard the well-being of study participants and to ensure scientific integrity. CTP monitoring will be performed on a regular basis throughout subject accrual, while study procedures are being conducted, and during follow-up periods. Information regarding data and safety monitoring shall be included in the clinical study protocol.

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

In addition to CTP Study Monitoring, FDA/CTP/OCE has the authority to audit this study at any time, with appropriate notification.

Task 6 – Draft Laboratory Study Protocol The Contractor shall develop a Draft Laboratory Study Protocol for the study titled “An Assessment of Nicotine Dose Discrimination in Marketed Cigarettes” based on the following study objectives and protocol requirements:

1. Four non-menthol marketed cigarette products (2 nicotine dose levels x 2 flavor strengths) and two Spectrum research cigarette products (0.03 mg vs. 0.8 mg nicotine yield, equivalent to 0.4 mg/g vs. 16 mg/g nicotine content) shall be puffed by participants in this study. For each cigarette product, the Contractor shall:

a. Ensure that each batch of each cigarette product is chemically characterized via laboratory testing.

b. Ensure that each batch of each cigarette product is physically characterized via laboratory testing.

2. Nicotine infusions (2 nicotine dose levels) shall be prepared and administered intravenously to participants in this study. For each of the two nicotine infusion doses, the Contractor shall:

a. Ensure that the nicotine content of each batch of nicotine infusion solution is chemically verified via laboratory testing and is safe for human administration.

3. In this study, puff volume shall be controlled during participant cigarette use 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.

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 Spectrum research cigarettes and the nicotine infusion solutions.

Selection of Marketed Cigarette Products The selection of marketed cigarettes to be used in this study will involve input from CTP’s Office of Science, Division of Product Science (DPS). Data from CTP’s 2011 interagency agreement comparative brand analysis study (“FDA50”) will be used to identify two nicotine dose (yield) levels (“low” and “high”), representative of the widest range of nicotine yield found in that study’s marketed cigarette products. Four marketed non-menthol cigarette products shall be chosen to be used in this study; two full flavored cigarettes with different nicotine (NIC) dose levels and two not full flavored (equivalent to “light” flavor) cigarettes with different NIC dose levels. Participants shall be matched to puff either two full flavored cigarettes differing in NIC dose, or two “light” flavored cigarettes differing in NIC dose, depending on their own brand preference for flavor strength. The Contractor shall chemically characterize samples of each of the four (2 NIC dose levels x 2 flavor strengths) cigarette products. The Contractor shall recommend procedures to match doses of intravenous nicotine to be used in this study as best as possible to the pre-measured, machine-based nicotine yields of puffs from the study cigarettes; similar procedures have been used in previous studies (Sofuoglu et al., 2008)2.

2Sofuoglu, M., Yoo, S., Hill, K. P., & Mooney, M. (2008). Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology, 33(4), 715.

Characterization of Cigarette Products The following chemical characteristics in the Spectrum research cigarettes and in the marketed cigarettes shall be measured and documented: nicotine content in the cigarette products, and amounts of total nicotine, free-base (unprotonated) nicotine, tar, pH, and CO in machine-produced smoke, verified using the International Organization for Standardization (ISO) and Canadian Intense (CI) smoking regimens. The Contractor shall recommend any additional chemical characteristics to be measured and documented as deemed necessary.

The following physical characteristics in the Spectrum research cigarettes and in the marketed cigarettes shall be measured and documented: ventilation percentage, rod length, rod weight, rod diameter, filter length, draw resistance, and tobacco filler weight. The Contractor shall recommend any additional physical characteristics to be measured and documented as deemed necessary.

Preparation, Administration, and Characterization of Intravenous Nicotine Infusions Laboratory methods shall include a description of procedures to prepare and administer the intravenous nicotine infusions; these methods shall be proposed by the Contractor. The laboratory methods shall include a description of how the nicotine concentrations of the resulting infusion solutions shall be verified (nicotine content and concentration, weight, and volume of the infusions will be documented), and how and when they will be dispensed to participants. The Contractor shall provide a protocol to follow, should the tested nicotine amount be outside of the acceptable range. All nicotine infusion solutions may be prepared by the Contractor on the same day which they shall be administered to participants, or on an alternate schedule recommended by the Contractor.

Control of Topography Parameters Prior to implementing the Clinical Study Protocol, the Contractor shall choose 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 chosen study cigarettes and the Spectrum research cigarettes. The Contractor shall validate the topography instrument using individual data points, averages, standard deviations, and target specifications, and validate puff parameters including, but not limited to, draw resistance, flow rate, puff volume, puff duration, and inter-puff interval to be able to determine at what pressure and/or flow rate the device begins and ends the measure of the puff duration. The Contractor may recommend additional validation approaches.

Multiple iterations of the protocol draft may be necessary to address feedback from all FDA review processes.

Task 7 – Final Clinical Study Protocol The Contractor shall deliver a Final Protocol for FDA approval. The Contractor shall incorporate FDA feedback from the Draft Clinical Study Protocol development phase in order 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. Study procedures will include descriptions of the three study visits, including the procedures used to administer all cigarette products and all IV nicotine infusions to participants. This would include, but is not limited to, procedures used to control the puffing regimen during cigarette use, procedures used to measure successful nicotine dose discrimination in participants, procedures used to collect subjective responses from exposures to cigarette and nicotine infusions, and procedures used to measure reinforcement from the cigarettes and nicotine infusions. The Clinical Protocol shall also include copies of questionnaires addressing participants’ urge to smoke, mood (Positive and Negative Affect Scale, PANAS), symptoms of nicotine withdrawal (Minnesota Nicotine Withdrawal Scale, MNWS), reward from the study cigarettes and nicotine infusions (12-item modified Cigarette Evaluation Scale, mCES), and sensory effects from the study cigarettes and nicotine infusions (Duke Sensory Questionnaire, DSQ). The Clinical Study protocol shall also describe procedures to be used to collect and analyze blood samples and vital signs; serial blood samples shall be collected and used to examine nicotine pharmacokinetics. 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.

Task 8 – Final Laboratory Study Protocol The Contractor shall incorporate FDA feedback from the Draft Laboratory Study Protocol development phase in order 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 both the Spectrum research cigarettes and the marketed cigarettes to be used by participants in this study, including measurements of nicotine content, nicotine yield, tar, pH, and CO in cigarette smoke determined using ISO and CI regimens, ventilation percentage, rod length, rod weight, rod diameter, filter length, draw resistance, and tobacco filler weight in the cigarette products. The Final Laboratory Study Protocol shall also include methods used to chemically verify the intravenous nicotine infusions to be given to participants in this study, including measurements of nicotine content and concentration, weight, and volume of each infusion. 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, and the Contractor shall recommend methods to prepare intravenous nicotine infusions, and methods for topography device validation.

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

Task 9 – Perform Laboratory Study The Laboratory Study shall begin within 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 8. The Contractor shall submit all source documents to the Study Sponsor(s).

The Contractor shall select the laboratory and research facilities which are equipped to perform the study. The Contractor shall provide laboratory technicians and other staff to perform the laboratory tests as required.

Task 10 – Investigational Tobacco Product (ITP) Submission The Contractor shall be responsible for working with the FDA Study Sponsor(s) to obtain ITP clearance to perform the study. This requires internal approval of the HSP-ITP checklist by the ITP Subject Matter Expert in CTP.

In regard to 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 investigational tobacco products from certain FD&C Act requirements. Until then, investigational tobacco products 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 investigational tobacco products are issued and finalized, FDA intends to evaluate specific uses of investigational tobacco products 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 investigational tobacco products 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.

The Contractor shall discuss ITP requirements with the Study Sponsor(s) prior to ITP submission. The Contractor shall submit all information relevant to the ITP process in electronic format to the Study Sponsor(s).

Time to ITP clearance is variable, but should take 1-2 months. Deliverable dates may be adjusted according to clearance times based on mutual agreement between the Contractor and Study Sponsor(s).

For any questions please contact CTP-OS-ITP@fda.hhs.gov.

Task 11 – 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. ITP clearance, if applicable

2. Institutional Review Board (IRB) approval, is applicable

3. 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 Sponsor(s) with the necessary information about the Contractor’s procedures for data collection.

Clearance from an IRB must be obtained prior to any data collection. If the FDA Research Involving Human Subjects Committee (herein referred to as FDA IRB) has not made the determination of exempt status or has not deferred its review authority to an external IRB by way of an IRB Authorization Agreement, the FDA will be responsible for preparing the package to obtain this clearance. The Contractor shall be responsible for providing to FDA the necessary information about the Contractor’s procedures for the study. If necessary, the final study materials will be submitted by FDA to the FDA IRB. Additional information to be provided by the Contractor may include information such as confidentiality and record-keeping procedures and personnel background, such as resumes and IRB training. FDA must provide written notice of IRB determination or deferment to the Contractor prior to the Contractor beginning any recruitment or initiating data collection processes. The Contractor shall provide this information to FDA within 10 business days of receiving FDA’s approval of the final study materials.

In addition, the Contractor shall obtain all necessary internal approvals, such as determination from its own IRB, if required, 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.

Upon mutual agreement between the Contractor and the Government, the deliverable schedule may be adjusted at no cost to accommodate OMB and IRB approvals, which may vary in length.

Task 12 – Perform Clinical Study The Clinical Study shall begin within 5 business days of IRB approval. If ITP authorization has not occurred within 5 business days of IRB approval, the Clinical Study shall begin immediately after ITP authorization. The Contractor shall perform the Clinical Study according to the procedures in the Final Clinical Study Protocol developed in Task 7. The Contractor shall submit all source documents to the Study Sponsor(s).

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 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 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, as needed.

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

Task 13 – Weekly Participant Recruitment Updates The Contractor shall deliver informal weekly updates via email to the CTP Study Monitor, the COR, and Study Sponsor(s) on the status of recruitment and progress of research for the duration of recruitment. Recruitment updates shall begin within 5 business days of IRB approval and should 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 as well as the number of participants scheduled/completed from the start of recruitment.

Task 14 – Draft Laboratory Study Report The Contractor shall deliver a draft laboratory study report to the COR and Study Sponsor(s) containing: the background and purpose of the project, data collection techniques including methods used to conduct chemical and physical characterization of study cigarettes, study cigarette smoke, and chemical verification of IV nicotine infusion solutions, final disposition of samples, methods used to validate each smoking topography device used, any significant problems encountered during the laboratory study and their solutions, data preparation and processing, coding procedures, and any common themes or problems encountered during execution of the laboratory study.

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

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

1. Delivered electronically in SAS transport format and Microsoft Excel

2. All data values shall be numeric rather than character

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

Task 15 – Final Laboratory Study Report The Contractor shall perform all data analyses and write study reports. All results shall be submitted to the Contracting Officer’s Representative (COR) and Study Sponsor(s) for evaluation, and all source documents shall be sent to the Study Sponsor(s).

The Contractor shall address all feedback and deliver a Final Laboratory Study Report to the COR and Study Sponsor(s) within 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.

Task 16 – Draft Clinical Study Report The Contractor shall deliver a draft clinical study report to the COR and Study Sponsor(s) containing: the background and purpose of the project, summary of recruiting, biological sampling frame, techniques used to collect pharmacokinetic, pharmacodynamic, puff topography, physiological effects, subjective effects, reinforcement data, and analyses, final disposition of samples, any significant problems encountered during the study and their solutions, data preparation and processing, coding procedures, and any common themes or problems encountered during execution of the study.

All raw data and data analysis files shall 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 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. Each record shall be uniquely identified and shall correspond to one respondent's data

3. All data values shall be numeric rather than character

4. Adverse events description with the time in the event table

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

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

Task 17 – Final Clinical Study Report The Contractor shall perform all data analyses and write study reports. All results shall be submitted to the Contracting Officer’s Representative (COR) and Study Sponsor(s) for evaluation, and all source documents shall be sent to the Study Sponsor(s).

The Contractor shall address all feedback and deliver a Final Study Report to the COR and Study Sponsor(s) within 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.

Task 18 – Storage of Biosamples The Contractor shall properly store all biosamples for one year after submission of the Final Study Report. An additional year for biosample storage shall allow the FDA sufficient time to review and analyze the study data to ensure that no clerical and/or technical errors have occurred. Sample storage shall also allow the FDA to perform additional post-hoc analyses if such analyses become necessary. Temperature logs shall be submitted to the Study Sponsor(s) every 3 months and temperature deviations should be reported within one week.

3.4 Inspection and Acceptance

The Contracting Officer’s Representative (COR) will, in accordance with FAR 52.212-4, perform inspection and acceptance of all the services. Acceptance shall be communicated within 30 days of receipt in writing.

3.5 Deliverables

3.6 Period of Performance

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

3.7 Place of Performance

All work will be performed at the contractor’s place of business.

PART 4: CONTRACT ADMINISTRATIOND DATA

4.1 Contract Specialist

The contact information for the Contracting Specialist are:

Department of Health and Human Services Food & Drug Administration, OAGS Attn: Tara Hobson 4041 Powder Mill Road Room 51035B Rockville, MD 20857 Tara.Hobson@fda.hhs.gov Phone: (240) 402-7586

4.2 Contracting Officer

The contact information for the Contracting Officer is:

Department of Health and Human Services Food & Drug Administration, OAGS Attn: Richard Robinson 4041 Powder Mill Road Room 51035B Rockville, MD 20857 Robert.Robinson@fda.hhs.gov Phone: (301) 796-6508

4.3 Contracting Officer Representative (COR)

The following COR(s) will represent the Government for the purpose of this contract:

Department of Health and Human Services Food & Drug Administration, CTP Jaime Golwalla 11785 Beltsville Drive Calverton, MD 20705 Jaime.Golwalla@fda.hhs.gov Phone: (301) 796-2878

The COR is responsible for: (1) monitoring the Contractor's technical progress, including the surveillance and assessment of performance and recommending to the Contracting Officer changes in requirements; (2) interpreting the statement of work and any other technical performance requirements; (3) performing technical evaluation as required; (4) performing technical inspections and acceptances required by this contract; and (5) assisting in the resolution of technical problems encountered during performance.

The Government may unilaterally change its COR designation.

4.4 Invoice Submission

FDA Three-Way Match Invoicing Procedures

A. The contractor shall submit all invoices to:

U.S. FOOD AND DRUG ADMINISTRATION

Attn: Vendor Payments Division of Payment Services 10903 New Hampshire Ave WO32 - Second Floor

MAIL HUB 2145

Silver Spring, MD 20993-0002 301-827-3742 FDAVendorPaymentsTeam@fda.hhs.gov

*** Acceptable methods of delivery include: E-mail (preferred) and Standard Mail. Provide a copy marked courtesy to the COR. The COR is Jaime Golwalla (301) 796-2878 Jaime.Golwalla@fda.hhs.gov B. Invoices submitted under this contract must comply with the requirements set forth in FAR Clauses 52.232-25 (Prompt Payment) and 52.232-33 (Payment by Electronic Funds Transfer - System for Award Management) and/or other applicable FAR clauses specified herein. To constitute a proper invoice, the invoice must be submitted on company letterhead and include each of the following:

(i) Name and address of the contractor;

(ii) Invoice date and invoice number;

(iii) Contract/Order number (including a reference to any base award for Indefinite-Delivery/Indefinite-Quantity Contracts or Blanket Purchase Agreements);

(iv) Description, quantity, unit of measure, unit price, and extended price supplies delivered or services performed, including:

(a) period of performance for which costs are claimed;

(b) itemized travel costs, including origin and…