FDA-19-SOL-1207956.pdf

FDA-19-RFQ-1207956

Solicitation Number: FDA-19-RFQ-1207956

Subject: Study of E-Cigarette Aerosol Toxicity in In Vivo Nonclinical Models.

PART 1 – Description

The U.S. Food and Drug Administration (FDA)’s Center for Tobacco Products (CTP) has a requirement for evaluating e-cigarette aerosols in in vivo nonclinical models.

This is a combined synopsis/solicitation for commercial items prepared in accordance with the format in Federal Acquisition Regulation (FAR) 12.6, as supplemented with additional information included in this notice. This announcement constitutes the only solicitation; quotes are being requested, and a separate written solicitation will not be issued.

This solicitation is a Request for Quote (RFQ) using FAR Parts 12 and 15 procedures. The solicitation document and incorporated provisions and clauses are those in effect through Federal Acquisition Circular (FAC) 2019-05. The North American Industry Classification System (NAICS) code for the proposed acquisition is 541380, Testing Laboratories.

PART 2 – Description of Services and Prices

2.1 Contract Type: Firm Fixed-Price

2.2 Pricing Table

Contract Line Item Number

(CLIN 1)

Service/Description Quantity Unit Price Total Price

Base Period: Task 1-Kick-off Meeting

Bask Period: Task 2- Regular Teleconferences/Web-Meetings

Base Period: Task 3-ACUC Approval Documentation and Study Conduct

Base Period: Task 4- Animal Subject Health Notifications

Base Period: Task 5- Draft Final Report

Base Period: Task 6- Final Report

Total Price: Base Period

Option Period 1: Task 1- Kick-off Meeting

Option Period 1: Task 2- Regular Teleconferences/Web- Meetings

Option Period 1: Task 3- ACUC Approval Documentation and

Study Conduct Optional Period 1: Task 4- Animal Subject Health Notifications

Optional Period 1: Task 5- Draft Final Report

Optional Period 1: Task 6- Final Report

Total Price: Option Period 2 Total Contract Firm-Fixed Price

PART 3 – Description/Statement of Work

3.1 Background

On June 22, 2009, President Barack Obama signed the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) into law (Public Law 111-31). The Tobacco Control Act amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) and granted the FDA authority to regulate the manufacture, marketing, and distribution of tobacco products to protect the public health and to reduce tobacco use by minors.

Electronic-cigarettes (e-cigarettes) have become very popular over the past years and although they have been promoted as potentially a less harmful alternative to conventional cigarettes for users and non-users (bystanders), the long-term health effects of e-cigarette use are unknown. E-cigarettes are battery-powered products with many configurations that deliver aerosolized nicotine. E-cigarettes include a power source (battery), a cartridge that contains an atomization chamber, and a liquid container (for e-liquid). E-liquids used in e-cigarettes are often composed of carrier solvents (such as propylene glycol, glycerin and glycol), flavoring chemicals, and typically also contain nicotine. Few peer-reviewed studies have characterized the constituents in the e-liquid and e-cigarette aerosols and compared them to the constituents found in conventional cigarette smoke, therefore, a thorough comparison of the chemical constituent levels in different e-cigarettes would be very informative and would improve future toxicological assessments. After an evaluation of the toxicological literature, we found that there is very limited toxicological information by the inhalation route of carrier solvents (propylene glycol and glycerin) and flavors for the top-selling e-cigarettes commercially available in the US1. In addition, little is known about the toxicity of e-cigarette aerosols and therefore, there is a need for in vivo toxicological studies on e-cigarettes pertaining to the acute and chronic toxicity effects resulting from aerosol inhalation exposure to. These types of studies would help us to understand the toxicological profiles of e-cigarette aerosols in nonclinical models and allow us to better assess the toxicological effects associated with e- cigarette use.

Currently, there is no guideline or standardized protocol to study e-cigarette aerosol inhalation toxicity in animals that can be reliably used to evaluate the toxic potential of various constituents in e-cigarette aerosols.

3.2 Scope of Work

Under this order, the Contractor shall perform a 28-day study with pharmacokinetic (PK) assessment, a pivotal 90-day nose-only inhalation study with 45-day recovery groups, and a pivotal 6-month nose-only

1 Orr, M.S., Electronic cigarettes in the USA: a summary of available toxicology data and suggestions for the future.

Tobacco Control, 2014. 23(suppl 2): p. ii18.

inhalation study in rodents. These will be follow-up studies to CTP’s ongoing studies. All studies will be conducted in male and female Sprague Dawley rats, preferably dosed 7 days per week.

The objective of the pivotal 90-day and 6-month studies is to perform a comprehensive sub-chronic rat study using top market share e-cigarettes products in the US to understand the potential toxicological effects of e-cigarette use. The 90-day and 6-month studies should use a low dose, medium-dose, and a high-dose.

The high-dose will be determined based on data from previous studies and the 28-day study and should be the maximum tolerated dose (MTD), or the maximum feasible dose (MFD).

The 28-day study will evaluate the toxicity of two e-cigarettes selected by FDA and provide toxicokinetic data. The results of the 28-day will be used to inform dose selection in the pivotal 6-month study.

All proposed studies shall be conducted under Good Laboratory Practice (GLP) conditions. The Contractor shall examine the in vivo pharmacokinetics of biomarkers based on e-cigarette aerosol inhalation exposure.

Moreover, the study shall include: aerosol concentration measurements (detailed below), in-life measurements such as food consumption, body weights, clinical observations, etc. urinary biomarkers of exposure (detailed below) and the post-mortem phase of the studies shall include a full necropsy with organ weights (lungs, liver, brain, spleen, heart, kidneys, reproductive organs, thyroid and parathyroids, thymus, and adrenal glands), examination of gross lesions and with histopathological endpoints in a complete battery of tissues to assess local and systemic toxicity.

The Contractor shall use commercial e-liquid flavors selected by CTP: e-liquid menthol flavor containing nicotine, e-liquid tobacco flavor containing nicotine, and e-liquid fruity flavor containing nicotine. The commercial e-liquid flavors selected for the studies shall include nicotine-containing flavors relevant to tobacco products (e-cigarettes) as documented by market trends (e.g. Giovenco et al., 20152). In addition, the study should include an e-liquid containing only the carrier solvent and nicotine, the carrier solvent and flavor (i.e., no nicotine), a non-flavor non-nicotine e-liquid (only carrier solvents, i.e. vehicle control), cigarette, and a sham group (i.e. air control). In addition, the Contractor shall analyze and characterize the e-liquid and aerosol for each selected product.

3.3 Tasks and Deliverables

The Contractor shall perform the following tasks and provide the following deliverables. The FDA COR will approve all tasks and deliverables. The Contractor shall incorporate the FDA’s feedback into its final versions of all deliverables. The Contractor shall deliver all documents to the COR electronically, not in hard copy form, with the document title, and the contract number identified in the subject line of the email submission. Deliverables shall be in MS Word, MS Excel, and/or SAS transport (.xpt). All submitted documents shall be verified virus-free.

Task 1-Kickoff Meeting The Contractor shall conduct a kickoff meeting with the COR ten calendar days after issuance of the contract. Within two business days after the kickoff meeting, the Contractor shall provide comprehensive meeting minutes, including a summary of issues and discussions, action items, and due dates.

Task 2 – Biweekly Meeting The Contractor shall conduct biweekly teleconferences or web meetings with the COR after the start of experiments. Within two business days after each meeting, the Contractor shall provide comprehensive

2 Daniel P. Giovenco, David Hammond, Catherine G. Corey, Bridget K. Ambrose, Cristine D. Delnevo; E-Cigarette Market Trends in Traditional U.S. Retail Channels, 2012–2013, Nicotine & Tobacco Research, Volume 17, Issue 10, 1 October 2015, Pages 1279–1283, https://doi.org/10.1093/ntr/ntu282 meeting minutes, including a summary of issues and discussions, action items, and due dates.

Task 3-Conduct the Study The Contractor shall conduct the 28-day, 90-day, and 6-month nose-only inhalation studies as follows:

1. The smoking regimen shall follow the puff protocol previously selected by CTP, ISO 20768 (2018) conditions: 55 ml puff volume, intervals of 30 seconds, with 3 second puff duration. In addition, the Contractor shall use daily exposure parameters (exposure time and aerosol dose concentrations) based on input from CTP. The Contractor must be able to achieve a daily exposure duration of 6 hours for the high dose groups.

2. For each of the four products (for the 28-day and 90-day studies), or two products (for the 6-month study), the study shall include a low-dose that is estimated to correspond to typical human exposure, a medium-dose, and a high-dose.

For each study, the high-dose should be the predicted maximum tolerated dose (MTD), or the maximum feasible dose (MFD), based on data from shorter-term studies. All proposed studies shall be conducted under Good Laboratory Practice (GLP) conditions. Blood and urine shall be collected to measure specific biomarkers of exposure of different types of toxicants as measured in the human study by Hecht et al 20143 (the Contractor shall develop a table to inform how many times and days this would be recorded, with consultation from CTP). The study shall include a low dose, medium dose, and high dose with the following flavors: e-liquid menthol flavor containing nicotine, e-liquid tobacco flavor containing nicotine, e-liquid fruity flavor containing nicotine. In addition, the study shall include: e-liquid containing only carrier solvents, e-liquid containing the carrier solvent and flavor (i.e., no nicotine), e- liquid containing carrier solvents and nicotine (i.e., no flavor), cigarette, and a sham group. The test materials (across e-cigarette brands), dose groups, and animals per group are outlined in Tables 1 and 2 below.

Table 1. 28-day Nose-only Inhalation Study in Male and Female Sprague-Dawley Rats Exposed to E-cigarette Aerosol

No . Test Materials

E-cigarette Brand/ Model*

Dose group

Number of Animals

F M

1 Air control 10 10 2 Cigarette 10 10 3 E-liquid carrier A 10 10 4 E-liquid carrier + nicotine A High 10 10 5 E-liquid carrier + nicotine A Mid 10 10 6 E-liquid carrier + nicotine A Low 10 10 7 E-liquid carrier + menthol + nicotine A High 10 10 8 E-liquid carrier + menthol + nicotine A Mid 10 10 9 E-liquid carrier + menthol + nicotine A Low 10 10

10 E-liquid carrier + Tobacco flavor + nicotine A High 10 10

11 E-liquid carrier + Tobacco flavor + nicotine A Mid 10 10

3 Hecht, S.S., et al., Evaluation of Toxicant and Carcinogen Metabolites in the Urine of E-Cigarette Users Versus Cigarette Smokers. Nicotine & Tobacco Research, 2015. 17(6): p. 704-709.

No . Test Materials

E-cigarette Brand/ Model*

Dose group

Number of Animals

F M

12 E-liquid carrier + Tobacco flavor + nicotine A Low 10 10

13 E-liquid carrier + Fruity flavor + nicotine A High 10 10

14 E-liquid carrier + Fruity flavor + nicotine A Mid 10 10

15 E-liquid carrier + Fruity flavor + nicotine A Low 10 10

16 E-liquid carrier + tobacco flavor A High 10 10 17 E-liquid carrier + tobacco flavor A Mid 10 10 18 E-liquid carrier + tobacco flavor A Low 10 10 19 E-liquid carrier B 10 10 20 E-liquid carrier + nicotine B High 10 10 21 E-liquid carrier + nicotine B Mid 10 10 22 E-liquid carrier + nicotine B Low 10 10 23 E-liquid carrier + menthol + nicotine B High 10 10 24 E-liquid carrier + menthol + nicotine B Mid 10 10 25 E-liquid carrier + menthol + nicotine B Low 10 10

26 E-liquid carrier + Tobacco flavor + nicotine B High 10 10

27 E-liquid carrier + Tobacco flavor + nicotine B Mid 10 10

28 E-liquid carrier + Tobacco flavor + nicotine B Low 10 10

29 E-liquid carrier + Fruity flavor + nicotine B High 10 10

30 E-liquid carrier + Fruity flavor + nicotine B Mid 10 10

31 E-liquid carrier + Fruity flavor + nicotine B Low 10 10

32 E-liquid carrier + Tobacco flavor B High 10 10 33 E-liquid carrier + Tobacco flavor B Mid 10 10 34 E-liquid carrier + Tobacco flavor B Low 10 10

*E-cigarettes (A and B) used will be selected by CTP.

E-liquid carriers are the vehicle, the concentration of propylene glycol and glycerin should be based on the concentration used in the commercial e-liquids.

Table 2. 90-Day Nose-only Inhalation Study with 45-day Recovery Groups and 6-Month Study in Male and Female Sprague-Dawley Rats Exposed to E-cigarette Aerosol

No . Test Materials

E-cigarett e Brand/ Model*

Dose group

Number of Animals (90-days only)

Number of Animals (90-days with 45-day recovery)

Number of Animals

(6-months only)**

F M F M F M 1 Air control 10 10 5 5 10 10 2 Cigarette 10 10 5 5 10 10 3 E-liquid carrier A 10 10 5 5 10 10 4 E-liquid carrier + nicotine A High 10 10 5 5 10 10 5 E-liquid carrier + nicotine A Mid 10 10 10 10 6 E-liquid carrier + nicotine A Low 10 10 10 10 7 E-liquid carrier + menthol + nicotine A High 10 10 5 5 10 10 8 E-liquid carrier + menthol + nicotine A Mid 10 10 10 10 9 E-liquid carrier + menthol + nicotine A Low 10 10 10 10

10 E-liquid carrier + Tobacco flavor + nicotine A High 10 10 5 5 10 10

11 E-liquid carrier + Tobacco flavor + nicotine A Mid 10 10 10 10

12 E-liquid carrier + Tobacco flavor + nicotine A Low 10 10 10 10

13 E-liquid carrier + Fruity flavor + nicotine A High 10 10 5 5 10 10

14 E-liquid carrier + Fruity flavor + nicotine A Mid 10 10 10 10

15 E-liquid carrier + Fruity flavor + nicotine A Low 10 10 10 10

16 E-liquid carrier B 10 10 5 5 10 10 17 E-liquid carrier + nicotine B High 10 10 5 5 10 10 18 E-liquid carrier + nicotine B Mid 10 10 10 10 19 E-liquid carrier + nicotine B Low 10 10 10 10 20 E-liquid carrier + menthol + nicotine B High 10 10 5 5 10 10 21 E-liquid carrier + menthol + nicotine B Mid 10 10 10 10 22 E-liquid carrier + menthol + nicotine B Low 10 10 10 10

23 E-liquid carrier + Tobacco flavor + nicotine B High 10 10 5 5 10 10

24 E-liquid carrier + Tobacco flavor + nicotine B Mid 10 10 10 10

25 E-liquid carrier + Tobacco flavor + nicotine B Low 10 10 10 10

26 E-liquid carrier + Fruity flavor + nicotine B High 10 10 5 5 10 10

27 E-liquid carrier + Fruity flavor + nicotine B Mid 10 10 10 10

28 E-liquid carrier + Fruity flavor + nicotine B Low 10 10 10 10

29 E-liquid carrier C 10 10 5 5

No . Test Materials

E-cigarett e Brand/ Model*

Dose group

Number of Animals (90-days only)

Number of Animals (90-days with 45-day recovery)

Number of Animals

(6-months only)**

F M F M F M 30 E-liquid carrier + nicotine C High 10 10 5 5 31 E-liquid carrier + nicotine C Mid 10 10 32 E-liquid carrier + nicotine C Low 10 10 33 E-liquid carrier + menthol + nicotine C High 10 10 5 5 34 E-liquid carrier + menthol + nicotine C Mid 10 10 35 E-liquid carrier + menthol + nicotine C Low 10 10

36 E-liquid carrier + Tobacco flavor + nicotine C High 10 10 5 5

37 E-liquid carrier + Tobacco flavor + nicotine C Mid 10 10

38 E-liquid carrier + Tobacco flavor + nicotine C Low 10 10

39 E-liquid carrier + Fruity flavor + nicotine C High 10 10 5 5

40 E-liquid carrier + Fruity flavor + nicotine C Mid 10 10

41 E-liquid carrier + Fruity flavor + nicotine C Low 10 10

42 E-liquid carrier D 10 10 5 5 43 E-liquid carrier + nicotine D High 10 10 5 5 44 E-liquid carrier + nicotine D Mid 10 10 45 E-liquid carrier + nicotine D Low 10 10 46 E-liquid carrier + menthol + nicotine D High 10 10 5 5 47 E-liquid carrier + menthol + nicotine D Mid 10 10 48 E-liquid carrier + menthol + nicotine D Low 10 10

49 E-liquid carrier + Tobacco flavor + nicotine D High 10 10 5 5

50 E-liquid carrier + Tobacco flavor + nicotine D Mid 10 10

51 E-liquid carrier + Tobacco flavor + nicotine D Low 10 10

52 E-liquid carrier + Fruity flavor + nicotine D High 10 10 5 5

53 E-liquid carrier + Fruity flavor + nicotine D Mid 10 10

54 E-liquid carrier + Fruity flavor + nicotine D Low 10 10

*E-cigarettes (A, B, C, D) used will be selected by CTP.

**E-cigarettes (A and B) used will be selected by CTP.

E-liquid carriers are the vehicle, the concentration of propylene glycol and glycerin should be based on the concentration used in the commercial e-liquids.

Task 4-Draft Study Report The Contractor shall report the results of the experiments to FDA in the form of a Study Report. The Study Report shall include the information as specified in section 3.4 Study Guidelines.

Task 5-Final Study Report The contractor shall submit all study data and a final study report to FDA. The final study report shall incorporate all of the edits to the draft study report received from the COR. All the data in the final study report shall be properly audited.

3.4 Study Guidelines

3.4.1 Animal Subject Protection and Clearance

NOTE: The Contractor shall not conduct any work involving the use of animals until the Contractor has provided FDA with a copy of an IACUC approval letter and animal study protocol. The Contractor’s proposed protocols shall include rationale for the use of animals, complete description of proposed animal uses, identification of species and approximate number of animals to be used, description of procedures to minimize discomfort and injury to animals and euthanasia methods, and documentation of prior approval from an external ACUC, as applicable.

The Contractor’s facilities must be appropriately certified by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

The Contractor shall notify the COR electronically within 24 hours of any animal subject issues, such as injury, disease, or death, including the nature of the disease or injury, course of action, and animal death not resulting from euthanasia due to completion of the experiment (e.g. deaths resulting from surgery or unknown cause).

3.4.2 Good Laboratory Practices

In accordance with the Code of Federal Regulations (CFR) Title 21, Part 58, Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies, the Contractor shall practice Good Laboratory Practices for all applicable work for this contract.

3.4.3 Experimental Parameters

The Contractor shall conduct all studies specified in this contract in male and female Sprague-Dawley rats according to the principles and procedures outlined in OECD413 for sub-chronic inhalation studies, with doses based on information from CTP’s ongoing studies. Animals will be dosed preferably 7 days per week. The smoking regimen for aerosol generation will have 55 ml puff volume at intervals of 30 seconds with 3 second puff duration.

The Contractor shall develop all applicable scientific protocols and methodologies: time points for collecting the relevant biological samples; equipment and materials to be used in each experiment; sufficient description of methodologies used to measure and analyze each endpoint; and incorporating the detailed procedures specified below and the statistical analysis. For the length of the studies, the contractor shall also indicate when the e-cigarette products are replaced for a new e-cigarette (based on the manufacturer user guide or best information available). The Contractor shall provide a written draft protocol with their proposal with the rationale, scientific protocols and methodologies that will be used for the proposed study.

The Contractor shall establish the final protocol by editing the draft protocol as needed, with input provided by FDA. The Contractor shall strictly adhere to the following procedures and include a table with the proposed study design, treatment groups (vehicle, sham group included), number of animals used (per group) for both male and female. It also should include a table for the study design for the analysis of the e-liquid and aerosol for all experiments, unless indicated by the COR:

1. Adult male and female Sprague-Dawley rats shall be used.

2. Animals shall be healthy, in-bred (genetically similar), obtained from a qualified vendor, and certified pathogen-free.

3. Adult male and female Sprague-Dawley rats shall be at an appropriate weight (approximately between 200-300 g) for conduct of this study length.

4. All experiments shall be conducted during the light cycle.

5. The contractor shall use the previously selected e-cigarette products as a test article and vary the exposure concentrations as defined above.

6. Aerosol will be generated according to the defined puffing regimens.

7. Contractor shall monitor (according to the study design) a reasonable measurement of the following for the study:

Exposure atmosphere before and within the exposure chamber (for example at 0, 30, 60, 90, 120, 150, 180-day timepoints and after 45-day recovery) including, but not limited to:

• Total particulate matter (TPM)

• Nicotine (free vs total nicotine)

• Carbonyls: Formaldehyde, acetaldehyde, acetone, and acrolein

• Thermal degradation products: Glycidol and propylene oxide

• Polycyclic aromatic hydrocarbons: Benzo[a]pyrene

Urinary biomarkers (for example at 0, 30, 60, 90, 120, 150, 180-day timepoints and after 45-day recovery) include, but not limited to:

• Nicotine, cotinine, 3-hydroxycotinine, 1-hydroxypyrene (1-HOP), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNK) and its glucuronides (Total NNAL), 3-hydroxypropylmercapturic acid (3-HPMA).

• Additional urinary biomarkers, perhaps including 3-4 biomarkers such as urinary protein.

Blood biomarkers (for example at 0, 30, 60, 90, 120, 150, 180-day timepoints and after 45-day recovery) include, but not limited to:

• Nicotine, cotinine, 3-hydroxycotinine, carboxyhemoglobin (COHb).

• Additional biomarkers, potentially covering inflammation, oxidative stress, metabolic profile, cardiovascular effects, or other outcomes.

8. Contractor shall quantitatively measure the following characteristics of the commercial e-liquids selected for the study and include the certificate of analysis from the manufacture:

• Nicotine concentration (mg/mL)

• Propylene glycol

• Vegetable glycerin

• Weight/volume (where applicable)

• Chemical characterization of flavor mixture

• Diethylene glycol

• pH

9. Conduct plethysmography and determine tidal volume, respiratory rate, and minute ventilation in rats (indicate the proposed days and time points to conduct this for the study).

10. Conduct cage-side observations on each animal regarding its health status during in-life stage. They include changes in the skin and fur, eyes, and mucous membranes; changes in the respiratory and circulatory systems; changes in the nervous system; and changes in somatomotor activity and behavior patterns. Examples of significant changes requiring documentation include tremors, convulsions, salivation, diarrhea, lethargy, sleep, and coma. Additional assessments may be included in the study protocol as deemed necessary.

11. Measure body weights of individual animals, and food and water consumption following the procedure of OECD413. Measure clinical pathology parameters recommended in OECD413 including urinalysis parameters.

12. Perform bronchoalveolar lavage (BAL) and determine total and differential leukocyte counts, total protein, and lactate dehydrogenase on BAL fluid. Other parameters that may be considered are those indicative of lysosomal injury, phospholipidosis, fibrosis, and irritant or allergic inflammation which may include the determination of pro-inflammatory cytokines/chemokines.

13. Conduct ophthalmological examinations of the fundus, refractive media, iris, and conjunctivae should be performed for all animals prior to the administration of the test article, and for all high concentration and control groups at termination. If changes in the eyes are detected, all animals in the other groups should be examined.

14. Collect all the organs and tissues listed in Table 2 of OECD413. Trim and weigh wet adrenals, brain, epididymides, heart, kidneys, liver, lung, spleen, testes, thymus, thyroid, consistent with OECD413. All gross pathological changes should be recorded for each animal, with particular attention to any changes in the respiratory tract.

15. Conduct histopathological evaluation of all the organs and tissues listed in Table 2 of OECD413 for the control and high concentration groups, and for all animals which die or are humanely euthanized during the study. If toxicity is observed in certain groups, additional tissue analysis shall be requested by CTP, such as additional staining or analytical measurement of biomarkers in tissue.

Retain and archive all tissues for a suitable period of time.

16. Conduct phenotyping and functional analyses on the cells obtained by bronchioalveolar lavage of rats.

17. Conduct toxicokinetic assessment (e.g., measurement of plasma concentrations to determine AUC, Cmax, Tmax and half-life) for nicotine, cotinine, and 3-hydroxycotinine.

18. Conduct all data analyses and write study reports, including:

a. Producing a Data Analysis Plan, which shall include details on the collection, organization, analysis, and interpretation of data, such as the personnel who shall conduct the statistical analyses and their credentials (e.g. training and courses completed), the statistical model(s) and software program(s) that shall be used to analyze the data, methods and criteria for outlier detection and removal, where applicable, and selection of the significance level and post-hoc analysis, when applicable.

b. Performing the data analysis indicated in the approved Data Analysis Plan, using pharmacokinetic software that is in compliance with FDA regulations (e.g., WinNonlin), for pharmacokinetic modeling and statistical data analyses.

19. Recommend, within the limits allowed, a timeline for execution, analysis, and reporting of the studies.

For the administration of e-cigarette aerosols:

• The e-cigarette aerosol shall be administered via nose-only inhalation. The Contractor shall select doses based on CTP’s previous studies.

• Blood and urine samples shall be collected at multiple time points and optimized, based on the half-life of nicotine (according to the study design and with reasonable measurements) and metabolites (e.g. cotinine). The Contractor shall propose the sampling schedules (time points) for urine in the study to the COR, providing their scientific rationale for the time points selected. Carboxyhemoglobin shall be measured in the blood for each time point, as appropriate.

• The inhalation exposure atmosphere shall be physically and chemically characterized at the ports by monitoring and measuring wet total particulate matter (by gravimetric filter analysis as well as a real time aerosol monitor), carbon monoxide concentration (in real time), nicotine concentration, particle size distribution (in MMAD and GSD), percent relative humidity, and temperature at a nose only inhalation exposure sampling port.

• For animals in all inhalation groups, a nose-only plethysmography sub-group within each group shall be used to measure appropriate respiratory parameters including the determination of minute volume. The Contractor shall propose sampling schedules (time points) to the COR, providing their scientific rationale for the time points selected.

3.4.4 Final Report Requirements

1. Specific protocols, methods, materials, and equipment used for each experiment, including test material, doses, number of animals, Sprague-Dawley rats strain supplier information (including city, state, and country for all animals, test material, equipment, and materials), and software information shall be provided to FDA.

2. Data analyses shall include appropriate statistical analyses. The details of analytical methods used according to the study design, such as urine nicotine, blood COHb level, and other parameter calculations should be adequately described and referenced.

3. Interpretation and summary of results. A brief paragraph summarizing the pertinent conclusions of the study shall be provided.

4. All individual data needed for conclusions shall be presented in coherent tables (as recommended above). A copy of the raw data shall be provided separately in an appendix.

5. Documentation shall be provided to demonstrate the sensitivity, linearity, specificity, and reproducibility of the analytical method, including sample chromatographs, recovery studies, etc.

3.5 Deliverable/Pricing Schedule:

Task/Deliverable Due Date

Task 1-Kickoff Meeting Within 10 days of contract award

Task 2-Regular Teleconferences/Web Meetings Bi-Weekly

Task 3-ACUC Approval Documentation and Study Conduct

28-day study (products A and B):

Sept 1 – Nov 30, 2019 (Milestone 1)

90-day study (products C and D only):

Sept 1, 2019 – May 31, 2020 (Milestone 2)

Task 4-Animal Subject Health Notifications

As Needed

Task 5-Draft Final Report July 31, 2020 Task 6-Final Report Aug 30, 2020

Optional Task/Deliverable Due Date

Optional Task 1-Kickoff Meeting Within 10 days of contract award

Optional Task 2-Regular Teleconferences/Web Meetings

Bi-Weekly

Optional Task 3-ACUC Approval Documentation and Study Conduct

90-day study (products A and B only):

Sept 1, 2020 – Aug 30, 2021 (Milestone 3)

6-month study (products A and B):

Sept 1, 2020 – Sug 30, 2022 (Milestone 4)

Optional Task 4-Animal Subject Health Notifications As Needed Optional Task 5-Draft Final Report Aug 30, 2022 Optional Task 6-Final Report Nov 30, 2022

3.6 Security

All data files (i.e. reports, word documents, excel files, etc.) must be virus-checked before submission to the Government.

3.7 Period of Performance

Sept. 1, 2019 through Nov. 30, 2022 (please note, these dates may be adjusted according to actual date of award).

3.8 Other Requirements

3.8.1 Release and Sharing of Final Research Data

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

Upon acceptance for publication, researchers are also responsible for submitting the author’s final manuscript of any peer-reviewed scientific publication resulting from research supported, in whole or in part, with FDA funds to the NIH National Library of Medicine's (NLM) PubMed Central (PMC). FDA defines the author's final manuscript as the final version accepted for journal publication, which includes all modifications resulting from the publishing peer review process. The PMC archive is the designated repository for these manuscripts for use by the public, health care providers, educators, scientists, and FDA. FDA expects timely release and sharing of final research data from FDA-funded studies for the research community’s use in accordance with the submitted Data Management Plan. Please see the FDA Public Access Policy (provided as Attachment/Exhibit XXYY; or, available at (http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/staffmanualguides/ucm479268.pdf).

3.8.2 Publications and Presentations:

The Contractor shall not present, publish, or otherwise release any information arising out of their contract without the express prior written permission of the COR. The COR will determine what, if any, information may be releasable for publication, presentation, or through another means and will determine the content of the released information, including any authorship decisions.

3.8.3 Contractor Performance Evaluations

In accordance with FAR 42.15, FDA will complete annual and final Contractor performance evaluations.

Annual evaluations will be prepared to coincide with the anniversary date of the contract. Additional interim performance evaluations may be prepared at the FDA’s Contracting Officer discretion, as necessary.

Final performance evaluations will be completed upon expiration of the contract.

FDA will use the Contractor Performance Assessment Reporting System (CPARS) to execute annual and final Contractor performance evaluations. CPARS is a secure Internet website located at the following address: https://cpars.cpars.gov/. FDA will register the Contractor in CPARS upon receipt of the names and email addresses of two individuals who will be responsible for serving as the Contractor’s primary and alternate CPARS contacts. Once FDA registers the Contractor in CPARS, the Contractor will receive an automated CPARS email message which contains user identification information and instructions for creating a password.

Once a performance evaluation is issued, the Contractor’s primary and alternate CPARS contacts will http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/staffmanualguides/ucm479268.pdf receive an email instructing them to access CPARS to review the performance evaluation. The Contractor has 14 days from the date of performance evaluation issuance in which to review the evaluation. If the Contractor is in agreement with the performance evaluation outcome, the evaluation becomes final. Should the Contractor be in disagreement with the performance evaluation outcome, the Contractor shall submit rebuttal comments via CPARS within 14 days from the date the evaluation was issued by the FDA. Any disagreement between the Contracting Officer and the Contractor will be referred to a contracting official one level above the Contracting Officer, whose decision will be final.

Copies of each performance evaluation and Contractor responses, if any, will be retained as part of the official contract file and will be used to support future award decisions. Evaluations will also be stored for a three year period in the Past Performance Information Retrieval System (PPIRS) at www.ppirs.gov.

The Contractor may obtain CPARS training material and register for on-line training at the following website: https://www.cpars.gov/allapps/cpcbtdlf.htm. There is no fee for registration or use of CPARS.

3.8.4 Section 508 Standard Requirements

The Contractor shall ensure all deliverables are in compliance with Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794d), as amended (508 standards), which requires electronic and information technology (EIT) to be accessible to people with disabilities. Information about Section 508 compliance is available at http://www.section508.gov/.

3.8.5 Security and Privacy

To ensure adequate security and privacy protections, the Contractor shall follow the following terms.Unless otherwise indicated below, the Contractor shall submit all security and privacy forms and other documentation to the COR or his or her designee for review and approval.

• Contractor personnel performing work under these contracts shall satisfy all requirements for appropriate security eligibility in dealing with access to sensitive information and information systems. Contractor personnel assigned to these contracts are required to complete and undergo a National Agency Check Inquiry (NACI) before the Contractor employee may be issued an identification badge for access to FDA facilities or networks. Unfavorable information security check results will be reported to the appropriate personnel and action may be taken.

• Because of the sensitivity of FDA data, Contractor personnel having access to FDA facilities or networks shall also undergo a Level 5 Public Trust Security Clearance, including finger printing, performed under the auspices of the FDA.

• Except as may otherwise be permitted by a data owner, Contractor personnel agree not to use, disclose, or reproduce proprietary data, other than as required in performance of the contract; provided, however, that nothing herein shall be construed as precluding the use of any data independently acquired by the Contractor without such limitation.

• Each Contractor or subcontractor personnel who may have access to non-public HHS information under this contract shall complete and submit a FDA Form 3398: Contractor’s Commitment to Protect Non- Public Information (NPI) Agreement. A copy of each signed and witnessed 3398 form shall be submitted to the COR or his or her designee prior to performing any work under this contract. The Contractor shall hold all discussions and deliberations under their contract as confidential and shall limit public access and distribution of the work resulting from their contract. The Contractor shall secure facilities and http://www.ppirs.gov/ http://www.section508.gov/ communications to limit the access and distribution of any materials, documents, data, findings, analysis, or conclusions arising out of their contract. The Contractor agree Contractor personnel shall not divulge or release data or other information developed or obtained in connection with the performance of their contract to anyone, unless made publicly available by the FDA or upon written approval of the COR or his or her designee.

• The U.S. Department of Health and Human Services (HHS) policies require contractors, including subcontractors, receive security training commensurate with their responsibilities for performing work under the terms and conditions of their contractual agreements. The Contractor shall ensure that all of its personnel and subcontractor personnel anticipated to work under this contract have completed all requisite training, including the FDA Computer Security Awareness Training course, prior to performing any work under their contract that requires FDA network access and that these personnel complete this course again annually during performance under their contract. HHS may change, add, or modify computer security awareness training requirements to enhance and protect the HHS computer security program.

• To ensure compliance with Federal laws, rules, procedures, policies, and regulations related to privacy and security, the COR or his or her designee may require other forms or training for Contractor personnel before or during their performance under their contract.

3.9 Contract Administration

The following COR will represent the FDA for the purpose of this contract: (To Be Determined Upon Contract Award)

The COR is responsible for the following: (1) monitoring the Contractor’s technical progress, including surveillance and assessment of performance and recommending to the FDA Contracting Officer changes in requirements; (2) interpreting Statement of Works and any other technical performance requirements; (3) performing technical evaluations; (4) performing technical inspections and acceptances; and (5) assisting in the resolution of technical problems encountered during performance.

The Contracting Officer is the only person with authority to act as agent of the Government under these contracts. Only the Contracting Officer has authority to direct or negotiate any changes in a contract or task order, including modifying or extending the period of performance, changing the delivery schedule, and authorizing reimbursement to the Contractor for any costs incurred during the performance of their contracts.

The contact information for the FDA Contracting Officer is the following:

Matthew J. Bucher

FDA/OFBA/OAGS/DAP

4041 Powder Mill Road Beltsville, MD 20705-4304 Telephone: (240) 402-7570 E-Mail: Matthew.Bucher@fda.hhs.gov

The contact information for the FDA Contract Specialist is the following:

Christopher R. McGucken

FDA/OFBA/OAGS/DAP

file://ocs04/groupe$/OFACS/OAGS/DAP/DAP2/SSB/FY19%20Actions/McGucken/-02-%20Pre-Solicitation/InVivo%20%20TO%201/Matthew.Bucher@fda.hhs.gov

4041 Powder Mill Road Beltsville, MD 20705-4304 Telephone: (240) 402-7566 E-Mail: Christopher.McGucken@fda.hhs.gov

The contact information for the Contractor is the following

TBD

3.10 Government-Furnished Property, Material, Equipment, or Information (GFP, GFM, GFE, or

GFI)

Government-furnished property will not be provided to the Contractor.

3.12 Key Contractor Personnel

The following labor categories are considered key: Project Director and Senior Scientist.

HHSAR 352.237-75 Key Personnel (December 18, 2015)

The key personnel specified in this contract are considered to be essential to work performance. At least 30 days prior to the contractor voluntarily diverting any of the specified individuals to other programs or contracts the Contractor shall notify the Contracting Officer and shall submit a justification for the diversion or replacement and a request to replace the individual. The request must identify the proposed replacement and provide an explanation of how the replacement's skills, experience, and credentials meet or exceed the requirements of the contract (including, when applicable, Human Subjects Testing requirements). If the employee of the contractor is terminated for cause or separates from the contractor voluntarily with less than thirty days notice, the Contractor shall provide the maximum notice practicable under the circumstances.

The Contractor shall not divert, replace, or announce any such change to key personnel without the written consent of the Contracting Officer. The contract will be modified to add or delete key personnel as necessary to reflect the agreement of the parties.

(End of clause)

PART 4- CLAUSES

FAR and HHSAR Clauses and Provisions incorporated by reference may be obtained at:

https://www.acquisition.gov/far/ http://www.hhs.gov/grants/contracts/contract-policies-regulations/hhsar/index.html

The clause at 52.212-4, Contract Terms and Conditions-Commercial Items (Oct 2018)(Deviation 2018- 01)(March 2018) applies to this acquisition. The following addenda apply:

52.217-8 Option to Extend the Term of the Contract (Mar 2000) “…The Contracting Officer may exercise the option by written notice to the Contractor within 10 days of contract expiration.”

52.217-9 Option to Extend the Term of the Contract (Mar 2000) mailto:Christopher.McGucken@fda.hhs.gov https://www.acquisition.gov/far/ http://www.hhs.gov/grants/contracts/contract-policies-regulations/hhsar/index.html

(a) “…written notice to the Contractor within 10 days of contract expiration;…at least 60 days before the contract expires…” (b)”…shall not exceed Five (5) years…”

52.232-39 Unenforceability of Unauthorized Obligations (Jun 2013) 52.243-1 Changes-Fixed Price (Aug 1987)-Alt I (Apr 1984) 52.252-6 Authorized Deviations in Clauses (Apr 1984) (b)”…The use in this solicitation or contract of any HHS FAR Class Deviation 18-01 (48 CPR Chapter 1, Subchapter H) clause with an authorized deviation is indicated by the addition of “(DEVIATION)” after the name of the regulation...”

FAR 52.227-14, Rights in Data - General (MAY 2014), Alternate V (DEC 2007)

FAR 52.227-16, Additional Data Requirements (JUN 1987).

HHSAR Clause 352.203-70, Anti-Lobbying (Dec 2015) HHSAR Clause 352.208-70, Printing and Duplication (Dec 2015) HHSAR Clause 352.211-3, Paperwork Reduction Act (Dec 2015) HHSAR Clause 352.219-70, Mentor Protégé Program (Dec 2015) HHSAR Clause 352.222-70, Contractor Cooperation in Equal Employment Opportunity Investigations (Dec 2015) HHSAR Clause 352.223-70 Safety and Health (DEC 2015) HHSAR Clause 352.224-71 Confidential Information (DEC 2015) HHSAR Clause 352.227-70 Publications and Publicity (DEC 2015) HHSAR Clause 352.231-70 Salary Rate Limitation (DEC 2015) HHSAR Clause 352.237-75, Key Personnel (DEC 2015) HHSAR Clause 352.239-73, Electronic Information and Technology Accessibility Notice (Dec 2015) HHSAR Clause 352.239-74 Electronic and Information Technology Accessibility (Dec 2015) HHSAR Clause 352.270-5b Care of Live Vertebrate Animals (Dec 2015) HHSAR Clause 352.270-11 Protection of Human Subjects- Research Involving Human Subjects Committee (RIHSC) Approval of Research Protocols Required (Dec 2015) HHSAR Clause 352.270-13 Continued Ban on Funding Abortion and Continued Ban of Funding Human Embryo Research HHSAR Clause 352.224-70 Privacy Act (Dec 2015)

FAR 52.212-5 Contract Terms and Conditions Required to Implement Statutes or Executive Orders- Commercial Items (Aug 2019)

(a) The Contractor shall comply with the following Federal Acquisition Regulation (FAR) clauses, which are incorporated in this contract by reference, to implement provisions of law or Executive orders applicable to acquisitions of commercial items:

(1) 52.203-19, Prohibition on Requiring Certain Internal Confidentiality Agreements or Statements (Jan 2017) (section 743 of Division E, Title VII, of the Consolidated and Further Continuing Appropriations Act 2015 (Pub. L. 113-235) and its successor provisions in subsequent appropriations acts (and as extended in continuing resolutions)).

(2) 52.204-23, Prohibition on Contracting for Hardware, Software, and Services Developed or Provided by Kaspersky Lab and Other Covered Entities (Jul 2018) (Section 1634 of Pub. L. 115-91).

(3) 52.204-25, Prohibition on Contracting for Certain Telecommunications and Video Surveillance Services or Equipment. (AUG 2019) (Section 889(a)(1)(A) of Pub. L. 115-232).

(4) 52.209-10, Prohibition on Contracting with Inverted Domestic Corporations (Nov 2015).

(5) 52.233-3, Protest After Award (AUG 1996) (31 U.S.C. 3553).

(6) 52.233-4, Applicable Law for Breach of Contract Claim (OCT 2004) (Public Laws 108-77, 108-78 (19 U.S.C. 3805 note)).

(b) The Contractor shall comply with the FAR clauses in this paragraph (b) that the contracting officer has indicated as being incorporated in this contract by reference to implement provisions of law or Executive orders applicable to acquisitions of commercial items:

X (1) 52.203-6, Restrictions on Subcontractor Sales to the Government (Sept 2006), with Alternate I (Oct 1995) (41 U.S.C. 4704 and 10 U.S.C. 2402).

X (2) 52.203-13, Contractor Code of Business Ethics and Conduct (Oct 2015) (41 U.S.C. 3509)).

(3) 52.203-15, Whistleblower Protections under the American Recovery and Reinvestment Act of 2009 (June 2010) (Section 1553 of Pub. L. 111-5). (Applies to contracts funded by the American Recovery and Reinvestment Act of 2009.)

X (4) 52.204-10, Reporting Executive Compensation and First-Tier Subcontract Awards (Oct 2018) (Pub.

L. 109-282) (31 U.S.C. 6101 note).

(5) [Reserved].

(6) 52.204-14, Service Contract Reporting Requirements (Oct 2016) (Pub. L. 111-117, section 743 of Div. C).

X (7) 52.204-15, Service Contract Reporting Requirements for Indefinite-Delivery Contracts (Oct 2016) (Pub. L. 111-117, section 743 of Div. C).

X (8) 52.209-6, Protecting the Government’s Interest When Subcontracting with Contractors Debarred, Suspended, or Proposed for Debarment. (Oct 2015) (31 U.S.C. 6101 note).

X (9) 52.209-9, Updates of Publicly Available Information Regarding Responsibility Matters (Oct 2018) (41 U.S.C. 2313).

(10) [Reserved].

(11) (i) 52.219-3, Notice of HUBZone Set-Aside or Sole-Source Award (Nov 2011) (15 U.S.C.657a).

(ii) Alternate I (Nov 2011) of 52.219-3.

(12)(i) 52.219-4, Notice of Price Evaluation Preference for HUBZone Small Business Concerns (Oct 2014) (if the quoter elects to waive the preference, it shall so indicate in its offer) (15 U.S.C. 657a).

(ii) Alternate I (Jan 2011) of 52.219-4.

(13) [Reserved]

(14)

(i) 52.219-6, Notice of Total Small Business Set-Aside (Nov 2011) (15 U.S.C.644).

(ii) Alternate I (Nov 2011).

(iii) Alternate II (Nov 2011).

(15)(i) 52.219-7, Notice of Partial Small Business Set-Aside (June 2003) (15 U.S.C. 644).

(ii) Alternate I (Oct 1995) of 52.219-7.

(iii) Alternate II (Mar 2004) of 52.219-7.

X (16) 52.219-8, Utilization of Small Business Concerns (Oct 2018) (15 U.S.C. 637(d)(2) and (3)).

X (17) (i) 52.219-9, Small Business Subcontracting Plan (Aug 2018) (15 U.S.C. 637(d)(4))

(ii) Alternate I (Jan 2017) of 52.219-9.

X (iii) Alternate II (Nov 2016) of 52.219-9.

(iv) Alternate III (Nov 2016) of 52.219-9.

(v) Alternate IV (Aug 2018) of 52.219-9

(18) 52.219-13, Notice of Set-Aside of Orders (Nov 2011) (15 U.S.C. 644(r)).

(19) 52.219-14, Limitations on Subcontracting (Jan 2017) (15 U.S.C.637(a)(14)).

X (20) 52.219-16, Liquidated Damages-Subcontracting Plan (Jan 1999) (15 U.S.C. 637(d)(4)(F)(i)).

(21) 52.219-27, Notice of Service-Disabled Veteran-Owned Small Business Set-Aside (Nov 2011) (15 U.S.C. 657f).

X (22) 52.219-28, Post Award Small Business Program Rerepresentation (Jul 2013) (15 U.S.C.

632(a)(2)).

(23) 52.219-29, Notice of Set-Aside for, or Sole Source Award to, Economically Disadvantaged Women- Owned Small Business Concerns (Dec 2015) (15 U.S.C. 637(m)).

(24) 52.219-30, Notice of Set-Aside for, or Sole Source Award to, Women-Owned Small Business Concerns Eligible Under the Women-Owned Small Business Program (Dec 2015) (15 U.S.C. 637(m)).

X (25) 52.222-3, Convict Labor (June 2003) (E.O.11755).

X (26) 52.222-19, Child Labor-Cooperation with Authorities and Remedies (Jan 2018) (E.O.13126).

X (27) 52.222-21, Prohibition of Segregated Facilities (Apr 2015).

(28)

X (i) 52.222-26, Equal Opportunity (Sept 2016) (E.O.11246).

(ii) Alternate I (Feb 1999) of 52.222-26.

X (29) (i) 52.222-35, Equal Opportunity for Veterans (Oct 2015) (38 U.S.C. 4212).

(ii) Alternate I (July 2014) of 52.222-35.

(30) (i) 52.222-36, Equal Opportunity for Workers with Disabilities (Jul 2014) (29 U.S.C.793).

(ii) Alternate I (July 2014) of 52.222-36.

(31) 52.222-37, Employment Reports on Veterans (Feb 2016) (38 U.S.C. 4212).

X (32) 52.222-40, Notification of Employee Rights Under the National Labor Relations Act (Dec 2010) (E.O. 13496).

X (33) (i) 52.222-50, Combating Trafficking in Persons (Jan 2019) (22 U.S.C. chapter 78 and E.O.

13627).

(ii) Alternate I (Mar 2015) of 52.222-50 (22 U.S.C. chapter 78 and E.O. 13627).

X (34) 52.222-54, Employment Eligibility Verification (Oct 2015). (Executive Order 12989).