FDA-21-SOL-1238789.pdf

FDA-21-SOL-1238789

In-Vitro Tools to Simulate Chewing of Pharmaceutical Opioid Drug Products

1. Description of Work/Statement of Objectives

1.1. Background

The growing epidemic of misuse, abuse, and addiction of prescription opioids is an imminent threat to U.S. public health. The pharmaceutical industry has responded to this public health concern by developing innovative abuse-deterrent (AD) oral solid dosage forms resistant to various forms of physical and chemical tampering. As of December 2017, the FDA has approved a total of ten brand-name oral opioid drugs whose labeling describes AD properties, but there is no approved generic version of these abuse-deterrent formulation (ADF) opioid products. In November 2017, FDA published the final guidance General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products (Ref 1) to provide a general framework and approach for designing in vitro studies to compare AD properties of generic ADF opioid products with their respective brand products.

One of the key regulatory challenges in abuse deterrence evaluation is the need to develop rigorous, yet meaningful and reliable measures to determine “no less abuse deterrence” of generic versions of proprietary ADF. Specifically, the oral ingestion of opioid products, via chewing an extended release product and by taking multiple tablets, is still the most preferred route of abuse, yet, there are a limited number of tools available to evaluate a dosage form’s AD performance in vitro. ADF products may have physicochemical properties that are expected to reduce oral abuse when the abusers intentionally chew the products to rapidly release the drug substances.

Previous work from the FDA laboratories utilized the Erweka DRT2 chewing apparatus to simulate chewing of a commercially available ADF product and resulted in initially faster drug release during chewing while subsequent dissolution testing demonstrated that the masticated tablets still maintained extended-release properties. However, there are some limitations with this method and apparatus. The only parameters that can be adjusted on the Erweka apparatus are the distance between the chewing surfaces (compression gap), the frequency of the chewing cycles (chewing frequency), and the torsion angle of the twisting movement (twisting angle). In addition, the maximum bite force of this apparatus is 400 Newtons. The objective of this study is to develop orthogonal in vitro chewing approaches to that of the Erweka DRT2.

The current study intends to evaluate the abuse deterrence properties of opioid drug products when chewed via in vitro chewing simulation studies. A systemic evaluation of the effect of simulated human chewing on drug release from the chewed bolus will help identify critical parameters when designing in vitro studies to compare oral abuse deterrence properties of a generic with its RLD when chewed.

ACRONYMS: reference listed drug (RLD), Food and Drug Administration (FDA), Institutional Review Board (IRB), Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP), Good Clinical Practice (GCP), Human subject Protection (HSP), Statement of Work (SOW), Contracting Officer Representative (COR), Principal Investigator (PI), Active Pharmaceutical Ingredient (API), Abuse-Deterrent Formulation

(ADF)

1.2. Objectives

The objectives of this contract are to develop in vitro chewing simulation methods that can predict inter subject and intra subject variability of human chewing, determine critical in human “chewing” variables that impact the extent of drug release from a chewed pharmaceutical dosage form and to also predict the extent of drug release in vivo for different types of abuse deterrent products that are chewed. The selected chewing apparatus or multiple apparatus should be different from the Erewka DRT2 for orthogonal data collection and comparison. The orthogonal chewing apparatus or multiple apparatus will assess factors that affect how much drug is released when chewing conditions are varied. Besides the three parameters (compression gap, chewing frequency, twisting angle), measured using Erweka DRT2, additional independent variables to be evaluated can include, but are not limited to, the type of chewing apparatus or multiple apparatus, extent of human chewing (e.g., overall chewing time, the total number of chewing cycles, pre-soaking vs not pre-soaking sample prior to chewing), salivary composition, salivary flow rate, shearing angle, and mandible force required to chew pharmaceutical products with different design shape and material composition (e.g. Hysingla, Xtampza, Targin). The extent of drug release during the chewing process under the specified conditions will be measured and dissolution studies on the chewed bolus, to measure the impact of the same chewing conditions on drug release, will be conducted. Additionally, measurements to physically characterize the chewed bolus will be implemented such as particle size distribution and other methods determined that may assist in obtaining the stated objectives. The inter subject and intra-subject variability on the effect of human chewing on drug release will be predicted and assessed. The outcome of this study may help determine critical in vitro study design parameters when comparing abuse deterrence of an opioid product via the oral route between a generic product and its RLD when chewed. The results from this study will also help validate and support current in vitro chewing study methods and results.

1.3. Detailed Description

For the Base tasks the Contractor shall:

1.3.1 In discussion with the FDA, select and procure opioid drug products with and without abuse deterrent features for the in vitro chewing simulation studies. For each abuse deterrent product selected, a non-abuse deterrent product with same active pharmaceutical ingredient as the ADF should be selected as a control. A minimum of 3 ADF products should be studied.

1.3.2 In discussion with the FDA, modify existing equipment or purchase equipment or rent equipment to simulate chewing to obtain the desired objectives. Modifications made to existing equipment should be validated.

1.3.3 Either calibrate, or validate, or both the instrument parameters required to simulate chewing of ADF products using the selected chewing simulator apparatus or multiple apparatus.

1.3.4 In discussion with the FDA, develop an in vitro chewing study protocol to assess the variables of interest, as described in the objectives, and that are determined to be feasible to measure per the apparatus or multiple apparatus being used. Additional independent variables of interest to study may be added if they assist in meeting the defined objectives.

The protocol should include experiments to design a range of values appropriate for each independent variable selected for the study. The number of replicates required should be appropriate for each independent variable studied.

1.3.5 Develop a validated analytical method to quantify extent of drug release into media that occurs during simulated chewing and quantify rate and extent of drug release from the chewed bolus in dissolution studies post simulated chewing. Analytical method validation should include all the procedures that demonstrate that a particular method used for quantitative measurement of analytes in a given matrix is reliable and reproducible for the intended use. The fundamental parameters for this validation include (a) accuracy,

(b) precision, (c) selectivity, (d) sensitivity, (e) reproducibility and (f) stability

1.3.6 Submit quarterly and yearly project progress reports

In discussion with the FDA, if the optional task is required, the contractor shall

1.3.7 In discussion with the FDA, procure either opioid product, or placebo tablets representative of ADF tablets, or nutraceutical products with similar material properties to abuse deterrent products. Placebo tablet or nutraceutical products will be used to conduct in vivo human chewing studies to calibrate the appropriate conditions for the chewing apparatus or multiple apparatus and may be used for in human studies to determine appropriate parameters.

1.3.8 In discussion with the FDA, develop a protocol for any planned in vivo human study determined to be necessary to calibrate chewing simulators for the planned opioid products studied. Where possible, alternative products (i.e. nutraceuticals or placebos) should be used to avoid subject exposure to opioids. If exact opioid products are required to calibrate chewing instrumentation, precautions should be taken to protect subject safety, including but not limited to administration of appropriate opioid antagonist prior to study and inclusion of additional end points to monitor subject safety. The protocol shall conform to all applicable Good Clinical Practice (GCP) regulations. The protocol shall include at a minimum and if applicable: Informed Consent Form (in compliance with 45 CFR 46.116 where applicable), Clinical and Analytical Site Identification, Key Personnel, Background Material, Demographics, Inclusion and Exclusion Criteria, Method of Subject Selection, Randomization Scheme, Study Design, Sample Size Determination, Safety measurement, Sample Storage, Potential Risks to the Subjects, Protection Against Risks, Potential Benefits to the Subjects and to Society, Risk/Benefit Assessment, Confidentiality of Subject Information, Data Safety Monitoring Plan, Subject Recruitment Oversight, Study Progress, and Adverse Event Reporting Plan. The protocol developed by the Contractor shall comply with the requirements of FDA IRB and/or requirements of the local IRB in addition to any local government requirements if applicable. The contractor shall submit to FDA a protocol that follows FDA IRB guidelines and applicable regulations for format and content.

1.3.9 Begin the in vivo study within 30 calendar days from the date the Contractor obtains FDA IRB approval and/or local IRB approval.

1.3.10 Establish and maintain the essential documents before, during and after the study.

The contractor shall follow good documentation practice (GDP) at all times.

1.3.11 Monitor and record any side effects or adverse reactions during the human study.

1.3.12 Generate a study report on the evaluation of study products and on safety outcome of the in vivo study.

1.3.13 Be responsible for subject recruitment, supplies, equipment, data collection, and computational software.

1.3.14 Adhere to all relevant regulations and FDA guidance documents including but not limited to Good Laboratory Practice, Good Clinical Practice and Good Manufacturing Practice where applicable.

1.3.15 Obtain and maintain any relevant authorization and regulations for use of opioid drugs in research per either state and country or both.

1.4. References

3.4.1 Final guidance on “General principles for evaluating the abuse deterrence of generic solid oral opioid drug products” (Nov 2017) https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan ces/UCM492172.pdf

3.4.2 A. Externbrink, et al. International Journal of Pharmaceutics 561 (2019) 305–313.

1.5 Research Involving Human Subjects

All research conducted, supported, or regulated by any U.S. Government Agency is subject to certain uniform requirements of the Federal Policy for the Protection of Human Subjects including Institutional Review Board (IRB) membership, IRB review and approval criteria, IRB operations and record keeping, and informed consent. The Contractor agrees that the rights and welfare of human subjects involved in research under this contract shall be protected in accordance with 45 CFR Part 46 and with the Contractor’s current Assurance of Compliance on https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM492172.pdf https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM492172.pdf file with the Office for Human Research Protections (OHRP), Department of Health and Human Services (HHS). Research supported by FDA may also be subject to FDA regulations, including 21 CFR parts 50, 312, 812 and 820.

The Institutional Review Board (IRB) specified in the Contractor’s Assurance of Compliance, hereafter referred to as "the local IRB," shall review the proposed research protocol. A letter from the local IRB stating that the proposed research protocol adequately protects the rights and welfare of human subjects involved, or a letter stating that the proposed research is exempt under 45 CFR 46.101(b) and shall be submitted to the FDA Contracting Officer’s Representative (COR).

The Contractor further agrees that research involving human subjects and funded by the FDA shall receive approval from FDA IRB prior to enrolling human subjects unless IRB Authorization Agreement (IAA) is executed or FDA is determined not to be engaged in human subject research (HSR). The Contractor shall submit its proposed research protocol and all related documents (including but not limited to the informed consent form, recruitment material, telephone script, questionnaire, and Investigator’s brochure or package insert of study drug(s) as appropriate) through the FDA COR or its delegate to the FDA IRB.

The Contractor shall understand and comply with ethical principles and regulatory requirements involving human subjects research as specified in the Federal regulations for the Protection of Human Subjects, 45 CFR 46. The Contractor shall remain in compliance with the HHS policies and procedures that concern the conduct of human subject research.

The Contractor shall bear full responsibility for the performance of all work and services involving the use of human subjects under this contract in a proper manner and as safely as is feasible. Nothing in this contract shall be deemed to constitute the Contractor or any sub- Contractor, agent or employee of the Contractor, or any other person, organization, institution, or group of any kind whatsoever, as the agent or employee of FDA. The Contractor agrees that it has entered into this contract and will discharge its obligations, duties, and undertakings and the work pursuant thereto, whether requiring professional judgment or otherwise, as an independent Contractor without imputing liability on the part of FDA for acts of the Contractor or its employees.

If at any time during performance of this contract, the Contracting Officer determines, in consultation with FDA IRB, that the Contractor is not in compliance with any of the requirements and/or standards stated in Section 3.5, the Contracting Officer may immediately suspend, in whole or in part, work and further payments under this contract until the Contractor corrects the noncompliance. Notice of the suspension may be communicated by telephone and confirmed in writing by the Contracting Officer. If the Contractor fails to complete the corrective action within the period of time designated in the Contracting Officer's written notice of suspension, the Contracting Officer may, in consultation with FDA IRB, terminate this contract in whole or in part, and the Contractor’s name may be removed from the list of those Contractors with approved Department of Health and Human Services Human Subject Assurances.

1.6 Compliance

The Contractor shall ensure compliance with the following requirements:

a. No FDA funds shall be expended to implement any part of the proposed research protocol funded in whole or part under this contract until approval is received from the local IRB and/or FDA IRB. Activities requiring approval include recruitment, enrollment, screening, records review or any other activity related to protocol implementation.

b. Should a portion of the FDA funds be applied to protocol development or other support activities conducted prior to protocol implementation, the Contractor shall provide an accounting of the use of these funds at the time of FDA IRB review.

c. All consent forms shall comply with HHS and FDA regulations at 5 CFR 46.116, 21 CFR

50.25 and 45 CFR 46 subpart A regarding the required elements of informed consent.

d. The FDA COR will serve as the responsible party for a trial which is determined to be an applicable clinical trial under Title VIII of FDAAA. If required, the FDA COR or its delegate shall register and submit the results of the research study to ClinicalTrials.gov.

https://clinicaltrials.gov/. For trials which do not meet the definition of an applicable clinical trial under Title VIII of FDAAA, the contractor may register and submit the results of the study with prior approval by the FDA COR or its delegate. In such a case, the contractor is responsible for all matters relating to the ClinicalTrials.gov databank. The information on the registry can be found at the link above.

e. If FDA is providing partial funding for the research study, details of the expenses paid for with FDA funds shall be tracked separately.

f. Should funds support any salaries, information on what activities are being performed by each individual for that salary support must be tracked and reported to the FDA.

g. Any changes to the protocol, informed consent form, recruitment materials or any other documents related to the protocol implementation shall be reviewed and approved by FDA IRB and/or the local IRB, prior to implementation. All study documents shall be available to the FDA COR or its delegate upon request. It may include, but not limited to: source documentations, deidentified case report forms, pharmacy records, and essential documents.

h. Research approved by the local IRB and/or FDA IRB may not continue beyond one year from the approval date unless a continuing review is conducted by the local IRB and/or FDA IRB and approved.

i. The FDA IRB or its designee shall review the research protocol to assure that the rights and welfare of human subjects involved are adequately protected. The FDA IRB shall also determine whether the proposed research is exempt under 45 CFR 46.l01 (b) where applicable.

j. Research involving human subjects may commence in a timely manner upon the Contractor’s receipt of FDA IRB and/or local approval provided by the FDA COR.

k. Where applicable, if the Contractor fails to obtain FDA IRB approval of its proposed research during FDA IRB's initial review, the Contractor shall have the opportunity to correct the deficiencies identified during the FDA IRB review and resubmit the proposed research protocol to FDA IRB for a second review. The Contractor is to solicit the FDA IRB's and/or FDA study team’s input during the resubmission process.

The Contractor must provide an internal monitoring plan that describes the procedures and documentation that shall be used for quality purpose.

The proposed research study protocol shall comply with ICHE6 Good Clinical Practice Consolidated Guidance which sets an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. All human subject research regulated by FDA may also be subject to FDA's regulations regarding the protection of human subjects (21 CFR parts 50 and 56).

1.7 FDA-IRB

Upon contract award, the Government will arrange a kickoff meeting with the Contractor to discuss requirements of the FDA IRB and the roles and responsibilities of Government personnel throughout the FDA IRB review process.

Following the kickoff meeting, the Contractor shall submit the proposed study documents including the research protocol, informed consent form(s), participant information sheet (if applicable), survey questions, phone scripts, and recruitment advertisements to the FDA COR.

The FDA COR or its delegate shall review the submission package to ensure completeness and will provide comments/suggestions. All final research documents shall be submitted to the FDA COR for review including CVs or resumes and appropriate training records of key personnel, a medical license of medically accountable officer, Investigator’s brochure or package insert of study drug(s) as appropriate, a federal wide assurance (FWA), active IRB registration number associated with FWA, local IRB and FDA form 1572. Following the review and sign off by the OGD Human Subject Protection (HSP) Liaison, the submission package shall be submitted electronically to the FDA IRB unless IAA is executed or FDA is determined not to be engaged in HSR. The FDA COR or its delegate will be copied on the submission to the FDA IRB.

If the Contractor has already received local IRB approval for the final study documents prior to submission to FDA IRB, a copy of the approval letter from the local IRB must be included in the submission package to the FDA COR if applicable. The IRB approval letter must state that the proposed research study documents adequately protect the rights and welfare of human subjects. The Contractor may submit the research study documents to their IRB at the same time the Contractor submits its package to the FDA COR for FDA IRB review if applicable. The Contractor is required to submit the approval letter from the local IRB to the FDA COR or its delegate upon receipt of the letter if applicable. This requirement would include proposed research that is exempt from IRB approval.

Note: Certification of local IRB review and approval must include the following: the PHS/HHS application number, title of the project, name of the program director/principal investigator, date of IRB approval, and appropriate signatures. The IRB must ensure that any corresponding protocol(s) are consistent with the specific application.

The FDA IRB will review the research study documents to assure that the rights and welfare of human subjects involved are adequately protected. The FDA IRB will also determine whether the proposed research is exempt under 45 CFR 46.101(b). The FDA COR will provide the Contractor with a copy of FDA IRB’s letter of approval/approval with stipulations/disapproval where applicable. If FDA IRB renders a decision other than approval of the proposed research study documents, the FDA COR or its delegate will assist the Contractor in revising the research study documents for re-submission for review and approval. Upon the study initiation, the contractor shall submit CDER study update form either monthly or bi-weekly.

The Contractor shall seek FDA IRB approval and/or local IRB review and approval whenever modifications, amendments or other changes are made to the research study documents.

Modifications and amendments include, but are not limited to, changes to the study protocol, consent form(s), recruitment materials, any planned deviations and the addition or deletion of key personnel/investigators. Where applicable, the Contractor shall submit modified/amended study documents to the FDA COR for FDA IRB review and approval. The FDA COR will provide the Contractor with a copy of FDA IRB’s letter of approval/approval with stipulations/disapproval if applicable. The Contractor shall also submit a copy of the local IRB approval of modifications/amendments to the FDA COR upon receipt if applicable.

Questions regarding FDA IRB shall be directed to OGD HSP liaison.

1.8 Reporting

a) Changes/amendments to the protocol/informed consent document must promptly report to the FDA COR or its delegate, all proposed changes in the research activity including any modifications to the Study Protocol, and Informed Consent document

b) Non-compliance: the Contractor must report any alleged breaches of the protocol, such as breakdowns in the informed consent process, violations of confidentiality of data or privacy of a research subject, complaints by participants or their representatives, and any serious or continuing noncompliance with federal regulations by the investigators or research staff via FDA COR or its delegate

c) Adverse event reporting: the Contractor must report to the FDA COR or its delegate, any unanticipated problems involving risk to human subjects or others and anticipated adverse events may be reported to the FDA IRB or its designee in the annual report for continuing review. Any serious adverse events (SAE) must be reported to the FDA COR or its delegate within 24 hours of learning of the event.

Local IRB Correspondence: The Contractor shall submit the key correspondence with local IRB and all submitted documents in the original forms to the FDA COR or its delegate.

Annual Submissions Requirements: Contractor shall provide an approval letter from their local IRB, at least annually; stating that the research protocol performed under this contract has been reviewed and approved to continue for another year. This shall be submitted to the FDA COR for inclusion in the contract file. Where applicable, the COR or its delegate will provide a copy of the approval letter from FDA IRB to the Contractor, at least annually, stating that the research protocol performed under this contract has been reviewed and approved to continue for another year.

1.9 Quality Assurance and Monitoring

The Government or its delegate will perform quality assurance monitoring (remotely and/or via on-site visits) to ensure human subject protections throughout the conduct of the study and document compliance with the regulations and the FDA IRB requirements that govern the conduct of research involving human subjects where possible. The OGD’s Clinical Studies Coordinator and/or its delegate will provide the Contractor with a report of all identified deviations and/or violations related to human subject protections. If significant deviations are found, the Contractor shall provide responses to the corrective actions listed in the report to the OGD’s Clinical Studies Coordinator and the FDA COR or its delegate within 2 weeks of receipt of the report/violation notice. If the Contractor has established a Steering Committee and/or a Monitoring Board (for monitoring quality assurance) for this contract, the Contractor shall submit the responses to the corrective actions of violations to the Steering Committee and/or Monitoring Board as established.

The Contractor must provide documentation of acknowledgement of the significant deviations either by the local IRB and/or Steering Committee/Monitoring Board to the OGD’s Clinical Studies Coordinator and the FDA COR. This documentation will be forwarded to FDA IRB for review and documentation of the review and any required actions will be provided to the Contractor where applicable.

2. Reporting Requirements and Deliverable Items

The reporting requirements and deliverables apply to each task order award.

All deliverables shall be 508 compliant. All electronic and information technology (EIT) must met the applicable accessibility standards at 36 CFR 1194, unless an agency exception to this requirement exists. 36 CFR 1194 implements Section 508 of the Rehabilitation Act of 1973, as amended, and is viewable at:

http://www.access-board.gov/sec508/standards.htm.

Pursuant to the HHSAR clause 352.270-19, the Section 508 standards applicable to the prospective award are:

• § 1194.41 Information, documentation, and support

• § 1194.21 Software applications and operating systems

• § 1194.22 Web-based intranet and internet information and applications

Disclaimer: Table below shows rough figures and can change depending on the study design.

Deliverable Table # Deliverable Date (NLT) 1 Project Management and

Start-up If required, execute necessary sub-contracts Have kick-off meeting Schedule regular meetings with FDA

30 days of the award date

2 In vitro protocol and study design

60 days of the award date

3 Validated analytical method and final method report to assess selected opioid in saliva during chewing and dissolution testing post chewing with defined limits of quantification and precision

90 days of the award date

4 33% completed in vitro studies

240 days of the award date

5 66% completed in vitro studies

360 days following the close of every third month from the contract award date/360 days of the award date

6 100% Completed in vitro studies

480 days of the award date http://www.access-board.gov/sec508/standards.htm

7 Quarterly reports and Final Study Data

90 days prior to the contract expiration date

8 Final Report Draft due 60 days prior to the contract expiration date for comments. Comments will be provided to contractor within 25 days of receipt and addressed in the final report.

9 Pass through including drug cost and equipment cost

360 days of the award date

10 Final Presentation at FDA (Optional)

To be determined by FDA, in consultation with the contractor, no later than the contract expiration date.

Base Period Optional Task 11 In vivo study protocol/ICF and implementation plan including timeline

30 days of the award date

12 Submission of IRB application package

90 days of the award date

13 IRB(s) approval and study set up

180 days of the award date

14 Clinical study report 300 days of the award date

15 Pass through Cost for opioid product, or placebo or nutraceuticals

300 days of the award date

Reports (i.e., quarterly progress reports, and final report), containing the description of experiments and data analysis, will be provided to the FDA using FDA recommended format in both paper and electronic format. In addition, all of the raw data from the experiments and studies will be provided to the FDA in electronic format, along with these reports.

No information furnished to or generated by the contractor in the performance of this contract will be released to the public until it has been reviewed by the Government Contracting Officer’s Representative for accuracy of factual data and interpretation. The Government will have sixty (60) calendar days after receipt of the manuscript or other written draft of the material to be released, to review, comment, and return to the contractor.

Scientific manuscripts/publications resulting from work conducted by the Contractor and Government site investigators will be prepared and published according to guidelines agreed upon at study initiation by the investigator team for that study. At study initiation, each study group shall determine the first and senior author positions. While the order of listing authors on each publication shall be determined on a case-by-case basis by mutual decision of all collaborative parties and shall reflect appropriately each author’s contribution to the project, it is likely that a Contractor employee will be offered the first author position for the primary manuscript arising from the study. However, the senior author position may be offered to any member of the study team who is willing to provide substantial input into study design, implementation, and manuscript preparation and oversight of all study procedures. Study Site Principal Investigator (PI) and Principal Investigators from the other sites, including FDA, will be listed as authors on the manuscripts, with ordering in these positions determined by consensus based on the amount of input into the actual production of the manuscript. All authors shall provide final approval of the manuscript as written. Even though the Contractor will likely be the first author on resulting publications, it is the Government’s discretion as to when the articles should be published. The Contractor shall not unduly delay publication or unilaterally decide that the data should not be published. This right is retained by the Government only.

3. Duration of Project

24 month period of performance

4. Site Visit Schedule

Two visits in response to yearly reports are planned.

5. Conflict of Interest

Organizational Conflict of Interest

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

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

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

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

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

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

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

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

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

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

(h) Prime Contractor Responsibilities.– The contractor shall identify and avoid, neutralize, or mitigate any subcontractor organizational conflict prior to award of the contract to the satisfaction of the Contracting Officer. If the subcontractor's organizational conflict cannot be avoided, neutralized, or mitigated, the contractor must obtain the written approval of the Contracting Officer prior to entering into the subcontract. If the contractor becomes aware of a subcontractor's potential or actual organizational conflict of interest after contract award, the contractor agrees that the Contractor may be required to eliminate the subcontractor from its team, at the contractor's own risk. The contractor shall obtain from its subcontractors or consultants the disclosure required in FAR Part 9.507

(i) Waiver. The contractor may seek a waiver from the Head of the Contracting Activity by submitting such waiver request to the Contracting Officer, including a full written description of the requested waiver and the reasons in support thereof.

6. Contract Administration Data

The following personnel shall represent the Government for the purpose of this contract:

Technical Representative: To be determined upon contract award

The Technical Representative 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.

Contracting Officer (CO):

Kyle Smith 4041 Powder Mill Road Beltsville, MD 20705 kyle.smith@fda.hhs.gov Tel: (240) 402-7553

The Contracting Officer is the only person with authority to act as agent of the Government under this contract. Only the Contracting Officer has authority to (1) Direct or negotiate any changes in the requirements; (2) Modify or extend the period of performance; (3) Change the delivery schedule; (4) Authorize reimbursement to the Contractor any costs incurred during the performance of this contract; or (5) Otherwise change any terms and conditions of this contract.

Contracting Officer’s Authority

The Contracting Officer is the only person with authority to act as agent of the Government under this contract. Only the Contracting Officer has authority to: (1) direct or negotiate any changes in the statement of work; (2) modify or extend the period of performance; (3) change the delivery schedule;

(4) authorize reimbursement to the Contractor any costs incurred during the performance of this contract; or (5) otherwise change any terms and conditions of this contract.

The Contracting Officer hereby delegates the COR as the Contracting Officer's authorized representative responsible for signing software license agreements issued as a result of this contract.

The Government may unilaterally change its COR designation.

Contracting Officer Representative’s Authority/FDA Project Manager

The COR and FDA Project Manager assigned to each order 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 mailto:kyle.smith@fda.hhs.gov 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 COR and FDA project manager assigned to each order responsible for the technical requirements covered by this contract, as contemplated above, "Technical Monitoring" hereof, will be designated by separate correspondence.

Section 508 Compliance

The Contractor shall be familiar with Section 508 requirements as described at http://www.section508.gov/ in order to ensure that documents generated as part of the tasks are fully Section 508-accessible using the available COTS tools. Each order will identify the standards applicable to that order.

Post Award Evaluation of Contractor Performance (CPARS)

In accordance with Federal Acquisition Regulation (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 Contracting Officer discretion, as necessary. Final performance evaluations will be completed upon contract expiration.

FDA will utilize the Contractor Performance Assessment Reporting System (CPARS) in order to execute annual and final contractor performance evaluations. CPARS is a secure Internet website located at http://www.cpars.csd.disa.mil/cparsmain.htm. FDA will register the contractor in CPARS upon receipt of the name and email address of two (2) 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 IDs and instructions for creating a password.

Once a performance evaluation is issued, the Contractor’s primary and alternate CPARS contact will receive an email instructing them to logon to CPARS in order 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, rebuttal comments must be submitted via the CPARS within 30 days from date the evaluation was issued by 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 3 year period in the Past Performance Information Retrieval System (PPIRS) at www.ppirs.gov.

http://www.section508.gov/ http://www.section508.gov/ http://www.cpars.csd.disa.mil/cparsmain.htm http://www.cpars.csd.disa.mil/cparsmain.htm http://www.ppirs.gov/ http://www.ppirs.gov/

Contractors may obtain CPARS training material and register for on-line training at http://www.cpars.csd.disa.mil/allapps/cpcbtdlf.htm. There is no fee for registration or use of the

CPARS.

Payment Schedule:

Unless otherwise agreed to by the Technical POC, the Contractor shall submit invoices subsequent to the delivery of the required equipment. Installation and training shall be invoiced after installation and training has been completed.

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 Srping, MD 20993-0002 301-827-3742 Fdavendorpaymentsteam@fda.hhs.gov

*** Acceptable methods of delivery include: E-mail (preferred) and Standard Mail.

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 destination;

(c) any other supporting information necessary to clarify questionable expenditures;

(d) the contractor shall include the award item number for each description, quantity, unit of measure, unit price, and extended price supplies delivered or services performed;

(v) Shipping number and date of shipment, including the bill of lading number and weight of http://www.cpars.csd.disa.mil/allapps/cpcbtdlf.htm http://www.cpars.csd.disa.mil/allapps/cpcbtdlf.htm mailto:Fdavendorpaymentsteam@fda.hhs.gov shipment if shipped on government bill of lading;

(vi) Terms of any discount for prompt payment offered (Prompt Payment terms other than NET

30);

(vii) Name and address of official to whom payment is to be sent (must be the same as that in the purchase order/award, or in a proper notice of assignment)

(viii) Name, title, and phone number of person to notify in event of defective invoice;

(ix) Taxpayer Identification Number (TIN);

(x) banking routing transit number of the financial institution receiving payment for Electronic funds transfer (EFT);

(xi) Name and telephone number of the FDA Contracting Officer Representative (COR) or other Program Center/Office point of contact, as referenced on the award;

(xii) For all Inspections, Time-and-Materials and Labor-Hour Awards, Contractor is required to attach an invoice log addendum to each invoice which shall include, at a minimum, the following information for contract administration and reconciliation purposes:

(a) list of all invoices submitted to date under the subject award, including the following:

(1) invoice number, amount, & date submitted

(2) corresponding payment amount & date received

(b) total amount of all payments received to date under the subject contract or order

(c) and, for definitized contracts or orders only, total estimated amounts yet to be invoiced for the current, active period of performance;

(xiii) Any other information or documentation required by the award.

C. An electronic invoice is acceptable if submitted in adobe acrobat (PDF) format. All items listed in

(i) through (xiii) of this clause must be included in the electronic invoice. Electronic invoices must be on company letterhead and must contain no ink changes and be legible for printing.

D. Questions regarding invoice payments should be directed to the Employee Resource and Information Center (ERIC) Helpdesk at 301-827-ERIC (3742) or toll-free 866-807-ERIC (3742); or, by email at ERIC@fda.hhs.gov. Refer to the Call-in menu options and follow the phone prompts to dial the option that corresponds to the service that's needed. All ERIC Service Now Tickets will either be responded to or resolved within 48 hours (2 business days) of being received. When emailing, please be sure to include the contract number, invoice number and date of invoice, as well as your name, phone number, and a detailed description of the issue.

7. Contract Provisions and Clauses

FAR 52.252-1 Solicitation Provisions Incorporated by Reference (Feb 1998) This solicitation incorporates one or more solicitation provisions by reference, with the same force and effect as if they were given in full text. Upon request, the Contracting Officer will make their full text available. The offeror is cautioned that the listed provisions may include blocks that must be completed by the offeror and submitted with its quotation or offer. In lieu of submitting the full text of those provisions, the offeror may identify the provision by paragraph identifier and provide mailto:ERIC@fda.hhs.gov the appropriate information with its quotation or offer. Also, the full text of a solicitation provision may be accessed electronically at this/these address(es): www.acquisition.gov/far

The following HHSAR and FAR clauses are incorporated by reference:

52.212-1 - Instructions to Offerors – Commercial Items (Oct 2018) 52.212-2 - Evaluation – Commercial Items (Oct 2014) 52.212-3 - Offeror Representations and Certifications-Commercial Items (OCT 2018) 52.204-7 - System for Award Management (Oct 2018) 52.204-16 - Commercial and Government Entity Code Reporting (Jul 2016) 52.204-18 - Commercial and Government Entity Code Maintenance (Jul 2016) 52.212-3 - Offeror Representations and Certifications -- Commercial Items (Oct 2018)

• If an offeror has not completed annual representations and certifications in the SAM database, offerors shall include a completed copy of the provision at 52.212-3 with this offer

52.219-1 - Small Business Program Representations (Oct 2014)

• If an offeror has not completed annual representations and certifications in the

SAM database, offerors shall include a completed copy of the provision at 52.219- 1 with this offer

52.203-18 Prohibition on Contracting with Entities that Require Certain Internal Confidentiality Agreements or Statements- Representation. (Jan 2017) 52.219-8 Utilization of Small Business Concerns (Oct 2018) 52.219-14 Limitations on Subcontracting (Jan 2017) 52.222-26 Equal Opportunity (Sept 2016) 52.222-41 Service Contract Labor Standards (Aug 2018) 52.222-70 Contractor Cooperation in Equal Employment Opportunity Investigations (Dec 2015) 52.227-14 Rights in Data-General (May 2014) 52.227-17 Rights in Data-Special Works (Dec 2007) 52.232-40 Providing Accelerated Payments to Small Business (Dec 2013)

Provisions:

52.217-5 Evaluation of Options (Jul 1990) 52.219-6 Notice of Total Small Business Set-Aside (Nov 2011) 52.203-19 Prohibition on Requiring Certain Internal Confidentiality Agreements or Statements (Jan 2017) 352.239-73 Electronic Information and Technology Accessibility Notice (Dec 2015)

Full Text FAR Clauses relevant to this requirement:

52.217-8 Option to Extend Services (Nov 1999) The Government may require continued performance of any services within the limits and at the rates specified in the contract. These rates may be adjusted only as a result of revisions to prevailing labor rates provided by the Secretary of Labor. The option provision may be exercised more than once, but the total extension of performance hereunder shall not exceed 6 months. The http://www.acquisition.gov/far

Contracting Officer may exercise the option by written notice to the Contractor at any time prior the end of the contract.(End of Clause)

52.217-9 Option to Extend the Term of the Contract (Mar 2000)

(a) The Government may extend the term of…