FDA-SOL-1099605.pdf

Solicitation Number: FDA-SOL-1099605

PART 1 – DESCRIPTION

THIS IS A COMBINED SYNOPSIS/SOLICITATION FOR COMMERICAL ITEMS PREPARED IN

ACCORDANCE WITH THE FORMAT IN FAR SUBPART 12.6 – STREAMLINED PROCEDURES

FOR EVALUATION AND SOLICITATION FOR COMMERICAL ITEMS - AS SUPPLEMENTED

WITH ADDITIONAL INFORMATION INCLUDED IN THIS NOTICE. THIS ANNOUNCMENT

CONSTITUTES THE ONLY SOLICITATION: PROPOSALS ARE BEING REQUESTED, AND A

WRITTEN SOLICITATION DOCUMENT WILL NOT BE ISSUED.

The solicitation document and incorporated provisions and clauses are those in effect through Federal Acquisition Circular 05-58. This requirement is not subject to any restrictions.

PART 2 – SUPPLIES OR SERVICES AND PRICES

2. DESCRIPTION OF SUPPLIES & SERVICES

2.1. The Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) has a requirement for Bioequivalence Studies of Antiepileptic Drugs. The FDA anticipates a single contract award of this effort.

2.2. Contract Type

2.2.1. Indefinite Delivery Indefinite Quantity Contract with Firm Fixed-Price Task Orders

2.3 Pricing

CLIN Description Price per Subject 0001 Single Dose BE Study – Base Ordering Period $ 0002 Single Dose BE Study – Ordering Period Year #1 $ 0003 Single Dose BE Study – Ordering Period Year #2 $ 0004 Single Dose BE Study – Ordering Period Year #3 $ 0005 Single Dose BE Study – Ordering Period Year #4 $

CLIN Description Price per Subject 0006 Multiple Dose BE/PK Study – Base Ordering Period $ 0007 Multiple Dose BE/PK Study – Ordering Period Year #1 $ 0008 Multiple Dose BE/PK Study – Ordering Period Year #2 $ 0009 Multiple Dose BE/PK Study – Ordering Period Year #3 $ 0010 Multiple Dose BE/PK Study – Ordering Period Year #4 $

CLIN Description Price 0011 Physico-Chemical Characterization Study – Base Ordering Period $ 0012 Physico-Chemical Characterization Study – Ordering Period #1 $ 0013 Physico-Chemical Characterization Study – Ordering Period #2 $ 0014 Physico-Chemical Characterization Study - Ordering Period #3 $ 0015 Physico-Chemical Characterization Study – Ordering Period #4 $

CLIN Description Price 0016 Analysis of all Studies $

2.4 Period of Performance

2.4.1 The period of performance is 5 years (60 months) as follows:

Base Ordering Period - September 4, 2012, through September 3, 2013 Ordering Period #1 – September 4, 2013, through September 3, 2014 Ordering Period #2 - September 4, 2014, through September 3, 2015 Ordering Period #3 - September 4, 2015, through September 3, 2016 Ordering Period #4 - September 4, 2016, through September 3, 2017

PART 3 – DESCRIPTION/SPECIFICATIONS

The contractor shall furnish the personnel, services, and facilities, as necessary to perform the work described below.

3.1 BACKGROUND

This study is to evaluate bioequivalence of antiepileptic drug products from different manufacturers that include innovator and generic companies. There are several research articles and statements from various patient advocacy groups stating that patients may experience seizures or increased seizure frequency after switching to generic formulations of antiepileptic drugs. In May of 2009, the Epilepsy Foundation stated on their website that “a significant number of people cannot be switched from brand name to generic, generic to brand, or among generic to generic versions of the same therapeutic agent, without experiencing side effects, toxicity, or unexpected “breakthrough” seizures”. Furthermore, in a statement paper summarizing a survey of patient experiences between November 2006 and March 2009, The Epilepsy Foundation made a number of recommendations, most notable in the context of this present contract, that patients should be informed of the risks of switching between different versions of the same AEDs. In addition, the American Academy of Neurology has also questioned generic drug substitution without a physician’s approval; this is based on clinical experience and traditional practice of neurology.

Most antiepileptic drugs are considered narrow therapeutic index drugs, therefore any changes in drug concentration in the blood could result in therapeutic failure, manifested as either a lack of efficacy (breakthrough seizure from low drug levels in the blood) or toxicity (as adverse events from too high concentrations in the blood). Therefore, it is important that the drug concentration in the blood be maintained constant and within a therapeutic range throughout patient therapy, regardless of the formulation prescribed, or dispensed.

Last year (2011), FDA initiated a study to look at the bioequivalence of lamotrigine in epileptic patients.

This contract is aimed at following up on research that has already been conducted by FDA, or is ongoing, by evaluating the adverse events profile of generic formulations of antiepileptic drugs, and correlating these adverse events to those of the innovator, as well as to other generics, and re-analyzing the respective PK profiles and bioequivalence criteria for the same drugs. The already completed portions of the above-mentioned work are currently being written up as a manuscript which is expected to be published in the coming year. Additionally, the results of the present proposed contract are expected to add to the body of knowledge that will be gained from the above-mentioned lamotrigine study, and to complement the already completed FDA work on the analysis of adverse events, pharmacokinetics and bioequivalence parameters for several antiepileptic drugs.

Acronyms: Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Office of Pharmaceutical Science (OPS), Immediate Office (IO), Science and Research Staff (SRS), Bioequivalence (BE), Pharmacokinetic (PK), Antiepileptic Drugs (AED), Extended Release (ER), Good Laboratory Practices (GLP), Good Clinical Practice (GCP), Standard Operating Procedures (SOP), Quality Assurance (QA), Institutional Review Board (IRB), Research Involving Human Subjects Committee (RIHSC)

3.2 Objective

The objective of this study is to evaluate whether generic antiepileptic drugs from different generic manufacturers are bioequivalent (BE) to each other as well as to the innovator drug product in healthy subjects and in adult epilepsy patients. In addition to conducting the described BE studies, the investigated drug products will be fully characterized in terms of potency, impurity, in vitro dissolution, and other quality attributes. The outcome of this study intended to help address the public concerns regarding the quality of generic antiepileptic drugs (AED) and to help improve review practices of generic AEDs if and when necessary.

3.3 Scope of work

The contractor shall complete the study design, single dose BE study in healthy subjects as well as in epilepsy patients, of the innovator and two generic antiepileptic drug products. Other tasks include multiple dose studies in adult epileptic patients, physico-chemical characterization studies and final analyses of all studies conducted under the contract, as identified by the FDA.

3.4 Types of Studies

3.4.1 Single Dose Studies

The single-dose bioequivalence studies shall be in healthy subjects and in epilepsy patients. The contractor shall perform a prospective, open-label, randomized single-dose crossover fasting or fed pharmacokinetic study in the above described subjects/patients according to the study design. The single-dose bioequivalence studies in adult epilepsy patients shall be conducted in two possible sets of patients:

those who are stable and those who are unstable with antiepileptic therapy. Subjects who are stable should not be currently treated with the antiepileptic being studied.

3.4.2 Multiple Dose Studies

The multiple-dose bioequivalence studies shall be conducted in epilepsy patients. The contractor shall perform a prospective, blinded, randomized crossover (steady-state) pharmacokinetic study according to the study design for adult patients with confident diagnoses of epilepsy, currently being treated with antiepileptic drugs and are either stable or epilepsy patients with breakthrough seizures while on antiepileptic drug therapy.

3.4.3 Physico-Chemical Characterization

The contractor shall conduct physico-chemical characterization of the innovator and generic drug products in terms of potency, impurity, in vitro dissolution, and other drug product quality attributes.

3.4.4 Analysis Of All Studies

The contractor shall submit a report of all the work identified by FDA to be completed for the entire contract.

The following tables are a representation of the potential studies being considered by FDA.

Table #1

Study Design The FDA estimates that a total of up to 4 items from the list may be ordered each year; depending on the need for such studies and available funds. Each Study may need to be repeated with additional AED’s as a function of regulatory need.

Single Dose Study

Study A: Single dose fasting BE study in healthy subjects Study B: Single dose fed BE study in healthy subjects Study C: Single dose fasting BE study in epilepsy patients who are not on the study AED and stable Study D: Single dose fed BE study in epilepsy patients who are not on the study AED and stable Study E: Single dose fasting BE study in epilepsy patients who are not on the study AED and unstable Study F: Single dose fed BE study in epilepsy patients who are not on the study AED and unstable

Multiple Dose Study

Study G: Multiple dose PK study in epilepsy patients who are on the study AED and stable Study H: Multiple dose PK study in epilepsy patients who are not on the study AED and stable Study I: Multiple dose PK study in epilepsy patients who are not on the study AED and unstable Study J: Multiple dose PK study in epilepsy patients who are on the study AED and unstable

Study K: Studies A-H could be modified by changing of the number of the subjects (i.e.

increase) or replicate design (Reference-Generic 1- Reference-Generic 1) to adjust the power of the study.

Physico-Chemical Characterization Study L: Study of physico-chemical characterization

Overall Analysis of All Studies Conducted Under the Contract

Study M: Overall Analysis of All Studies Conducted Under the Contract.

Table #2 - Tabular representation of Table 1 – Study Design by variables:

*Studies A-J could be modified by changing of the number of the subjects (i.e. increase) or replicate design (Reference-Generic A or B-Reference-Generic A or B) to adjust the power of the study.

3.5 REQUIREMENTS FOR SINGLE DOSE AND MULTIPLE DOSE STUDIES.

3.5.1 Study Design

The contractor shall design clinical studies to assess fasting and/or fed bioequivalence of antiepileptic drugs between innovator vs. generic A, innovator vs. generic B, and generic A vs. generic B in healthy subjects as well as in adult patients. According to the task order, bioequivalence study shall be conducted on adult patients with a confident diagnosis of epilepsy, who are either stable or unstable while on another antiepileptic drug. FDA/CDER/OPS/IO/SRS will select study drugs and their manufacturers after the each task is ordered. The approximate sample size for healthy subjects shall not exceed 30 adults.

However, the contractor shall justify in the study protocol, the sample size for healthy subjects as well as epilepsy patients for BE studies, such that the 90% Confidence Interval of the geometric mean ratio (GMR) of AUC0-24hr, pAUC0-t, AUC0-∞, Cmax falls within 80 - 125% according to the FDA guidelines.

Study Name

Single Dose

Multiple Dose

Fasting Fed Healthy Subjects

Epilepsy Patients Stable

Epilepsy Patients Unstable

On Study Drug

Not on Study Drug

Study A X X X Study B X X X Study C X X X X Study D X X X X Study E X X X X Study F X X X X Study G X X X Study H X X X Study I X X X Study J X X X Study K* Study L Physico-Chemical Characterization Study M Analysis of All Studies

3.5.2 Clinical Study Protocol

The contractor shall develop an acceptable protocol for each planned study, which shall include at a minimum: IRB approval, Informed Consent Form, 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, Fasting and Fed Conditions, Blood Sampling Times and Volume, 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 (via MedWatch). The protocol developed by the contractor shall comply with FDA's Institutional Review Board (IRB), the Research Involving Human Subjects Committee (RIHSC) in addition to contractor’s IRB board. The contractor shall submit to FDA a protocol that follows RIHSC guidelines for format and content. The protocols for all studies shall be submitted to the contractor’s IRB simultaneously, for approval. Following approval by the contractor’s IRB, all protocols shall be revised in the format required by the FDA RIHSC, and these protocols shall be submitted to the RIHSC for approval. All studies conducted shall begin as soon as RIHSC approval is obtained.

The contractor shall follow http://first.fda.gov/Rihsc/document/RIHSCwrittenproceduresfinal.doc for complete information on FDA policies and procedures on research involving human subjects.

3.5.3 Subject Recruitment and Study Start Date

It is not required that all subjects be recruited before starting the study; the study shall begin as soon as the first subject recruited (within 15 days of RIHSC approval) and continue with subsequent subject recruitment.

3.5.4 Randomization

During the study each subject will receive the innovator drug two times and two different generic drugs from two different manufacturers (to be determined by FDA/CDER/OPS/IO/SRS after the contract is awarded and in each Task Order). For example, after randomization, a subject might receive [Innovator - Generic A-Innovator-Generic B], [Generic A-Innovator- Generic B-Innovator], [Innovator-Generic A- Innovator-Generic A], [Innovator -Generic B-Innovator-Generic B] etc.

3.5.5 Blinding Process

The contractor shall develop a blinding process to ensure that patients do not become familiar with one particular generic product and cannot detect that they are being switched. The contractor shall submit a proposal of blinding process and ensure that the blinding process will not alter the physicochemical properties or the clinical performance of the drug prior to beginning the study.

3.5.6 Patient Adherence

In the multiple-dose bioequivalence studies, the contractor shall monitor patient adherence. The contractor shall submit a plan to assess patient adherence.

3.5.7 FDA Guidance Documents

The contractor shall adhere to all relevant FDA guidance documents including but not limited to the following, Bioequivalence Studies for Orally Administered Drug Products (1), Statistical Approaches to Establishing Bioequivalence for more information on how to determine the sample size (3), Food Effect Bioavailability and Fed Bioequivalence Studies (4), and Bioanalytical Method Validation (5, 6), Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations (7) (http://www.fda.gov/RegulatoryInformation/Guidances/default.htm).

3.5.8 Adverse Event Reporting

The contractor shall monitor any side effects or adverse reactions during the BE studies and shall submit an Adverse Event Reporting Plan in place prior to the beginning of the study.

3.5.9 Bioanalytical Study

The contractor shall perform the bioanalytical study according to Good Laboratory Practice Regulations (21 CFR Part 58); any deviations from these regulations shall be documented and justified. Bioanalytical method validation includes all the procedures that demonstrate that a particular method used for quantitative measurement of analytes in a given biological matrix such as blood, plasma, serum 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.

3.5.10 Statistical Analysis

The contractor shall conduct statistical analyses of BE parameters with Statistical Analysis Software SAS® 9.2 to determine the pharmacokinetic parameters (Cmax, Tmax, pAUC(0-t), AUC(0-24h), AUC(0- ∞), T1/2, Kel) and calculate the 90% Confidence Interval of the geometric mean ratio (GMR) of [Innovator to Generic A], [Innovator to Generic B], and [Generic A to Generic B] of pAUC(0-t), AUC(0- 24h), AUC(0-∞), and Cmax. For multiple dose PK studies, the contractor shall determine Cmax, Cmin, and Css (steady-state). The contractor shall also calculate the variability within subject. The control shall submit SAS Export Transport format along with the description of each study. The contractor shall follow the same FDA Bioequivalence Formatting Summary Tables found in the following link.

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApprov ed/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf

3.6 REQUIREMENTS FOR PHYSICO-CHEMICAL CHARACTERIZATION STUDIES

The contractor shall purchase the innovator drug product and generic drug products selected by FDA/CDER/OPS/IO/SRS and characterize them in terms of potency, impurity, in-vitro dissolution, and other drug product quality attributes. The contractor shall submit a protocol for conducting physicochemical characterization studies of the product under investigation, prior to the beginning of studies in each specific task order. The raw and analyzed characterization shall be submitted in an electronic format (Microsoft Word Document). The characterization studies shall follow FDA guidelines.

BE studies shall be conducted on the same lot of drug product that has undergone complete characterization. The contractor shall reserve samples (100 tablets) of each drug product (innovator and generics) and if requested by FDA, provide samples to FDA for further analysis.

3.7 REQUIREMENTS FOR OVERALL ANALYSIS OF ALL STUDIES CONDUCTED

The contractor shall compare study results from all the studies and make recommendations towards an optimal study design for future bioequivalence studies on other AEDs in epilepsy patients, providing appropriate rationale for such recommendations.

PART 4 - CONTRACT MANAGEMENT REQUIREMENTS

4.1 Quality Control and Assurance:

The Government will periodically evaluate the Contractor’s performance and progress in accordance with the Contractor’s submitted work schedules and contract requirements. FDA will retain all decision-making authority during the project. FDA will be engaged throughout the project.

4.2 Performance Standards:

The contractor shall implement and maintain a quality assurance system to ensure the product integrity of all deliverables meets or exceeds the requirements established in the SOW. General quality measures, as set forth below, shall be applied to each work product received from the contractor under the statement of work:

Content – Work Products shall be inclusive of all items mentioned in the objectives and scope along with content identified in (or by) the assessments.

Accuracy – Work Products shall be accurate in presentation, technical content, and adherence to accepted elements of style.

Clarity – Work Products shall be clear and concise. Diagrams and graphics shall be clearly defined and be relevant to the supporting narrative.

Consistency to Requirements – Work Products shall satisfy the requirements of the statement of work.

File Editing – Text and diagrammatic files shall be editable by the Government.

Format – Work Products shall be submitted electronically and in media mutually agreed upon prior to submission.

Timeliness – Work Products shall be submitted on or before the due date specified in the statement of work or submitted in accordance with the scheduled date determined by the Government.

PART 5 – KEY PERSONNEL

5.1 Principal Investigator (Project Manager or Physician or Nurse) shall have a graduate or professional degree and extensive experience in monitoring and managing clinical studies. Documented experience will be required in the management of all aspects of clinical trials, both from a technical understanding of the processes involved in the design and conduct of a clinical study and in managing issues related to staffing of the study, running the facilities and quality assurance procedures and interactions with the IRB and other responsible parties. Additionally, expertise in documentation of all relevant issues related to the clinical study as well as how to report these issues to the client should be demonstrated.

5.2 Board Certified Neurologist with experience in clinical study design and monitoring will be required for interpretation of safety data from studies, especially in studies including epileptic patients. Since the studies conducted in this contract will be to evaluate the therapeutic equivalence of antiepileptic drugs, using plasma levels of drug as a surrogate, experience in recognizing and understanding symptoms of epilepsy, evaluating success of therapy and identifying adverse effects of antiepileptics will be necessary.

5.3 Pharmacokineticist shall have expertise in calculation of pharmacokinetic parameters in BE studies, and extensive experience with Statistical Analysis Software (SAS® 9.2). Additionally, evidence of completed coursework in Clinical Pharmacology, pharmacokinetics and biostatistics is required.

The contractor’s key personnel shall be full-time employees at the time of contract award. All key personnel shall be assigned full time to the project within fifteen (15) business days after contract award.

During the first 180 days of award, no Key Personnel substitutions will be permitted unless an individual’s sudden illness, death, or termination of employment necessitates such substitutions. In any of these events, the Contractor shall promptly notify the COR. After the first 180 days, Key Personnel cannot be removed from the contract without at least thirty (30) days written notification to the COR and submission of appropriate replacement staff with equal or better qualifications. The Government shall reserve the right to identify or require the designation of additional key personnel during contract performance.

PART 6 – SAFEGUARDING OF INFORMATION AND INTELLECTUAL DATA RIGHTS

6.1 Safeguarding of Information

The Contractor and its employees shall exercise the utmost discretion in regard to all matters relating to their duties and functions. They shall not communicate to any person any information known to them by reason of their performance of services under this contract which has not been made public, except in the course of their duties or by written authorization of the Contracting Officer. Further, no article, book, pamphlet, recording, broadcast, speech, television appearance, film, or photographs concerning any aspect of the contract shall be published or disseminated through any media without the prior written authorization of the Contracting Officer. These obligations do not cease upon termination of this contract. The Contractor shall include the substance of this provision in all contracts for employment and in all subcontracts hereunder.

6.2 Intellectual Data Rights

The government shall own intellectual rights on the data and analysis resulting from this contract and the contractor cannot present or publish without written permission from the Government. 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. The Government will decide on the authorship of any scientific paper(s) resulting from this contract.

PART 7 – DELIVERABLES

7 Reports and Communications

7.1 Teleconferences (monthly) and reports (i.e., quarterly progress reports, draft clinical study report, final clinical study reports and final reports for physico-chemical characterization study and overall analysis of all studies), containing the description of experiments and data analysis, shall be provided to the FDA in both paper (5 copies each) and electronic format. In addition, one hardcopy of each report shall be submitted to the Contracting Officer.

7.2 Quarterly progress reports will contain a brief summary of the progress on the tasks and deliverables to date and identify any issues that would delay completion of the tasks by the specified due date.

Quarterly Report shall also include at a minimum, description of study results, data analysis in FDA summary table format (Appendix 1) and PK data in SAS® export transform format. As part of the deliverables, the contractor shall include at a minimum a report containing pre-study bioanalytical method validation, assay validation, SOP’s (general and specific such as SOP’s dealing with Bioanalytical Repeats and Reanalysis of Samples), and five percent of the chromatographs.

7.3 Draft and final clinical study report shall include at a minimum: Executive Summary of the Study, Study Subject Demographics and Other Relevant Data, Summary of Study Design and Protocol, Description of Study Results, Data Analysis, and Summary Tables in the format provided below as Appendix 1. PK data shall be provided in SAS® Export Transport format. Twenty percent of the chromatographs shall be submitted as sample chromatographs for review

7.4 Final Report for Physico-chemical Characterization shall include at a minimum executive summary and description and calibration evidence of instrumentation, results and analysis of the results, including any statistical evaluations. Study protocols should be included in the final report, and any deviation from the study protocol should be documented.

7.5 Final Report for Overall Analysis of All Studies Conducted shall include all the work completed in the entire contract and include at a minimum executive summary, description of study results and all analyzed data in a format typically used for ANDA submission (Appendix 1) and table data comparing the study results from all the studies conducted in the entire contract and recommendations towards an optimal study design for future BE studies for other AEDs. The final report shall report everything included in the draft report, including any revisions and recommendations provided by the FDA.

7.6 End of each Task Order Presentation at FDA shall include audio visual power point presentation which contains the pertinent data included in the study reports. Slides shall be provided to FDA two weeks prior to presentation.

7.7 All raw data from the experiments shall be provided to the FDA in hard copy & electronic format.

FDA reserves the right to conduct an independent analysis of the data. All data complied as a result of this contract shall be owned by FDA.

DELIVERABLE TABLE

TYPE OF REPORT/DOCUMENT DELIVERY DATE SPECIFICS

Work Plan

30 calendar days after each task order award

Detailed work plan at a minimum shall include study designs and precise timelines of deliverables and shall include following proposals:

Blinding Process (Refer to Section 3.5.5) Adverse Event Reporting Plan (Refer to Section 3.5.8) Quality Assurance Plan (Refer to Section 4) Template for Quarterly Report (Refer to Section 7.2) Template for Clinical Study Report (Refer to Section 7.3)

Study Protocols for BE studies

60 calendar days after each task order award

Study protocols for all Studies

Study Protocol for Physico-chemical Characterization

60 calendar days after task order award

Study protocol shall include procedures for conducting potency, impurity, in vitro dissolution, and other drug product quality attributes.

Physicochemical Characterization Data Report

15 days before final report submission for each task order

At a minimum, description of the experimentation, analysis of the data, and raw data shall be submitted in electronic Microsoft Word or Excel as appropriate.

Monthly teleconferences 30 days following the close of every month from the contract award date

The contractor is responsible for scheduling teleconferences with FDA/CDER/OPS/IO/SRS at the end of each month. The progress of deliverables shall be covered during t-cons. If any data are expected to be discussed during the t-con, data shall be sent to FDA electronically 3 business days before the scheduled t-con.

Each t-con shall not take more than 30 minutes. T-cons can be cancelled by FDA if not needed. A timeline of all scheduled teleconferences shall be provided in the workplan.

Quarterly Progress Report

15 days before every third monthly teleconference date

Fourth quarter report will integrate the results from first three quarter report as well as the last quarter report, and the fourth quarter report shall identify the results from each quarter.

Clinical Study Report

60 days after the study is finished; FDA may provide comments to be included in each study report

FDA may exercise the option to revise the final report at a minimum once, and the contractor shall incorporate the FDA comments in the final report.

End of each Task Order Presentation at

FDA

The contractor shall schedule, no later than 60 days following the submission of the final clinical report

At a maximum the presentation shall not take more than 2 hours. Slides shall be provided to FDA two weeks prior to presentation.

Final Report for Overall Analysis of All Studies Conducted

30 days following the final presentation. FDA may exercise option to revise final report at a minimum once, and the contractor shall incorporate the comments in the final report.

Final Report shall include all the work completed in the entire contract and include at a minimum, an executive summary, description of study results and all analyzed data in a format typically used for ANDA submission and table data comparing the study results from all the studies conducted and recommendations towards an optimal study design for future BE studies for other AEDs.

PAYMENT SCHEDULE:

Payment for completion of tasks shall be according to the following criteria:

Single dose studies:

Completion of specific task Payment (percent of total cost for the type of study) Workplan and Protocols 10% IRB approval 5% Start of first subject dosing 5% 50% of patients dosed 10% 100% of patients dosed 10% Completion of plasma level measurement (Bioanalytical work completed)

15%

Calculation of PK parameters, statistical analysis, and BE criteria calculations for entire study

15%

Draft Clinical Study Report 10% Final Clinical Study Report 15% Final Study Report 5%

Multiple dose studies:

Completion of specific task Payment (percent of total cost for the type of study) Workplan and Protocols 10 % IRB approval 5% Start of first patient dosing 5% 50% of patients dosed 10% 100% of patients dosed 10% Completion of plasma level measurement (Bioanalytical work completed)

15%

Calculation of PK parameters, statistical analysis, and BE criteria calculations for entire study

15%

Draft Clinical Study Report 10% Final Clinical Study Report 15% Final Study Presentation 5%

Physico-chemical characterization:

study) Study Design 10% Study Results 40% Final Report of PCC 50%

Analysis of all Studies:

study) Draft Report of Summary of All Studies 50% Final Report with Recommendations for next steps and lessons learned

50%

This space left blank intentionally

PART 8: CONTRACT ADMINISTRATION

8.1. CONTRACTING OFFICERS REPRESENTATIVE (COR)

8.1.1. The COR is responsible for: (1) monitoring the Offeror'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.

8.1.2. 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 RFQ; (2) modify or extend the period of performance; (3) change the delivery schedule; (4) authorize reimbursement to the Offeror any costs incurred during the performance of this contract; or (5) otherwise change any terms and conditions of this contract.

8.1.3. The contact information for the Contracting Officer:

Doreen Williams Doreen.Williams@fda.hhs.gov 301-827-3366

8.1.4. The contact information for the Contract Specialist:

Christopher E. Cunningham Christopher.Cunningham@fda.hhs.gov

(301) 827-7185

8.1.5. The contact information for the Contractor Point-of-Contact:

Name:

Email:

Phone#

8.2. INVOICE SUBMISSION

A. The contractor shall submit all invoices to all addresses in the manner specified below:

(I) One original to the Contract Specialist:

U.S. Food and Drug Administration Office of Acquisition and Grants Services

ATTN: Christopher E. Cunningham, Contract Specialist 5630 Fishers Lane

Room 2086, HFA-500 Rockville, MD 20852

Email: Christopher.Cunningham@fda.hhs.gov

****Acceptable methods of delivery include: mail, hand delivery, and email*****

(II) One copy to the Contracting Officer Representative (COR) clearly marked “Courtesy Copy Only”:

U.S. Food and Drug Administration ATTN: (To be determined upon contract award); COR

Address:

Email: XXXXX@fda.hhs.gov

*****Acceptable methods of delivery include: mail, hand delivery, and email*****

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 – Central Contractor Registration) and/or 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) Purchase order/Award Number;

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

(V) Shipping number and date of shipping, including the bill of lading number and weight of shipment if shipped on government bill of lading;

(VI) Terms of any discount for prompt payment offered;

(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) Electronic Funds Transfer (EFT) banking information, including routing transit number of the financial institution receiving payment and the number of the account into which funds are to be deposited;

(XI) Name and telephone number of the FDA Contracting Officer Technical Representative (COTR) or other program center/office point of contact, as referenced on the purchase order; and, (XII) Any other information or documentation required by the purchase order/award.

(XIII) 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 and Date Submitted; 2) Corresponding payment amount and 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.

C. An electronic invoice is acceptable if submitted in Adobe Acrobat (PDF) Format. All items listed in (I) through (XII) 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 FDA Payment Office at:

Office of Financial Services Food and Drug Administration

W032- Second Floor

MAIL HUB 2145

10903 New Hampshire Avenue Bldg 32, Rm# 2162, Mail Hub 2145

Silver Spring MD 20993-0002 Attn: Vendor Payments

(301) 827-3742 or (866) 807-3742 fdavendorpaymentsteam@fda.gov

PART 9 - CONTRACT CLAUSES

FAR CLAUSES INCORPORATED BY REFERENCE

52.252-2 Clauses Incorporated by Reference (FEB 1998)

This contract incorporates one of more clauses 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. Also, the full text of a clause may be accessed electronically at www.acquistion.gov/far/index.html

52.212-4 Contract Terms and Conditions - Commercial Items (Feb 2012) 52.203-5 Covenant Against Contingent Fees (Apr 1984) 52-233-2 Service of Protest (Sep 2006)

FAR CLAUSES BY FULL TEXT

52.212-3 Offeror Representations and Certifications—Commercial Items.

As prescribed in 12.301(b)(2), insert the following provision:

OFFEROR REPRESENTATIONS AND CERTIFICATIONS—COMMERCIAL ITEMS (APR 2012)

An offeror shall complete only paragraph (b) of this provision if the offeror has completed the annual representations and certifications electronically via https://www.acquisition.gov. If an offeror has not completed the annual representations and certifications electronically at the ORCA website, the offeror shall complete only paragraphs (c) through (o) of this provision.

(a) Definitions. As used in this provision— “Economically disadvantaged women-owned small business (EDWOSB) concern” means a small business concern that is at least 51 percent directly and unconditionally owned by, and the management and daily business operations of which are controlled by, one or more women who are citizens of the United States and who are economically disadvantaged in accordance with 13 CFR part 127. It automatically qualifies as a women-owned small business eligible under the WOSB Program.

“Forced or indentured child labor” means all work or service—

(1) Exacted from any person under the age of 18 under the menace of any penalty for its nonperformance and for which the worker does not offer himself voluntarily; or

(2) Performed by any person under the age of 18 pursuant to a contract the enforcement of which can be accomplished by process or penalties.

“Inverted domestic corporation”, as used in this section, means a foreign incorporated entity which is treated as an inverted domestic corporation under 6 U.S.C. 395(b), i.e., a corporation that used to be incorporated in the United States, or used to be a partnership in the United States, but now is incorporated in a foreign country, or is a subsidiary whose parent corporation is incorporated in a foreign country, that meets the criteria specified in 6 U.S.C.

395(b), applied in accordance with the rules and definitions of 6 U.S.C. 395(c). An inverted domestic corporation as herein defined does not meet the definition of an inverted domestic corporation as defined by the Internal Revenue Code at 26 U.S.C. 7874.

“Manufactured end product” means any end product in Federal Supply Classes (FSC) 1000-9999, except—

(1) FSC 5510, Lumber and Related Basic Wood Materials;

(2) Federal Supply Group (FSG) 87, Agricultural Supplies;

(3) FSG 88, Live Animals;

(4) FSG 89, Food and Related Consumables;

(5) FSC 9410, Crude Grades of Plant Materials;

(6) FSC 9430, Miscellaneous Crude Animal Products, Inedible;

(7) FSC 9440, Miscellaneous Crude Agricultural and Forestry Products;

(8) FSC 9610, Ores;

(9) FSC 9620, Minerals, Natural and Synthetic; and

(10) FSC 9630, Additive Metal Materials.

“Place of manufacture” means the place where an end product is assembled out of components, or otherwise made or processed from raw materials into the finished product that is to be provided to the Government. If a product is disassembled and reassembled, the place of reassembly is not the place of manufacture.

“Restricted business operations” means business operations in Sudan that include power production activities, mineral extraction activities, oil-related activities, or the production of military equipment, as those terms are defined in the Sudan Accountability and Divestment Act of 2007 (Pub. L. 110-174). Restricted business operations do not include business operations that the person (as that term is defined in Section 2 of the Sudan Accountability and Divestment Act of 2007) conducting the business can demonstrate—

(1) Are conducted under contract directly and exclusively with the regional government of southern Sudan;

(2) Are conducted pursuant to specific authorization from the Office of Foreign Assets Control in the

Department of the Treasury, or are expressly exempted under Federal law from the requirement to be conducted under such authorization;

(3) Consist of providing goods or services to marginalized populations of Sudan;

(4) Consist of providing goods or services to an internationally recognized peacekeeping force or humanitarian organization;

(5) Consist of providing goods or services that are used only to promote health or education; or

(6) Have been voluntarily suspended.

“Sensitive technology”—

(1) Means hardware, software, telecommunications equipment, or any other technology that is to be used specifically—

(i) To restrict the free flow of unbiased information in Iran; or

(ii) To disrupt, monitor, or otherwise restrict speech of the people of Iran; and

(2) Does not include information or informational materials the export of which the President does not have the authority to regulate or prohibit pursuant to section 203(b)(3) of the International Emergency Economic Powers Act (50 U.S.C. 1702(b)(3)).

“Service-disabled veteran-owned small business concern”—

(1) Means a small business concern—

(i) Not less than 51 percent of which is owned by one or more service-disabled veterans or, in the case of any publicly owned business, not less than 51 percent of the stock of which is owned by one or more service-disabled veterans; and

(ii) The management and daily business operations of which are controlled by one or more service-disabled veterans or, in the case of a service-disabled veteran with permanent and severe disability, the spouse or permanent caregiver of such veteran.

(2) Service-disabled veteran means a veteran, as defined in 38 U.S.C. 101(2), with a disability that is service-connected, as defined in 38 U.S.C. 101(16).

“Small business concern” means a concern, including its affiliates, that is independently owned and operated, not dominant in the field of operation in which it is bidding on Government contracts, and qualified as a small business under the criteria in 13 CFR Part 121 and size standards in this solicitation.

“Subsidiary” means an entity in which more than 50 percent of the entity is owned—

(1) Directly by a parent corporation; or

(2) Through another subsidiary of a parent corporation.

“Veteran-owned small business concern” means a small business concern—

(1) Not less than 51 percent of which is owned by one or more veterans (as defined at 38 U.S.C. 101(2)) or, in the case of any publicly owned business, not less than 51 percent of the stock of which is owned by one or more veterans; and

(2) The management and daily business operations of which are controlled by one or more veterans.

“Women-owned business concern” means a concern which is at least 51 percent owned by one or more women;

or in the case of any publicly owned business, at least 51 percent of its stock is owned by one or more women; and whose management and daily business operations are controlled by one or more women.

“Women-owned small business concern” means a small business concern—

(1) That is at least 51 percent owned by one or more women; or, in the case of any publicly owned business, at least 51 percent of the stock of which is owned by one or more women; and

(2) Whose management and daily business operations are controlled by one or more women.

“Women-owned small business (WOSB) concern eligible under the WOSB Program” (in accordance with 13 CFR part 127), means a small business concern that is at least 51 percent directly and unconditionally owned by, and the management and daily business operations of which are controlled by, one or more women who are citizens of the United States.

(b)

(1) Annual Representations and Certifications. Any changes provided by the offeror in paragraph (b)(2) of this provision do not automatically change the representations and certifications posted on the Online Representations and Certifications Application (ORCA) website.

(2) The offeror has completed the annual representations and certifications electronically via the ORCA website accessed through https://www.acquisition.gov. After reviewing the ORCA database information, the offeror verifies by submission of this offer that the representations and certifications currently posted electronically at FAR 52.212-3, Offeror Representations and Certifications—Commercial Items, have been entered or updated in the last 12 months, are current, accurate, complete, and applicable to this solicitation (including the business size standard applicable to the NAICS code referenced for this solicitation), as of the date of this offer and are incorporated in this offer by reference (see FAR 4.1201), except for paragraphs ______________.

[Offeror to identify the applicable paragraphs at (c) through (o) of this provision that the offeror has completed for the purposes of this solicitation only, if any.

These amended representation(s) and/or certification(s) are also incorporated in this offer and are current, accurate, and complete as of the date of this offer.

Any changes provided by the offeror are applicable to this solicitation only, and do not result in an update to the representations and certifications posted electronically on ORCA.]

(c) Offerors must complete the following representations when the resulting contract will be performed in the

United States or its outlying areas. Check all that apply.

(1) Small business concern. The offeror represents as part of its offer that it o is, o is not a small business concern.

(2) Veteran-owned small business concern. [Complete only if the offeror represented itself as a small business concern in paragraph (c)(1) of this provision.] The offeror represents as part of its offer that it o is, o is not a veteran-owned small business concern.

(3) Service-disabled veteran-owned small business concern. [Complete only if the offeror represented itself as a veteran-owned small business concern in paragraph (c)(2) of this provision.] The offeror represents as part of its offer that it o is, o is not a service-disabled veteran-owned small business concern.

(4) Small disadvantaged business concern. [Complete only if the offeror represented itself as a small business concern in paragraph (c)(1) of this provision.] The offeror represents, for general statistical purposes, that it o is, o is not a small disadvantaged business concern as defined in 13 CFR 124.1002.

(5) Women-owned small business concern. [Complete only if the offeror represented itself as a small business concern in paragraph (c)(1) of this provision.] The offeror represents that it o is, o is not a women-owned small business concern.

(6) WOSB concern eligible under the WOSB Program. [Complete only if the offeror represented itself as a women-owned small business concern in paragraph (c)(5) of this provision.] The offeror represents that—

(i) It o is,o is not a WOSB concern eligible under the WOSB Program, has provided all the required documents to the WOSB Repository, and no change in circumstances or adverse decisions have been issued that affects its eligibility; and

(ii) It o is, o is not a joint venture that complies with the requirements of 13 CFR part 127, and the representation in paragraph (c)(6)(i) of this provision is accurate for each WOSB concern eligible under the WOSB Program participating in the joint venture. [The offeror shall enter the name or names of the WOSB concern eligible under the WOSB Program and other small businesses that are participating in the joint venture: __________.] Each WOSB concern eligible under the WOSB Program participating in the joint venture shall submit a separate signed copy of the WOSB representation.

(7) Economically disadvantaged women-owned small business (EDWOSB) concern. [Complete only if the offeror represented itself as a WOSB concern eligible under the WOSB Program in (c)(6) of this provision.] The offeror represents that—

(i) It o is, o is not an EDWOSB concern, has provided all the required documents to the WOSB Repository, and no change in circumstances or adverse decisions have been issued that affects its eligibility; and

(ii) It o is, o is not a joint venture that complies with the requirements of 13 CFR part 127, and the representation in paragraph (c)(7)(i) of this provision is accurate for each EDWOSB concern participating in the joint venture. [The offeror shall enter the name or names of the EDWOSB concern and other small businesses that are participating in the joint venture: __________.] Each EDWOSB concern participating in the joint venture shall submit a separate signed copy of the EDWOSB representation.

Note: Complete paragraphs (c)(8) and (c)(9) only if this solicitation is expected to exceed the simplified acquisition threshold.

(8) Women-owned business concern (other than small business concern). [Complete only if the offeror is a women-owned business concern and did not represent itself as a small business concern in paragraph (c)(1) of this provision.] The offeror represents that it o is a women-owned business concern.

(9) Tie bid priority for labor surplus area concerns.