Amendment_2_-_BAA-NIAID-DMID-NIH-AI-2014028.pdf

BAA-NIAID-DMID-NIH-AI-2014028 Page 1 of 6

Amendment Two (2)

BAA-NIAID-DMID-NIH-AI-2014028

“TARGETED CLINICAL RESEARCH TO ADDRESS SELECT VIRAL INFECTIONS”

AMENDMENT TWO (2)

OFFICE OF ACQUISITIONS

National Institute of Allergy and Infectious Diseases (NIAID)

5601 Fishers Lane, Room 3D38, MSC 9821

Bethesda, MD 20892-9821

Solicitation Number: BAA-NIAID-DMID-NIH-AI-2014028

Date of Solicitation Issuance: December 15, 2014

Date of Amendment One (1) Issuance: March 20, 2015

Date of Amendment Two (2) Issuance: April 20, 2015

Proposal Due Date and Time: Tuesday, May 12, 2015, 3:30 PM Eastern

(UNCHANGED)

Number of Pages: 6

Point of Contact:

PRIMARY:

Swee L. Teo, Contracts Specialist

Email: teosl@niaid.nih.gov

Phone: 240-669-5173

SECONDARY:

George W. Kennedy, J.D., Contracting Officer

Email: kennedyg@mail.nih.gov

Phone: 240-669-5170

The purpose of Amendment Two is to:

1. Revise Section VIII.2. Small Business Subcontracting Plan;

2. Respond to questions received regarding this solicitation;

3. Provide a sample DMID Clinical Trial Agreement (CTA) template.

Offerors MUST acknowledge receipt of the amendment by Amendment number (s) and date of the amendment. Failure to receive your acknowledgment of this amendment may result in the rejection of your proposal.

mailto:teosl@niaid.nih.gov mailto:kennedyg@mail.nih.gov

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Except as provided herein, all terms and conditions of the solicitation remain unchanged and in full force and effect.

I. Section VIII.2. Small Business Subcontracting Plan – paragraph d.11 is hereby revised to remove the language, “which is provided as an attachment to this RFP in SECTION J” and replace with “which can be found at:

http://www.hhs.gov/asfr/ogapa/osbdu/Small%20Business/subcontractplan.html, to read as follows:

11. List the types of records the offeror will maintain to demonstrate procedures that have been adopted to comply with the requirement and goals in the plan, including establishing source lists. Also, the offeror shall describe its efforts to locate Small, Small Disadvantaged, Women- Owned, HUBZone, Veteran-Owned, and Service Disabled Veteran-Owned Small Businesses and award subcontracts to them.

For additional information about each of the above elements required to be contained in the subcontracting plan, see FAR Clause 52.219-9, Small Business Subcontracting Plan, and the Sample Subcontracting Plan, which can be found at:

http://www.hhs.gov/asfr/ogapa/osbdu/Small%20Business/subcontractplan.html.

HHS expects each procuring activity to establish minimum subcontracting goals for all procurements. The anticipated minimum goals for this RFP are as follows:

33% for Small Business; 5% for Small Disadvantaged Business; 5% for Women-Owned Small Business; 3% for HUBZone Small Business; and 3% for Veteran-Owned Small Business and Service-Disabled Veteran-Owned Small Business.

II. The Government’s responses to questions received regarding this solicitation are as follows:

A. Section II. Background and Technical Objectives

1. Question: Can the characterization of microbiome associated to the infection(s) be included in the natural history studies of viral infection in a targeted population?

Response: Because this is being solicited as a competitive contract acquisition, NIAID cannot provide specific guidance regarding your approach to preparing a proposal. As stated in Section II.B.

Technical Objective of the BAA, “Natural history studies are defined as those that evaluate the contemporary clinical course of the viral disease in a target patient population, with the goal of providing data to design interventional clinical trials. Important aspects include evaluation of a disease’s incidence, variability in patients, causes of morbidity and mortality, and response to standard of care”. A study that is designed primarily to characterize the microbiome in a targeted population would not meet this definition. However, a study that is designed to characterize the Clinical course of the viral disease in a targeted patient population that also includes an analysis of the microbiome as an endpoint or assessment in the evaluation of disease’s incidence, variability in patients, causes of morbidity and mortality, and response to standard of care may meet the http://www.hhs.gov/asfr/ogapa/osbdu/Small%20Business/subcontractplan.html http://www.hhs.gov/asfr/ogapa/osbdu/Small%20Business/subcontractplan.html

BAA-NIAID-DMID-NIH-AI-2014028 Page 3 of 6 requirements. Please carefully review the content of the solicitation for information regarding the technical objectives of this broad agency announcement and exercise your professional judgment in compiling your proposal.

2. Question: Natural history studies are eligible while surveillance studies are not. According to the BAA, natural history studies are defined as those that evaluate the contemporary clinical course of the viral disease in a target population. What is the exact difference between natural history studies and surveillance studies? How is surveillance defined?

Response: As stated in Section II.B Technical Objective of the BAA, “Natural history studies are defined as those that evaluate the contemporary clinical course of the viral disease in a target patient population, with the goal of providing data to design interventional clinical trials.” These natural history studies should target identification of meaningful clinical endpoints (including timing, incidence, duration of the measurable clinical/laboratory endpoint) for over the course of the disease in one of the targeted populations in the setting of current practice of medicine.

Conversely, surveillance studies typically are designed to look at the incidence of a disease in a population or outbreaks of a disease in a population. Because this solicitation is designed to solicit research needed to develop therapies, surveillance studies are not eligible.

B. Section III. General Proposal Instructions and Information

3. Question: In the above‐referenced BAA, there are page limits provided for the technical proposal

(not to exceed 75 pages, inclusive of all attachments except CV's). However, no guidance on font size or type, minimal margin size, or other formatting/style recommendations (e.g.. Justified, etc.)

was provided. Is there any specifications for formatting?

Response: Yes, there is formatting requirements for the subject BAA. Please review Section III. A.5.

Formatting, Number of copies, and Page Limitations for instructions in formatting your proposal.

C. Section V. Reporting Requirements

4. Question: Does the BAA support clinical trial alone with an FDA approved protocol/IND? Is a new protocol/IND required?

Response: Because this is being solicited as a competitive contract acquisition, NIAID cannot provide specific guidance regarding your approach to preparing a proposal. This BAA will not support ongoing research studies; proposals should be new research and include a new protocol.

As stated in Section V.C.1., Clinical Protocol Implementation Requirements, the NIAID Division of Microbiology and Infectious Diseases (DMID) will be the sponsor and holder of the IND. Please carefully review the content of the solicitation for information regarding the technical objectives of this broad agency announcement and exercise your professional judgment in compiling your proposal.

D. Section VI. Technical Proposal Instructions

5. Question: On page 22, the BAA states that “…DMID will hold the IND and will assume all responsibility and oversight roles, the company will be granted a copy of the dataset and the

BAA-NIAID-DMID-NIH-AI-2014028 Page 4 of 6 clinical study report at the end of the study ownership of intellectual …” Is there any flexibility on this item?

Response: There is no exception; DMID will hold the IND for the specific study conducted. The Contractor/Principal Investigator can request for a complete dataset at the end of the trial as stated in Question 13, Amendment One.

6. Question: On page 23, the BAA states that “For IND studies, a formal statistical analysis plan (SAP) will be required prior to enrolling subjects on the study. The contractor shall be responsible for working with the NIAID DMID Statistical Data and Coordinating Center (SDCC) to develop and update the plan as needed.” Is this a requirement of the terms, or is there room for negotiation with the right proposer?

Response: Yes, this is a requirement as stated in Section VI.4.B. Statistical, Data, and Quality Management; there is no exception.

7. Question: Can subheadings be added to the Technical Requirements on page 28 of Section VI.5.

Statement of Work of the BAA.

Response: Yes, subheadings can be added to the Technical Requirements, as appropriate to your proposed research.

8. Question: On page 25 Section E—Limit CV’s to 2 pages. Are these supposed to be CV’s or biosketches, which is noted to be up to 5 pages? Is there a specific format for the CVs or biosketches?

Response: As stated in Section VI.4.E. Scientific and Technical Team of the BAA, offeror’s should submit CVs limited to 3 pages in length. There is no specific format for the CVs; you may use a format of your choosing. Please be aware that these CVs will be reviewed in accordance with Section IX. Evaluation Factors for Award.

9. Question: Will DMID provide a secure website for individual clinical sites to electronically submit data, such as case report forms from study participants, or will there be an alternate plan for having data from study participants from individual sites to be transmitted to the data management center at DMID?

Response: The DMID Data Management Contract provides a secure website for electronic data submission (directly from the sites). In the event that e‐data submissions are not viable, such as under conditions with limited internet connectivity, alternative plans would be possible.

10. Question: Will DMID provide the primary study data to the offeror for analysis by its own statistician, or will all statistical services be provided internally within DMID? Should statistical support be budgeted?

BAA-NIAID-DMID-NIH-AI-2014028 Page 5 of 6

Response: An offeror may choose to have its own statistician as part of the study team working with the DMID data coordinating center to complete the protocol defined analyses prior to the end of the study.

11. Question: Will data management by DMID include: resolution of data queries, QC checks, training on data capture/transmittal?

Response: Yes.

12. Question: For a high risk trial, should an offeror budget resources for safety monitoring and reporting (adverse events, serious adverse events) for the overall study, or will all of these safety monitoring and reporting functions be done by the data management team at DMID.

Response: The safety monitoring and reporting responsibilities for high‐risk clinical trials under DMID‐held IND shall be performed by DMID staff and/or DMID Clinical Research Operations Management Support (DMID‐CROMS) contractors in accordance with Section V.C.2. Clinical Research Support Services; therefore, an offeror should not budget for these activities

13. Question: For a proposed trial that is classified as a "high‐risk clinical trial", will all the central pharmacy functions (acquisition and storage of study drug, distribution to clinical sites, drug accountability, etc.) be conducted by DMID (BRR)? Should any central study pharmacy‐related costs or functions be included in the proposal?

Response: Yes, DMID will provide the central investigational agent repository; therefore, any central study pharmacy‐related costs or functions should not be included in your proposal.

14. Question: On page 31 Section VI.6.F. Information Security Requirements, it states that “the government will require that each offeror selected for negotiations will have to submit an E- Authentication Risk Assessment, E-Authentication Threshold Analysis and a System Security Plan with the their Final Proposal Revision”. Is it correct to assume that these documents do not need to be submitted with the proposal on May 12, 2015, but will be required if selected for negotiations?

What are E-Authentication Risk Assessment or an E-Authentication Threshold Analysis? Are there templates for these documents?

Response: Yes, an E-Authentication Risk Assessment (ERA), E-Authentication Threshold Analysis (ETA)and a System Security Plan are not required with the proposal submission on May 12, 2015;

however, if selected for negotiations, an offeror will need to submit these requirements. OMB M‐ 04‐04, E‐Authentication Guidance for Federal Agencies requires agencies to review new and existing electronic transactions to ensure that authentication processes provide the appropriate level of assurance. As system documentation is developed for a particular system, an ETA is required to determine if a full ERA is necessary. These documents will be provided if selected for negotiations.

E. Section VIII. Special Contracts Requirements

15. Question: On page 49 4.b., it indicates that a document should be completed and included as part of the business proposal. Is the document to be included the Section K Representations, Certifications, BAA-NIAID-DMID-NIH-AI-2014028 Page 6 of 6 and Other Statements of Offerors updated through FAC 2005-76 last updated 07/2014?

Additionally, should this document be completed for the prime contractor and all subcontractors?

Response: Yes, a Representations and Certification must be completed and included as part of your Business Proposal. However, as stated in Section VIII.4. Representations, Certifications and Other Statements of Offerors of the BAA, an offeror must go to the System for Award Management (SAM), not FAC 2005‐76, to complete the Representations and Certifications, The SAM website may be accessed at: https://www.sam.gov/. A Representations and Certification must be completed for the prime offeror and each of its subcontractor(s).

F. Section IX. Evaluation Factors for Award

16. Question: Is Section 508 Product Assessment Template required for just the Offeror (e.g. 1 template for the proposal and not for each subcontractor)?

Response: Yes, only the offeror must submit a completed HHS “Section 508 Product Assessment Template” in accordance with Section IX.5. Evaluation of Electronic and Information Technology Accessibility – Section 508 of the BAA; subcontractor(s) not required.

G. Other

17. Question: Is there a template for the CTA? If no, can the DMID specifications for CTAs with industry partners be provided?

Response: Yes, a template for the DMID CTA is attached herewith.

III. Attachment:

A. Sample DMID Clinical Trial Agreement Template Version 5.0 https://www.sam.gov/

25 Feb 2015 CTA Template Version 5.0 DMID CTA Template For DMID-Held IND

Trials Conducted Under Contract

IND SPONSOR: DMID

CLINICAL TRIAL AGREEMENT

BETWEEN

THE DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES

THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

(DMID/NIAID)

AND

[Insert Company or Institution name]

DMID Protocol # [Insert DMID Protocol no.]

[Insert Company or Institution Protocol no. (if applicable)]

[Insert Protocol title]

Version [0.x, (Date)]

Commented [JD([1]:

INSTRUCTION:

DRAFT CTA VERSIONS ARE NUMBERED 0.1, 0.2, ETC.

FINAL VERSION IS NUMBERED 1.0

Note: The CTA version number and date should also be added to the header (see next page).

NIAID Extramural Clinical Trial Agreement DMID Protocol # _________

[Company - DMID] Version [0.X, (Date)]

The National Institute of Allergy and Infectious Diseases (NIAID), an institute of the National Institutes of Health (NIH), which is part of the United States Government Department of Health and Human

Services (HHS), as represented by the [Insert Division] and [Insert company name] (“the Company”), located at [Insert company address] (individually referred to as the “Party” and collectively referred to as the “Parties”) have agreed to cooperate in the conduct of a clinical trial designated as Protocol No. [Insert

Protocol Number] for [Insert name(s) of product(s)], entitled “[Insert Protocol title.]”

This clinical trial will be conducted through NIAID extramurally funded clinical research sites with the

NIAID serving as the Investigational New Drug application (IND) sponsor. However, neither the clinical research sites nor their investigators are parties to this Agreement.

This Agreement sets forth the terms and conditions under which this protocol will be conducted and the clinical trial will be managed.

The Company and the NIAID agree as follows:

1. DEFINITIONS

“Adverse Event” (AE) means any untoward medical occurrence in a Human Subject to whom the Test

Article has been administered. An adverse event does not necessarily have a causal relationship with the

Test Article, that is, it can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the Test Article, whether or not it is related to it. Adverse Event is further defined in ICH E6 Section 1.2 and 21 C.F.R 312.32.

“Affiliates” With respect to the Company, “Affiliates” means,

(i) any legal entity of which the securities or other ownership interests representing fifty per cent (50%) or more of the equity or fifty per cent (50%) or more of the ordinary voting power or fifty per cent

(50%) or more of the general partnership interest are, at the time such determination is being made, owned, controlled or held, directly or indirectly, by such legal entity, or

(ii) any legal entity which, at the time such determination is being made, is controlling or under common control with, such legal entity.

As used herein, the term "control,” whether used as a noun or verb, refers to the possession, directly or indirectly, of the power to direct, or cause the direction of, the management or policies of a legal entity, whether through the ownership of voting securities, by contract or otherwise.

“Agreement” means this Clinical Trial Agreement or “CTA,” all executed amendments and supplements to this Agreement and all schedules to this Agreement.

“Case Report Form” (CRF) means the data collection form(s) to be completed for each Human Subject participating in the Clinical Trial.

“Clinical Research Site(s)” means the clinical research site(s) including its subcontractors and its

Investigators where the Clinical Trial will be conducted in strict accordance with the Protocol. The clinical research site(s) conduct clinical research/trials for DMID, NIAID under a U.S. federal government funded Contract. Clinical research sites may be changed or other clinical sites or sub-sites may be added as necessary in order to complete the Protocol. Each clinical research site will be responsible for the data and scientific reporting of all results/data obtained from the Clinical Trial at that clinical research site.

“Clinical Study Report” in accordance with ICH E6 Section 1.13, means a written description of a

Clinical Trial in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report. The Clinical Study Report contains information on results including reactogenicity, adverse events, immunogenicity and other clinical or laboratory observations made with respect to the intervention employed in conducting the trial. A detailed description of the contents of a

Clinical Trial Report is found in ICH E3 “Structure and Content of Clinical Study Reports.”

Commented [ON([2]:

If a research institution rather than a company, replace Company with Institution globally.

Commented [JD([3]:

Insert:

Division

Company name

Company address

Protocol number

Name(s) of products(s)

Protocol title

Commented [ON([4]:

a. The terms listed in this Section have the meanings indicated throughout this Agreement. To the extent a definition of a term as provided in this Section is inconsistent with a corresponding definition in the applicable sections of either the United States Code (U.S.C.) or the Code of Federal

Regulations (C.F.R.), the definition in the U.S.C. or C.F.R. will control.

b. Delete Definitions that are not used in the text of the agreement or add new definitions as applicable.

“Clinical Trial” is defined by the NIH as a research study1 in which one or more human subjects2 are prospectively assigned3 to one or more interventions4 (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.5 In this

Agreement, Clinical Trial means the Clinical Trial for the Protocol. (1See Common Rule definition of research at 45 C.F.R. 46.102(d). 2See Common Rule definition of human subject at 45 C.F.R.

46.102(f). 3The term “prospectively assigned” refers to a pre-defined process (e.g., randomization) specified in an approved protocol that stipulates the assignment of research subjects (individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) of a clinical trial. 4An intervention is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints. 5Health-related biomedical or behavioral outcome is defined as the pre-specified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life.) (See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html for more information.)

“Completion of the Clinical Trial” means the Clinical Trial is complete when all data analyses under the Protocol have been performed and the Clinical Study Report has been submitted to the FDA/HA.

“Confidential Information” means confidential scientific, proprietary, business, or financial information provided that Confidential Information does not include:

(a) information that is within the public domain prior to the time of the disclosure by the disclosing

Party to the receiving Party or thereafter becomes within the public domain other than as a result of disclosure by the receiving Party or any of its representatives in violation of this Agreement;

(b) information that was, on or before the date of disclosure in the possession of the receiving Party;

(c) information that is acquired by the receiving Party from a third party not under an obligation of confidentiality;

(d) information that is hereafter independently developed by the receiving Party, without reference to the Confidential Information received from the disclosing Party;

(e) information that the disclosing Party expressly authorizes the receiving Party to disclose;

(f) information that is reasonably required by scientific standards for publication of the results of the

Clinical Trial (including Clinical Trial methods and/or data) or any information that is necessary for other researchers to verify the results of the Clinical Trial;

(g) information that relates to potential hazards or cautionary warnings associated with the production, handling, or use of the Test Article.

“Contract” means any one or more, as appropriate, of the Government contracts between NIAID and the awardee who may subcontract the Clinical Research Sites.

“Data and Safety Monitoring Board” (DSMB) is an independent group of experts that advises the

NIAID and the Investigators. The primary responsibilities of the DSMB are: (i) to periodically review and evaluate the accumulated data of the Clinical Trial for participant safety, Clinical Trial conduct and progress, and when appropriate, efficacy; and (ii) to make recommendations to NIAID concerning the continuation, modification, or termination of the Clinical Trial.

“Data Coordination Center” (DCC) means an organization funded by the NIAID that receives, reviews, and performs data management tasks on the individual Human Subject Case Report Forms completed for this Clinical Trial. The Data Coordination Center for this Clinical Trial is [Insert name].

“Distributor” is the NIAID contractor who will be distributing the Test Article to the Clinical Research

Sites. The Distributor for this Clinical Trial is [Insert name].

http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html

“Effective Date” means the date of the last signature of the authorized representatives of the Parties executing this Agreement.

“Electronic Case Report Form” (eCRF) means the electronic data collection form(s) submitted to the study database for each Human Subject participating in the Clinical Trial.

“Food and Drug Administration” (FDA) means the U.S. Food and Drug Administration.

“Genome-Wide Association Study” (GWAS) means any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition.

“Government” means the federal government of the United States of America.

“Health Authority” (HA) means any non-U.S. Health Authority used when the Clinical Trial is being conducted in whole or in part at a non-U.S. Clinical Research Site requiring the use of non-U.S.

regulatory agencies.

“Human Subject” means, in accordance with the definition in 45 C.F.R. Part 46.102(f), a living individual about whom an Investigator conducting research obtains:

(a) Data through intervention or interaction with the individual, or

(b) Identifiable Private Information.

“Identifiable Private Information” (IPI) means private information about a Human Subject from which the identity of the Human Subject is or may readily be ascertained. Regulations defining and governing this information include 45 C.F.R. Part 46 and 21 C.F.R. Part 50.

“Independent Safety Monitor” (ISM) is a physician or other expert who is independent of a study and readily available to review and recommend actions on adverse events and other safety issues.

“Informed Consent Form” (ICF) means a signed and documented form in which each Human Subject voluntarily consents or confirms his or her willingness to participate in a particular clinical trial after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate.

The informed consent form satisfies the requirements of ICH E6, 45 C.F.R. Part 46 and 21 C.F.R. Part 50.

“Institutional Review Board” (IRB) means, in accordance with 45 C.F.R. Part 46, Protection of Human

Subjects (Revised November 13, 2001) and 21 C.F.R. Part 56, Subpart C: IRB Functions and Operations

(as amended June 18, 1991), and other applicable regulations, an independent body comprising medical, scientific, and nonscientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of the Human Subjects involved in a Clinical Trial. It may also be referred to as an

Independent Ethics Committee in accordance with ICH E6, Section 1.27.

“The International Conference on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human Use” (ICH). ICH refers to one or all of the following requirements used throughout this Agreement:

(a) ICH E2F: “Development Safety Update Report,” including the latest finalized revision.

(b) ICH E3: “Structure and Content of Clinical Study Reports,” including the latest finalized revision.

(c) ICH E6: “Good Clinical Practice: Consolidated Guidance,” published in the Federal register (62

Federal Register 25692 (1997)), including the latest finalized revision. Also referred to as “FDA

Good Clinical Practice Guidelines.”

(d) ICH Q7: “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients” published in the Federal register (66 Federal Register 49028-9 (2001)), including the latest finalized revision.

“Invention” means any invention or discovery that is or may be patentable or otherwise protected under

35 U.S.C., or any novel variety of plant which is or may be protectable under the Plant Variety Protection

Act, 7 U.S.C. §§ 2321 et seq.

“Investigational New Drug Application” (IND) is filed in accordance with 21 C.F.R. Part 312 under which clinical investigation of a Test Article (an experimental drug or biologic) is performed in Human

Subjects in the United States or intended to support a United States licensing action.

“Investigator” means, in accordance with 21 C.F.R. Part 312.3, an individual who actually conducts a clinical trial, that is, who directs the administration or dispensation of Test Article to a subject, and who assumes responsibility for studying Human Subjects, for recording and ensuring the integrity of research data, and for protecting the welfare and safety of Human Subjects. In this Agreement, “Investigator(s)” means the individual(s) identified as responsible for the conduct of the Clinical Trial at the designated

Clinical Research Site(s).

“Investigator Brochure” (IB) means, in accordance with the definition in 21 C.F.R. Part 312.23(a)(5), a document containing information about the Test Article, including animal screening, preclinical toxicology, and detailed pharmaceutical data, including a description of possible risks and side effects to be anticipated on the basis of prior experience with the Test Article or related drugs, and precautions, such as additional monitoring, to be taken as part of the investigational use of the Test Article.

“Office of Human Research Protections” (OHRP) means the HHS office that oversees protection of human subjects from research risks under 45 C.F.R. Part 46 (the Common Rule).

“Package Insert” means an FDA approved document which provides essential information about an approved drug.

“Party” means an entity entering into this Agreement, referred to individually as the “Party” and collectively as the “Parties.”

“Patent” means any issued United States patent, any international counterpart and any corresponding grant by a non-U.S. government in place of a patent.

“Protocol” means the formal, detailed description of the Clinical Trial to be performed as provided in

Protocol [Insert Protocol Number.] for [Insert name(s) of product(s)], titled “[Insert Protocol title].” A

Protocol describes the objective(s), design, methodology, statistical considerations, and organization of a clinical trial. For the purposes of this Clinical Trial, the term Protocol includes any and all associated documents, including informed consent forms, to be provided to Human Subjects and potential participants in the Clinical Trial. This Clinical Trial Agreement will be governed by the most recent version of the Protocol, and should this Agreement be executed prior to complete finalization of the

Protocol, the last-dated version thereof will be considered to be incorporated by reference in place of any prior versions. In the event that there is a conflict between the terms of the Protocol and the terms of the

Agreement in other matters, the terms of this Agreement will govern.

“Protocol Team” means the team, under the direction of NIAID, responsible for the development and management of the Protocol, evaluation of data, proposal of amendments, and all issues related to the

Protocol or aspects of Protocol development and modification. The Protocol Team will include the representatives from the Company, if they wish to participate, the Principal Investigators, representatives from the NIAID, and the persons involved with statistical and data analysis for the Clinical Trial.

Participation on the Protocol Team will be as agreed by the Parties and will take into account any special requirements of the Protocol design.

“Regulatory Application” (RA) means an IND-equivalent, non-U.S. Regulatory Application, applicable when the Clinical Trial is being conducted in whole or in part at a non-U.S. Clinical Research Site.

“Safety Monitoring Committee” (SMC) means an independent group of experts that advises NIAID and the Investigators for clinical trials. The primary responsibility of the SMC is to monitor Human Subject

Commented [ON([5]:

If Test Article is a marketed product in the US replace Investigator

Brochure with a relevant Package

Insert or labeling definition. Replace with the name of the equivalent literature for Test Articles from other market regions as applicable.

safety. The SMC considers study-specific data as well as relevant background information about the disease, test agent, and target population under study.

“Serious Adverse Event” or “Serious Suspected Adverse Reaction” means an adverse event or suspected adverse reaction that in the view of either the investigator or sponsor, results in any of the following outcomes:

(a) Death,

(b) A life-threatening adverse event,

(c) Inpatient hospitalization or prolongation of existing hospitalization,

(d) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or

(e) A congenital anomaly/birth defect.

(f) Important medical events that may not result in death, be life-threatening, or require hospitalization, but, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes (a) through (e).

“Sponsor” means, in accordance with the definition in 21 C.F.R. Part 312.3, an organization or individual who assumes legal responsibility for supervising or overseeing Clinical Trials with Test Article, and is sometimes referred to as the “IND/RA holder.”

“Suspected Adverse Reaction” means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the adverse event.

Suspected Adverse Reaction is further defined in 21 C.F.R. 312.32.

“Test Article” means, in accordance with 21 C.F.R. Part 50.3(j), any drug (including a biological product), medical device, food additive, color additive, electronic product, material or any other article subject to regulation under the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 301, et seq., Pub.

L.No.75-717, 52 Stat. 1040 (1938), as amended. In this Agreement, [Insert name(s) of product(s), placebo, and/or other appropriate equipment, if applicable, as identified in this Protocol] is/are collectively referred to as the “Test Article.”

“Unexpected Adverse Event” or “Unexpected Suspected Adverse Reaction” means an adverse event or suspected adverse reaction which is considered "unexpected" because it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, when an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. Unexpected Adverse Event and Unexpected

Suspected Adverse Reaction are further defined in 21 C.F.R. 312.32.

2. CLINICAL RESEARCH SITES AND INVESTIGATORS

2.1 The Company acknowledges that the NIAID funds the Clinical Research Sites and is the IND/RA

Sponsor for the Protocol and, therefore, the Clinical Research Site has certain existing legal obligations to the NIAID.

2.2 The Company will not provide any funding or material for any aspect of the Clinical Trial to any

Clinical Research Site participating in the Clinical Trial without the prior written approval of the

NIAID. In addition, subject to Section 12.4 of this Agreement, the Company will not enter into any separate Agreements, including, but not limited to material transfer agreements, with the Clinical

Research Sites or the Investigators at the Clinical Research Sites that interfere with the conduct of this Clinical Trial under the Contract.

Commented [ON([6]:

Protocol definitions of Serious Adverse Event and Serious

Suspected Adverse Reaction must be the same as this template definition.

Commented [ON([7]:

Protocol definitions of Suspected Adverse Reaction must be the same as this template definition

Commented [ON([8]:

Protocol definitions of Unexpected Adverse Event and Unexpected

Suspected Adverse Reaction must be the same as this template definitions

2.3 The NIAID will not knowingly utilize:

2.3.1 Any organization performing services in connection with this Clinical Trial that has been:

(i) Debarred under the provisions of the Generic Drug Enforcement Act of 1992, 21

U.S.C. § 335a(a) and (b); or

(ii) Suspended by the Office for Human Research Protections (OHRP) as a clinical research site under 45 C.F.R. Part 46, and

2.3.2 Any person convicted of a felony under federal law for conduct:

(i) Relating to the development or approval, including, but not limited to, the process for development or approval, of any drug, product, medical device, New Drug

Application (NDA), Pre-Market Application (PMA), 510(k) or IND or similar application; or

(ii) Otherwise relating to the regulation of any drug product or medical device under the

FD&C Act.

2.3.3 Any person performing services in connection with this Clinical Trial that has been disqualified as a clinical investigator under 21 C.F.R. Part 312.70.

2.3.4 Any Investigator who is not qualified by training and experience as an appropriate expert to conduct the Clinical Trial, as required under 21 C.F.R. Part 312.53.

2.4 If either Party becomes aware that any organization or person involved in the Clinical Trial is debarred, threatened with debarment, disqualified, threatened with disqualification, or suspended, that Party will notify the other Party immediately.

2.5 The Investigators at the Clinical Research Sites are required to conduct the Clinical Trial in accordance with good clinical practice, including as defined by the ICH and comply with all applicable U.S. and foreign government, state and local laws, regulations and guidelines.

2.6 The Company agrees that this Protocol will be conducted only at the Clinical Research Sites defined in the Protocol. However, the Company can conduct, at its own expense and under its own

IND/RA, additional Clinical Trials with the Test Article, at non-NIAID-funded sites. The Company agrees to inform the NIAID in writing of any other Clinical Trials it may support for the use of the

Test Article that would compete with this Clinical Trial for the same Human Subject population.

3. INVESTIGATIONAL NEW DRUG APPLICATION SPONSORSHIP

3.1 IND/RA. The NIAID will submit an IND/RA covering the Protocol to the FDA/HA. The IND/RA will satisfy all of the requirements of the FDA/HA. The Company will provide a letter granting the

FDA/HA permission to cross-reference the Company’s pertinent Drug Master File (DMF), New

Drug Application (NDA), Biologics License Application (BLA), and/or IND/RAs in support of the

NIAID IND/RA, and in return, the NIAID will also provide a letter to the Company, if requested, granting the FDA/HA permission to cross-reference the IND/RA filed by the NIAID for this

Clinical Trial.

3.2 Protocol Monitoring. The NIAID will be responsible for Clinical Research Site monitoring and quality assurance of all data in accordance with the clinical monitoring plan. Monitoring will be done in compliance with FDA/HA Good Clinical Practice Guidelines (ICH) (E6). The NIAID will communicate any clinically significant findings from clinical monitors to the Company in a timely manner.

3.3 Safety Reporting.

3.3.1 The NIAID will collect safety reports according to the procedure outlined in the Protocol.

The NIAID will assume responsibility for the reporting of safety reports to the FDA/HA and will provide copies of the reports to the Company.

3.3.2 (i) For any safety report that meets all of the following criteria of (i) Serious

(ii) Unexpected and (iii) Suspected Adverse Reaction, the NIAID will provide to the

Company a completed copy of the safety report at the time the report is submitted to the FDA/HA, the NIAID will provide follow up information to Company at the time the follow up safety report is submitted to FDA/HA. The reporting will be completed in the timeframes consistent with 21 CFR 312.32.

(ii) The NIAID will report all other Serious and non-serious Adverse Events to the

FDA/HA and to the Company on a timely basis consistent with 21 C.F.R. Part 312.33.

3.3.3 As the manufacturer, the Company will, in a timely manner consistent with FDA/HA requirements and during the term of this Clinical Trial, provide the NIAID with any information it now has or may obtain in the future regarding the safety and/or the toxicity of

Test Article. The NIAID will promptly transmit that information to all Investigators.

3.4 Safety Monitoring.

In accordance with NIH guidelines the Company and the NIAID agree that the following type(s) of safety monitoring is (are) necessary and appropriate for this Clinical Trial:

[Independent Safety Monitor (ISM). If deemed necessary, the NIAID will appoint an ISM for the Clinical Trial.]

AND/OR

[Safety Monitoring Committee (SMC). If deemed necessary, the NIAID will appoint an SMC for the Clinical Trial. If an SMC is constituted for the Clinical Trial, the NIAID will notify the

Company in advance of any SMC review. The Company may participate in the open sessions of the meetings and will receive the open session reports of the SMC. The recommendations derived from the closed sessions will also be communicated to the Company. Prior to the Completion of the Clinical Trial, data and reports distributed for SMC review will be used only for the purposes of the SMC meeting and will be held in confidence.]

OR

[Data and Safety Monitoring Board (DSMB). If a DSMB is constituted for the Clinical Trial, the NIAID will notify the Company in advance of any DSMB review. The Company may participate in and will receive the open session reports of the DSMB. The recommendations derived from the closed sessions will also be communicated to the Company. Prior to the

Completion of the Clinical Trial, data and reports distributed for DSMB review will be used only for the purposes of the DSMB meeting and will be held in confidence.]

4. FDA/HA MEETINGS/COMMUNICATIONS

4.1 With respect to any discussions with the FDA/HA involving data obtained from this Clinical Trial under the NIAID’s IND/RA, the NIAID, in consultation with the Company, will take the initiative in arranging meetings or conference calls with the FDA/HA. Formal meetings with the FDA/HA concerning the Clinical Trial design and/or data will be discussed and agreed upon in advance by the Company and the NIAID. The Company will have the right to participate in all formal meetings with the FDA/HA. The Company agrees not to contact the FDA independent of the

NIAID concerning this Clinical Trial. However, the Company may contact the FDA on separate product-related issues. The Company will be provided with copies of formal questions and

Commented [N9]:

Depending on the Protocol Team’s decision, select ISM and/or

SMC or DSMB and delete option(s) not selected. Delete unselected option in the “Definitions” section also.

Commented [JD([10]:

Depending on the Protocol Team’s decision, SMC or DSMB and delete option(s) not selected.

Commented [JD([11]:

Depending on the Protocol Team’s decision, SMC or DSMB and delete option(s) not selected.

Commented [ON([12]:

If appropriate, insert specific provisions for contact if using non-

US Regulatory Authorities.

http://www.niaid.nih.gov/dmid/clinresearch/dsm_pol_guide.pdf responses that have been submitted to the FDA/HA, except to the extent that those documents contain the Confidential Information of the other Party.

4.2 The Company will promptly notify the NIAID of any FDA/HA correspondence related to the

Protocol that is received by the Company, or its Affiliates; any FDA/HA enforcement actions directed toward the Company or its Affiliates including but not limited to: warning letters, seizures, recalls, injunctions/consent decrees, rejection of regulatory submissions or withdrawal of approval for a Test Article, criminal investigations, and proceedings to debar the Company or its Affiliates or individuals employed under a contract to the Company and/or its Affiliates.

4.3 The Company will also promptly notify the NIAID of any action taken by the FDA/HA regarding manufacturing of the Test Article that would impact the safety of subjects in the Clinical Trial.

5. SUPPLY, DISTRIBUTION, AND USE OF TEST ARTICLE

5.1 Supply.

5.1.1 The NIAID will provide the Company with an estimate of the quantity of Test Article that will be required to complete the Protocol. The NIAID will also provide the Company with an additional estimate of the quantity of Test Article required, as applicable, for training and demonstration purposes.

5.1.2 The Company will supply the Test Article to the NIAID without charge and in quantities and conditions sufficient to complete the Protocol and on a schedule mutually agreed upon by the Parties to ensure a sufficient supply of unexpired Test Article.

5.1.3 The [Insert NIAID or Company] will be responsible for labeling the Test Article used in the Clinical Trial.

5.2 Distribution.

5.2.1 The Company will ship the Test Article to the Distributor, as mutually agreed by the Parties.

The Company will provide specific storage and/or shipping instructions for the Test Article to the NIAID and/or the Clinical Research Sites, who will be responsible for adhering to them, as mutually agreed by the Parties. The Company warrants that any packaging for hazardous material provided by the Company meets Department of Transportation regulatory requirements for use at all Clinical Research Sites.

5.2.2 The Test Article must be received by the Distributor in usable condition and accompanied by specific storage and shipping instructions, Material Safety Data Sheet (MSDS), a signed and dated Certificate of Analysis (COA), and stability or expiration dating information for each lot of Test Article sent. If the Company performs ongoing stability testing for each lot of

Test Article sent, then the Company will also provide updated retest or expiration dates for those respective lots to the NIAID in a timely manner.

5.2.3 If there is evidence that the Test Article that arrived at the Distributor or Clinical Research

Site has not been maintained according to the defined shipping instructions or there is evidence of damage to the Test Article container or container closure system, NIAID will contact the Company to inform them of the condition of the received Test Article and to determine together with the Company whether the Test Article is usable or if it must be replaced. During the course of the Clinical Trial, the same process will be used whenever there is evidence that the Test Article has not been maintained according to the Company’s recommended storage conditions. If the Test Article must be replaced, the Company will replace it at no cost to NIAID, the Distributor or the Clinical Research Sites.

5.3 Use.

5.3.1 The NIAID will neither transfer the Test Article to parties other than the Distributor or the

Clinical Research Sites nor will the NIAID chemically modify, replicate, make derivatives of, or reverse engineer the Test Article unless required by the Protocol or mutually agreed in writing by the Parties.

5.3.2 The NIAID will request that the Investigators:

(i) use the Test Article only in accordance with the Protocol and for no other purpose;

(ii) not transfer the Test Article to any parties except the Company; and

(iii) not chemically modify, replicate, make derivatives of, or reverse engineer the Test

Article unless required by the Protocol or as mutually agreed to, in writing, by the

Parties.

5.4 Investigator Brochure. The Company will provide a current Investigator Brochure for all applicable components of the Test Article, and any later revisions and addenda to the Investigator

Brochure for the Test Article to the NIAID, as mutually agreed by the Parties.

OR

[Package Insert. The Company will provide a current Package Insert for all applicable components of the Test Article, and any later revisions and addenda for the Test Article to the

NIAID, as mutually agreed by the Parties.]

5.5 Disposition of Unused Test Article. The NIAID will require the Clinical Research Sites

[to destroy any unused or expired Test Article upon completion of the Protocol.

OR

at the Company’s request, to return any unused or expired Test Article to the Company upon completion of the Protocol. The Company will pay for the cost of transporting unused or expired

Test Article from the Clinical Research Sites to the Company.]

5.6 Warranty. The Company represents and warrants that the Test Article supplied shall be manufactured and released according to the principles of current Good Manufacturing Practice and when administered in accordance with Protocol it is suitable for human use.

5.7 Source. In the event the Company elects to terminate its development of Test Article for reasons other than safety, without the transfer of its development efforts and obligations under this

Agreement to another party acceptable to the NIAID within ninety (90) calendar days of discontinuation, then the Company will provide the NIAID with Test Article for all then-enrolled

Human Subjects sufficient to complete the Clinical Trial in the manner described in the Protocol.

5.8 Termination of Development. The Company hereby grants to the NIAID a nonexclusive, nontransferable, irrevocable, paid-up license to practice or have practiced for or on behalf of the

United States any invention which the Company may have or obtain on Test Article, its manufacture, or on the process for use of Test Article, throughout the world, for medical research purposes related to [Insert disease or disorder]. This license will only become effective in the event the Company terminates its development of Test Article for reasons other than safety, without the transfer of its development efforts to another party within ninety (90) calendar days of termination, and the NIAID elects to continue the development of Test Article. This provision will become null and void upon FDA approval of the Test Article indications and marketing of the Test

Article by the Company.

Commented [JD([13]:

If Test Article is a U.S. marketed product, replace Investigator

Brochure text with Package Insert text.

Commented [JD([14]:

Insert one of these options and delete the other

6. PROTOCOL DEVELOPMENT