Flu BAA Amend 3.docx.pdf

ASPR-BARDA

330 lndependence Avenue, SW Room G640 Washington, DC 20201

PAGE OF PAGES

1 I 10 AMENDMENT OF SOLlClTATlONlMODlFlCATlON OF CONTRACT

6. ISSUED BY CODE

ASPR-BARDA

330 lndependence Avenue, SW Room G640 Washington, DC 20201

2. AMENDMENTIMODIFICATION NO. ) 3. EFFECTIVE DATE 14. REQUlSlTlONlPURCHASE REQ. NO. 5. PROJECT NO. (If applicable)

1. CONTRACT ID CODE

I

8. NAME AND ADDRESS OF CONTRACTOR (No.. street, county, State andZlP Code) 9A. AMENDMENT OF SOLICITATION

NO.

1010612011

ASPR-BARDA

1 1-1 00-SOL-00021

98. DATED (SEE ITEM 11)

NIA 1 NlA

7. ADMINISTERED BY (Ifotherthan Item 6) CODE ASPR-BARDA02

06/20/2011

10A. MODIFICATION OF CONTRACTIORDER NO.

lo The above numbered solicitation is amended as set forth in ltem 14. The hour and date spci tkd for receipt of Offers is extended, is not extended.

lOB. DATED (SEE ITEM 13)

CODE FACILITY CODE

I B. THE ABOVE NUMBERED CONTRACTIORDER IS MODIFIED TO REFLECT THE ADMINISTRATIVE CHANGES (such as changes in paying office, appropriation 1 date, etc.) SET FORTH IN ITEM 14. PURSUANT TO THE AUTHORITY OF FAR 43.103(b),

11. THlS ITEM ONLY APPLIES TO AMENDMENTS OF SOLICITATIONS

Offers must acknowledge receipt of this amendment prior to the hour and date specified in the solicitation or as amended, by one of the following methods:

(a) By completing items 8 and 15, and returning copies of the amendment; (b) By acknowledging receipt of this amendment on each copy of the offer submitted;

or (c) By separate letter or telegram which includes a reference to the solicitation and amendment numbers. FAILURE OF YOUR ACKNOWLEDGMENT TO BE RECEIVED AT THE PLACE DESIGNATED FOR THE RECEIPT OF OFFERS PRIOR TO THE HOUR AND DATE SPECIFIED MAY RESULT IN REJECTION OF YOUR OFFER. If by virtue of this amendment your desire to change an offer already submitted, such change may be made by telegram or letter, provided each telegram or letter makes reference to the SOliCitatlOn and this amendment, and is received prior to the opening hour and date specified.

12. ACCOUNTING AND APPROPRIATION DATA (If required)

NIA

13. THlS ITEM ONLY APPLIES TO MODIFICATION OF CONTRACTSIORDERS.

IT MODIFIES THE CONTRACTIORDER NO. AS DESCRIBED IN ITEM 14.

CHECKONE

n

E. IMPORTANT: Contractor is not, is required to sign this document and return copies to the issuing office.

14. DESCRIPTION OF AMENDMENTIMODIFICATION (Organized by UCF section headings, including solicitation/contract subject matter where feasible.)

A. THlS CHANGE ORDER IS ISSUED PURSUANT TO: (Specify authority) THE CHANGES SET FORTH IN ITEM 14 ARE MADE IN THE CONTRACT ORDER NO.

IN ITEM 10A.

The purpose of this amendment is to:

C. THlS SUPPLEMENTAL AGREEMENT IS ENTERED INTO PURSUANT TO AUTHORITY OF:

D. OTHER (Specify type of modification and authority)

1. Provide details on Pre-Proposal Conference #2

2. Add two new Areas of Interest.

The above numbered solicitation is hereby amended as reference in the attached pages.

Except as pmvided herein, all terms and conditions of the document referenced in ltem 9A or 10A, as heretofore changed, remains unchanged and in full force and effect.

15A. NAME AND TITLE OF SIGNER (Type orprint)

158. CONTRACTORIOFFEROR

(Signature ofperson authorized to sign)

16A. NAME AND TITLE OF CONTRACTING OFFICER (Type orprint)

Dorothy M. McMillan

NSN 7540-01-152-8070 STANDARD FORM 30 (RN. 10-83)

Previous edition unusable

Prescribed by GSA FAR (48 CFR) 53.243 orgnatore of Contracting ofice0

16C. DATE SIGNED

b/k / l i

BARDA BAA- 1 1-1 00-SOL-0002 1 Amendment #3

The following changes are made to the above referenced solicitation.

Pre-Proposal Conferences - a second Pre-Proposal conference for Areas of lnterest 2 and 3 are scheduled as follows:

Pre-Proposal Conference #2: October 14, 201 1 1 :00PM-2:OOPM EST via teleconference for two new development Areas of Interest.

#3 Antiviral Therapeutics for Treatment and/or Prophylaxis of Influenza A & B Infections

#4 Multi-Purpose, Broad-Spectrum Antiviral Therapeutics for Treatment and/or Prophylaxis of Influenza Virus Infections.

Please note the following regarding the pre-proposal conference:

1. Attendance is limited to a maximum of two (2) people per company. Email the names of your attendees to FLU-BAA@?hhs.gov by Wednesday, October 12,201 1 by 3:OOPM

EST.

2. Tape recorders and videos are prohibited.

3. Presentation material from the conference will be posted on FedBizOpps in an amendment to the BAA following the pre-proposal conference.

4. Questions from industry, to be addressed during the Pre-Proposal Teleconference, may be emailed to FLU-BAA@hhs.gov no later than Wednesday, October 12,201 1 by

3:OOPM EST.

5. Questions that arise during the Pre-Proposal Conference may be emailed to FLU- BAA@hhs.gov no later than Friday, October 14, 201 1 by 5:OOpm EST.

6. Attendees should login for both the teleconference and the web conference.

Teleconference (Dial-in attendees will be muted) 888-469-2057 Passcode: ANTIVIRAL

Web Conference https:l/www,rnvmeetings.com/nc/ioin/ Conference Number PW8613874 Passcode: ANTIVIRAL

Part I: Development Areas of Interest - is revised to add Areas of lnterest 3 and 4 as follows:

The following are special instructions for offerors submitting White Papers and Quad Charts for Area of lnterest #3 Antiviral Therapeutics for Treatment and/or Prophylaxis of Influenza A & B

BARDA BAA-1 1 - 100-SOL-0002 1 Amendment #3 lnfections AND #4 Multi-Purpose, Broad-Spectrum Antiviral Therapeutics for Treatment andlor Prophylaxis of Influenza Virus Infections.

Area of lnterest #3: Antiviral Therapeutics for Treatment andlor Prophylaxis of Influenza A & B lnfections Offerors for Area of Interest #3 should propose activities for products which alone and in combination can currently be described as having a maturity level equal to or greater than Technology Readiness Level (TRL) 6. A product can be described as achieving a TRL if it has completed all activities identified in that TRL, The Technology Readiness Level ranking criteria can be found in Attachment I of this solicitation.

1 . I Advanced development of antiviral therapeutics at TRL6 or greater with a novel mechanism of action relative to currently approved anti-influenza therapeutics. Preference will be given to therapeutics with a mechanism of action other than neuraminidase inhibition. Small molecule compounds, monoclonal antibodies, therapeutic proteins, peptides or oligonucleotides targeting an essential virus function are examples of therapeutics that would be considered. Therapeutics with a mechanism of action that precludes the rapid emergence of drug resistance and with proven broad influenza strain susceptibility are preferred.

1.2 Development of combination therapeutic approaches using influenza antivirals which in combination have achieved TRL 6 or greater. Combination therapies should utilize drugs with different mechanisms of action to reduce the risk of resistance development and to increase the potential for synergistic treatment effects. The contribution of each component is relevant and the combination of drugs should be superior to the components when administrated as a single drug.

1.3 Development of alternative formulations of influenza antivirals for treatment of populations under high risk of influenza-related complications such as pediatric or hospitalized patients.

Other special groups to consider are elderly, persons with underlying respiratory or cardiac diseases, immunocompromised patients and pregnant women. The therapeutic under development must be at TRL6 or greater for its primary indication and formulation to be considered.

1.4 Activities to support identification and validation of surrogate endpoints to predict clinical benefits in patients treated with influenza antiviral therapeutics. Virology and non-virology parameters that reliably predict clinical outcomes in influenza trials that are being conducted to evaluate influenza antivirals at TRL 6 or greater are of high interest. Surrogate endpoints should facilitate accelerated approval of novel anti-influenza treatments, emergency use authorization mechanisms and risk-benefit evaluation.

Technical inquiries can be directed to FLU-BAA-ANTIVIRAL@HHS.GOV

Development programs at a maturity level less than TRL6 should consider funding opportunities offered by NlAlD or other federal agencies that fund earlier stage research and development projects.

Information about NlAlD resources can be found at:

http://www.niaid.nih.~ov/LabsAndResources/resources/dmid/Pagesltherapeutics.as~x Technical inquiries about funding through NlAlD programs can be directed to:

DMIDResources@niaid.nih.qov

BARDA BAA- 1 1 - 100-SOL-0002 1 Amendment #3

Area of lnterest #4: Multi-Purpose, Broad-Spectrum Antiviral Therapeutics for Treatment and/or Prophylaxis of Influenza Virus Infections Offerors for Area of Interest #4 should propose activities for products which can currently be described as having a maturity level equal to or greater than TRL 6. A product can be described as achieving a TRL if it has completed all acfivities identified in that TRL. The Technology Readiness Level ranking criteria can be found in Attachment 1 of this solicitation.

2.1 Therapeutics at TRLG or greater tarqetinq viral functions essential for influenza virus replication and with a mechanism of action offerinq the potential for broad-spectrum antiviral activity. Antiviral activity against seasonal and pandemic strains of influenza should have been demonstrated in vitro and in vivo. Advanced development activities should focus on treatment and/or prophylaxis of influenza with strategies to expand into multi-purpose, broad-spectrum antiviral indications.

2 Therapeutics at TRLG or greater targeting host factors that result in reduced influenza virus replication and amelioration of symptoms. lmmunomodulatory therapeutics and host factors critical for viral replication are examples of targets that could lead to broad-spectrum antiviral activity against influenza and other relevant human viral diseases.

Antiviral activity against influenza and other viruses should have been demonstrated in appropriate preclinical model systems. Advanced development activities should focus on treatment andlor prophylaxis of influenza with strategies to expand into multi-purpose, broad-spectrum antiviral indications.

2.3 Development of combination therapeutic approaches using an influenza antiviral and a host modulating therapeutic for control of severe influenza disease. The contribution of each component is relevant and the combination of drugs should be superior in amelioration of symptoms to the components when administrated as a single drug. The combination of therapeutics being used (not the individual therapeutic agents themselves) should be at TRLG or greater.

Technical inquiries can be directed to FLU-BAA-ANTIVIRAL@HHS.GOV

Development programs at a maturity level less than TRLG should consider funding opportunities offered by NlAlD or other federal agencies that fund earlier stage research and development projects.

Information about NlAlD resources can be found at:

http://www.niaid.nih.qov/LabsAndResources/resources/dmid/Paqes/thera~eutics.aspx Technical inquiries about funding through NlAlD programs can be directed to:

DMIDResources@niaid. nih.aov

Part 11: Product Development and Technical Objectives - is revised to add Area of Interest 3 and 4 as follows:

This information is provided to assist and guide Offerors in preparing their Statement of Work (SOW). Offerors shall submit a SOW in their proposal that addresses these topics as appropriate, and shall provide as much detail as may be necessary to fully explain the proposed

BARDA BAA- 1 1-1 00-SOL-0002 1 Amendment #3 technical approach or method. The topics listed below exemplify some of the typical developmental activities in the areas of clinical research, manufacturing, clinical evaluation, project management, and regulatory strategy contained in a typical drug development effort.

Proposal preparation and submission instructions are contained in Part IV.

The following elements represent additions to the Part II activities as outlined in the original BAA document.

A. Development Approach:

Antiviral Advanced Research and Development Representative Activities may include but are not limited to:

a. Assessment of antiviral potential for therapeutics previously approved for other indications.

b. Evaluation of the safety, efficacy, pharmacokinetics, pharmacodynamics, bioavailability, solubility, formulation, dose, route and schedule of novel or reformulated countermeasures.

c. Development of analytical methods and assays appropriate for product characterization and product release, including tests for the identity, purity, potency, and stability of the bulk drug substance and final drug product. Offerors shall identify a stable source and availability of reagents and reference standards for these assays required.

d. Development of validation protocols for analytical and assay methods to define product manufacturing control, performance, potency and product stability indication.

Antiviral Process Development, Formulation, and Manufacturing Development Representative Activities may include but are not limited to:

a. Development of master and working cell banks under Good Manufacturing Practice guidelines (GMP: as defined in the U.S. Code of Federal Regulations 21

CFR 321 1).

b. Process development activities to increase efficiency, yield, and quality, and to reduce the variability and risk factors in the manufacturing of the drug substance and drug product.

c. Formulation development to evaluate combinations of excipients and their influence on the target product profile and on product stability.

e. Manufacture of GMP lots of candidate products in amounts sufficient to carry out requiredlproposed clinical trials that would seek to enhance the effectiveness of existing biologics and pharmaceuticals.

f. Identification of Critical Quality Attributes (CQA) and Critical Process Parameters.

g. Manufacturing scale-up plan to lead to consistency lot manufacturing of the candidate product.

h. Process flow for personnel, material and waste disposal.

I . Proposed packaging design and execution of fill-finish of final drug product.

j. Design of stability testing plan and conduct of stability studies on bulk and final product.

k. Development of Risk Evaluation and Mitigation Strategies or similar risk mitigation strategy proposals

BARDA BAA- 1 1 - 100-SOL-0002 1 Amendment #3

I. ManufacturingiTesting facility plan to support clinical trial lots through commercial scale product supply, including consideration of capacity for surge manufacturing in the event of an influenza pandemic

Antiviral Clinical Evaluation Representative Activities may include but are not limited to:

a. Design and conduct of clinical trials (Phase 2, and/or 3) to evaluate candidate medical countermeasure and device products in humans in accordance with Good Clinical Practice guidelines (GCP: as defined by 21 CFR §312 and ICH Guidelines document E6).

b. Design and conduct of clinical trials to evaluate safety and/or efficacy of candidate products in at-risk populations (e.g., elderly, pediatric, or immunocompromised persons).

c. Development of a clinical development plan that outlines key milestones and activities to mature the candidate product through FDA approval/licensure.

Development programs at a maturity level less than TRL6 should consider funding opportunities offered by NlAlD or other federal agencies that fund earlier stage research and development projects.

Information about NlAlD resources can be found at:

htt~://www.niaid.nih.nov/LabsAndResources/resources/dmidlPaes/therapeutics.aspx Technical inquiries about funding through NlAlD programs can be directed to:

DMIDResources@niaid.nih.qov

BARDA BAA- 1 1- 100-SOL-00021 Amendment #3

Part VII: Attachments

Attachment 1: Technology Readiness Level (TRL) Criteria - is revised to add Areas of Interest 3 and 4 as follows:

For Areas of Interest 3 and 4, Offerors must identify in their Quad Chart and White Paper that the criteria for TRL 6 have been met for the proposed antiviral product, using the Technology Readiness Levels for Medical Countermeasure Products (Drugs and Biologics) as shown below.

Please note that all activities within a TRL level (or sublevel) must be completed to have achieved that TRL status.

Technology Readiness Levels for Medical Countermeasure Products (Drugs a n d Biologics)

FOR USE WITH AREAS OF INTEREST 3 AND 4

NOTE: When using these criteria, a medical countermeasure product should be rated at a particular level only after fhe sponsor has completed all activities listed in that level (e.g., a product is rated at TRL 4 once it completes all of the activities listed in TRL 4).

TRL Review o f Scientific Knowledge Base

Active monitoring of scientific knowledge base. Scientific findings are reviewed and 1 assessed as a foundation for characterizing new technologies.

Development o f Hypotheses and Experimental Designs

TRL

Scientific "paper studies" to generate research ideas, hypotheses, and experimental

2 designs for addressing the related scientific issues. Focus on practical applications based on basic principles observed. Use of computer simulation or other virtual platforms to test hypotheses.

TargeVCandidate Identification and Characterization o f Preliminary Candidate(s)

Begin research, data collection, and analysis in order to test hypothesis. Explore alternative concepts, identify and evaluate critical technologies and components, and TRL begin characterization of candidate(s). Preliminary efficacy demonstrated in vivo.

3 3A Identify target andlor candidate.

3B Demonstrate in vitro activity of candidate(s) to counteract the effects of the threat agent.

3C Generate preliminary in vivo proof-of-concept efficacy data (non-GLP (Good Laboratory Practice)).

BARDA BAA- 1 1-1 00-SOL-00021 Amendment #3

Candidate Optimization and Non-GLP In Vivo Demonstration of Activity and Efficacy

Integration of critical technologies for candidate development. lnitiation of animal model development. Non-GLP in vivo toxicity and efficacy demonstration in accordance with the product's lntended use. lnitiation of experiments to identify markers, correlates of protection, assays, and endpoints for further non-clinical and clinical studies.

Animal Models: lnitiate development of appropriate and relevant animal model(s) for the desired indications.

Assays: lnitiate development of appropriate and relevant assays and associated TRL reagents for the desired indications.

4 Manufacturing: Manufacture laboratory-scale (i.e nonGMP (Good Manufacturing Practice)) quantities of bulk product and proposed formulated product.

4A Demonstrate non-GLP in vivo activity and potential for efficacy consistent w~th the product's intended use (i.e. dose, schedule, duration, route of administration, and route of threat agent challenge).

4B Conduct initial non-GLP toxicity studies and determine pharmacodynamics and pharmacokinetics andlor immune response in appropriate animal models (as applicable).

4C lnitiate experiments to determine assays, parameters, surrogate markers, correlates of protection, and endpoints to be used during non-clinical and clinical studies to further evaluate and characterize candidate(s).

Advanced Characterization of Candidate and lnitiation of GMP Process Development

Continue non-GLP in vivo studies, and animal model and assay development. Establish draft Target Product Profiles. Develop a scalable and reproducible manufacturing process amenable to GMP.

Animal Models: Continue development of animal models for efficacy and dose-ranging studies.

Assays: lnitiate development of in-process assays and analytical methods for product characterization and release, including assessments of potency, purity, identity, TRL strength, sterility, and quality as appropriate.

Manufacturing: lnitiate process development for small-scale manufacturing amenable to

5 ""'.

Target Product Profile: Draft preliminary Target Product Profile. Questions of shelf life, storage conditions, and packaging should be considered to ensure that anticipated use of the product is consistent with the intended use for which approval will be sought from FDA.

5A Demonstrate acceptable Absorption, Distribution, Metabolism and Elimination characteristics and/or immune responses in non-GLP animal -studies as necessary for IND filing.

58 Continue establishing correlates of protection, endpoints, and/or surrogate markers for efficacy for use in future GLP studies in animal models. Identify minimally effective dose to facilitate determination of "humanized" dose once clinical data are obtained.

BARDA BAA- 1 1 - 100-SOL-0002 I Amendment #3

GMP Pi lot L o t Production, IND Submission, and Phase I Clinical Trial(s)

Manufacture GMP-compliant pilot lots. Prepare and submit Investigational New Drug (IND) package to FDA and conduct Phase 1 clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article.

Animal Models: Continue animal model development via toxicology, pharmacology, and immunogenicity studies.

Assays: Qualify assays for manufacturing quality control and immunogenicity, if TRL applicable.

6 Manufacturing: Manufacture, release and conduct stability testing of GMP-compliant bulk and formulated product in support of the IND and clinical trial(s).

Target Product Profile: Update Target Product Profile as appropriate.

6A Conduct GLP non-clinical studies for toxicology, pharmacology, and immunogenicity as appropriate.

66 Prepare and submit full IND package to FDA to support initial clinical trial@).

6C Complete Phase 1 clinical trial(s) that establish an initial safety, pharmacokinetics and immunogenicity assessment as appropriate.

Scale-up, Init iation o f GMP Process Validation, and Phase 2 Clinical Trial(s)'

Scale-up and initiate validation of GMP manufacturing prycess. Conduct animal efficacy studies as appropriate. Conduct Phase 2 clinical trial(s).

Animal Models: Refine animal model development in preparation for pivotal GLP animal efficacy studies.

Assays: Validate assays for manufacturing quality control and immunogenicity if applicable.

TRL

Manufacturing: Scale-up and validate GMP manufacturing process at a scale

7 compatible with USG requirements. Begin stability stud~es of the GMP product in a formulation, dosage form, and container consistent with Target Product Profile. Initiate manufacturing process validation and consistency lot production.

Target Product Profile: Update Target Product Profile as appropriate.

7A Conduct GLP animal efficacy studies as appropriate for the product at this stage. '

7B Complete expanded clinical safety trials as appropriate for the product (e.g., Phase 2).3

I Identification of later regulatory stages of clinical development in this document (e.g., Phase 2, Phase 3) may not apply to some products being developed under the "Animal Rule". Other than human safety studies, no additional clinical data may be feasible or ethical to obtain. For additional information on the "Animal Rule", please see:

http:/lwww.fda.qovl0HRMSIDOCKETS198fr1053102a.htm

BARDA BAA- 1 1-1 00-SOL-00021 Amendment #3

Completion of GMP Validation and Consistency Lot Manufacturing, Pivotal Animal Efficacy Studies or Clinical Trials3, and FDA Approval or Licensure

Finalize GMP manufacturing process. Complete pivotal animal efficacy studies or clinical trials (e.g., Phase 3), andlor expanded clinical safety trials as appropriate. Prepare and submit NDAIBLA.

Manufacturing: Complete validation and manufacturing of consistency lots at a scale TRL compatible with USG requirements. Complete stability studies in support of label expiry dating.

8 Target Product Profile: Finalize Target Product Profile in preparation for FDA approval.

8A Complete pivotal GLP animal efficacy studies or pivotal clinical trials (e.g., Phase 3), and any additional expanded clinical safety trials as appropriate for the p r ~ d u c t . ~

8B Prepare and submit New Drug Application (NDA) or Biologics Licensing Application (BLA) to the FDA.

8C Obtain FDA approval or licensure.

Post-Licensure and Post-Approval Activities

TRL 9A Commence post-licensure/post-approval and Phase 4 studies (post-market~ng commitments), such as safety surveillance, studies to support use in special populations, and clinical trials to confirm safety and efficacy as feasible and appropriate.

9B Maintain manufacturing capability as appropriate.