Amendment 2 Addendum A -GTRP Renewal._Pharm-Tox_.pdf

AMENDMENT OF SOLICITATION/MODIFICATION OF CONTRACT

1. CONTRACT ID NO. PAGE OF PAGES

1 1

2. AMENDMENT/MODIFICATION NO. 3. EFFECTIVE DATE 4. REQUISITION/PURCHASE REQ. NO. 5. PROJECT NO. (if applicable)

002 Addendum A April 11, 2011 NA

6. ISSUED BY

CODE 7. ADMINISTERED BY (if other than Item 6) CODE

National Heart, Lung, and Blood Institute Rockledge II Building, Room 6136A 6701 Rockledge Drive, MSC 7902 Bethesda, MD 20892-7902

See Block 6

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

X

NHLBI-CSB-HV-2012-06-

NIR

9B. DATED (SEE ITEM 13)

04/01/2011

10A. MODIFICATION OF CONTRACT/

ORDER NO.

10B. DATED (SEE ITEM 13)

CODE FACILITY CODE

11. THIS ITEM APPLIES TO AMENDMENTS OF SOLICITATIONS

The above numbered solicitation is amended as set forth in Item 14. The hour and date specified for receipt of Offers is extended, is not extended.

Offerors 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 1 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 RECEIPT OF OFFERS PRIOR TO THE HOUR AND DATE SPECIFIED MAY RESULT IN REJECTION OF YOUR OFFER. If by virtue of this amendment you 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 solicitation and this amendment, and is received prior to the opening hour and date specified.

12. ACCOUNTING AND APPROPRIATION DATA (if required)

13. THIS ITEM APPLIES ONLY TO MODIFICATIONS OF CONTRACTS/ORDERS,

IT MODIFIES THE CONTRACT/ORDER NO. AS DESCRIBED IN ITEM 14.

A. THIS 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.

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

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

D. OTHER (Specify type of modification and authority)

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

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

PURPOSE: To amend the Specific/Additional Instructions, Assumptions, Conditions, and Notices to Offerors for the GTRP Pharmacology/Toxicology Core Laboratory

(1) Change – items under “e” should be in numerical order beginning with the number 1.

All other terms and conditions of this solicitation remain unchanged.

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

15A. NAME AND TITLE OF SIGNER (Type or print) 16A. NAME AND TITLE OF CONTRACTING OFFICER (Type or print)

, Nora I. Rivera, Contracting Officer 15B. CONTRACTOR/OFFEROR 15C. DATE SIGNED 16B. UNITED STATES OF AMERICA 16C. DATE SIGNED

BY

4/7/09 (Signature of person authorized to sign.) (Signature of Contracting Officer)

NSN 7540-01-152-8070

PREVIOUS EDITION UNUSABLE

30-105 STANDARD FORM 30 (REV. 10-83)

Prescribed by GSA

FAR (48 CFR) 53.243

SPECIFIC/ADDITIONAL INSTRUCTIONS, ASSUMPTIONS, CONDITIONS, AND NOTICES TO OFFERORS

a. General Description of the Required Objectives

This program is designed to facilitate clinical gene therapy studies in heart, lung, and blood diseases by offering the specialized services of five national core laboratories (a clinical coordinating center, a preclinical-grade vector production core laboratory, a clinical-grade adeno-associated (AAV) vector production core laboratory, a clinical-grade lentivirus vector production core labor-atory, and a pharmacology/toxicology core laboratory) at no cost to NHLBI-funded investigators. The core laboratories will be charged with implementing the rapid, safe, and equitable transition of basic research ideas to clinical practice, as well as supplying clinical-grade products produced in a manner that is compliant with all regulatory requirements. The clinical coordinating center (CCC) will coordinate the organizational and regulatory aspects of the program.

In addition, the program will also provide funding for Phase I/II gene transfer trials that are within 6-12 months of initial patient enrollment. Examples of clinical Phase I/II trials in gene therapy that may be supported under this program include, but are not limited to, protocols focusing on:

• Cardiovascular diseases such as ischemic heart disease, restenosis, heart failure, and peripheral arterial disease

• Blood disorders such as hemophilia, thalassemia, and sickle cell disease

• Lung diseases such as alpha-1 anti-trypsin deficiency and cystic fibrosis

• Immunodeficiencies such as adenosine deaminase deficiency and X-linked severe combined immunodeficiency (X-SCID).

The organizational structure of the GTRP is as follows:

• Clinical Coordinating Center (CCC) - Oversee and coordinate the logistics of the Core Laboratories, provide regulatory assis-tance to investigators registered with the GTRP, and to administer the funding support for clinical trials in the GTRP.

• Preclinical Vector Production Core Laboratory- Produce large-scale, preclinical-grade vectors for use by NHLBI-funded in-vestigators.

• AAV Vector Production Core Laboratory - Produce scalable clinical-grade adeno-associated viruses for use by NHLBI-funded investigators.

• Lentivirus Vector Production Core Laboratory - Produce scalable clinical-grade lentiviral viruses for use by NHLBI-funded investigators.

• Pharmacology/Toxicology Core Laboratory - Conduct pharmacological/ toxicological studies using gene therapy vectors for

NHLBI-funded investigators.

• GTRP Steering Committee (SC) - The SC will be comprised of representatives from the NHLBI, the CCC, and each of the

Core Laboratories.

• Scientific Review Board (SRB) - The SRB will be comprised of experts in the design and production of viral and non-viral vectors and in the field of clinical gene therapy. The SRB will review clinical protocols and make recommendations to the NHLBI. The SRB does not meet in person. The written reviews by the SRB members are submitted to the CCC and discus-sions with the SC are via teleconference.

• NHLBI-appointed Data and Safety Monitoring Board (DSMB) - The DSMB will be comprised of individuals with relevant scientific expertise, including experts in the field of clinical gene therapy. The DSMB will monitor GTRP-funded clinical tri-als.

• NHLBI Gene Therapy Group (GTG) - The Group will be comprised of Program Officers from each division of the NHLBI and members of the Contracts Operations Branch.

NHLBI Program and Contracts Offices - NHLBI Program and Contracts officials will be responsible for the administration and monitoring of the program. These officials will participate in and monitor the activities of the program.

b. Background Information

In June 2005 the NHLBI convened an expert Working Group to better understand the impediments to clinical progress in gene therapy and to advise the NHLBI how to best direct its limited resources to facilitate translational research in the field of gene therapy. The NHLBI responded to these recommendations by establishing the NHLBI Gene Therapy Resource Program (GTRP) in March 2007. The GTRP consists of a Clinical Coordinating Center (CCC) and four Core Laboratories. The pharmacol-ogy/toxicology core laboratory is to conduct preclinical vector toxicology testing and biodistribution studies using all types of gene therapy vectors for NHLBI-funded investigators who are actively involved in gene transfer studies using large and small animal models. Fulfilling the various service requests requires extensive interactions with all parties involved and the process can take months to years, particularly those aspects related to preclinical toxicology testing and biodistribtuon studies. Therefore, it is critical that the Pharmacology/toxicology Core Laboratory have demonstrated experience in the management of complex research programs and human clinical trials.

c. Detailed Description of Technical Objectives

The primary objective of the pharmacology/toxicology core laboratory is to conduct preclinical vector toxicology testing and bio-distribution studies using all types of gene therapy vectors for NHLBI-funded investigators who are actively involved in gene transfer studies using large and small animal models.

d. Data, Data Rights, Patents, Copyrights

The primary goal of the core laboratories (Preclinical, AAV and Lentivirus, and Pharmacology/Toxicology) of the Gene Therapy Resource Program is to serve NHLBI-funded investigators by providing preclinical vectors, AAV and Lentiviral GMP vectors, and to conduct pharmacological/toxicological studies as requested. The Core Laboratories shall disseminate the methodologies of the vectors produced, if needed, to research investigators for whom they are fulfilling the request. All issues related to intellectual property shall be appropriately addressed and resolved during Phase I of the Program. All Core Laboratories and research investi-gators receiving funds from the NHLBI GTRP shall adhere to NIH policies and procedures.

The following are specific details applicable to each component of the GTRP:

1. The Preclinical Core Laboratory shall produce preclinical vectors (customized, non-customized, viral and non-viral) for use by NHLBI investigators. The Core Laboratory may hold the rights to any new processes and procedures that it develops in the performance of its contract. However, the Core is required to disclose all relevant information necessary to enable the subsequent production of a clinical grade vector by one of the GTRP GMP Vector Production Cores and/or NIH National Gene Vector Core Laboratories. A delay of six months will be permitted for disclosure so that the Core Laboratory can ap-ply for intellectual property rights. This does not supersede any intellectual property rights conceived and first actually re-duced to practice by the requesting investigator prior to involvement with the GTRP.

2. The AAV and Lentivirus Core Laboratories shall produce customized vectors for use by NHLBI investigators. The Core La-boratories may hold rights to any new vectors and to any new processes and procedures that have been developed in the performance of their respective contracts. This does not supersede any intellectual property rights conceived and first ac-tually reduced to practice by the requesting investigator prior to involvement with the GTRP.

3. The Pharmacology/Toxicology Core Laboratory shall conduct pharmacological and toxicological studies using vectors. The Core Laboratory will not hold the intellectual rights to data from these studies. According to NIH policies, the data will be-long to the investigator requesting these services, who may disseminate the information in a publication or at a meeting.

The NHLBI may request the investigator to place the data in an FDA Master File. The assays developed by the Core La-boratory will belong to that Core Laboratory.

4. The Clinical Coordinating Center (CCC) may be involved with regulatory affairs activities for research investigators. The IND-holder may delegate certain responsibilities to the CCC, but the CCC shall release confidential information only as al-lowed by the IND-holder.

It is expected that the Cores will apply for copyrights and patents on data/processes collected and developed in the performance of this Program. Contractors will be required to include in their semiannual technical reports, full disclosure of intents to file patent applications and actual filings on materials, reagents, animal models or procedures derived or established, whether in the US or outside the US. They will also be required to fully disclose any efforts to transfer their technology or receipt of support from out-side entities interested in future access, partnering, or license to the developing technologies.

e. Offers must address the following points in their proposal:

1. Provide the names, degrees, training, qualifications, experience, role in project, and effort for each individual named in the offeror’s proposal and proposed subcontract(s).

2. Describe institutional continuing education/training requirements of the offeror and proposed subcontractor(s)

3. Provide evidence of an established toxicology core infrastructure, including experience in animal models of disease and unique delivery methods specific to the product type and the disease.

4. Identify specific studies that have been performed, how quality control was ensured and monitored, and the costs associated with performance of each study. This information shall also be provided for all proposed subcontractor(s).

5. Identify the types of assays that can be performed, the animal models that are available and the number of studies that can be done on a monthly basis (rate of turn-over).

6. Provide a detailed description of proposed monitoring plans for toxicology testing to be conducted, from initiation to comple-tion, including regulatory requirements that would be applicable.

7. Propose detailed plans for the preparation and submission of reports about pharmacological/toxicological studies conducted.

8. Describe the offeror’s abilities to interface with other databases.

9. Propose plans to maintain a registry/database of all requests made for toxicological studies. Plans should identify the name of the requesting investigator, name of the project, name of the vector, procedures adopted for vector testing, information on quality control, quality assurance methods, vector lot numbers, and date testing is completed.

10. Describe the offeror’s and proposed subcontractor(s)’ experience working with other organizations and the Food and Drug Administration (FDA). Describe plans to interact with the CCC, NHLBI, the investigators, and the FDA if needed.

11. Provide a detailed description of laboratory facilities available to the offeror and proposed subcontractor(s) to conduct the Statement of Work.

12. Describe in detail the administrative structure of the proposed Core Laboratory, including the offeror and proposed subcon-tractor(s).

13. Describe in detail the offeror’s and proposed subcontractor(s)’ plans to secure and dispose of animals.

14. Describe practices, equipment, and facilities that ensure biosafety of all personnel directly or indirectly involved in conducting pharmacological/toxicological studies.

15. Provide evidence of institutional commitment for this program. Provide evidence of commitment to adhere to the Data, Data Rights, Patents, and Copyrights provisions spelled out in item (d) above.

16. Provide any other information needed to allow reviewers to judge the capability of the offeror to accomplish the Statement of Work.

f. Reference Material

This acquisition is a renewal of the existing GTRP program which is comprised of one clinical coordinating center and four core laboratories. Information about this program can be found at http://www.gtrp.org/. Additionally, the Government recommends review of Request for Proposals for the GTRP Clinical Coordinating Center, Preclinical Vector Production Core Lab, Adeno-associated Virus VectorProduction Core Lab, and Lentivirus Vector Production Core Lab which are located in FedBizOpps .

Failure of offeror to examine the reference materials prior to proposal preparation and submission will be at the offeror's risk.

BUDGET ASSUMPTIONS

g. Pharmacology/Toxicology Studies

The Government considers that the uniform study cost assumptions matrix below will be required for successful completion of the program objectives. The uniform study cost assumptions are for information only and are not to be considered restric-tive for proposal purposes. The assumptions are formulated by NHLBI staff utilizing recent experience.

UNIFORM STUDY COST ASSUMPTIONS MATRIX

Year Study Type Study Duration

Number of Stu-dies

Number and Type of An-imals

Est. Study Costs

Year-1 Toxicology 60 Days 1 144/Mice Toxicology 60 Days 1 144/Mice Toxicology 60 Days 1 144/Mice

Year-2 Toxicology 60 Days 1 144/Mice Biodistribution 70 Days 1 38/Pigs Biodistribution 60 Days 1 32/Mice Biodistribution 112 Days 1 12/Baboons

Year-3 Biodistribution 60 Days 1 32/Mice Toxicology 60 Days 1 144/Mice Biodistribution 112 Days 1 12/Baboons Biodistribution 70 Days 1 38/Pigs

Year-4 Toxicology 60 Days 1 144/Mice Biodistribution 70 Days 1 38/Pigs Biodistribution 60 Days 1 32/Mice

Year-5 Toxicology 60 Days 1 144/Mice Toxicology 60 Days 1 144/Mice Subtotal $ Travel $

ODC

Other Core

Costs

Subtotal $ Other Fees $

TOTAL $

h. Travel

The Government considers that the travel assumptions identified below will be required for successful completion of the pro-gram objectives. The travel assumptions are for information only and are not to be considered restrictive for proposal purpos-

es. The assumptions are formulated by NHLBI staff utilizing recent experience.

TRAVEL ASSUMPTIONS FOR THE PHARM-TOX CORE LAB

STEERING COMMITTEE MEETINGS Year 1 Year 2 Year 3 Year 4 Year 5

Estimated Number of Meetings 2 2 2 2 2

Estimated Number of Days Per Meeting 2 2 2 2 2

Estimated Number of Lab Staff 2 2 2 2 2

SITE VISITS Year 1 Year 2 Year 3 Year 4 Year 5

Estimated Number of Site Visits 2 2 1 1 1

Estimated Number of Days Per Meeting 1 1 1 1 1

Estimated Number of Lab Staff 2 2 2 2 2

SCIENTIFIC MEETINGS Year 1 Year 2 Year 3 Year 4 Year 5

Estimated Number of Trips 2 2 2 2 2

Estimated Number of Days Per Meeting 3 3 3 3 3

Estimated Number of Lab Staff 2 2 2 2 2

1. Govt. Rates verified at: http://www.gsa.gov/portal/category/100000

2. Per Diem should be based on the Govt. Rate from Chicago, IL to Bethesda, MD (Washington, DC metropolitan area).

3. Ground Transportation costs are for taxis to and from airports.

4. 3% escalation calculated through the period of performance.

i. Level of Effort

The Government considers that the personnel and estimated levels of effort identified below will be required for successful completion of the program objectives. Effort is shown as a percentage of full time equivalent (FTE) labor. The personnel and levels of effort listed are for information only and are not to be considered restrictive for proposal purposes. The levels are formulated by NHLBI staff utilizing recent experience.

EMPLOYEE *PERCENT

POSITION EFFORT

Principal Investigator 20% Co-Investigator 50% Co-Investigator 50% DNA Extraction Technician 100% Office Administrator 25% Senior Programmer 5% ----------------------- Total 250%

*The specified levels are equivalents for each 12 month period over the 5-year planned contract period.