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Attachment Number 1 – CBLI SOW
W9113M-10-C-0088

 
 
Statement of Work
 
2.1
Statement of Work (SOW) (L.3.2.1; M.3.2.2.1) Dated August 10, 2010 (amended June
23, 2011)

 
Cleveland BioLabs, Inc.’s (CBLI) lead product, CBLB502, is currently being
tested in Phase 1b clinical trials.  Both preclinical and clinical evidence
support CBLB502’s use to repair Gastrointestinal (GI) damage from Acute
Radiation Syndrome (ARS) and to restore the anatomic integrity and normal
physiological functioning of the GI tract following radiation exposure.  CBLI is
developing CBLB502 as a post-exposure Medical Radiation Countermeasure (MRC) in
the treatment of ionizing radiation (IR) injury, specifically the GI subsyndrome
of ARS (GI-ARS).  Further, our MRC will decrease incapacity of affected military
forces following exposure to IR such that they can maintain operational
effectiveness within a contaminated area, regardless of radiation source.  The
completed work items listed in the Statement of Objectives (SOO) are included in
this SOW for completeness and are indicated in italic below.
 
Technology Development Phase
 
CBLI shall arrange for, supervise, and provide all the human resources,
facilities and expertise to prepare, submit and maintain an IND for ARS.  These
activities include, but are not limited to, the activities listed below.
 
C.3.1.1.  CBLI completed cGMP compliant (21 CFR Part 210 and 211) small-scale
manufacturing process development and qualification for CBLB502 and currently
manufactures CBLB502 in a cGMP compliant manufacturing facility operated by
SynCo Bio Partners N.V.  Two small-scale (5L) consistency batches with purity >
96% (Lots 09-COB4-3040-I01 and 09-COB4-3040-I02) were successfully manufactured
in Nov-Dec 2009.
 
C.3.1.2.  CBLI successfully manufactured a cGMP compliant lot of CBLB502 for use
in nonclinical toxicology and Phase 1 studies.  This lot of CBLB502 was used to
support the ARS IND (#100,480) filed by CBLI for CBLB502 (CBLB502 IND) with the
FDA (see Section C.3.1.6).
 
C.3.1.3.  CBLI completed development and validation of analytical assays for
cGMP compliant product characterization and lot release.  The lot release
specifications for small-scale process development were fortified based on a FDA
recommendation and were used to release product for CBLI’s completed and ongoing
clinical trials.  The lot release specifications for Bulk Drug Substance (BDS)
include tests for appearance, pH, ID, purity, content, potency, endotoxin,
residual DNA, residual host cell protein, and sterility.
 
 
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Attachment Number 1 – CBLI SOW
W9113M-10-C-0088

 
 
C.3.1.4.  CBLI completed Good Laboratory Practices (GLP) compliant acute
toxicology studies in mice and non-human primates (NHPs) to support the CBLB502
IND.  These studies were reviewed and approved by the FDA and will support the
CBLB502 BLA filing for ARS (see Section C.3.2.10).  Animal protocols were
approved by the local Institutional Animal Care and Use Committee (IACUC), for
all studies, and DoD’s Animal Care and Use Review Office (ACURO), for all DoD
funded studies.
 
C.3.1.5.  CBLI is in the process of conducting appropriate pilot animal model
studies to support approval under the Animal Rule.  CBLI has established the
Rhesus macaque (Macaca mulatta) and mice (Mus musculus) as the relevant animal
models.  CBLI shall conduct such efficacy studies at a radiation dose sufficient
to cause GI-ARS.  Animal protocols for studies occurring prior to or concurrent
with the date hereof were approved by the local IACUC, for all studies, and
ACURO, for all DoD funded studies.  All animal protocols for studies funded
under this Statement of Work will be approved by the local IACUC and
ACURO.  CBLI shall perform all necessary and appropriate steps to ensure
agreement with the FDA on the animal models to be used in pivotal studies
required for BLA submission under the Animal Rule.
 
C.3.1.5.1.  CBLI shall conduct such efficacy studies in Rhesus macaque (Macaca
mulatta) at a radiation dose sufficient to cause GI-ARS with drug administered
at 24 hours post irradiation.
 
C.3.1.5.2.  Option. CBLI shall conduct such efficacy studies in Rhesus macaque
(Macaca mulatta) at a radiation dose sufficient to cause GI-ARS with drug
administered at 48-120 hours post irradiation.
 
C.3.1.5.3.  CBLI shall conduct such efficacy studies in Rhesus macaque (Macaca
mulatta) at a radiation dose sufficient to cause GI-ARS with drug administered
at 4 hours post irradiation.
 
C.3.1.5.4.  CBLI shall provide for housing/recovery of up to 26 Rhesus macaque
(Macaca mulatta) used as blood donor animals in pilot animal studies conducted
under this SOW.
 
C.3.1.5.5.  Option. CBLI shall conduct such efficacy studies in mice (Mus
musculus) at a radiation dose sufficient to cause GI-ARS with drug administered
at 4-120 hours post irradiation.
 
C.3.1.5.6.  Option.  CBLI shall conduct a preclinical toxicity study to evaluate
uterine weight in sexually mature mice (Mus musculus).
 
C.3.1.6.  CBLI submitted and received approval for an IND for use of CBLB502 in
the treatment of ARS (IND 100,480).
 
C.3.1.7.  CBLI completed a Phase 1a dose escalation clinical safety/PK/PD study
in a 50 healthy human subjects in accordance with FDA Good Clinical Practices
(GCP). CBLI is currently conducting a Phase 1b dose validation study in 100
human subjects.  Institutional Review Board (IRB) approval was obtained at all
institutions conducting the clinical trials.
 
 
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Attachment Number 1 – CBLI SOW
W9113M-10-C-0088

 
 
C.3.1.8.  CBLI will store product from the same lot as was used in the Phase 1a
and Phase 1b (Phase 1 product) clinical trials under cGMP controlled conditions
for two years following the end of each trial.  CBLI has current storage data on
the product used in both the Phase 1a and Phase 1b clinical trials (Phase 1
Product) beginning Sep 2007.
 
C.3.1.9. Perform an International Conference on Harmonisation (ICH-compliant
stability testing program on the product referenced in C.3.1.8.
 
C.3.1.8 CBLI will perform program management and regulatory affairs tasks
associated with SOW tasks C.3.1.1 – C.3.1.9.
 
Engineering, Manufacturing and Development Phase (CLIN0003 and CLIN0004)
 
CBLI shall arrange, for, supervise, and provide all the human resources,
facilities and expertise to prepare and submit a BLA for GI-ARS indication under
the FDA Animal Rule.  These activities include, but are not limited to, the
activities listed below.
 
C.3.2.1.  CBLI completed development of a Lyo drug product formulation that is
suitable for administration in humans and a delivery system that is suitable for
military use.  Our envisioned delivery system will involve the drug product
stored either at 2-8 oC or controlled room temperature (20-25oC) in single dose
vials that would be administered intramuscularly after reconstituting the drug
product using Water for Injection (WFI) using a syringe. This injection could be
performed in the field and would not require a sterile environment or hospital
bed.
 
C.3.2.2.  CBLI completed development and validation of analytical assays for
cGMP compliant product characterization and lot release.  Lot release
specifications shall be further refined for the large-scale consistency batches
in consultation with the FDA.
 
C.3.2.3.  CBLI shall scale-up the manufacturing process to achieve a cGMP
compliant large-scale manufacturing process for Lyo product formulation.  CBLI
shall conduct product comparability studies to demonstrate cGMP compliant
product comparability between each manufacturer.
 
C.3.2.4.  CBLI shall manufacture GMP product suitable for expanded nonclinical
safety studies, definitive animal efficacy studies, and Phase 2 clinical
trials.  CBLI shall manufacture consistency lots and perform large-scale process
validation and proactively cooperate with the FDA Pre-Approval Inspection as
required for product approval.
 
C.3.2.5.  CBLI shall perform an ICH-compliant stability testing program on drug
product manufactured using validated manufacturing process for Phase 2 expanded
safety clinical study and non-clinical definitive animal efficacy studies to
establish a shelf life for the drug product in a delivery system suitable for
military use.
 
 
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Attachment Number 1 – CBLI SOW
W9113M-10-C-0088

 
 
C.3.2.6.  CBLI shall perform stability testing to establish operational storage
and distribution temperature ranges. Using the established stability profile
CBLI shall select the appropriate Time Temperature Indicator (TTI).
 
C.3.2.7.  CBLI shall conduct GLP-compliant Segment I and III reproductive
toxicology studies to support submission of a BLA for CBLB502.  CBLI conducted
GLP-compliant Segment II reproductive toxicology studies in Wistar rats and New
Zealand white rabbits.  The reports were submitted to the FDA in June 2010.
 
C.3.2.8.  CBLI shall conduct necessary definitive efficacy studies in relevant
animal models in accordance with GLP regulations and guidelines to support
submission of a BLA for CBLB502.  CBLI shall discuss the design of these studies
with the FDA for product approval under the Animal Rule.  All animal protocols
for studies funded under this Statement of Work will be approved by the local
IACUC and the DoD ACURO.
 
C.3.2.9.  CBLI shall conduct a Phase 2 expanded safety clinical study in a
relevant human subject population in accordance with GCP.   The clinical
protocol for this study will be approved by the DoD HSRRB, if the study is
funded by the DoD, and the local IRB.
 
C.3.2.10.  CBLI shall prepare and submit in electronic CTD format a BLA for the
GI-ARS indication for FDA review.  CBLI shall prepare and submit responses to
requests for additional information from the FDA during the review process.
 
C.3.2.11.  CBLI shall deliver to the Government a minimum of one dose of the FDA
approved medical radiation countermeasure (MRC) as part of CLIN 00004.
 
C.3.2.12.  CBLI shall partner with the DoD and support the submission of an EUA
by preparation of letters that cross-reference the IND file and/or other
regulatory documentation.
 
C.3.2.13. CBLI will perform program management and regulatory affairs tasks
associated with SOW tasks C.3.2.1 – C.3.2.12.
 
C.3.3  Provision of a MRC.  CBLI shall provide a MRC that is supportable
throughout the contemporary operating environment. The MRC shall have, at a
minimum, the following key system attributes: (C.3.3.1.) it shall be operational
across a wide range of temperatures; a shelf life of 2 years at  a storage
temperature of – 20 to 0 degrees Celsius, (preferably having a shelf life > 2
years at a storage temperature of 20 to 35°C); (C.3.3.2.) it shall be suitable
for administration in humans and a delivery system suitable for military use;
and (C.3.3.3) it shall be labeled in compliance with FDA requirements and shall
incorporate the following enabling technologies critical for the use of the MRC
throughout the contemporary operating environment: (1) Item Unique
Identification (IUID) labeling for each individual unit (e.g. vial) of CBLB502
IAW DFAR 252.211-7003, (2) incorporating Radio Frequency Identification (RFID)
technology IAW DFAR 252.211-7006 on each shipping container, and (3)
incorporating Time Temperature Indicators (TTI’s) on each MRC unit to provide an
easy to read device to indicate any potential heat damaged product.
 
 
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Attachment Number 1 – CBLI SOW
W9113M-10-C-0088

 
 
C.3.4 Prepare a SOW, IMS, CWBS, CWBS Dictionary, and Integrated Risk Management
Plan.  CBLI shall submit a SOW, IMS (CDRL A003), CWBS (CDRL A002), CWBS
dictionary and Integrated Risk Management Plan for the proposal that encompasses
the entire scope of the project. The IMS shall be updated monthly to track
progress. The CWBS elements shall define the complete scope of the contract to a
breadth and depth necessary to describe the proposed effort to a minimum of
Level 4. The IMS, CWBS, and SOW shall be structured to correlate with each
other.
 
C.3.5.  Option: Prepare a Technical Data Package (TDP).  CBLI shall prepare a
TDP (CDRL A009) for the use of CBLB502 to treat GI-ARS. This TDP shall include
all necessary documentation and technical data for the Government, or its
designee, to continue the development or production of CBLB502 to treat
GI-ARS.    If at any time CBLB502 ceases to be marketed and is retired, or in
the event CBLI defaults and fails to remedy said default before or after
approval, CBLI shall transfer the TDP to the Government or its designee under a
term specified in the contract.  CBLI shall also assist in technical
transfer.  .
 
C.3.6  Option: Prepare and Deliver a Drug Master File (DMF).  CBLI shall prepare
and deliver a DMF within 90 days of the Government exercising this option.
 
C.3.7.  Option: Utilize an Earned Value Management System (EVMS).  If total cost
of efforts under cost type Contract Line Item Numbers is equal to or greater
than $20M, CBLI shall utilize an Earned Value Management (EVM) System (EVMS)
recognized by the cognizant Administrative Contracting Officer (ACO) as
complying with the criteria provided in American National Standards Institute
(ANSI)/Electronic Industries Alliance (EIA) EVMS standard (ANSI/EIA-748), DoD
5000.2-R, Mandatory Procedures for Major Defense Acquisition Programs (MDAPs)
and Major Automated Information System (MAIS) Acquisition Programs (DFARS
252.242-7001 and DFARS 252.242-7002) as well as the policy letter, “Revision to
DoD Earned Value Management Policy” dated March 7, 2005.  In the event this
option is triggered, (i) CBLI shall hold an Integrated Baseline Review (IBR)
within six months, unless otherwise agreed, to assess the realism and accuracy
of the integrated performance measurement baseline, and (ii) CBLI shall provide
monthly EVM reports and quarterly Contract Funds Status Reports using DD Form
1568.
 
C.3.8.  Option:  Produce 2,500 – 37,500 Troop Equivalent Doses.  CBLI shall
produce between 2,500 and 37,500 Troop Equivalent Doses (TED) of CBLB502 and
shall deliver the drug product to the government as directed.
 
C.4.  General
 
C.4.1.  CBLI shall provide the necessary qualified personnel, facilities,
equipment, supplies, services, subcontractors, and related administrative and
information technology support to accomplish the objectives.
 
 
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Attachment Number 1 – CBLI SOW
W9113M-10-C-0088

 
 
C.4.2.  CBLI shall allow access to records, files, and other data derived from
the work conducted under this Statement of Work for the purposes of audit by the
FDA and/or by CBMS-MITS or its designees.
 
C.4.3  CBLI shall prepare a written Quality Plan that spells out the roles and
responsibilities and allow the Government, or its designee, to audit CBLI or its
Subcontractors for regulatory compliance and quality assurance purposes.
 
C.4.4.  CBLI shall package, handle, store and transport product in compliance
with U.S. Pharmacopeia 1079 (Good Storage and Shipping Practices) and in
accordance with FDA cGMP/DOD regulations and conformance to the intended
military user. If required CBLI shall use proven commercial or military best
inventory management practice to facilitate supply chain management.
 
C.4.5.  CBLI shall provide copies of all communications with the FDA and include
the Government in all discussions with the FDA in accordance with CDRL.  CBLI
shall also provide copies of study reports and Target Product Profile in
accordance with CDRL.
 
C.4.6.  CBLI shall provide monthly Progress, Status and Management Reports that
describe progress made within the period, summarize projected vs. actual
progress, report costs, and inform the Government of existing or potential
problem areas and risk mitigation plans. CBLI shall include with the submission
of these reports invoices submitted during the report month.
 
C.4.7.  CBLI shall participate in a monthly teleconference to include Integrated
Product Team meetings in accordance with CDRL or as needed.  CBLI shall provide
minutes of teleconferences within one week.
 
C.4.8.  CBLI shall provide a summary report within three working days, of events
that will cause more than a two week delay in schedule, or an increase in cost
Estimate at Completion in accordance with CDRL.
 
C.4.9.  To ensure that CBLI is utilizing best business practices for clinical
and nonclinical study data collection and reporting, CBLI shall employ an
automated information system (AIS) in accordance with electronic common
technical document (eCTD) and ICH guidance for electronic submissions to the
FDA.  CBLI shall provide MITS JPMO with remote access via CBLI’s AIS to clinical
and nonclinical data, within a timely manner following CBLI’s quality assurance
review and acceptance.
 
C.4.10.  CBLI provided a copy of company’s Code of Business Ethics and Conduct
as a Final Proposal Revision submission.
 
 
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