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Exhibit 10.11
SUPPLY AND DISTRIBUTION AGREEMENT: INVESTIGATIONAL PHASE
THIS AGREEMENT (the "AGREEMENT") is entered into by and between
OMRIX
BIOPHARMACEUTICALS, LTD., an Israeli company (hereinafter,
"OMRIX"), and FFF
ENTERPRISES, INC., a United States ("US") corporation organized and
existing
under the laws of California (hereinafter, "FFF") together with
Omrix, the
"PARTIES" and each individually a "PARTY," as of December 21, 2005
(the
"EFFECTIVE DATE").
WHEREAS:
A. Omrix
manufactures Omrigam NF, a proprietary immune globulin
intravenous
(IGIV), which has not been cleared by the United States (US) Food
and Drug
Administration (FDA) for marketing in the US;
B. Omrix wishes
to obtain FDA approval of a Biologics License Application
(BLA) to market Omrigam NF in the US;
C. Omrix is the
sponsor of an active Investigational New Drug Application
(hereinafter "OMRIX IND") to use Omrigam NF in clinical trials of
patients
with
primary immune deficiency (hereinafter "CLINICAL TRIALS");
D. FFF is a
wholesale distributor of pharmaceutical products, including
IGIV
products, in the US and wishes to be the exclusive distributor of
Omrigam
NF
in the US;
E. FFF wishes to
take over sponsorship of the amended Omrix IND (referred to
as
the FFF IND);
F. FFF also
wishes to be responsible for conducting the Clinical Trials and
Omrix will use the data collected in the Clinical Trials to prepare
a
Biologics License Application ("BLA") to submit to the FDA under
Omrix's
name
to market Omrigam NF commercially in the US;
G. FFF wishes to
distribute Omrigam NF in the US under a TREATMENT PROTOCOL,
as
defined below, until the BLA is approved by the FDA;
H. FFF will
conduct both the Clinical Trials and the Treatment Protocol
under
the
FFF IND ;
I. Omrix wishes
to supply Omrigam NF exclusively to FFF for use in the
Clinical Trials and under a Treatment Protocol (collectively
the
"INVESTIGATIONAL PHASE");
J. Omrix wishes
to designate FFF as its exclusive authorized distributor to
market Omrigam NF in the US subsequent to FDA approval of the BLA
for
Omrigam NF (the "COMMERCIAL PHASE," as defined in section 1.5,
below); and
K. Simultaneous
execution of the agreement between the Parties for the
Commercial Phase, SUPPLY AND DISTRIBUTION AGREEMENT: COMMERCIAL
PHASE,
attached hereto as Exhibit A) is a concurrent condition to the
complete
execution of this Agreement:
NOW, THEREFORE, in consideration of the mutual promises and
covenants contained
herein, effective upon the Effective Date, the Parties agree as
follows:
1.
DEFINITIONS
As used in this Agreement the following definitions shall apply in
each case
where the defined term appears in capitalized form:
1.1.
"BLA" - means a Biologics License Application, as defined in 21
CFR
Section 601.2.
FFF - Omrix Agreement: Investigational Phase
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PORTIONS OF THIS EXHIBIT MARKED BY AN *** HAVE BEEN OMITTED
PURSUANT TO A
REQUEST FOR CONFIDENTIAL TREATMENT FILED SEPARATELY WITH THE
SECURITIES AND
EXCHANGE COMMISSION.
<PAGE>
1.2.
"CFR" - means the U.S. Code of Federal Regulations, as may be
amended
from time to time, and any successor thereto.
1.3.
"CGMP" - means current Good Manufacturing Practices and General
Biological Products Standards as defined in 21 CFR Parts 210, 211
and
600 and 606.
1.4. "CLINICAL TRIALS"
- means the Phase 2 and the Phase 3 Clinical Trials,
as defined below.
1.5.
"COMMERCIAL PHASE" - means the phase of a relationship between
the
Parties after FDA approval of a Biologics License Application has
been
obtained and Omrigam NF may be marketed in the U.S. The
agreement
between the Parties for FFF to be the exclusive distributor of
Omrigam
NF for the Commercial Phase is attached hereto as Exhibit A
(SUPPLY
AND DISTRIBUTION AGREEMENT: COMMERCIAL PHASE).
1.6.
"DATA" - means data collected in the Clinical Trials.
1.7.
"DCI" - means DCI Management Group, LLC.
1.8.
"DCI CONTRACT" - means the Plasma Supply Agreement between Omrix
and
DCI Management Group, LLC, attached hereto as Exhibit B, execution
of
which is a condition precedent to this Agreement.
1.9.
"FDA" - means the US Food and Drug Administration.
1.10. "FFF IND" -- means the Investigational New Drug Application
approved
by the FDA and held by FFF for Omrigam NF. This is the amended
version
of the Omrix IND
1.11. "IGIV" - means immune globulin intravenous.
1.12. "IND" - means an Investigational New Drug Application, as
described
in 21 CFR Part 312.
1.13. "INSTITUTIONAL REVIEW BOARD" (IRB) - means the committee
responsible
for reviewing and approving biomedical research involving human
subjects, as described in 21 CFR 50.3(i).
1.14. "INVESTIGATIONAL DRUG" - means cGMP quality Omrigam NF prior
to
approval by the FDA of a Biologics License Application.
1.15. "INVESTIGATIONAL PHASE" - means the phase of the relationship
between
the Parties described in this Agreement, which covers exclusive use
by
FFF and its agents of Omrigam NF in Clinical Trials and
exclusive
distribution by FFF of Omrigam NF under a Treatment Protocol,
providing a Treatment Protocol is approved by the FDA.
1.16. "INVESTIGATOR" - means an individual who actually conducts a
clinical
investigation (i.e., under whose immediate direction the drug
is
administered or dispensed to a subject), as defined in 21 CFR
Section
312.3. In a team of investigators, the Investigator is the leader
of
the team. A licensed practitioner who receives and dispenses
the
Investigational Drug under a Treatment Protocol is an Investigator,
in
accordance with 21 CFR Section 312.35(a)(3).
1.17. "MANUFACTURING SPECIFICATIONS" - means the specifications in
the
Omrix IND, as amended from time to time, for compliance with
cGMP
standards and specifications for the chemistry, manufacturing
and
quality control, labeling, packaging and shipping of the
Investigational Drug.
1.18. "OMRIX IND" - means the Investigational New Drug
Application
submitted to the FDA by Omrix in 2001 and held by Omrix for
Omrigam
NF, until amended in December 2005 -- the amended IND is the FFF
IND.
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1.19. "OMRIGAM NF" - means Omrix's proprietary polyvalent IGIV.
1.20. "OMRIX TECHNOLOGY" - means all the technical information,
whether
tangible or intangible, including (without limitation) any and
all
data, techniques, discoveries, inventions, processes,
formulations,
know-how, patents (including any divisional, continuation,
extension,
reissue, reexamination certificate, or renewal patents), patent
applications, inventor certificates, trade secrets, method of
production and other proprietary information, that Omrix has rights
to
(as either owner, licensee or sublicense), or may hereafter
obtain
rights to, relating to Omrigam NF.
1.21. "PHASE 2 CLINICAL TRIAL" - means a Phase 2 clinical trial
conducted
by FFF or its agents in which the safety and efficacy of the
Investigational Drug are evaluated in up to five (5) human
patients
with primary immune deficiency for the purpose of obtaining
approval
from the FDA of a Biologics License Application and a Treatment
Protocol.
1.22. "PHASE 3 CLINICAL TRIAL" - means a Phase 3 clinical trial
conducted
by FFF or its agents in which the safety and efficacy of the
Investigational Drug are evaluated in up to fifty (50) human
patients
with primary immune deficiency for the purpose of obtaining
approval
from the FDA of a Biologics License Application and a Treatment
Protocol.
1.23. "REGULATORY FILINGS" - means any document required under the
US
Federal Food, Drug and Cosmetics Act and associated regulations
in
Title 21 of the CFR.
1.24. "SPONSOR" - means the same as in 21 CFR Section 312.3 and
refers to
the entity that holds the IND for the investigational drug. The
Sponsor is responsible for compliance with all sponsor
responsibilities set forth in 21 CFR Part 312. FFF is the Sponsor
of
the FFF IND, as defined in Section 1.10, above.
1.25. "TAXES" - means all taxes associated with the distribution,
sale and
delivery
of Omrigam NF, including but not limited to sales, use,
excise, withholding, value-added and similar taxes and all
customs,
duties or other governmental impositions, but excluding taxes
calculated on Omrix's net income.
1.26. "TREATMENT PROTOCOL" - under this Agreement means a
treatment
protocol ("TREATMENT PROTOCOL"), as described in 21 CFR Section
312.35(a), that will be submitted by FFF under the FFF IND to use
the
Investigational Drug to treat US patients with primary immune
deficiency and other immune diseases who are not enrolled as
subjects
in the Clinical Trials. The FDA may approve a Treatment Protocol
as
early as during a Phase 2 clinical trial (21 CFR Section
312.34(a)).
Under a Treatment Protocol, the Investigational Drug may be
distributed to a specified group of physicians, who function as
Investigators, and who may provide the Investigational Drug to
patients in accordance with applicable informed consent (21 CFR
Part
50) and Institutional Review Board (21 CFR Part 56) requirements.
In
contrast to use in the Clinical Trials, the Parties may charge for
the
use of the Investigational Drug under a Treatment Protocol
under
conditions specified in 21 CFR Section 312.7(d)(2).
1.27. "TREATMENT PROTOCOL CHARGE PRICE" - means the price
authorizedby the
FDA under 21 CFR Section 312.7(d)(2) to charge patients or
their
insurance for the Investigational Drug provided to patients under
the
Treatment Protocol.
1.28. "TREATMENT PROTOCOL PURCHASE PRICE" - means the price FFF
shall pay
Omrix for the Investigational Drug that will be provided to
patients
under the Treatment Protocol.
2.
INVESTIGATIONAL DRUG
2.1.
Omrigam NF. The Investigational Drug under this Agreement is
Omrigam
NF, which may be used in the US only in the Clinical Trials and
under
a Treatment Protocol, prior to approval by
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the FDA of a Biologics License Application. Omrix is and remains
under
this Agreement the exclusive owner of Omrigam NF.
2.2.
Regulatory Status. The Investigational Drug is a biologic for which
a
BLA has not yet been submitted to the FDA to obtain approval to
market
the product in the US. FFF will be the sponsor of an amended IND
for
the Investigational Drug (i.e., the FFF IND). The Parties'
intent
under this Agreement is for FFF to use data collected in the
Clinical
Trials to prepare a BLA that Omrix will submit to the FDA for
approval
to
market Omrigam NF in the US in the Commercial Phase, as defined
in
section 1.5, above, and in accordance with section 3, below.
2.3.
Quality Standards and Rejections.
a. Quality
Standards. Omrix shall be responsible for supplying all
Investigational Drug used under this Agreement in compliance
with
cGMP standards, the specifications in the Omrix IND for the
chemistry, manufacturing and quality control and all applicable
FDA requirements set forth in 21 CFR Part 312 for labeling,
packaging and shipping of investigational drugs (hereafter
collectively "MANUFACTURING SPECIFICATIONS").
b. Change in
Manufacturing Specifications. Omrix will advise FFF in
writing of any proposed modifications to the Manufacturing
Specifications prior to implementation. Omrix will only
implement
the modified Manufacturing Specifications after submitting to
the
FDA (through FFF) an information amendment to supplement the
IND,
if necessary under 21 CFR 312.23.
c. Rejections.
FFF shall have the right to return to Omrix any
Investigational Drug FFF that upon receipt from Omrix does not
comply with Omrix's Manufacturing Specifications. FFF shall
have
ten (10) calendar days ("Inspection Period") from receipt of a
shipment to perform a visual inspection for damage to the
packaging or immediate container and to reject any damaged
Investigational Drug in the shipment. FFF must send a written
rejection notice to Omrix within the ten (10) day Inspection
Period and must detail the basis for the rejection. FFF shall
return any damaged units of Investigational Drug to Omrix.
Omrix
shall replace any rejected and returned damaged units of
Investigational Drug without cost to FFF providing that the
damage was not sustained after receipt of the Investigational
Drug by FFF. If FFF does not deliver written notice to Omrix
within the applicable Inspection Period of receipt of a
shipment
that FFF rejects such shipment because of non-compliance, FFF
will be deemed to have accepted the shipment. If after an
inquiry
by Omrix it will be determined that any rejection was made in
error, FFF will bear
all costs associated with making such
determination and will immediately pay Omrix the above cost
together with any unpaid sum relating to the alleged
non-complying Investigational Drug, and any other cost incurred
by Omrix in connection with the alleged non-compliance.
2.4.
Investigational Use. The Investigational Drug may be used under
this
Agreement in the US only in the Clinical Trials and under a
Treatment
Protocol, in compliance with all applicable FDA regulations and
approvals and in accordance with this Agreement.
2.5.
Supply and Purchase Commitments.
a. Omrix shall
supply all Investigational Drug necessary for timely
completion of the Clinical Trials and as needed to meet demand
under the Treatment Protocol, subject to the supply of
recovered
plasma volume provided to Omrix under the DCI Contract.
b. Omrix agrees
to sell to FFF and FFF shall purchase all
Investigational Drug produced by Omrix from recovered plasma
purchased pursuant to the DCI Contract provided, however, that
under no circumstances shall FFF be responsible for purchasing
more than *** of the Investigational Drug in any calendar year
unless Omrix has obtained prior written approval of FFF to
purchase such additional
FFF - Omrix Agreement: Investigational Phase
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amounts. Notwithstanding the foregoing, during any partial
calendar year under this Agreement, the number of grams of
Investigational Drug which FFF shall be required to purchase
shall be a pro rata amount based on the actual number of days
during such calendar year in which this Agreement is in force
and
during which the Treatment Protocol is approved and effective.
c. Omrix shall
assure that the Investigational Drug is shipped with
the statement, "Caution: New Drug - Limited by United States
law
to investigational use," on the package label as required by 21
CFR Section 312.6.
2.6.
Exclusive Distributor. FFF shall be the exclusive distributor of
the
Investigational Drug in the US.
2.7.
Handling Specifications. FFF shall be responsible for assuring
that
the Investigational Drug is handled by FFF, Investigators, and
FFF's
agents and subcontractors according to Omrix's specifications
set
forth in the FFF IND for the handling, storage, use, transport
and
general possession of Omrigam NF ("HANDLING SPECIFICATIONS").
FFF
shall be responsible for maintaining accurate and current
records
regarding handling, storage and transport of the Investigational
Drug
for review by Omrix and the FDA or other regulatory agencies.
2.8.
Unused Investigational Drug. All unused quantities of
Investigational
Drug that have been provided to FFF under this Agreement for use
in
the Clinical Trials shall be destroyed by FFF, or, at Omrix's
option,
returned to Omrix, at Omrix's cost, upon any of the following
events:
i) the conclusion or termination of the Clinical Trials; ii) the
IND
or Treatment Protocol is placed on clinical hold by the FDA under
21
CFR Section 312.34(d) and Section 312.42 for in excess of six
(6)
months unless otherwise agreed by the Parties; iii) upon approval
of a
BLA for Omrigam NF; or iv) upon termination of this Agreement.
FFF
shall be responsible for assuring that Investigators return all
unused
Investigational Drug to FFF for destruction or return to Omrix,
as
applicable.
2.9.
DCI Contract. The Parties recognize that Omrix has entered into
a
5-year supply agreement with DCI (the "DCI Contract") that is
necessary for Omrix to provide Investigational Drug to FFF for
use
under this Agreement. If this Agreement is terminated under
Sections
15.2.b, 15.2.c, 15.3.a, 15.3.c or 15.3.d, then the Parties agree
to
share equally any loss incurred or profit realized by Omrix under
the
DCI Contract, provided, however, that FFF shall not be responsible
for
any loss based on DCI providing Omrix with more than *** liters
of
recovered plasma per calendar year unless Omrix has obtained
FFF's
prior written agreement that FFF will bear responsibility for
such
loss. If this Agreement is so terminated as set forth in the
previous
sentence, Omrix will make commercially reasonable efforts to
resell
such plasma and FFF agrees to be responsible to Omrix for an
amount
equal to *** of the difference, if any, that the price Omrix pays
for
such plasma is greater than the price that Omrix receives upon
a
resale of such plasma *** and Omrix agrees to pay FFF an amount
equal
to *** of the difference, if any, that the price Omrix pays for
such
plasma is less than the price that Omrix receives upon a resale
of
such plasma ***. Accordingly, FFF shall pay to Omrix fifty
percent
(50%) of the amount due by Omrix under the DCI Contract at least
five
(5) business days prior to the date that Omrix is due to pay
such
amounts to DCI, and Omrix shall reimburse FFF such amount, less
the
*** (or plus ***),if any, upon receipt of payment by a third
party
for the plasma. For the purposes of this Section 2.9, the amount
that
Omrix receives upon a resale shall be calculated net of all
taxes,
shipping and other associated out of pocket expenses incurred
by
Omrix in the resale of the plasma. Alternatively, if Omrix
assigns
the DCI Contract, or agrees with DCI on a termination fee, or
enters
into any other arrangement for disposal of the DCI Contract, then
FFF
agrees to reimburse Omrix for *** of any cost or loss incurred
by
Omrix resulting from entering into any such arrangement,
provided
that such arrangement has been approved by FFF in advance and
Omrix
agrees to pay FFF *** of any profit realized by Omrix resultin
from
entering into any such arrangement. In addition, if this Agreement
is
terminated by Omrix under Section 15.2.a or 15.2.d, or by FFF
under
Section 15.3.e, FFF shall
FFF - Omrix Agreement: Investigational Phase
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be responsible for all amounts committed by Omrix in connection
with
the DCI Contract; provided, however, that if Omrix requires FFF
to
bear such costs in connection with such contract, FFF will have
the
option to have the DCI Contract assigned to FFF, subject to the
approval of DCI, and Omrix shall have no obligations or
liability
after such assignment. This Section 2.9 shall survive termination
of
this Agreement. If Omrix enters into any other long term supply
agreements for recovered plasma during the Term, which are approved
by
FFF in writing, then each party's responsibilities under such
agreements will be treated in the same manner as described in
this
Section regarding the DCI Contract.
2.10. Payments to Fund Expansion. FFF shall pay to Omrix
non-refundable
payments aggregating to ***, which Omrix will apply to expansion
of
Omrix's capacity to manufacture Omrigam NF. Notwithstanding the
foregoing, Omrix will refund this amount to FFF only if the
Agreement
is terminated under Section 15.2.b or 15.3.e (as regards the
Treatment
Protocol Charge Price), to the extent such amount has not been
expended on such expansion. These payments will be made in six
(6)
equal monthly installments of *** each. In the event the FDA
approves
the use of the Investigational Drug in the Treatment Protocol for
the
primary immune deficiency, ITP, CLL. BMT, pediatric HIV and
Kawasaki's
Disease disease states, the first payment will commence ninety
(90)
days after the Treatment Protocol is approved by the FDA. In the
event
the FDA approves the use of the Investigational Drug in the
Treatment
Protocol for the foregoing six (6) disease states and also for
the
CIDP, GBS and Myasthenia Gravis neurological disorders, then the
first
payment will instead commence thirty (30) days after the
Treatment
Protocol is approved by the FDA.
3. COMMERCIAL
PHASE
3.1.
Post-FDA Approval. The Commercial Phase means the phase of the
relationship between the Parties after FDA approval of a
Biologics
License Application has been obtained and Omrigam NF may be
marketed
in the US.
3.2.
Exclusive Distributor. The terms and conditions between the
Parties
for the Commercial Phase are set forth in the agreement, SUPPLY
AND
DISTRIBUTION AGREEMENT: COMMERCIAL PHASE ("COMMERCIAL PHASE
AGREEMENT"), attached hereto as Exhibit A. Under the Commercial
Phase
Agreement, FFF shall be the exclusive distributor of Omrigam NF in
the
US.
3.3.
Commercial Phase Agreement. Execution of the Commercial Phase
Agreement is a concurrent condition of execution of this
Agreement.
4. CLINICAL
TRIALS
4.1.
General Responsibilities.
a. FFF. FFF will
be the sponsor of the Clinical Trials under the FFF
IND, as defined in section 1.10, above. FFF shall be
responsible,
at its own
cost, for conducting the Clinical Trials through a
qualified Contract Research Organization (CRO). FFF will be the
exclusive contact with the FDA on all matters related to the
FFF
IND, the Clinical Trials and the Treatment Protocol. FFF shall
use its best reasonable efforts to conduct the Clinical Trials
in
a timely manner and in accordance with this Agreement, the
approved protocol for the individual Clinical Trial and all
applicable federal, state and local regulatory requirements.
FFF
shall keep Omrix informed in a timely manner of all regulatory
issues, the conduct of the Clinical Trials and use of the
Investigational Drug under the Treatment Protocol and will
obtain
Omrix's approval prior to all regulatory decisions.
b. Omrix. Omrix
shall use its best reasonable efforts to work
collaboratively and in a timely manner with FFF in meeting all
regulatory requirements related to the FFF IND, including
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without limitation providing information requested by FFF for
use
in correspondence with the FDA related to the Clinical Trials.
4.2.
FFF Responsibilities.
a. Sponsor's
Obligations. FFF shall be responsible for assuring that
all Sponsor obligations under 21 CFR Part 312 are met either by
FFF or as delegated by FFF to the CRO.
b. Contract
Research Organization. FFF shall be responsible for
selecting and hiring a CRO to conduct the Clinical Trials,
within
thirty (30) days of notice from the FDA of approval of the FFF
IND. FFF shall be responsible for overseeing and paying the CRO
to conduct the Clinical Trials.
c. Clinical
Trials. FFF shall contract with the CRO to conduct the
following Clinical Trials:
1. Phase 2
Clinical Trial. Immediately upon hiring the CRO and
obtaining all necessary regulatory approvals from the FDA
and the IRB, the CRO shall initiate a Phase 2 Clinical Trial
with qualified Investigators in which the safety and
efficacy of the Investigational Drug will be evaluated in
five (5) or fewer patients with primary immune deficiency.
FFF and Omrix shall work closely with the CRO in preparing
detailed protocols for the Phase 2 Clinical Trial as needed
to obtain FDA clearance.
2. Phase 3 Clinical Trial. Upon
conclusion of the Phase 2
Clinical Trial and obtaining all necessary regulatory
approvals from the FDA and the IRB, the CRO shall initiate a
Phase 3 Clinical Trial with qualified Investigators in which
the safety and efficacy of the Investigational Drug will be
evaluated in fifty (50) or fewer patients with primary
immune deficiency. FFF and Omrix shall work closely with the
CRO in preparing detailed protocols for the Phase 3 Clinical
Trial as needed to obtain FDA clearance.
d. Protection of
Human Subjects. FFF shall be responsible for
assuring that the Clinical Trials are conducted in compliance
with all applicable FDA regulations protecting human subjects
as
set forth in 21 CFR Parts 50 and 56. FFF shall assure that no
subject will receive the Investigational Drug until the
Investigator's IRB has obtained IRB approval of the Clinical
Trial protocol and informed consent form, the subject has been
fully informed of the risks and benefits of participating in
the
Clinical Trial and the subject has signed the approved informed
consent form.
e. Regulatory
Compliance. FFF shall be responsible for assuring that
the Clinical Trials are conducted in compliance with all
applicable FDA regulations, including without limitation the
following:
1. Compliance
with Good Clinical Practices ("GCPS"), prudent
research practices and the IRB-approved protocol for the
individual Clinical Trial.
2. Compliance
with the Health Insurance Portability and
Accountability Act of 1996, as codified at 42 USC Section
1320d ("HIPAA") and its implementing regulations, including
without limitation 45 CFR Parts 160 and 164 ("the Privacy
Regulations") and 45 CFR Parts 142 (the "Security
Regulations"), collectively the "HIPAA REQUIREMENTS." FFF
shall assure compliance with applicable HIPAA Requirements
for obtaining and disclosing protected health information
("PHI"), as that term is defined in 45 CFR Section 164.501,
in
the Clinical Trials.
3. The CRO shall
not retain, employ or involve any person in
conducting the Clinical Trials if such person is (i)
debarred by the FDA under 21 USC 335a; (ii) the subject of a
disqualification proceeding or is disqualified as a clinical
investigator pursuant to 21 CFR.
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Section 312.70; or (iii) has been excluded from
participation in any federal health care program pursuant to
Title XI of the Social Security Act.
4. FFF shall be
responsible for obtaining from all
Investigators information regarding financial interests as
necessary for Omrix to comply with any disclosure
requirements to the FDA under 21 CFR Part 54.
f.
Investigator's Brochure. FFF shall be responsible for assuring
that all Investigators receive a copy of the Investigator's
Brochure as required under 21 CFR Section 312.55(a).
g. Safety
Information. FFF shall be responsible for assuring that
safety information regarding life-threatening, serious and/or
unexpected adverse drug experiences is collected during the
Clinical Trials as required under 21 CFR Section 312.32 and in
accordance with FDA guidance published November 30, 2005. FFF
shall promptly provide to Omrix written reports of any and all
such adverse drug experiences for Omrix's review and
evaluation.
FFF shall notify Omrix immediately by telephone of any
unexpected
or life-threatening adverse event associated with use of the
Investigational Drug. FFF shall be responsible for
investigating
all safety information it receives and following-up as
appropriate under 21 CFR Section 312.32(d). FFF shall be
responsible for preparing and submitting written IND safety
reports as required under 21 CFR Section 312.32(c) on all
serious
and unexpected adverse drug experiences to the FDA as soon as
possible but not later than fifteen (15) calendar days of
receiving notice of such experiences. FFF shall be responsible
for notifying the FDA of any unexpected fatal or
life-threatening
drug experience by telephone or facsimile as soon as possible
but
not later than seven (7) calendar days of receiving information
about such experiences.
h. Distribution
and Disposition Investigational Drug. FFF shall be
responsible for assuring that the Investigational Drug is
distributed only to qualified Investigators for use in the
Clinical Trials in accordance with the approved protocol. FFF
shall assure that any and all unused quantities of the
Investigational Drug dispensed to Investigators for use in the
Clinical Trials are returned by Investigators to FFF and
disposed
of by FFF in accordance with section 2.8, above. FFF shall
maintain complete, accurate and current records of the
disposition of all Investigational Drug as required under 21
CFR
Section 312.59 and provide such records to Omrix at the
conclusion of the Clinical Trials.
i. IND
Information. FFF shall provide to Omrix the complete FFF IND
and copies of any amendments to the IND at least twenty-four
(24)
hours
prior to submission to the FDA.
j. Maintain FFF
IND. FFF shall be responsible for complying with all
regulatory requirements necessary to maintain the FFF IND and
providing the FDA with any supplemental information to amend
the
IND as required under 21 CFR Section 312.31.
k. Reports and
Records. FFF shall be primarily responsible for
preparing all FDA required reports and records in consultation
with Omrix. FFF shall submit all required reports to the FDA.
FFF
shall maintain all FDA required records for two (2) years after
approval of the BLA as required under 21 CFR Section 312.57(c)
or
two (2) years after termination of this Agreement, whichever
occurs earlier.
4.3.
Omrix Responsibilities.
a. Supply
Investigational Drug. Omrix shall supply to FFF all
Investigational Drug necessary for the Clinical Trials at its
expense and free of charge, subject to volumes of recovered
plasma provided to Omrix under the DCI Contract. Omrix shall
provide the Investigational Drug in compliance with all
applicable FDA requirements for labeling, packaging and
shipping
of investigational drugs set forth in 21 CFR Part 312. Such
packaging shall include all materials needed to infuse the
Investigational Drug or placebo.
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b. Maintenance
of FFF IND. Omrix shall cooperate with FFF in
complying with all regulatory requirements necessary to
maintain
the FFF IND as far as such requirements relate to the
manufacturing, labeling and shipping of the Investigational
Drug
and providing FFF with any supplemental information needed to
amend the IND as required under 21 CFR Section 312.31.
c. Records. FFF
and Omrix shall maintain adequate records of
shipments of Investigational Drug, as required under 21 CFR
Section 312.57(a) including the recipient, date, quantity, and
batch or code mark of each shipment.
d. Safety
Information. Omrix shall review and evaluate all safety
information received from FFF and provide timely feedback to
FFF
to allow FFF to comply with its safety reporting obligations as
described in section 4.2.g, above. Omrix shall cooperate with
FFF
in investigating all serious adverse events associated with use
of the Investigational Drug, as required under 21 CFR Section
312.32(d).
e. Reports.
Omrix shall cooperate with FFF as needed to prepare all
reports required by the FDA to assure timely submission of
complete and accurate reports.
4.4.
Data. FFF shall own all data generated in the Clinical Trials.
The
Parties shall consult with each other in the interpretation of
the
data. FFF shall maintain the data as needed to prepare reports
and
maintain records required under 21 CFR Part 312 and Omrix will use
the
data to prepare the BLA. FFF shall provide Omrix with copies of
all
data generated in the Clinical Trials on a regular basis, and, in
any
case, no less frequently than quarterly. Upon termination of
this
Agreement, Omrix shall cease to use all data provided to Omrix by
FFF
pursuant to this section 4.4 unless FFF agrees otherwise in writing
or
until the transfer of the data from FFF to Omrix in accordance
with
section 15.4 of this Agreement.
5. TREATMENT
PROTOCOL
5.1.
FFF Responsibilities.
a. Treatment
Protocol. FFF shall be responsible for obtaining a
Treatment Protocol, as defined in section 1.26, under the FFF
IND
and in accordance with the provisions of this section 5.1.
1. Treatment
Protocol. FFF shall prepare a treatment protocol
("Treatment Protocol") in consultation with and information
provided by Omrix and in accordance with 21 CFR Section
312.35(a) to use the Investigational Drug to treat patients
with primary immune deficiency who are not enrolled as
subjects in the Clinical Trials. FFF has been engaged in
discussions with the FDA regarding the Treatment Protocol
and shall continue to be responsible for negotiating the
terms of the Treatment Protocol with the FDA. FFF shall
prepare the Treatment Protocol in time for FFF to submit it
to the FDA immediately after initiation of the Phase 2
Clinical Trial with the goal of obtaining approval during or
immediately after the conclusion of the Phase 2 Clinical
Trial. FFF shall be the sponsor of the Treatment Protocol
and shall submit the Treatment Protocol to the FDA under the
FFF IND. In addition, FFF will provide Omrix with an
electronic copy of the packaging material which will be used
in the Treatment Protocol consistent with all FDA
requirements.
2. Approval of
the Treatment Protocol. The Treatment Protocol
shall be deemed approved thirty (30) days after the date the
FDA receives the Treatment Protocol unless the FDA either:
(a) provides earlier notification that treatment use of the
Investigational Drug may begin or (b) places the Treatment
Protocol on clinical hold under 21 CFR Section 312.34(d). If
no communication has been received from the FDA within forty
(40) days of submission of the Treatment Protocol, Omrix and
FFF shall confirm with the FDA that treatment use of the
Investigational Drug may begin.
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b. Contract
Research Organization. FFF shall be responsible for
selecting and hiring a CRO or equivalent within thirty (30)
days
of approval of the Treatment Protocol, as defined in Section
5.1.a.2, above, to implement the Treatment Protocol, including
without limitation selecting qualified physicians as
Investigators, obtaining approval as needed by local IRBs,
assuring patients who receive the Investigational Drug have
been
fully informed of the risks and benefits and have signed an IRB
approved informed consent form.
c. Distribution
and Disposition of Investigational Drug. FFF shall
be the exclusive distributor of the Investigational Drug under
the Treatment Protocol. FFF shall assure that the Investiga
