CLINICAL TRIAL SERVICES AGREEMENT

This Agreement is effective October 4, 2011 (“Effective Date”) by and between:

Harvard Clinical Research Institute, Inc. (“HCRI”)
930 Commonwealth Avenue
Boston, Massachusetts 02215

and

InspireMDLtd. (“InspireMD”)
3 Menorat Hamor St.
Tel Aviv, Israel

“MGuard Stent System Clinical Trial in
Patients with Acute Myocardial Infarction”
 
 
 
 
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WHEREAS, InspireMD (“Sponsor”) desires to engage HCRI for the purpose of
providing Clinical Trial Services, as defined in Exhibit A to this Agreement,
which will serve as the Scope of Work and budget for the Agreement, for the
protocol for the “MGuard Stent System Clinical Trial in Patients with Acute
Myocardial Infarction” Study, which shall be developed by HCRI under a separate
consulting agreement, with such Protocol being incorporated by reference; and
 
WHEREAS, HCRI and its professionals have experience in the development and
administration of clinical trials of various Investigational Products; and
 
WHEREAS, the parties hereto deem it to be in their individual and mutual best
interest to set forth the terms and conditions of their relationship herein; and
 
NOW, THEREFORE, in consideration of the mutual covenants and promises herein
contained, HCRI and Sponsor agree as follows:
 
1.
Definitions.

 
 
·
“Clinical Sites” shall mean the hospitals and other medical institutions that
are participating as clinical study sites in the Trial.

 
 
·
“Clinical Trial Data” shall mean data provided to HCRI by the Clinical Sites
during the Trial and may include, but shall not be limited to, information
contained in case report forms, core laboratory data, if any, and clinical
laboratory data, if any.

 
 
·
“Clinical Trial Services” shall mean the Services described in Exhibit A to this
Agreement, which shall serve as the Scope of Work and budget for this Agreement.

 
 
·
“Investigational Product” shall mean the device, pharmaceutical, or
biopharmaceutical product under investigation for the Trial.

 
 
·
“Pre-Existing Intellectual Property” means all proprietary rights, including
inventions, patents, patent applications, registered or unregisterd copyrights
and works of authorship (whether or not published), trade secrets and other
proprietary information relating to the Investigational Product and owned or
licensed by Sponsor.

 
 
·
“Principal Investigators” shall mean collectively the investigator who functions
as overall principal investigator for the Trial and the investigators who
function as principal investigators at the Clinical Sites.

 
 
·
“Protocol” shall mean the investigational plan developed by HCRI and approved by
Sponsor pursuant to the parties’ consulting agreement for performing the Trial.

 
 
·
“Study” or “Trial” shall mean the clinical trial described in the Protocol.

 
 
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2.
Sponsor Liaison.

 
Sponsor shall designate a person who shall be Sponsor’s primary liaison (the
“Liaison”) with HCRI for all purposes pursuant to this Agreement.  The Liaison’s
duties shall include responding promptly and fully to all reasonable requests
from HCRI.  The Liaison may consult informally with HCRI’s representatives, both
in person and by telephone, regarding the Trial.  All notices and approvals to
be made by Sponsor pursuant to this Agreement shall be made by or through the
Liaison, in accordance with Section 18(f) (“Notices”), and HCRI shall be
entitled to look solely to the Liaison for such notices and
approvals.  The Liaison shall be Eli Bar, Vice President of Research and
Development.
 
3.
Primacy of Health Care Mission.

 
Sponsor acknowledges that the primary mission of HCRI is health care, education
and the advancement of knowledge and, consequently, all Clinical Trial Services,
(described in Exhibit A), provided by HCRI under this Agreement shall be
performed in a manner best suited to carry out that mission.  Furthermore, HCRI
does not guarantee specific results of the Trial.
 
4.
Data Ownership.

 
Sponsor shall have exclusive ownership rights to the Clinical Trial Data, as
well as to the content of analyses and reports relating to the Trial which are
delivered to Sponsor by HCRI.  Sponsor shall be free to use the Clinical Trial
Data and the content of such analyses and reports for its own business purposes,
provided however that Sponsor agrees that it shall be solely liable for the
content of the analyses or reports if it changes or otherwise modifies
such analyses or reports in any way at any time from the form in which they were
delivered to Sponsor.  HCRI shall own all rights to the procedures,
methodologies, computer programs, analytic tools, work papers, and know-how used
and/or generated by HCRI in conducting such analyses relating to the Trial
(collectively, “HCRI Know-How”).  Sponsor agrees not to reproduce and/or
disseminate such HCRI Know-How for its benefit or the benefit of any third
party.
 
 
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5.
Compensation.

 
 
a.
Compensation and Payment. In consideration for its services which shall be
performed in a workmanlike manner in accordance with industry good practice
standards, HCRI will receive remuneration equal to an estimated fee of
$$6,994,456 USD, as detailed in Exhibit A. Additional costs described in Exhibit
A as “TBD” shall be agreed to in writing by the parties prior to being
incurred.  Sponsor and HCRI expressly agree that such fee represents an estimate
arrived upon in good faith and based on the parties’ mutual understanding of the
Scope of Work at the outset of this Agreement. Notwithstanding the conditions of
Section 5(b) regarding changes in scope, it is hereby agreed that Sponsor shall
not be required or obligated to pay any amount exceeding the aforesaid estimated
amount including costs set forth in this Agreement unless agreed upon in writing
between the parties and signed by their authorized signatory persons. This
estimated fee will be invoiced according to the payment schedule provided in
Exhibit B. Sponsor agrees to pay each undisputed invoice upon receipt.  To the
extent there is no good faith dispute as to the validity of the invoice,
accounts not paid within forty-five (45) days of receipt thereof will be
considered overdue.  Overdue accounts will be charged 0.5% of the amount
outstanding for each month that the invoice remains unpaid.  Sponsor shall
inform HCRI in writing of any disputed amounts invoiced within forty-five (45)
days of receipt of invoice. Sponsor shall communicate such objection in a timely
manner to HCRI after its discovery. Failure to inform HCRI as aforesaid shall
not prejudice any of Sponsor's rights to disagree to any invoice at any time
subject to statute of limitation.

 
 
b.
Changes in Scope.  Amounts paid by Sponsor under this Section 5 may be increased
if the Scope of Work detailed in Exhibit A changes and if such amount increases
the total contract value set forth above by more than $100,000 it should be pre
approved in writing by Sponsor. If changes in scope are required, a Contract
Change Order describing the modification to the Scope of Work and detailing the
associated adjustment to the project costs will be issued by HCRI and agreed to
in writing and signed by HCRI and Sponsor as soon as practicable.  If requested
by Sponsor in writing, or required by circumstances beyond either party’s
control, HCRI may continue performing services outside the Scope of Work
(provided that the charge for such services shall not increase the total costs
described in Exhibit A by more than $100,000 without Sponsor's written
pre-approval) prior to the parties’ execution of a Contract Change Order if
interruption of performance would delay the Study or delivery of the Services
contained in Exhibit A. Sponsor acknowledges that the timely continuation of
Services is contingent upon Sponsor’s prompt review and execution of proposed
Contract Change Orders. Additionally, Sponsor acknowledges that certain
adjustments to the estimated fee may be necessary during the term of this
Agreement along with a detailed explanation of same; provided that the charge
for such services shall not increase the total costs described in in Exhibit A
by more than $100,000 without Sponsor's written pre-approval.  HCRI shall
provide Sponsor with prompt notice of any adjustment deemed necessary.  Further,
the parties shall review and address any dispute relating to all such
adjustments.

 
6.
Sponsor Obligations and Representations.

 
 
a.
Representations Concerning the Investigational Product. Sponsor represents,
warrants and agrees that the Investigational Product will be produced in
accordance with all applicable laws and regulations.  Sponsor further
represents, warrants and agrees that appropriate federal and state government
authorization has been or will be obtained for the use of the Investigational
Product for the Trial.

 
 
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b.
Adverse Reactions.  Sponsor agrees that HCRI is not responsible for the costs of
diagnosis, care and treatment of any undesirable side effects, adverse
reactions, illness or injury to a participant in the Trial which result from
participation in the Trial, except to the extent such costs arise directly from
HCRI’s gross negligence or reckless or intentional misconduct.  This section is
not intended to create any third-party contractual benefit for any participants
or Clinical Sites in the Trial.

 
 
c.
Immediate Notification of Adverse Reactions.  Sponsor shall immediately transmit
to HCRI any information regarding any Serious Adverse Events associated with the
use of the Investigational Product.  HCRI shall immediately transmit to Sponsor,
or its designee, any information regarding previously unreported Serious Adverse
Events experienced by participants in the Trial.

 
7.
HCRI Obligations

 
 
a.
HCRI shall carry out the Clinical Trial Services in the highest professional
standards and in accordance with any law, regulation and rules including of the
respective ethic committee.

 
 
b.
In the event that HCRI receives a Notice of Inspection (a “Notice”) from a
regulatory agency which relates to the Project, HCRI shall:  (a) notify Sponsor
promptly of such Notice; (b) keep Sponsor informed of the progress of the
inspection; and (c) provide to Sponsor a copy of any documents produced to the
regulatory agency pursuant to such Notice.

 
 
c.
Sponsor’s authorized representatives may visit HCRI’s site and facilities at
reasonable times and with reasonable frequency during normal business hours and
upon reasonable advance written notice, to observe the progress of the Clinical
Trial Services.  All such visits shall be subject to HCRI’s restrictions and
procedures relating to safety, security and protection of Confidential
Information (as defined below), and in connection therewith, Sponsor’s
authorized representatives may be required to sign a confidentiality agreement,
or an access agreement for special access-controlled areas.  The terms of this
Section are not intended to govern audits.

 
8.
Confidentiality.

 
 
a.
Confidential Information Defined.  “Confidential Information” shall mean
information provided by the party disclosing information (“Disclosing Party”) to
the other party (“Recipient”) pursuant to this Agreement, or in anticipation
hereof, which is preferably marked “Confidential” when disclosed or is otherwise
treated as confidential by the Disclosing Party, except as excluded from this
definition in Section 8(b).  If not in tangible form, the Disclosing Party
agrees to identify such information as confidential when disclosed and make
reasonable efforts to confirm in writing the confidential nature of the
information within thirty (30) days of such disclosure.  Confidential
Information shall include any reports or documents created by the Recipient that
include, summarize, or refer to Confidential Information.  Examples of
Confidential Information include, but are not limited to, any information, data,
or know-how relating to the Disclosing Party’s business interests, products,
procedures, pharmaceutical or device development efforts, trade secrets,
information regarding marketing or pricing or vendors or suppliers, or other
technological information. It is hereby acknowledged that all Clinical Trial
Data and other materials prepared using the same or derived therefrom shall be
treated as Confidential Information, and treatment of same will be in accordance
with the Section entitled Publication.

 
 
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b.
Exclusions to Confidential Information.  Confidential Information shall not
include information or materials: (i) which was available to the public prior to
the disclosure by the Disclosing Party; (ii) which were not acquired directly or
indirectly from the Disclosing Party and which Recipient lawfully had in its
possession prior to the Effective Date of this Agreement or any underlying
confidentiality agreement between the parties, as demonstrated by proof in
Recipient’s records before the Effective Date; or (iii) which Recipient can
demonstrate was developed by or for Recipient independently of the disclosure of
Confidential Information by the Disclosing Party, as demonstrated by proof in
Recipient’s records.

 
 
c.
Obligations of the Recipient.  The Recipient of Confidential Information shall:
(i) receive, maintain, and hold the Confidential Information in strict
confidence and use at least the same level of care in protecting it that it uses
with its own confidential material of a similar nature, but in no event less
than reasonable care; (ii) take all reasonable steps necessary and appropriate
to verify that Recipient’s employees, subcontractors, officers, and/or agents
treat the Confidential Information as confidential and to verify that such
employees, subcontractors, officers, and/or agents are familiar with and abide
by the terms of this Agreement; and (iii) not utilize Confidential Information,
except as provided for herein, without first obtaining the Disclosing Party’s
written consent to such utilization.  All obligations under this Section shall
expire five (5) years after the termination of this Agreement.

 
 
d.
Permitted Disclosure.  Recipient may disclose Confidential Information only to
the extent required by law or order of a court of competent jurisdiction,
provided that Recipient promptly provide the Disclosing Party with advance
notice of such imminent disclosure and provide assistance in obtaining an order
to limit the scope of information being disclosed and to protect such
Confidential Information using its best efforts.  Such permitted disclosure
shall not otherwise negate the obligation for Recipient to maintain the
confidentiality of such information for any other purpose under this Agreement.

 
 
e.
Retention and Destruction.  At any time upon the request of the Disclosing
Party, Recipient shall return or destroy all Confidential Information in its
possession (and have an officer certify the scope of such return or
destruction), including copies, and/or any other form or reproduction and/or
description and/or analysis thereof made by Recipient.  However, Recipient
reserves the right to retain one (1) copy of such Confidential Information for
purposes of verifying the Confidential Information that was provided pursuant to
this Agreement.  Recipient shall, at minimum, retain such copy of the
Confidential Information in accordance with the time periods proscribed by
applicable law.

 
 
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f.
Limited Delivery of Sponsor Confidential Information.  The free dissemination of
information is an important policy of HCRI.  To minimize questions concerning
the confidentiality of disclosures, trade secrets, or proprietary data or
information, Sponsor agrees to limit to the extent possible the delivery of
Sponsor Confidential Information to HCRI.

 
9.
Publication; Publicity.

 
 
a
Publication.  In accordance with this subparagraph (a), HCRI shall have the
right to publish or otherwise publicly disclose the results of the Study and
other information gained in the course of this Agreement after the occurrence of
the first of the following: (i) Sponsor’s initial publication; (ii) written
notification from Sponsor that an initial publication is no longer planned;
(iii) one (1) year after termination of the Study or data lock.  Prior to any
publication, for a period of five (5) year following the date on which HCRI’s
right to publish arises, in the interest of protecting patent rights and Sponsor
Confidential Information, HCRI shall submit manuscripts, abstracts and similar
material generated by HCRI as a result of this Agreement (“Publications”) to an
independent publications committee, for review and comment at least forty-five
(45) days prior to the planned publication or disclosure date.  The independent
publications committee will include representation by HCRI, Sponsor, and
Principal Investigator(s).  The procedure of treatment of such publication shall
be determined by the publications committee. For purposes of publications
pursuant to this Section, the results of the Study and other information gained
in the course of this Agreement shall not be considered Sponsor’s Confidential
Information.

 
 
b
Publicity.  Neither party shall make any press release, presentation,
advertising, promotional sales literature, or other promotional oral or written
statements to the public that reference or allude to this Agreement, work
performed under this Agreement, or the parties hereto, without the other party’s
prior written consent.  HCRI shall, however, have the right to acknowledge
Sponsor’s support of the investigations under this Agreement in HCRI’s brochure,
web site, scientific publications, and other scientific communications. Sponsor
shall be entitled to list HCRI and acknowledge HCRI's services to Sponsor
hereunder at Sponsor's web site and other publications with notice to HCRI.

 
10.
Inventions.

 
HCRI acknowledges Sponsor’s ownership interest in all Pre-Existing Intellectual
Property in the Investigational Product.  HCRI agrees to take no action
inconsistent with Sponsor’s ownership of such Pre-Existing Intellectual
Property.
 
 
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HCRI hereby assigns, and agrees to assign, to Sponsor all right, title and
interest HCRI may have in any invention, technology, trade secrets or know-how,
data, information, works of authorship, indicia of sources, and other
intellectual property rights, and any goodwill associated with the foregoing,
resulting from HCRI’s provision of the Clinical Trial Services hereunder and
relating to the Investigational Product or to Sponsor’s Confidential Information
(“Sponsor Intellectual Property”), and HCRI agrees to assist Sponsor, at
Sponsor’s expense, in obtaining or extending protection thereto.  At Sponsor’s
request and expense, HCRI shall execute all necessary documents to effectuate
the assignment of any Sponsor Intellectual Property to Sponsor. Notwithstanding
the foregoing, and as further described in Section 4 (Data Ownership), all other
inventions or discoveries, innovations, suggestions or ideas (whether or not
patentable or copyrightable) made or developed by HCRI during the term of this
Agreement as a result of HCRI’s general knowledge and unrelated to the
Investigational Product or Sponsor’s Confidential Information, shall be solely
owned by HCRI.
 
Notwithstanding the foregoing but without derogating therefrom, the parties
agree that nothing in this Agreement by implication or otherwise shall
constitute a grant of rights to any Pre-Existing Intellectual Property, and that
this Agreement is not intended to transfer any intellectual property rights that
either party owned or in-licensed before entering this Agreement.
 
11.
Indemnification.

 
 
a.
Sponsor Indemnification.  Sponsor shall indemnify, defend and hold harmless HCRI
and its trustees, officers, medical and professional staff, employees, agents,
subcontractors and their respective successors, heirs and assigns (the “HCRI
Indemnitees”), against any liability, damage, loss, or expense (including
reasonable attorneys’ fees and expenses of litigation) (collectively “Losses”)
incurred by, or imposed upon, an HCRI Indemnitee arising out of performance of
the Study, infringement of intellectual property rights, the Investigational
Product, or Sponsor’s performance under this Agreement, except to the extent
that such Losses are the direct result of an HCRI Indemnitee’s gross negligence,
or intentional misconduct.

 
 
b.
HCRI Indemnification.  HCRI shall indemnify, defend and hold harmless Sponsor
and its trustees, directors, officers, employees and agents (collectively, the
“Sponsor Indemnitees) from and against any Losses incurred by, or imposed upon,
a Sponsor Indemnitee arising out of HCRI’s gross negligence, wrongful act or
omission, or willful malfeasance, except to the extent caused by a Sponsor
Indemnitee’s gross negligence or intentional misconduct.

 
 
c.
Attorneys. The Indemnifying party agrees, at its own expense, to provide
attorneys reasonably acceptable to the indemnitee to defend against any actions
brought or filed against any party indemnified hereunder with respect to the
subject of indemnity contained herein, whether or not such actions are
rightfully brought.

 
 
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d
Notice.  Each party agrees to provide the other party with prompt written notice
of any Losses which it has actual knowledge or a reasonable belief thereof.  No
party shall settle or pay any claim which may trigger an indemnification
obligation without the indemnifying party’s prior written consent.

 
 
e
This Section shall survive expiration or termination of this Agreement.

 
12.
Insurance.

 
 
a.
Sponsor Insurance. Sponsor shall, at its sole cost and expense, procure and
maintain product/completed operations liability insurance coverage as required
by law in the country where the Study is conducted if local admitted insurance
is required. Where no local admitted insurance is required the following shall
apply:

 
Sponsor shall, at its sole cost and expense, procure and maintain
product/completed operations liability insurance coverage in amounts of five
million ($5,000,000) dollars each and every loss and in the aggregate for the
period of insurance which names the HCRI Indemnitees as additional
isureds.  Such product/completed operations liability insurance shall include
coverage for (i) clinical trials liability, and (ii) contractual liability. If
Sponsor elects to self-insure all or part of the limits described above
(including deductibles or retentions which are in excess of two hundred fifty
thousand ($250,000) dollars annual aggregate) such self-insurance program must
be acceptable to HCRI and HCRI’s insurance carrier. Such product/completed
liability coverage will be maintained for three (3) years after the conclusion
of the Study.  The minimum amounts of insurance coverage required under this
Section shall not be construed to create a limit of Sponsor’s liability with
respect to its indemnification under the preceding Section of this Agreement.
 
 
b.
Proof of Insurance.  Sponsor shall provide HCRI with written evidence of such
insurance upon execution of this Agreement.  Sponsor shall provide HCRI with
written notice at least fifteen (15) days prior to the cancellation, non-renewal
or material change in such insurance.

 
 
c.
Maintenance of Insurance. Sponsor shall maintain such comprehensive general
liability insurance: (i) during the continuance of the Trial or the term of this
Agreement, whichever is longer; and (ii) for a reasonable period after the
period referred to in the preceding subpart (i), which in no event shall be less
than six (6) years.

 
 
d.
This Section shall survive expiration or termination of this Agreement.

 
 
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13.
Limitation of Liability and Remedies.

 
 
a.
IN THE EVENT OF ANY MATERIAL BREACH, OMISSION, OR NEGLIGENCE BY HCRI IN THE
PERFORMANCE OF ITS OBLIGATIONS UNDER THIS AGREEMENT, SPONSOR AGREES THAT ITS
FIRST RECOURSE SHALL BE TO SEEK REPERFORMANCE BY HCRI OF THE SERVICES
DETRIMENTALLY IMPACTED BY SUCH ERROR OR OMISSION AT THE SOLE COST AND EXPENSE OF
HCRI.  IN NO EVENT SHALL HCRI’S LIABILITY FOR SUCH MATERIAL BREACH OR OMISSION
EXCEED 1.5 TIMES FEES PAID TO HCRI FOR THE AFFECTED SERVICE.  SPONSOR FURTHER
AGREES THAT HCRI SHALL NOT BE LIABLE TO SPONSOR FOR ANY SPECIAL, INDIRECT,
EXEMPLARY, INCIDENTAL OR CONSEQUENTIAL DAMAGES INCLUDING BUT NOT LIMITED TO ANY
DAMAGES RESULTING FROM LOSS OF DATA, DELAY IN THE STUDY, LOSS OF PROFITS OR LOSS
OF BUSINESS ARISING OUT OF OR IN CONNECTION WITH THIS AGREEMENT OR ANY PRODUCTS,
SERVICES OR MATERIALS FURNISHED HEREUNDER, EVEN IF HCRI HAS BEEN ADVISED OR
SHOULD KNOW OF THE POSSIBILITY OF SUCH DAMAGES.

 
 
b.
EXCEPT AS EXPRESSLY STATED TO THE CONTRARY, THE LIMITATIONS STATED IN THIS
SECTION’S SUBPARAGRAPH (a) SHALL APPLY WHETHER THE ASSERTED CLAIM, LIABILITY OR
DAMAGES ARE BASED ON CONTRACT (INCLUDING BUT NOT LIMITED TO BREACH OF WARRANTY),
TORT (INCLUDING BUT NOT LIMITED TO NEGLIGENCE AND STRICT LIABILITY) OR ANY OTHER
LEGAL OR EQUITABLE GROUNDS, AND REGARDLESS OF WHETHER THE ASSERTED CLAIM,
LIABILITY OR DAMAGES ARISE FROM PERSONAL INJURY, PROPERTY DAMAGE, ECONOMIC LOSS
OR ANY OTHER KIND OF INJURY, LOSS OR DAMAGE.  EACH OF SUCH LIMITATIONS IS
INTENDED TO BE ENFORCEABLE REGARDLESS OF WHETHER ANY OTHER EXCLUSIVE OR
NON-EXCLUSIVE REMEDY UNDER THIS AGREEMENT FAILS OF ITS ESSENTIAL PURPOSE. THE
LIMITATIONS STATED IN THIS SECTION’S SUBPARAGRAPH (a) SHALL NOT APPLY TO CLAIMS,
LIABILITIES OR DAMAGES WHICH ARE THE RESULT OF ARE A WILFULL MISCONDUCT BY HCRI.

 
 
c.
Allocation of Risk. Sponsor acknowledges that the fees described in Exhibit A
and the other economic terms of this Agreement and its Exhibits reflect the
allocation of risks and the limitations of HCRI’s liability hereunder.

 
14.
Term; Termination.

 
 
a.
Term.  This Agreement shall continue in full force and effect until Sponsor has
provided final payment to HCRI for the services actually provided and completed
by HCRI pursuant to Exhibit A and any CCOs as described in Section
5(b).  Termination of this Agreement, however, shall not relieve the obligations
undertaken by the parties in Sections 4 (Data Ownership), 6 (Sponsor Obligations
and Warranties), 8 (Confidentiality), 9 (Publication; Publicity), 10
(Inventions), 11 (Indemnification), 12 (Insurance), and 13 (Limitation of
Liability and Remedies), 16 (Non-Solicitation; Financial Interest in Sponsor),
and 19 (Miscellaneous).

 
 
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b.
Termination without Cause.  Either party may terminate this Agreement without
cause by providing sixty (60) days written notice to the other party.

 
 
c.
Termination for Bankruptcy/Insolvency.  Either party may immediately terminate
this Agreement if the other party files a petition in bankruptcy or is
adjudicated as bankrupt or insolvent, or makes an assignment for the benefit of
creditors, or an arrangement pursuant to any bankruptcy law, or if the other
party discontinues its business or if a receiver is appointed for the other
party or the other party’s business who is not discharged within sixty (60)
days.

 
 
d.
Termination for Cause.  Either party may terminate this Agreement for cause
after providing the breaching party with thirty (30) days’ written notice of the
breach and the opportunity to cure the breach during such period.

 
 
e.
Effect of Termination.  Upon termination of this Agreement for any reason,
Sponsor shall promptly pay HCRI on a time and materials basis for all work
performed and expenses incurred through the effective date of termination
including, without limitation, amounts due for closeout costs and non-cancelable
commitments incurred through that date, if such costs exceed the amounts
previously paid under this Agreement.

 
15.
Compliance with Laws and Policies.

 
 
a.
Compliance with Law.  Sponsor and HCRI shall comply with all applicable federal,
state and local laws, regulations and guidelines, including but not limited to
any such laws, regulations or guidelines concerning human subject research.

 
 
b.
Adherence to Policies.  Sponsor recognizes that in performing services under
this Agreement, HCRI is bound by and all rights of Sponsor will be subject to
the Faculty of Medicine of Harvard University’s Faculty Policies on Integrity in
Science  (www.hms.harvard.edu/integrity/).

 
 
c.
HIPAA and Data Protection. The parties acknowledge that HCRI is a non-covered
entity under the federal Health Insurance Portability and Accountability Act of
1996 (“HIPAA”).  To the extent applicable, HCRI shall comply with all applicable
international, federal and state laws and regulations governing patient privacy
and confidentiality of health information, including without limitation HIPAA,
and the Health Information Technology for Economic and Clinical Health Act of
2009 (“HITECH Act”) and their implementing regulations.  As applicable, HCRI
shall take all actions necessary to comply with such laws and regulations,
including, without limitation, agreeing to amend this Agreement as necessary for
compliance.

 
 
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16.
Non-Solicitation; Financial Interest in Sponsor.

 
 
a.
Sponsor shall not solicit for employment or employ, at any time during the term
of this Agreement, and for a period of one (1) year thereafter, any
subcontractor performing services or person employed by HCRI at any time during
the term hereof, without the prior written consent of HCRI.  If Sponsor employs
a staff member of HCRI without HCRI’s prior written consent, Sponsor agrees to
pay a fee of 200% of the individual’s salary or expected compensation for the
first year of service.

 
 
b.
Neither Sponsor, nor any affiliate or subsidiary of Sponsor, shall grant, issue
or provide, or agree to grant, issue or provide, any financial interest,
including any consulting or other fee, stock, or other equity interest, to any
person employed by HCRI or any immediate family member of any person employed by
HCRI, without the prior written consent of the President and Chief Executive
Officer of HCRI.

 
17.
Arbitration.

 
 
a.
The parties shall settle by arbitration any controversy or claim between them
arising directly or indirectly under this Agreement, whether based on contract,
tort, fraud, misrepresentation or other legal theory, and whether or not
arbitration has been expressly referenced elsewhere in a particular section or a
particular subsection of this Agreement.  The arbitration shall occur in Boston,
Massachusetts under the then current rules and supervision of the American
Arbitration Association.  If the dispute involves a claim for money in the
amount of five hundred thousand ($500,000) dollars or less and does not involve
any claims relating to ownership, use, or disclosure of intellectual property,
the arbitration shall be before a single arbitrator whom the parties shall
select from a panel of persons knowledgeable in the therapeutic area addressed
by the Trial and clinical research; otherwise, the arbitration shall be before
three arbitrators, one selected by Sponsor, one selected by HCRI, and the third
selected by the two arbitrators so selected.  The arbitrator or arbitrators
shall not have the power to award punitive or exemplary damages.  The decision
and award of the arbitrator or arbitrators shall be final and binding and the
award rendered may be entered in any court having competent jurisdiction.  The
parties shall each pay their own attorneys’ fees associated with the
arbitration, and shall pay the other costs and expenses of the arbitration as
the rules of the American Arbitration Association or the arbitrator provide.

 
 
b.
Any party may request arbitration to resolve any controversy or claim, between
them, as provided above, by written notice to the other proposing an
arbitrator.  The other party receiving such written notice shall have thirty
(30) days in which to agree with such choice of arbitrator or, if three
arbitrators are required, to propose its arbitrator.

 
 
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18.
Force Majeure.

 
 
a.
Neither party shall be liable for any unforeseeable event beyond its reasonable
control not caused by the fault or negligence of such party, which causes such
party to be unable to perform its obligations under this Agreement, and which it
has been unable to overcome by the exercise of due diligence.

 
 
b.
In the event of the occurrence of such a force majeure event, the party unable
to perform shall promptly notify the other party.  It shall further use its best
efforts to resume performance as quickly as possible and shall suspend
performance only for such period of time as is necessary as a result of the
force majeure event.

 
19.
Miscellaneous.

 
 
a.
Independent Contractors.  For the purposes of this Agreement, the parties shall
be deemed to be independent contractors of one another and not employees or
agents of the other.

 
 
b.
Entire Agreement and Modification. This Agreement and its Exhibits constitute
the entire agreement between the parties, and all prior negotiations,
representations, agreements and understandings are superseded hereby.  No
agreements amending, altering or supplementing the terms hereof may be made
except by means of a written document signed by a duly authorized representative
of each party.

 
 
c.
Use of Headings.  The headings in this Agreement are for convenience of
reference only and shall not alter or otherwise affect the meaning hereof.

 
 
d.
Severability and Waiver.  The invalidity or unenforceability of any term or
provision hereof shall not affect the validity or enforceability of any other
term or provision hereof.    Failure of either party to enforce a right under
this Agreement shall not constitute a waiver of that right or the ability to
later assert that right.

 
 
e.
Assignment. This Agreement shall be binding upon and inure to the benefit of
each of the parties hereto and their successors and permitted assigns; provided,
however, that this Agreement may not be assigned by either party without the
prior written approval of the other party.

 
 
13

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f.
Notices. Any notice or other communication, including invoices, required or
permitted by this Agreement will be in writing and will be considered given as
of the date it is received by the addressee.  Such notice will be given to the
parties at these addresses:

 
To Sponsor:
To HCRI:
InspireMD
Harvard Clinical Research Institute
3 Menorat Hamor St.
930 Commonwealth Avenue, 3rd Floor
Tel Aviv, Israel
Boston, MA 02215
Attention: Eli Bar, VP R & D
Attention: Contracts Department
   
Phone:  +972-3-6917691
Phone: 617-307-5486
Fax:  +972-3-6917692
Fax: 617-307-5605
Email: elib@inspire-md.com
Email: Kevin.Hart@hcri.harvard.edu

 
Upon receipt of invoice Sponsor will provide written confirmation of same to
Claudia Thum, by email at Claudia.Thum@hcri.harvard.edu
 
 
g.
Governing Law and Jurisdiction/Venue.  This Agreement shall be governed by and
construed in accordance with the laws of The Commonwealth of Massachusetts.  The
parties hereto agree that all actions or proceedings arising in connection with
this Agreement, which are unresolved by the means proscribed in Section 16,
shall be tried and litigated exclusively in the State and Federal courts located
in Suffolk County, in the Commonwealth of Massachusetts.  The aforementioned
choice of venue is intended by the parties to be mandatory and not permissive in
nature, thereby precluding the possibility of litigation between the parties
with respect to or arising out of this Agreement in any jurisdiction other than
that specified in this Section.  Each party agrees that the State and Federal
courts located in Suffolk County, Commonwealth of Massachusetts, shall have in
personam jurisdiction and venue over each of them for the purpose of litigating
any dispute, controversy, or proceeding arising out of or related to this
Agreement.

 
 
14

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IN WITNESS WHEREOF, the parties have caused this Agreement to be executed by
their duly authorized representatives in two (2) counterparts, each of which
shall be considered one and the same original.
 
 
InspireMD
 
Harvard Clinical Research Institute, Inc.
         
By:
/s/ Asher Holzer
 
By:
/s/ J. Spencer Goldsmith
                         
Name: 
Asher Holzer
 
Name: 
J. Spencer Goldsmith
                         
Title:
President
 
Title:
President
                         
Date:
October 5, 2011
 
Date:
October 4, 2011
                                                 
By:
/s/ Ofir Paz
                               
Name:
Ofir Paz
                               
Title:
CEO
                               
Date:
October 5, 2011
                               

 
 
15

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EXHIBIT A
 
Project Parameters:
 
The Scope of Work is summarized below. Should there be a change in the project
assumptions or Scope of Work outlined herein, HCRI reserves the right to reflect
such modifications with a revision of fees.
 

   
Number of Patients Enrolled
654
Number of Clinical Sites
50 Sites
(16 US, 34 OUS)
Study Duration:
 
Planning & Start Up Period
38 Weeks
Enrollment Period
61 Weeks
Follow-Up Period (Including LTFU)
52 Weeks
Database Closure & Reporting Period
8 Weeks
Total Project Period
159 Weeks
 (37 Months)
eCRF Programming:
 
Standard eCRF pages to be Programmed
14
Event eCRF pages to be Programmed
2
ECG eCRF pages to be Programmed
1
Angio Core Lab eCRF pages to be Programmed
2
eCRF Randomization page to be Programmed
1
Total eCRF pages to be Programmed
20
Total Number of Edit Checks
200
Data Processing:
 
Standard CRF forms to be processed per patient
37
Event CRF forms to be processed per event
4
ECG CRF forms to be processed per patient
2
Angio Core Lab CRF forms to be processed per patient
2
Randomization forms to be processed per patient
1
Total Number of CRF forms to be processed per patient
46
Total Number of CRF forms to be processed
27,403
Query Rate / Total Estimated Queries
10%/2,740
Electronic Data Capture:
 
Total Number of Users
110
Help Desk (hours per day/days per week)
24/7
Total Number of Datapoints processed
274,030
Statistical Reports:
 
Primary Endpoint Statistical Report – 12 Month (# of TLGs)
1 (25, 2, 8)
Interim Statistical Report (# of TLGs)
1 (8, 1, 4)

 
 
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Annual Report (# of TLGs)
1 (5, 1, 4)
Total Number of Statistical Reports
3
Frequency of Study Metric Reports
Weekly
Core Laboratories (Angio)
Entered
Safety Reports:
 
Regulatory Reports (Cumulative)
1 Report/Month during Enrollment and Follow-up
Regulatory Reports (Weekly)
1 Report/Week during Enrollment and Follow-up
CEC & SAE Processing:
 
CEC Events Adjudicated
 
Total CEC Events
131 (20%)
SAEs Processed
 
Total SAEs Processed
229 (35%)
Source Document Tracking:
 
Source Documents per Event
5
Number of Events
360
Total Source Documents to be Tracked
1,800
Medical Coding:
 
Adverse Event Coding
10 Per Patient
Concomitant Medication (ConMed) Coding
10 Per Patient
Data Monitoring Committee (DMC) Services:
 
Estimated Number of DMC Meetings
4
Total Number of DMC Reports (# of Tables and Graphs for each)
3 (5, 2)
ECG Core Lab:
 
2 ECGs to be read per patient (Pre-Procedure, Hospital discharge, events
estimated 10% of patients)
1,373 Total Reads

 
 
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Clinical Site Monitoring:
 
US Site Monitoring
# of Visits Per Site
# of Number Sites
Total Visits Per Site
Qualification/ Initiation Visits*
1
16
16
Interim Visits
5
16
80
Closeout Visits
1
16
16
Total Visits
   
112

 
* At the request of the Sponsor, US Clinical Sites will have a combination
qualification and initiation visit. This is only possible when the sites are
known to HCRI or InspireMD.
 
**For OUS Clinical Sites, at request of the Sponsor, no qualification visits
will be performed. This is only possible when the sites are known to the OUS
Vendor or InspireMD. In case sites are selected that are unknown to the OUS
Vendor, a site call must be made to obtain the relevant start up information.
 
 
18

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Tasks & Responsibilities
 
HCRI’s Roles & Responsibilities
     
PROJECT MANAGEMENT
 
Develop and manage HCRI’s study timelines
Yes
Manage completion of HCRI’s study deliverables
Yes
Participate in / coordinate teleconferences
Yes
Schedule and attend Sponsor Meetings
Yes
Investigator Meetings (attendance)
Yes
Coordinate core lab(s)
Yes
Coordinate printing of protocol (used in Manual of Operations; Printing costs
not included)
N/A
Case Report Forms (CRFs)
 
Print CRFs/guidelines (via subcontract, billed to sponsor as a pass-through
cost)
N/A
Ship CRFs/guidelines (billed to sponsor as a pass-through cost)
N/A
Coordinate distribution, tracking & re-ordering of CRFs
N/A
   
CLINICAL DOCUMENT DEVELOPMENT
 
Protocol (contracted separately)
 
Perform literature review
N/A
Develop protocol summary
N/A
Develop full protocol (2 drafts)
N/A
Draft protocol amendments
N/A
Biostatistician input into clinical trial protocol
N/A
Review protocol only (by project team during Planning phase)
Yes
   
DATA MANAGEMENT ACTIVITIES / ELECTRONIC DATA CAPTURE (EDC)
 
Develop data management plan (DMP) (up to 3 drafts)
Yes
Database development
 
Edit checks development
Yes
eCRF and database specifications
Yes
eCRF and database build
Yes
Edit check mock data testing
Yes
Edit check test plan
Yes
Specify, build, test and implement edit checks
Yes
Develop export specifications
Yes
Case Report Forms (CRFs)
 
Develop eCRFs (3 drafts)
Yes

 
 
19

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HCRI’s Roles & Responsibilities
 
Creation of annotated eCRFs
Yes
Develop eCRF completion guidelines
Yes
Prepare training materials for EDC system
Yes
Train PIs and end users on EDC system
Yes
Maintain electronic study file library
Yes
Study portal setup
Yes
Site assessments
Yes
Facilitate database hosting
Yes
Facilitate help desk and support
Yes
Facilitate system change control
Yes
Tracking
Yes
Data entry
N/A
Data cleaning
Yes
Medical coding
 
Adverse events
Yes
Concomitant medications
Yes
Database audit
N/A
Facilitate closeout and database decommission
Yes
   
MEDICAL OVERSIGHT
 
Participation by physician in regulatory agency meeting
No
Protocol and CRF review by physician
Yes
Oversight of trial conduct by physician
Yes
   
CLINICAL EVENTS COMMITTEE (CEC)
 
Event review, coding and narration of endpoint events
Yes
CEC review and adjudication of endpoint events
Yes
Development and drafting of CEC Manual of Operations for sponsor review
Yes
Produce and distribute meeting minutes to sponsor
Yes
CEC management and meeting coordination
Yes
Limited querying for data related to review and adjudication of endpoint events
Yes
Contracting with CEC physicians and COI management
Yes
   
CLINICAL SAFETY
 
SAE review/processing with narratives
Yes
Notification of SAE to Sponsor
Yes
Safety regulatory reporting (MedWatch/CIOMS)
 
Submission of SAE regulatory report to sponsor
Yes
Submission of SAE regulatory report to FDA or other regulatory authorities
No

 
 
20

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HCRI’s Roles & Responsibilities
 
Distribution of SAE regulatory report to sites
No
Medical Monitoring
Yes
   
DATA MONITORING COMMITTEE (DMC)
 
DMC Management
Yes
   
STATISTICAL ANALYSIS
 
Write statistical section of protocol (including sample size)
N/A (under separate agreement)
Statistical analysis plan (SAP) and definition of data displays
Yes
Design and implement randomization scheme
Yes
Program statistical tables, listings, and graphs
Yes
Develop export specifications
Yes
   
REPORTS
 
Provide 1 interim report (2 drafts)
Yes
Provide 1 primary endpoint report (2 drafts) at 12 Months
Yes
Provide 3 DMC reports
Yes
Provide 1 annual safety report
Yes
Provide medical writing
Yes
Exploratory analyses (to be billed as out of scope, if requested)
Yes
   
ARCHIVING
 
Organize and index all necessary study-related documents to be archived
Yes
Arrange archiving of the study-related documents
Yes
Box and transfer documents to archive
Yes
   
SITE MANAGEMENT/SITE MONITORING ACTIVITIES (US Sites Only)
 
Investigator selection in collaboration with the Sponsor
Yes
Develop informed consent form (ICF) template in English
Yes
Conduct on-site qualifying site assessment visits
No
Collect/review regulatory documents
Yes
Assist sites with IRB requirements
Yes
Negotiate site agreements in collaboration with Sponsor
Yes
Attend and present at investigator/coordinator meeting
Yes
Conduct on-site qualifying/initiation visits
Yes
Develop monitoring plan in collaboration with OUS team
Yes

 
 
21

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HCRI’s Roles & Responsibilities
 
Conduct on-site interim monitoring visits
Yes
Provide ongoing site management and site monitoring services
Yes
Distribute serious adverse event reports to the sites for submission to their
IRB
Yes
Administer payments of investigator grants
Yes
Participate in project team meetings
Yes
Participate in teleconferences
Yes
Conduct on-site close-out visits
Yes
   
ECG CORE LAB
 
Develop ECG MOP, ECG labels
Yes
Evaluate study ECGs
Yes
   
EQOL SERVICES
N/A
   
OUTSOURCED ACTIVITIES
 
OUS Site Management & Monitoring (specific tasks for OUS vendor TBD)
No
Angiographic Core Laboratory (via subcontract)
Yes

 
 
22

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Estimated Budget:
 

   
Trial Design & Development
 
Protocol Development
$6,210
CRF Design
$18,430
Develop DMC Charter
$5,330
Subtotal
$29,970
   
Medical Management
$26,033
   
Medical Monitoring
$66,025
   
Safety Management
 
Review & Processing of SAE CRFs
$99,558
Safety Reconciliation
$43,882
Cumulative Safety Reports
$34,422
Weekly Safety Reports
$18,645
Subtotal
$196,506
   
Project Management
 
Project Oversight
$291,717
Internal/External Conferencing
$220,035
Investigator Meeting
$0
Subtotal
$511,752
   
Data Management
 
Data Management Plan
$7,165
CRF Completion Guidelines
$6,940
Database Development
$98,937
Randomization Programming
$15,733
Event & Safety Database Programming
$12,800
Database Maintenance
$31,335
EDC Database Administration
$10,952
Dictionary Coding
$23,180
Data Processing Status Reports
$41,840
Data Cleaning
$474,045
Data Maintenance & Administration
$12,800
Subtotal
$735,728
   

 
 
23

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Electronic Data Capture
 
Site Assessments & Support Documentation
$11,250
Training
$36,300
Hosting
$85,550
Help Desk
$81,000
Licensing Fee
$49,325
Portal Set Up
$10,000
Submission Closeout
$15,000
User Management Utility
$4,500
Subtotal
$292,925
   
Statistical Analysis & Reporting
 
Statistical Analysis Plan
$23,260
Primary Endpoint Report
$109,410
Statistical Report
$44,220
Annual Safety
$30,725
Subtotal
$207,615
   
DMC Services
 
DMC Reports
$83,760
Estimated DMC Participant Costs
$16,000
Subtotal
$99,760
   
CEC Services
 
Event Review & Processing
$113,277
Estimated CEC Participant Costs
$45,850
Subtotal
$159,127
   
Clinical Site Management Services (US Only)
 
Site Management Services
$280,281
Project Administration
$23,862
Develop & Negotiation Site Contract/Budget
$10,440
Regulatory Document Collection
$28,240
Site Selection
$10,000
CRA Management
$18,303
Administration of Investigator Payments
$10,669
Subtotal
$381,795
   
Clinical Site Monitoring Services (US Only)
 
Qualification/Initiation Visits
$47,840
Interim Visits
$278,720
Closeout Visits
$45,760

 
 
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Ongoing Clinical Site Monitoring Services
$231,772
Subtotal
$604,092
   
ECG Core Laboratory Services
 
ECG Start Up Costs
$4,758
ECG Read Costs
$96,110
Subtotal
$100,868
   
CSA Discount*
-$12,500
   
Total Non Pass Through HCRI Estimated Costs
$3,399,696
   
Total Non Pass Through OUS Vendor Estimated Costs**
TBD
 
PASS THROUGH COSTS
   
Pass Through Costs (HCRI)
     
Clinical Site Payments*** (16 US Clinical Sites)
 
Clinical Site Start Up Payments
$80,000
IRB Initial Payments
$40,000
IRB Amendment Payments
$24,000
IRB Annual Payments
$36,000
Clinical Site Closeout Payments
$4,000
Subtotal
$184,000
   
Estimated Pass Through for Teleconferences
$2,760
   
Estimated Travel Costs
$138,000
   
Estimated Travel Costs Investigator Meeting
TBD
   
Total Pass Through HCRI Estimated Costs
$324,760
   
Pass Through Costs (OUS Vendor)
     
Clinical Site Payments*** (34 OUS Sites)
 
Site Start Up Payment
TBD
EC Initial Payment (Local)
TBD
EC Initial Payment (Lead)
TBD
EC Amendment Payments (Local)
TBD

 
 
25

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EC Amendment Payments (Lead)
TBD
Clinical Site Close Out Payments
TBD
Subtotal
TBD
   
Other Estimated OUS Vendor Pass Through Costs
 
Translations
TBD
Travel
TBD
Phone
TBD
Courier
TBD
Inflation/Stability
TBD
Subtotal
TBD
   
Total Pass Through OUS Vendor Estimated Costs**
TBD
   
Clinical Site Patient Payments (US & OUS)***
$3,270,000
   
Angio Core Lab Services
 
Baseline Angio Analysis
TBD
Follow Up Angio Analysis
TBD
Data Entry
TBD
Subtotal
TBD
   
Grand Total
$6,994,456 (plus costs TBD as outlined above)

 
Source Budget:  InspireMD – MGC10 MGuard Study Budget v9.0
 
* A $12,500 Credit on the Trial Design work has been given to InspireMD for
paying the invoice HCRI sent on 12/20/2010 for Trial Design work.
 
** It is not anticipated that HCRI will subcontract with the OUS Vendor.  If,
ultimately, HCRI does contract with the OUS Vendor, all OUS Vendor costs will be
billed from HCRI to InspireMD as a pass-through expense. It is the understanding
of the parties that amounts due to the OUS Vendor will be invoiced to HCRI in
the Euro. All OUS Vendor costs will be billed as a pass-through expense,
reflecting the actual amount HCRI paid to the OUS Vendor in US Dollars at the
time of payment.
 
*** Investigator Grants/Per-Patient Costs (for all patients) and IRB costs (for
all US sites only) are included as shown above. Site payments for US and OUS
sites will be billed according to the payment schedule, and shall be billed
without markup.
 
**** Costs are based on 2010 labor rates. HCRI reserves the right to review and
renegotiate labor rates with InspireMD on an annual basis, beginning one year
from the date of this Agreement.
 
***** The budget contained herein does not include any potential fees HCRI may
incur for administering site and/or patient payments to OUS sites. It is not
anticipated that this service will be required, however, if requested by
InspireMD, HCRI will assess potential wire fees at that time and a Contract
Change Order will be issued.
 
 
26

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Estimated Site Costs
 
Clinical Site Payments – US Only
 
Category
Unit Cost
Units
Cost
Site Start-Up Payments
$5,000/Site
16 Sites
$80,000
IRB Initial Payments
$2,500/Site
16 Sites
$40,000
IRB Protocol Amendments Payments
$500/Amendment/Site
3 Amendments, 16 Sites
$24,000
IRB Annual Renewal Payments
$750/Year/Site
3 Years, 16 Sites
$36,000
Site Study Close Out Payments
$250/Site
16 Sites
$4,000
Total Cost (per budget)
   
$184,000

 
Patient Payments – US and OUS
 
Region
Patients
Rate
Cost
US and OUS
654
$5000/patient
$3,270,000
Total Cost (per budget)
   
$3,270,000

 
 
27

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Budget Companion
 
Study Start-Up
 
·
Protocol Review

 
The study protocol is reviewed by many operating departments at HCRI, as well as
clinical experts from the therapeutic area being studied. This will assist
Project Team personnel in understanding the important scientific elements of the
study. The review process will help to confirm not only the completeness of the
scientific and clinical justifications, but also the clearness of detail for
site compliance and conformity with both US and outside of the US regulatory
guidelines.
 
Medical Management
 
Medical Management will be performed by physicians at HCRI. Their
responsibilities will include protocol and case report form review, oversight
for Clinical Event Committee (CEC) and Data Monitoring Committee (DMC) services,
consultation to InspireMD and the HCRI Team for trial strategy issues, provision
of overall medical support to HCRI Project Teams, and clinical review of report
deliverables generated by HCRI. In addition, these physicians will be available
as members of the Project Team for additional medical support, to answer study
related clinical questions, and to provide medical review of SAE Regulatory
Reports.
 
Safety Management
 
·
SAE Review & Processing with Narratives

 
HCRI uses an Empirica™Trace database to track incoming SAEs which are received
from sites through an e-mail notification system from the EDC database.
InspireMD will also receive a notification of the SAE once it is received at
HCRI. The SAE is entered into the Empirica™Trace database and MedDRA coded at
the time of entry. We may contact the sites to gather sufficient information to
generate a clear narrative of the event. If applicable, a Safety Regulatory
Reporting document (MedWatch, CIOMS) may be generated for the SAE. All Safety
Regulatory Reports will be sent to InspireMD, who will be responsible for
submission to the appropriate regulatory authorities.
 
A coding review of adverse events will be performed on a periodic basis and
prior to any report deliverable. This review will ensure that the appropriate
medical concept is assigned through the standardized coding dictionary to every
adverse event and that all events are coded in a consistent manner.
 
 
28

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·
SAE Reconciliation

 
The SAEs entered in Empirica™Trace will be reconciled with the SAEs in the EDC
database based on information obtained on the eCRF. A Reconciliation Plan will
be created which details all data elements to be reconciled and a timeline for
review. This Reconciliation Plan will be reviewed with InspireMD prior to
inclusion into the Data Management Plan. According to the timeline outlined in
the Reconciliation Plan, periodic listings of all SAEs will be generated from
Empirica™Trace and matched/reconciled against the EDC database. Queries will be
generated for any data elements pertaining to an SAE that are inaccurate or not
consistent between the two databases.
 
·
Weekly Safety Reports & Monthly Cumulative Reports

 
Weekly Safety Reports provide an update for any UADE’s and Deaths received in
the previous week, with password-protect Word narrative attachments for new and
follow up cases. Monthly Cumulative Reports list all SAEs processed within a
pre-determined reporting frequency (i.e., monthly). The Weekly Safety Reports
are provided manually while the Monthly Cumulative Reports are pre-programmed.
Examples of such reports can be provided upon request.
 
Medical Monitoring
 
The Medical Monitor (MM) will be an interventional cardiologist- boarded and
active in this area of clinical research.  Prior to assuming duties, the MM will
first complete all document training on applicable HCRI SOPs with regard to
trial medical monitoring, good clinical practice, safety reporting, clinical
trial management as well as training on this study protocol and the investigator
brochure and protocol referenced literature and source documents.
 
The Medical Monitor will provide the following essential services for this study
during normal business hours (weekdays) unless contacted by the Sponsor or the
clinical site personnel for after hour emergencies.
 
The MM will ensure compliance with study protocol, regulatory requirements, and
the integrity of data and safety of Trial subjects and will determine causality
assessments of SAE events and determine their relationship and clinical
significance to the Trial using medical judgment. The MM will also perform
review of case report forms for events, narrative, concomitant medication,
medical history to identify trend, discrepancy and will consult with site
Principal Investigators to clarify inclusion/exclusion criteria for potential
Trial subjects and verify eligibility prior to site access to subject
randomization system as applicable. This will also include consulting with site
Principal Investigator and Site Coordinator(s) in cases of premature subject
discontinuation.
 
The MM will be available to the trial DMC and the CEC on an as needed basis
regarding any background information with respect to any significant safety or
compliance issues. The MM will also perform laboratory data review of study
subject and determine clinical significance in consultation with Sponsor and
Investigator based on information in Investigator’s Brochure (IB) and scientific
literature.
 
 
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The MM will review any Trial protocol violations/deviations and initiate
remedial action and site training to ensure corrective action is applied and the
accuracy of the clinical trial data is intact. The MM will work with the Medical
Director, Clinical Safety and the assigned Clinical Safety Associate of HCRI
assigned to the Trial to monitor all Serious Adverse Events (SAEs) until
resolution.
 
The MM also may be called upon to participate in meetings/teleconferences as
required with the Sponsor, Study Team members and/or regulatory agencies as
deemed appropriate.
 
Project Management
 
·
Project Oversight

 
A Project Manager (PM) will lead the HCRI team in completing HCRI’s Scope of
Work for this project. The PM will facilitate communication among all team
members and serve as InspireMD’s point of contact for all study-related
activities performed by HCRI. In addition, the PM will manage HCRI personnel’s
adherence to the study timelines, budgets and deliverables and provide review of
study deliverables, including the CRFs, CRF completion guidelines, and reports.
HCRI’s Project Management team will include Project Assistants who will provide
services such as meeting minutes, meeting scheduling, and other study
administrative needs.
 
Additionally, it is anticipated that HCRI’s PM will oversee the activities of
the OUS Site Management and Monitoring vendor, but it is understood that
InspireMD maintains responsibility for their performance unless the OUS vendor
contracts directly with HCRI.
 
·
Internal/External Conferencing

 
HCRI’s Project Team will meet periodically to review all current matters
relating to the study. The team members for this study will include the Project
Manager, Project Assistant, Lead CRA, HCRI Physician, Data Manager, Clinical
Reviewer, Safety Officer, Biostatistician, and Programmer, and EDC
representative. In addition, a weekly conference call with InspireMD will be
coordinated by the HCRI Project Manager and will include a review of study
timelines and milestones as well as any other issues which may arise during the
course of the study.
 
·
Investigators Meeting

 
Investigators Meeting costs have been removed from the budget and Agreement
pending further discussion between HCRI and InspireMD related to logistics and
responsibilities.
 
 
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Data Management Electronic Data Capture
 
This Agreement and budget is based on using HCRI’s EDC resources and the InForm
EDC system. In the event that HCRI’s EDC services are not used, costs for all
resources are subject to modification and a Contract Change Order will be
issued.
 
·
Data Management and EDC

 
Data management will be performed according to ICH-GCP and other applicable
guidelines. HCRI will evaluate the trial in the design phase in order to create
an efficient data management process specific to the study requirements, and in
conjunction with EDC activities, that tracks toward delivering a clean, locked
database within the required timelines. Every major element of the data
management process is closely monitored by a lead Data Manager (DM) in
accordance with HCRI’s standard operating procedures (SOPs).
 
The DM will create eCRF Specifications and Edit Check Specifications in
conjunction with review by the Project Team. To ensure delivery of a database
that reflects the specifications and meets the quality expectations of HCRI, the
DM will coordinate the database testing process. Once the trial goes live, the
DM will review the eCRF data, including automated and manual queries, and raise
manual queries as necessary. A 10% manual query rate is assumed based on HCRI
experience with similar trials. A higher query rate will incur additional cost.
The DM will address the status of queries and follow up with the sites to close
automated and manual queries. The DM will lock the eCRF forms in accordance with
the scope and definition of the project. The DM will produce standard enrollment
and eCRF status reports throughout the trial and provide them to study
management as defined in the Data Management Plan. Custom reports are available
at additional cost to InspireMD.
 
The DM will prepare a Data Management Plan (DMP) that defines and documents the
data management activities being performed. The DMP covers the scope of DM
activities for the trial and includes a description of the data collection
process, the workflow, documentation on the logic and processes for data review
and validation, critical timelines and milestones, types of and timing of
management reports, description and timing of data transfers, and documentation
of external data reconciliation, as applicable. Early development and approval
of the DMP is intended to enhance communication between all parties concerned,
thereby leading to more efficient and accurate data collection. This plan will
be reviewed and updated during the course of the project.
 
The DM will compile eCRF Completion Guidelines (CCGs) to instruct sites on
accurate completion of the eCRFs. The CCGs will be reviewed and finalized with
input from InspireMD and may be updated during the course of the project. Two
drafts and one final version of the CCGs are assumed for this Agreement and
budget. Additional drafts will incur additional cost.
 
 
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·
eCRF Design

 
HCRI will design eCRFs that capture the information needed to describe the
eligible study population, patient characteristics, procedural details, safety
and efficacy information of the investigational product, and of the study
endpoints to be analyzed. It is assumed that HCRI standard eCRFs will be
utilized. Changes to or requirements beyond the standard eCRFs may result in
additional programming time and/or cost. eCRF specifications and versions will
be developed collaboratively with InspireMD. Two iterations of drafts and one
final draft with approval on the eCRF content and specifications are assumed for
the purpose of providing this cost estimate. Additional changes may impact both
cost and timelines for eCRF implementation.
 
·
Study Start-up and Database Build

 
Once specifications are approved, the eCRFs will be programmed and a database
established. HCRI will outline edit check specifications for consistency and
accuracy of the data as it is being entered to the EDC system. These
specifications will be reviewed internally by the database design team and
presented to InspireMD for input and review. Once approved, these specifications
will be programmed and added to the EDC database.
 
HCRI will create a formalized test plan for InspireMD’s approval prior to
database testing. Based on that plan, HCRI will develop test scripts and test
data which will be executed internally to resolve any issues. InspireMD is
invited to view and test the database during this timeframe. Once testing is
complete and issues have been resolved, a Test Summary document will be prepared
for review. After the final phase of trial verification occurs, HCRI will review
and approve the documented process. The Project Team and InspireMD are required
to approve the release of the study to the production environment.
 
·
Site Assessments and Support Documentation

 
HCRI will electronically assess each site to ensure internet access and
compatibility. HCRI will also collect user information and establish the site
and user database for the trial. System configuration settings will be reviewed
by the Project Team and InspireMD before incorporation into the system. All
documentation is kept in a secure electronic library with version control.
 
·
Training

 
InForm training will be provided using PhaseForward’s InStruct Online solution. 
This internet based training is an easy to use e-learning system that allows
users to learn in a self-paced training environment and provides worldwide
documented course certification and re-certification. Upon course completion and
a formal testing process, users will receive a Certificate of Completion in
electronic PDF format and each user receives access to the course materials for
one (1) year.
 
·
Hosting

 
Hosting charges are based on the number of users and the number of patients in
the study. Hosting is an ongoing monthly server charge, beginning at the
“Go-Live” date, or the date the study is first made available for data entry.
Hosting is terminated on the date the final study report is accepted by
InspireMD at which point the server is decommissioned. If the study runs longer
than projected, the monthly server charge is continued until the server can be
decommissioned.
 
 
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·
Data points/Licensing

 
The licensing charge is a one-time fee based on the total number of expected
forms/data points. If additional forms are programmed per sponsor request and
the number of data points increases, the licensing fee may increase. This fee is
reflective of server space being sectored and dedicated for this trial and is
incurred in full at the time the trial goes live. Due to server and data
integrity issues, the sectored database is “fixed”; this fee may not be reduced,
and may be increased if the volume of data points increases from that shown in
the Parameter Table in this Agreement.
 
·
Help Desk

 
The technical Help Desk for EDC trials is billed monthly based on the number of
sites. Help Desk is available in multiple languages and has been priced for 24
hours per day, 7 days per week. The Help Desk charge has been calculated from
the “Go-Live” month until the trial is locked. An extended requirement for Help
Desk services will incur additional costs.
 
·
EDC Database Administration/Maintenance

 
EDC administration covers the required time to support the EDC system throughout
the trial on teleconference and responding to questions from InspireMD and
users. HCRI also monitors Help Desk and server issues, escalating or researching
problems that may occur.
 
Changes to the database after “Go-Live” may result in a contract change order
for out-of-scope requests. Changes that are made to forms or edit checks as a
result of a protocol amendment or per client request will incur additional
charges.
 
·
Study Portal

 
The study portal is a central repository for site users to access the most
recent versions of the protocol, CRF completion guidelines, and contact
information. In addition, memos, newsletters, and FAQs can be posted on the
portal for ease of access by all study users.
 
·
Submission Closeout

 
Once the final study report has been issued, and the trial is ready to be
archived, site-specific study data will be provided to each site and a complete
set of data will be created for InspireMD. This data will be provided as a PDF
(or other universally acceptable format) for easy navigation and to meet the
applicable regulatory guidelines.
 
Statistical Analysis & Reporting
 
·
Statistical Analysis Plan

 
The Statistical Analysis Plan (SAP) is a comprehensive and detailed description
of the statistical methods and presentation of data analyses proposed for a
clinical trial. The SAP is finalized prior to database locking and treatment
code unblinding, in order to avoid post hoc decisions that may affect the
interpretation of the statistical analysis. The SAP includes templates of
tables, listings, and figures to be presented in the statistical report as well
as definitions of all the populations to be analyzed (e.g., intention-to-treat,
as-randomized, per-protocol). A unique SAP is designed for every study at HCRI.
 
 
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·
Statistical Reports

 
Statistical reports will be prepared based on the approved SAP. The statistical
report includes tables, listings and graphs, as referenced in the study
parameters above, generated using SAS and output using the ODS feature in SAS. A
brief description of the study, statistical methods used in the analysis,
results of the study and conclusions are also included. The report will also
contain the event narratives, safety information, and a medical conclusion.
 
The tables and graphs are validated using double programming and 100% QC of all
the statistics displayed. The listings are validated by checking 10% of the data
displayed in the listings. The statistical report undergoes internal review at
HCRI prior to being released.
 
HCRI has budgeted for 1 interim report, 1 primary endpoint report at 12 Months,
and 1 annual report.
 
Clinical Events Committee (CEC) Services
 
HCRI has established a standing Clinical Events Committee under the guidance of
the Executive Director of Clinical Investigations, Donald Cutlip, MD. The CEC
will be responsible for adjudicating complications reported during the study
that are related to the study endpoints.
 
This committee is comprised of 3-5 physicians with experience in clinical trial
event adjudication, including at least one physician with expertise in each area
of the study, who are not participants in the study and who meet regularly
throughout the study to adjudicate events in an ongoing fashion. CEC members are
chosen based on their clinical expertise and have no association with any trial
for which they adjudicate events. The CEC is blinded to treatment assignment
during all deliberations. Three voting members comprise a quorum.
 
The CEC drafts and agrees upon its working charter for each study prior to
performing any work. This includes explicit rules outlining the minimum amount
of data required, and the algorithm followed in order to classify a clinical
event. HCRI will prepare the CEC Manual of Operations (MOP) based on this
information and the CEC MOP will serve as the guideline for adjudication for the
specific trial under review.
 
Clinical events related to the primary and secondary endpoints are identified
through the use of pre-specified edit checks which identify potential endpoint
related events. After review of the identified events by HCRI, support
documentation for identified events is obtained from the site, if necessary, and
a summary is written to describe the significant details of the event. These
summaries, with appropriate support documentation, are presented to the
physician members of the CEC. The results of the adjudications are entered into
the Complications database as well as on an Adjudication eCRF within the Inform
database after the CEC meeting. The Complications database is specifically
created within the overall study database and is used in the preparation of DMC
reports, as well as in all analyses of endpoint results.
 
 
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CEC meetings are held approximately 3 times per month at HCRI’s offices in
Boston, MA. As documentation of the CEC meeting and each event under review,
HCRI provides to InspireMD relevant supporting documentation and/or meeting
minutes. The format of the information will vary depending on whether or not
HCRI is involved with event narration.
 
Data Monitoring Committee (DMC) Services & Reporting
 
HCRI will manage Data Monitoring Committee (DMC) services for this study. A DMC
charter will be generated by HCRI, for approval by the DMC. DMC members will be
identified (either by InspireMD or InspireMD and HCRI), and HCRI will negotiate
and execute confidentiality and consulting agreements with the members.
 
The PM will provide oversight for all DMC-related activities including:
 
 
·
Holding meetings with the HCRI Project Team as well as with relevant Sponsor
representatives prior to initiating contact with the DMC.

 
·
Assuring that all members who accept the DMC invite are vetted through the HCRI
Conflict of Interest process.

 
·
Inviting potential DMC Members to participate on the DMC.

 
·
Holding an initial kick-off meeting/teleconference with DMC Members to review
the DMC Charter.

 
·
Scheduling and facilitating the DMC Meetings/Teleconferences that occur at a
mutually acceptable time for the DMC Members and the InspireMD.

 
·
Distributing DMC Reports to the DMC Members for review and distributing feedback
to InspireMD.

 
·
Addressing any post-DMC Meeting/Teleconference questions or correspondence with
regard to questions on the DMC Report or data integrity.

 
Prior to initiating contact with the DMC, the PM will schedule a teleconference
with the relevant Sponsor representatives in order to discuss the process
utilized by HCRI for DMC Management. Topics should include:
 
 
·
Reviewing the overall HCRI DMC process.

 
·
Describing the DMC Charter generation and review process.

 
·
Identifying any potential concerns in advance of the first DMC meeting.

 
·
Reviewing the process of inviting potential DMC Members.

 
·
Participating in Open and Closed Session of DMC Meetings/Teleconferences.

 
 
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·
Recording DMC Meeting/Teleconference minutes.

 
·
Ensuring that the DMC Meeting/Teleconference minutes are distributed and
communication occurs between the DMC and InspireMD per the DMC Charter.

 
·
Distributing the DMC Report to the DMC Members within the timeframe specified in
the DMC Charter.

 
·
DMC Charter

 
A study-specific DMC Charter will be created to guide the DMC. A Medical Writer
drafts the DMC Charter upon reviewing the protocol and receiving specific
guidance from InspireMD with respect to such issues as membership and number of
meetings. Following internal review by HCRI team members, the draft is reviewed
by InspireMD before being sent to the DMC via the Chair so that the DMC can
review and provide feedback.
 
·
DMC Reports

 
The DMC reports are usually generated from live data, which has not completed
the “cleaning” process. HCRI will provide a dataset to a statistician who is not
a member of the Project Team for analysis. This independent statistician will
generate the unblinded tables and listings. The DMC report will undergo
independent medical review by an HCRI physician and statistical review by an
independent statistician before being distributed to the DMC. The HCRI Project
Team and InspireMD will remain blinded to the interim analysis results.
 
This Agreement budgets for 3 DMC Reports and 4 DMC Meetings. Additional meetings
or reports will result in additional costs.
 
Clinical Site Management and Monitoring (US ONLY)
 
HCRI will have managerial oversight of the study from study start-up through
close-out as described below.
 
This study will be staffed with an experienced in-house team and with
regionally-based contract monitors with an expertise in monitoring medical
device studies. Each contract monitor assigned to the study will go through an
interview process to ensure that they have the necessary background and
experience to meet the needs of the study. InspireMD may also be involved in the
interview process, if requested. All monitors assigned to the study will have
extensive experience in training sites and conducting site visits in accordance
with FDA Regulations and International Conference on Harmonization (ICH
)guidelines.
 
 
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·
Investigator Selection

 
HCRI will collaborate with InspireMD to identify a list of potential
Investigators with proven experience at successfully enrolling patients and
providing quality data. As soon as InspireMD approves the first list of Clinical
Sites and Investigators, HCRI will begin contacting those Clinical Sites to
assess their interest and capabilities to conduct the study. HCRI will develop a
site selection questionnaire that will focus on the following areas:
 
 
·
Overall clinical trial set up

 
·
Available patient population

 
·
Enrollment potential including an ability to screen patients or receive
referrals

 
·
Current research staff including 24/7 screening and enrollment coverage

 
·
Competing studies – both for the same patient population and for research
staff’s time

 
·
Device storage requirements

 
·
Key IRB timelines

 
·
Budget requirements

 
Once the site selection questionnaire has been returned to HCRI, it will be
reviewed in collaboration with InspireMD. After a final list of Clinical Sites
has been agreed upon and approved by InspireMD, a Confidential Disclosure
Agreement (CDA) will be forwarded to each Clinical Site for signatures so the
study start-up process can begin.
 
·
Informed Consent

 
HCRI can assist InspireMD as needed with drafting a template informed consent in
English to be used by each Clinical Site for submission to its Institutional
Review Board (IRB). The informed consent will meet the ICH Guidelines for Good
Clinical Practice as published in the Federal Register May 9, 1997. HCRI will
review each Clinical Site’s informed consent template to ensure it meets
regulatory standards prior to IRB submission.
 
·
Study Start-Up and Clinical Site Qualifications

 
Per Sponsor request, a combination QSA/Initiation visit will be conducted if
HCRI or InspireMD has previously qualified the Clinical Site for the same
indication.
 
Clinical Sites selected will receive a complete regulatory document packet
customized for the study to assist with IRB submissions. HCRI will collect and
review all regulatory documents for accuracy, completeness, and regulatory
compliance. Once each Clinical Site has all its regulatory documents in order,
an Investigator Study Binder will be provided to each Clinical Site to store all
study related documents as well as house instructional manuals and study tools.
 
Once a Clinical Site has been approved to commence enrollment, a combination
Qualification/Initiation Visit will be conducted. This visit will ensure that
the study staff understands all aspects of the study, including protocol and CRF
review, review of regulatory requirements, specific study procedures, the
informed consent process, and device accountability. This visit will be
conducted once each site has received IRB approval and has executed a clinical
study agreement with InspireMD, and once all study supplies, including study
device, have been received by the site. An Initiation Visit report will be
submitted to InspireMD.
 
 
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·
Clinical Site Study Aids

 
HCRI will work with InspireMD to develop any study aids for the Clinical sites.
These include such aids as inclusion and exclusion cards, source document
worksheets, and protocol flip cards.
 
·
Clinical Site and Study Metrics

 
Study metrics will be provided to InspireMD on an agreed upon schedule. The
metrics will include an overview of Clinical Site status, enrollment by site, a
monitoring visit schedule and completed visits. HCRI will work with InspireMD at
the start of the study to determine the preferred metrics and timeframes for
providing these metrics.
 
·
Interim Monitoring Visits

 
Interim monitoring visits will be conducted at each Clinical Site at a regular
frequency according to the study needs during enrollment and follow-up. Each
visit can last anywhere from 6-8 hours and will be dependent upon the Clinical
Site’s patient enrollment rates and the complexity of the source document
verification. Between monitoring visits, the Clinical Research Associates (CRAs)
will contact Clinical Sites to assess enrollment activity, answer study related
questions, resolve queries and assist with any other issues regarding study
conduct. This contact will occur every one to two weeks. If additional onsite
interim monitoring visits are needed, InspireMD will be consulted for approval.
Interim Site Visit Reports will be submitted to InspireMD following each visit.
 
At the Interim Monitoring Visits the CRA will:
 
 
·
Assess enrollment and continuing protocol adherence;

 
·
Review all relevant source documents, in accordance with the Monitoring Plan;

 
·
Report any previously unreported SAEs to HCRI and InspireMD;

 
·
Investigate and resolve any outstanding queries;

 
·
Ensure that the investigational product is accounted for and that records are
accurate;

 
·
Conduct a continuing review of the Investigator study file for regulatory
adherence and to ensure that GCP/ICH guidelines are being followed, and

 
·
Perform 100% source documentation of the data entered, unless otherwise
specified by InspireMD.

 
·
Close-Out Monitoring Visits

 
A Closeout Monitoring Visit will be performed at each Clinical Site at the end
of the study to ensure regulatory compliance with regard to record retention,
proper disposition and accountability of the study device, and, most
importantly, that the site is audit-ready. A Close-Out Visit report will be
submitted to InspireMD.
 
 
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·
Clinical Site Contracts & Clinical Site Payments

 
HCRI will negotiate Clinical Site contracts and budgets on behalf of InspireMD.
HCRI will also administer grant payments to the Clinical Sites to include IRB
fees, startup fees, and per-patient stipends for US Clinical Sites and at the
request of InspireMD may do payments for the OUS vendor, subject to an agreed
upon CCO. Site budget estimates have been included in this Agreement.
 
·
Clinical Trial Management System (CTMS)

 
HCRI has an in-house Clinical Trial Management System to manage and monitor
Clinical Site information and status, Clinical Site documentation, subject
screening and enrollment and Clinical Site monitoring. Internal HCRI employees
will utilize the system for tracking study related activities. Contracted
Clinical Site monitors will utilize the system to document all Clinical Site
visits and submit site visit reports.
 
·
OUS Site Management and Monitoring

 
InspireMD will subcontract site management and monitoring services for OUS
Clinical Sites to a yet-to-be-determined OUS vendor.
 
ECG Core Laboratory Services
 
Incoming 12 lead ECGs will be evaluated for demographic consistency and
recording quality. ECG tracings will be manually evaluated by board certified
Cardiologists/Electrophysiologist. ECG tracings will be read and interpreted
with the comprehensive evaluation of rhythm, conduction intervals, and
morphology. ECGs will be evaluated at pre-procedure, hospital discharge, and
events.
 
 
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Budget Assumptions & Notes
 
Estimates Contained Herein:
 
The Estimated Budget for the Agreement is based upon the Project Parameters and
Task Matrix detailed above. Should any of these Parameters or Responsibilities
change, HCRI will prepare a Contract Change Order.
 
Timelines
 
InspireMD acknowledges and agrees that HCRI’s ability to meet agreed upon
timelines will be critically dependent upon the actions, approvals, directions
and/or information of or to be provided by InspireMD or its agents that directly
or indirectly impact HCRI Services. If HCRI considers any such actions,
approvals, directions and/or information or omissions of same problematic and
potentially having an adverse effect on its ability to provide Services and meet
established timelines, HCRI will promptly advise InspireMD of such concerns.
InspireMD agrees to provide any reasonable assistance and take any related
actions to address the concerns presented by HCRI with regard to InspireMD’s
requests. In the event that HCRI does not receive adequate assistance to address
the concerns presented as required to meet established timelines, the timelines
will be revised by InspireMD, if necessary, subject to mutual agreement by HCRI.
In the event that the project duration or other factors vary from those
estimated for this Agreement, HCRI may renegotiate the timing and amounts of the
payment schedule to reflect actual conduct of the project.
 
Documents and Deliverables:
 
All study documents and deliverables shall be delivered by HCRI in accordance
with timelines established. The determination of deliverable timelines shall
reflect the reporting requirements of InspireMD together with the operational
requirements and capabilities of HCRI. All study deliverables will require two
(2) drafts before finalization. InspireMD will submit one (1) set of
consolidated comments for the review of all draft documents and deliverables.
 
InspireMD recognizes that any delay by InspireMD or a 3rd party relied on by
InspireMD for the purpose of this Study may result in delays in HCRI
deliverables and/or the overall timeline which may result in a change in scope.
 
Costs are based on 2010 labor rates. HCRI reserves the right to review and
renegotiate labor rates with InspireMD on an annual basis, beginning one year
from the date of the Agreement.
 
At the request of InspireMD, estimates of Investigator Grants and IRB costs have
been included, beginning in this Agreement.  Because HCRI has not had the
opportunity to specifically contact sites with a study protocol and obtain
estimates, these amounts are subject to change.
 
Estimated travel costs for attending and participating in the investigators
meeting are included. Actual travel costs will be invoiced to InspireMD on a
time and materials basis. Meeting expenses will be invoiced to InspireMD as a
pass-through expense.
 
 
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Out of scope meetings with InspireMD are not included in the budget and will
incur additional charges. For all out of scope meetings, HCRI will invoice
InspireMD on a time and materials basis for actual time associated with meeting
attendance. Travel expenses (flight, lodging, food) associated with this
Agreement, if any, will be invoiced as a pass-through expense.
 
Teleconference costs for DMC Meetings and other team teleconferences that are
hosted by HCRI using HCRI’s dial-in number will be invoiced to InspireMD as a
pass-through cost.
 
Estimated costs for ECG Core Laboratory services have been provided. InspireMD
will be invoiced for a $4,758 startup fee and for actual ECG Core Laboratory
costs based on the actual number of readings conducted at a rate of $70 per ECG.
 
Costs associated with the preparation, processing and narrative generation of
Serious Adverse Events (SAE) estimated in this budget is a variable cost based
on the following assumptions:
 
 
·
Maximum of 2 manual queries per SAE

 
·
Maximum of 2 updates to the initial SAE review

 
·
Review of 5 pages of source documents per SAE

 
Increases to any of the parameters outlined above will be subject to
out-of-scope fees and revisions to the SAE review/processing cost(s).
 
Estimates for DMC participant costs have been estimated at a rate of $4,000 per
meeting and will be invoiced to InspireMD separately based upon the actual
number of meetings held.
 
Costs associated with the preparation, processing and adjudication of clinical
endpoints estimated in this budget is a variable cost based on the following
assumptions:
 
 
·
Receipt of a completed dossier as outlined by the minimum data requirements
sheet (which includes CRF data and source documentation).

 
·
Maximum of 2 manual queries per event

 
·
Review of an average of 5 pages of source documents per event identified for
adjudication

 
Increases to any of the parameters outline above will be subject to out-of-scope
fees and revision to the CEC services costs.
 
CEC physician costs will be invoiced at a rate of $350 per actual event
adjudicated by the CEC.
 
Costs for developing the CEC MOP include up to two (2) drafts for finalization.
Additional drafts are subject to out-of-scope fees.
 
Monitoring travel costs have been estimated at a rate of $1,200 per trip.
 
HCRI will invoice InspireMD for any printing, shipping, or binding required
during the course of the project as a pass-through expense.
 
 
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Distribution of MedDRA terminology, or analysis based on MedDRA terminology, to
the sponsor or the sponsor’s use of MedDRA will require the sponsor to have and
maintain a valid MedDRA license. DMC reports will be exempt from this
requirement if the DMC is managed by HCRI. Information can be found regarding
licensing on the MSSO web page, www.msso.org.
 
InspireMD will be responsible for obtaining a license to the WHO DD, WHO DDE or
WHO DDE+WHO HD. HCRI will not offer any compensation for such license. It is the
responsibility of both HCRI and InspireMD to validate via the UMC that the other
party has the proper license. The validation request application is to be found
at the following URL: http://www.umc-products.com/validation.
 
InspireMD is responsible for notifying the FDA of its  intent to use electronic
signatures in compliance with 21 CFR, Part 11.
 
 
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EXHIBIT B
 
Schedule of Fees
 
The fees identified below will be paid by Sponsor to HCRI for the services
described in the Agreement.
 
Milestone
EDC Services
Trial Services
Site Management Services
Site Monitoring Services (US)
Site Monitoring Services (OUS)
Site & Patient Payments
Monitor Travel
Total
Upon execution of CTSA
$27,844
$86,783
$22,351
$10,530
$0
$37,500
$2,400
$187,408
Upon 60 days after execution of CTSA
$27,844
$86,783
$22,351
$10,530
$0
$37,500
$2,400
$187,408
Upon Sponsor approval of eCRFs
$0
$18,430
$0
$0
$0
$0
$0
$18,430
Upon Establishing Date for Investigators' Meeting
$0
$0
$0
$0
$0
$0
$0
$0
Upon Submission of Regulatory Packet to 1st US Site
$0
$0
$14,900
$14,994
$0
$15,000
$4,800
$49,694
Upon 50% of US Sites Initiated
$0
$0
$14,900
$14,994
$0
$15,000
$4,800
$49,694
Upon 100% of US Sites Initiated
$0
$0
$14,900
$14,994
$0
$15,000
$4,800
$49,694
Upon EDC Database Go-Live
$55,688
$173,565
$0
$0
$0
$0
$0
$229,253
Upon Delivery of the Statistical Analysis Plan
$0
$23,260
$0
$0
$0
$0
$0
$23,260
                 
Report Milestones
               
Upon database lock for Primary Endpoint (12M) report
$0
$54,705
$0
$0
$0
$0
$0
$54,705
Upon delivery of Primary Endpoint report
$0
$54,705
$0
$0
$0
$0
$0
$54,705
Upon delivery of Statistical (30D) report
$0
$44,220
$0
$0
$0
$0
$0
$44,220
Upon delivery of 1st DMC report
$0
$27,920
$0
$0
$0
$0
$0
$27,920
Upon delivery of 2nd DMC report
$0
$27,920
$0
$0
$0
$0
$0
$27,920
Upon delivery of 3rd DMC report
$0
$27,920
$0
$0
$0
$0
$0
$27,920
Upon delivery of Annual Safety report
$0
$30,725
$0
$0
$0
$0
$0
$30,725
                 
Enrollment Milestones
               
Upon enrollment of 1st patient
$12,108
$81,764
$19,493
$35,870
$0
$0
$7,920
$157,155
Upon enrollment of 50th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 100th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 150th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 200th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 250th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 300th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 350th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148

 
 
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Upon enrollment of 400th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 450th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 500th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 550th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of 600th patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon enrollment of last patient
$12,103
$81,762
$19,493
$35,870
$0
$0
$7,920
$157,148
Upon completion of last patient follow up
$12,103
$81,762
$19,491
$35,869
$0
$0
$7,920
$157,145
                 
Quarterly Milestones (Calendar Quarters)
               
Upon Q1 after first patient enrolled
$0
$0
$0
$0
$0
$553,000
$0
$553,000
Upon Q2 after first patient enrolled
$0
$0
$0
$0
$0
$553,000
$0
$553,000
Upon Q3 after first patient enrolled
$0
$0
$0
$0
$0
$553,000
$0
$553,000
Upon Q4 after first patient enrolled
$0
$0
$0
$0
$0
$335,000
$0
$335,000
Upon Q5 after first patient enrolled
$0
$0
$0
$0
$0
$335,000
$0
$335,000
Upon Q6 after first patient enrolled
$0
$0
$0
$0
$0
$335,000
$0
$335,000
Upon Q7 after first patient enrolled
$0
$0
$0
$0
$0
$335,000
$0
$335,000
Upon Q8 after first patient enrolled
$0
$0
$0
$0
$0
$335,000
$0
$335,000
                 
To Be Billed as Incurred (Monthly/Quarterly)
               
Medical Management (Quarterly - $2,893/quarter)
$0
$26,033
$0
$0
$0
$0
$0
$26,033
Medical Monitoring (Monthly - $2,063/month)
$0
$66,025
$0
$0
$0
$0
$0
$66,025
CEC Participant Costs (131 events @ $350/event)
$0
$45,850
$0
$0
$0
$0
$0
$45,850
DMC Participant Costs (4 meetings @ $4,000/mtg)
$0
$16,000
$0
$0
$0
$0
$0
$16,000
Teleconference Pass Through Charges
$0
$2,760
$0
$0
$0
$0
$0
$2,760
ECG Read Costs (1373 reads @ $70/read)
$0
$96,110
$0
$0
$0
$0
$0
$96,110
Travel Costs for Investigators' Meeting
$0
$0
$0
$0
$0
$0
$0
$0
Credit for CSA Trial Design
$0
-$12,500
$0
$0
$0
$0
$0
-$12,500
Total
$292,925
$2,136,145
$381,795
$604,092
$0
$3,454,000
$138,000
$6,994,456

 
 
44

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Sponsor agrees to pay each invoice upon receipt of the invoice.  Accounts not
paid within forty-five (45) days of receipt of an invoice will be considered
overdue.
 
In the event the Agreement is terminated prior to reaching a payment milestone,
Sponsor agrees to pay HCRI for a pro-rated portion of the milestone on a time
and materials basis for actual work performed and documented.
 
Note:  The amounts presented above are for Clinical Trial Services provided by
HCRI and for estimated CEC meeting and Core Laboratory costs.  Sponsor will pay
HCRI for CEC meeting and Core Laboratory fees based on the actual number of
potential events brought to the CEC for adjudication and the actual number of
ECGs read, respectively.  Costs such as printing and shipping of CRFs and
related materials, travel expenses, overnight shipping, and other expenses
incurred in connection with the trial are not included and will be invoiced to
Sponsor as a pass-through expense.
 
 
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PAYMENT INSTRUCTIONS:

BY CHECK:

Checks should be payable to “Harvard Clinical Research Institute, Inc.”
All funds must be remitted in US Dollars

Tax ID #: 04-3521077

Contact:
John Cunningham

John.Cunningham@hcri.harvard.edu
Phone: (617)307-5496

Regular Mail:

Harvard Clinical Research Institute, Inc.
P.O. Box 846057
Boston, MA 02284

Overnight Carriers:

Harvard Clinical Research Institute, Inc.
Lockbox Department MMF250
20 Cabot Road
Medford, MA 02155

BY WIRE TRANSFER:

Account Name:
Harvard Clinical Research Institute, Inc.

Account Number:
1105095700

Bank Name:
Citizens Bank

870 Westminster
Providence, RI 02195
ABA Number:
011500120

Bank Telephone:
(800) 361-2472

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