NOTE: Information in this document marked with an "[*]" has been omitted and
filed separately with the Commission. Confidential treatment has been requested
with respect to the omitted portions.
Exhibit 10.41
MASTER SERVICES AGREEMENT
This Master Agreement ("AGREEMENT") made this 9th day of July 2001 by and
between Introgen Therapeutics, Inc., with its principal executive offices
located at 301 at Congress Avenue, Suite 1850, Xxxxxx, Xxxxx 00000, XXX
("SPONSOR"), and PPD Development, LLC, a Texas limited liability company with
its principal executive offices located at 0000 00xx Xxxxxx Xxxxxxxxx,
Xxxxxxxxxx, Xxxxx Xxxxxxxx 00000, XXX along with its affiliate PPD Global Ltd
(collectively "PPD").
WHEREAS, Sponsor is engaged in the development, manufacture, distribution,
and sale of pharmaceutical product; and
WHEREAS, PPD is a contract research organization engaged in the business
of managing clinical research programs; and
WHEREAS, Sponsor may wish to retain the services of PPD from time to time
to perform clinical research services in connection with certain clinical
research programs Sponsor is conducting (individually, "STUDY") as more fully
set forth in various project specific addenda to be attached to this Agreement
and incorporated herein by reference ("PROJECT ADDENDA"), which Study Sponsor
intends to submit to the United States Food and Drug Administration ("FDA") and
other international regulatory authorities as part of a marketing approval
application; and
WHEREAS, PPD is willing to provide such services to Sponsor in accordance
with the terms and conditions of this Agreement and attached Project Addenda.
NOW, THEREFORE, for good valuable consideration contained herein, the
exchange, receipt and sufficiency of which are acknowledged, the parties agree
as follows:
1. PROJECT ADDENDA.
----------------
1.1 In the event that the parties hereto shall reach agreement with
respect to a particular project (a "PROJECT") in connection with a Study, a
Project Addendum for said Project shall be attached and incorporated into this
Agreement, and the two shall collectively, independent from other Project
Addenda, constitute the entire agreement for the specific Project. At a minimum,
the Project Addenda for each Project shall include schedules that describe each
of the following:
(a) - Scope of services and deliverables to be provided by PPD
("SERVICES");
(b) - Milestones for the Services ("MILESTONES");
(c) - Budget for the PPD's provision of Services ("PROJECT BUDGET"); and
(d) - Payment schedule for the Services ("PAYMENT SCHEDULE").
1.2 No Project Addendum shall be attached to this Agreement without first
being executed by the parties hereto. To the extent any terms set forth in a
Project Addendum shall conflict with the terms set forth in this Agreement, the
terms of this Agreement shall control, unless the
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conflicting terms in this Agreement are specifically referenced in the Project
Addendum and stated to be superceded.
2. SERVICES.
---------
2.1 PPD hereby agrees to provide to Sponsor the Services described in
each Project Addendum attached to this Agreement. In performing the Services,
PPD shall comply with the terms of this Agreement, the applicable Project
Addendum (including the Protocol described), the written instructions of
Sponsor, standard operating procedures approved by Sponsor, relevant
professional standards and all applicable laws, rules and regulations,
including, but not limited to, the Federal Food, Drug and Cosmetic Act and the
regulations and guidelines promulgated pursuant thereto for the conduct of
Clinical Trials used to support marketing approval for pharmaceutical products.
2.2 In the event that PPD is requested or required to perform services
and/or deliverables for a Project beyond those that are specifically set forth
in the pertinent Project Addendum's description of Services, any such
additional services and/or deliverables, and the milestones, project budget and
payment schedule therefor, must be mutually agreed upon by the parties in
writing prior to the provision of said services and deliverables. Said mutually
agreed upon writing shall be an amendment to the pertinent Project Addendum.
The services and deliverables, and the corresponding milestones, project budget
and payment schedule set forth in that amendment shall be deemed to be included
within the Services, Milestones, Project Budget and Payment Schedule for the
pertinent Project Addendum.
3 COMPENSATION AND PAYMENT.
-------------------------
3.1 The Project Budget set forth in each Project Addendum shall be fully
transparent and include all planned activities and all planned costs for the
applicable Project. For each Project, Sponsor need not pay for any costs-nor
reimburse PPD for any out-of-pocket expenses-other than those set forth in the
applicable Project Budget, unless the parties otherwise agree in writing.
3.2 Except as otherwise provided in an applicable Payment Schedule, PPD
shall, on a monthly basis, submit to Sponsor invoices for each Project Addendum
describing the Milestones successfully performed by PPD during the preceding
month. Sponsor shall pay said invoices within thirty (30) days of receipt,
subject to Section 3.4.
3.3 Travel and other out-of-pocket expenses that PPD reasonably incurs in
connection with its performance of Services and that are provided for in an
applicable Project Budget shall be reimbursed by Sponsor within thirty (30)
days of Sponsor's receipt of PPD's invoice, subject to Section 3.4 and the
following:
(a) PPD's invoice shall include an itemized statement listing all
such expenses, together with any appropriate supporting documentation therefor.
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(b) In situations where expenses incurred by PPD may also be
allocated to PPD's other customers (e.g., a site visit to an institution
participating in a Study and a clinical study sponsored by one or more of PPD's
other customers), PPD shall invoice Sponsor for only its equitable portion of
such expenses. Whenever possible, PPD shall manage its activities on behalf of
Sponsor and its other customers in such a fashion as to maximize the
opportunity for the sharing of expenses.
(c) In order to receive reimbursement for any out-of-pocket
expenses, PPD must provide a copy of a written receipt of any expense of [*] or
more. Specific prior approval shall be obtained for any expense of [*] or more.
PPD will not be asked to initiate work before such approval is given. PPD will
conform to PPD's Travel Policy.
(d) It is expressly understood that all out-of-pocket expenses shall
not have profit, overhead or general administration factors applied to them and
shall be separately accounted for by PPD. Any savings due to under-spending in
Investigator grants or laboratory charges may not be applied to labor or other
out-of-pocket costs without the prior written approval of Sponsor. As used in
this Agreement, "INVESTIGATOR" means a licensed health-care professional who PPD
or Sponsor engages to conduct a Study. PPD will not make investigator payments
on behalf of the Sponsor until such payment is first received from the Sponsor.
3.4 Sponsor need not pay for any portion of an invoice that contains
disputed amounts. Any disagreement between Sponsor and PPD regarding Services
performed or expenses incurred by PPD and specified on an invoice must be
resolved in full before that portion of the invoice shall be paid by Sponsor.
Sponsor need not pay for any time or expense incurred by PPD in reconciling
invoices. In the event of a dispute regarding an invoice, Sponsor shall pay the
undisputed portion and the parties shall negotiate in good faith in an effort
to resolve promptly such dispute. In no event shall Sponsor be obligated to pay
any invoices which are received more than one hundred and twenty (120) days
after completion or termination of the Project. Sponsor should contact PPD ten
(10) days after receiving an invoice with any disputes to allow resolution and
prompt payment.
3.5 Payments to PPD shall be made to:
PPD Development, LLC
X.X. Xxx 00000
Xxxxxxxxx, XX 00000-0000
Tax ID# 00-0000000
3.6 Taxes (and any penalties thereon) imposed on any payment made by
Sponsor to PPD shall be the responsibility of PPD.
3.7 Sponsor, or its auditors, may audit any financial records of PPD
associated with this Agreement upon 48 hours notice until two years after the
expiration or termination of this Agreement. Such records may include, invoices
from third parties, contracts with third parties and payments relating to the
project or Study. To the extent such records are not separable from other
customer records, PPD shall grant reasonable access to the record to an
independent auditor
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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selected by Sponsor. In no event shall such auditors be entitled to disclose to
Sponsor any information relating to projects for PPD's other customers. In the
event it is determined that PPD has overcharged Sponsor for any out-of-pocket
expenses, PPD shall promptly reimburse Sponsor for the amount of such overcharge
and, if such overcharge represents more than five percent (5%) of the
out-of-pocket expenses for a particular Project, pay Sponsor's reasonable fees
and expenses incurred in connection with such audit.
4. PROJECT MANAGEMENT.
------------------
4.1 PERFORMANCE METRICS. PPD understands that the Studies described in the
Project Addenda are pivotal studies for Sponsor and will be filed by Sponsor as
part of a marketing application to worldwide regulatory authorities, including
the U.S. FDA, and, therefore, Sponsor has established particular timeframes for
filing marketing applications to various regulatory authorities. PPD shall
exercise all reasonable efforts to meet said established timelines. Accordingly,
for any particular Study, in the event PPD's services do not conform to its
obligations set forth in the Study contract, PPD shall be obligated to reperform
the non-conforming services at no cost to Sponsor. In the event reperformance
does not cure the non-conforming services within 30 days of written notice of
the non-conformance, PPD shall not be entitled to compensation for the non-
conforming services.
4.2 MUTUALLY ACCEPTABLE SOLUTION. In the event a particular Project or
Study falls behind schedule, PPD shall propose, and the parties shall endeavor
to agree upon, a mutually acceptable solution to bring the Project or Study back
onto schedule or to take whatever other action is required to remedy the
problem. Sponsor will not be responsible for reimbursing PPD for any costs or
expenses incurred in accordance with this Article 4 unless such delay is a
product of Force Majeure or Sponsor delay. For the avoidance of doubt, nothing
in this Article 4 is intended to limit or prevent Sponsor from exercising its
rights under Section 4.1 (Performance Metrics) or Article 6 (Term and
Termination of Agreement) hereof.
5. TRANSFER OF OBLIGATIONS.
-----------------------
This Agreement contemplates that Sponsor will transfer various regulator
responsibilities to PPD, as defined by a Project Addendum. PPD agrees to accept
the transferred responsibilities and agrees to carry out diligently all
transferred obligations. Pursuant to 21 CFR section 312.52, or other applicable
regulatory law, rules or regulation, Sponsor and PPD shall cooperate in the
completion of a Transfer of Obligations Form in conjunction with each Project
Addendum. Any responsibilities not specifically transferred by Sponsor in the
Transfer of Obligations Form or similar document with the FDA, where
appropriate, or as required by law or regulation, shall remain the
responsibility of Sponsor.
6. TERM AND TERMINATION.
--------------------
6.1 The term of this Agreement shall commence as of the date hereof and,
unless earlier terminated in accordance with this Section 6, continue for [*]
years from the commencement date; Project Addenda executed under this Agreement
prior to this Agreement's termination shall continue
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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uninterrupted under the terms and conditions of this Agreement unless the
Project Addenda are otherwise terminated as provided herein."
6.2 This Agreement and any Project Addendum may be terminated with or
without cause by Sponsor upon thirty (30) days prior written notice. Sponsor
may also, without terminating this Agreement or the applicable Project
Addendum, elect to assume responsibility for managing and monitoring all or any
portion of a Project or Study (in which case, the Project Budget for the
Services, and the Payment Schedule for the various Milestones shall be reduced
accordingly).
6.3 If either party materially defaults under this Agreement ("DEFAULTING
PARTY"), the other ("NON-DEFAULTING PARTY") may give the Defaulting Party
written notice of the default and elect to terminate this Agreement upon
written notice to the Defaulting Party if, within thirty (30) days after
delivery of the default notice by the Non-Defaulting Party, the Defaulting
Party fails to resolve the default by (i) curing the default or beginning the
cure of the default and diligently completing the cure of the default by the
end of the aforementioned thirty (30) day time period, (ii) providing a written
explanation reasonably satisfactory to the Non-Defaulting Party that a default
has not occurred, or (iii) entering into a written agreement with the
Non-Defaulting Party for the cure or other resolution of the default. The
rights granted to the Non-Defaulting Party pursuant to this Section 6.3 shall
be in addition to and not in substitution for any other remedies that may be
available to such party. Except as otherwise expressly stated herein,
termination shall not relieve the Defaulting Party from liability and damages
to the other party for breach of this Agreement.
6.4 This Agreement may be terminated by a party upon written notice to
the other in the event that (i) the other party shall make an assignment for
the benefit of its creditors, file a petition in bankruptcy, petition or apply
to any tribunal for the appointment of a custodian, receiver or any trustee for
it or a substantial part of its assets, or shall commence any proceeding under
any bankruptcy, reorganization, arrangement, readjustment of debt, dissolution
or liquidation law or statute of any jurisdiction, whether now or hereafter in
effect; or (ii) if there shall have been filed against the other party any such
bona fide petition or application, or any such proceeding shall have been
commenced against it, in which an order for relief is entered or which remains
undismissed for a period of ninety (90) days or more; or (iii) if the other
party by any act or omission shall indicate its consent to, approval of, or
acquiescence in any such petition, application, or proceeding or order for
relief or the appointment of a custodian, receiver or trustee for it or any
substantial part of its assets, or shall suffer any such custodianship,
receivership or trusteeship to continue undischarged for a period of ninety
(90) days or more. Termination shall be effective upon the date specified in
such notice.
6.5 Subject to the second sentence of Section 6.2, the termination of
this Agreement by either party shall automatically terminate any and all
Project Addenda, unless otherwise agreed.
6.6 Upon termination of this Agreement or a Project Addendum pursuant to
this Section 6, PPD shall cooperate with Sponsor to provide for an orderly
wind-down and transfer of the data and work product provided by PPD hereunder.
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6.7 The obligations of the parties contained in Articles 3, 6 and 7
through 25 hereof shall survive termination of this Agreement.
7. PERSONNEL.
----------
7.1 The Services with respect to each Project shall be performed by PPD
under the direction of the person identified as the "PROJECT MANAGER" in the
applicable Project Addendum or such other person acceptable to Sponsor as PPD
may from time to time designate the Project Manager, such Sponsor acceptance to
be in writing and not to be unreasonable withheld.
7.2 PPD shall perform the Services with respect to each Project with
highly qualified, trained and educated personnel knowledgeable in U.S. and
international Good Clinical Practices (GCPs), applicable regulatory
requirements, clinical project management, pharmaceutical drug development and,
if possible, in Sponsor therapeutic areas and products. PPD is responsible for
the training of its staff in order to maintain their knowledge to the state of
the art. The costs for such training will be fully covered by PPD.
7.3 Any "KEY PERSONNEL" described in a Project Addendum shall not - be
removed from the relevant Project, nor shall the responsibilities of such Key
Personnel be materially reduced or altered except where said Key Personnel has
terminated employment with PPD, has been promoted, is out on medical leave, is
otherwise physically unable to perform the required services or without the
prior written consent of Sponsor, which consent shall not be unreasonably
withheld.
7.4 PPD shall terminate immediately the assignment of any PPD staff
member working under this Agreement for reasonable cause identified by Sponsor.
7.5 PPD shall not subcontract or assign any Services under a Project
Addendum without the prior written consent of Sponsor.
7.6 During the period in which a particular Project is being conducted,
neither party shall recruit, hire or employ any personnel of the other who is
material to the performance of the particular Project without the prior written
consent of the other party.
8. CONFIDENTIALITY.
----------------
8.1 PPD agrees to treat any confidential or proprietary information
obtained from Sponsor or generated or created by PPD as a direct and sole
result of performing the Services under this Agreement (other than, unless
specifically included in a Project Addendum, any PPD Property as defined in
Section 9.3)(to be referred to herein as the "CONFIDENTIAL INFORMATION"), as
the confidential and exclusive property of Sponsor.
8.2 PPD agrees that it will use the Confidential Information only to
provide the Services and for no other purpose without the prior written consent
of Sponsor. PPD agrees not to disclose any of the Confidential Information to
any third party without first obtaining the written consent of Sponsor. PPD
further agrees not to disclose the Confidential Information to any of its
directors,
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officers, employees, agents, representatives and advisors other than those who
have a need to know such information in order to perform Services and who are
bound in writing by obligations of confidentially and non-use with respect to
the Confidential Information at least as stringent as those provided in this
Agreement.
8.3 The above provisions of confidentiality shall not apply to that part
of the Confidential Information which PPD is able to demonstrate by documentary
evidence:
(a) was in PPD's possession prior to receipt from Sponsor, as
established by contemporaneous written records, or is developed independent
from a Project; or
(b) was in the public domain at the time of receipt from Sponsor; or
(c) becomes part of the public domain without breach of
confidentiality by PPD, its directors, officers, employees, agents,
representatives or advisors; or
(d) is lawfully received by PPD from some third party having a right
of further disclosure.
8.4 In the event that PPD is required by law to disclose any Confidential
Information, PPD will, as soon as possible (and in any event prior to such
disclosure), notify Sponsor of such requirement so that Sponsor may seek a
protective order or other appropriate remedy, or in its sole discretion, waive
compliance with this Section 8.4. In the event that no such protective order or
other remedy is obtained, or in the event that Sponsor waives compliance with
this Section 8.4, PPD will furnish only that portion of the Confidential
Information which it is advised by counsel it is legally required to furnish
and will exercise all reasonable efforts to obtain reasonable assurance that
confidential treatment will be accorded the Confidential Information so
furnished.
8.5 PPD agrees that upon termination or expiration of this Agreement or,
at Sponsor's request, it shall (and shall cause its directors, officers,
employees, agents, representatives and advisors to) return to Sponsor all parts
of the Confidential Information provided by Sponsor in documentary form and
return or destroy any copies thereof made by PPD, its directors, officers,
employees, agents or representatives. Notwithstanding the foregoing, PPD may
retain copies of any such Confidential Information as is reasonably necessary
for regulatory, insurance or business purposes, subject to the ongoing
obligation to maintain the confidentiality of such information.
8.6 PPD acknowledges that disclosure or distribution of the Confidential
Information or use of the Confidential Information contrary to the terms of this
Agreement may cause irreparable harm for which damages at law may not be an
adequate remedy, and agrees that the provisions of this Agreement prohibiting
disclosure or distribution of the Confidential Information or use contrary to
the provisions hereof may be specifically enforced by a court of competent
jurisdiction in addition to any and all other remedies available at law or in
equity.
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8.7 All Confidential Information containing personal data shall be handled
in accordance with all applicable law, including, but not limited to the
European Data Protection Directive [EC/95/46], Health Insurance Portability and
Accountability Act and applicable implementing regulations.
9. OWNERSHIP.
----------
9.1 Neither anything contained herein nor the delivery of any information
to a party shall be deemed to grant the receiving party any right or licenses
under any patents or patent applications or to any know-how, technology or
inventions of the disclosing party.
9.2 Sponsor Property.
(a) Inventions. Subject to Section 9.3 below, PPD shall disclose to
Sponsor, hereby assigns to Sponsor, and shall continue to assign to Sponsor
immediately upon creation during the term of this Agreement, all rights PPD or
its directors, officers, employees, agents or representatives may have in any
invention, technology, know-how or other intellectual property that is: (1)
conceived of, made and/or reduced to practice in the course of performing work
under this Agreement; or (2) specifically set forth as a deliverable under a
Project Addendum (collectively, "INVENTIONS"). In addition, PPD agrees to
assist Sponsor, at Sponsor's expense, in obtaining or extending protection
therefor. Without limiting the foregoing, whenever requested to do so by
Sponsor, PPD shall execute any and all applications, assignments, or other
instruments, and give testimony which Sponsor shall deem necessary to apply for
and maintain letters of patent of the United States or any other country or to
protect otherwise Sponsor's interest in the Inventions.
(b) Information. Subject to section 9.3 below, as between PPD and
Sponsor, all budgets, bids, proposals, Protocols, coding dictionaries and other
materials, documents, information, and programs of every kind and description
supplied to PPD or Investigators by or on behalf of Sponsor, and, all
materials, documents and information prepared or developed by PPD or
Investigators in the course of performing the work provided for in this
Agreement, shall be the sole and exclusive property of Sponsor, and upon
request, PPD will provide Sponsor with all or any designated portion of such
property, or copies thereof.
9.3 PPD Property. It is acknowledged that PPD possesses certain
inventions, processes, know-how, trade secrets, improvements, other
intellectual properties and other assets, including but not limited to, data
processes, technology, means or know-how developed by PPD which relate to data
collection or data management and laboratory analyses, analytical methods,
procedures and techniques, computer technical expertise and software (including
codes) which have been independently developed without the benefit of any
information provided by Sponsor (collective, "PPD Property"). Sponsor and PPD
agree that any PPD Property or improvements thereto are the sole and exclusive
property of PPD.
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9.4 In furtherance of the limitations set forth in this Article 9, it is
expressly understood that PPD will not use any materials provided by or on
behalf of Sponsor in connection with the Project or Study for any purposes
other than for fulfilling its obligations hereunder.
10. PUBLICATION.
------------
PPD may not publish any articles or make any presentations relating
to the Services or referring to data, information or materials generated as
part of the Services, in whole or in part, without the prior written consent of
Sponsor.
11. INDEMNIFICATION.
----------------
11.1 Sponsor shall indemnify PPD, it directors, officers, employees, and
affiliates ("PPD INDEMNITEES") for any and all damages, costs, expenses and
other liabilities, including reasonable attorney's fees and court costs,
incurred by PPD as a result of any claim, suit action, demand or judgment for
personal injury (i) suffered by a patient participating in the Study as a
result of the administration of the Study Drug in accordance with the Protocol
provided to PPD by Sponsor, from protocol required procedures; or (ii) arising
from or growing out of the negligence of Sponsor or the breach by it of this
Agreement, or resulting from PPD following the written directive of Sponsor,
provided in each case that such injury was not the result of the failure to
administer the Study Drug in accordance with the Protocol or the negligence or
willful misconduct of any PPD Indemnitee or their respective employees or
agents. For the purpose of this Agreement, "STUDY DRUG" means any drug (in
monotherapy or in combination) to be used in a Study, as described in the
Protocol.
11.2 PPD shall indemnify Sponsor, its directors, officers, and employees
("SPONSOR INDEMNITIES") for any and all damages, costs, expenses and other
liabilities, including reasonable attorney's fees and court costs, incurred by
Sponsor as a result of any claim, suit, action, demand or judgment arising from
or growing out of (i) the negligence or willful misconduct of PPD or its
employees or agents or the breach of any provision of this Agreement, or (ii)
the claimed or alleged status of any employee or agent of PPD as an employee or
agent of Sponsor, provided in each case that such claim, suit, action, demand
or judgment was not the result of the negligence or willful misconduct of any
Sponsor Indemnitee or their respective employees or agents.
11.3 Any party liable to provide the indemnification hereunder shall be
entitled, at its option, to control the defense and settlement of any claim on
which it is liable, provided that the indemnifying party shall act reasonably
and in good faith with respect to all matters relating to the settlement or
disposition of the claim as the disposition or settlement relates to the party
being indemnified. The indemnified party shall reasonably cooperate in the
investigation, defense and settlement of any claim for which indemnification is
sought hereunder and shall provide prompt notice of any such claim or reasonably
expected claim to the indemnifying party. An Indemnified party shall have the
right to retain its own separate legal counsel at its own expense.
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12. INSURANCE.
----------
Each party will procure and maintain throughout the term of this Agreement
Comprehensive or Commercial Form General Liability Insurance, and PPD will
additionally procure and maintain throughout the term of this Agreement
Professional Liability Insurance (contract liability included), or in each case
an equivalent program of self insurance with limits not less than:
(a) Combined Single Limit Per Occurrence - [*]
(b) General and Professional Annual Aggregate - [*]
Each party agrees to furnish the other, upon request, an original
certificate of insurance reasonably acceptable to the other indicating the
required coverage. Each party agrees that the insurance will not be canceled
while this Agreement is in effect without thirty (30) days prior written notice
to the other party. Should PPD at any time neglect or refuse to provide the
insurance required herein, or should such insurance be canceled, Sponsor shall
have the right to procure the same and the cost thereof shall be deducted from
any compensation then due or thereafter to become due to PPD. PPD shall not
commence work under this Agreement until the insurance required herein has been
obtained.
13. REPRESENTATION AND WARRANTIES
-----------------------------
13.1 PPD represents and warrants to Sponsor that:
(a) it is authorized to enter into this Agreement, and that its
execution, delivery and performance of this Agreement will not conflict with or
constitute a default under any other agreement to which it is a party or by
which its assets are bound; and
(b) all aspects of PPD's facilities which may be used in the
performance of any Services, including without limitation the databases to be
used by PPD for the tracking, handling, recording, reporting and transmitting
of data generated during the Projects and Studies have been fully verified and
validated according to applicable industry standards.
(c) It is not a party to any agreement that would prevent it from
fulfilling its obligations under this Agreement and that, during the term of
this Agreement, it will not enter into any agreement to provide services that
would in any way prevent it from providing the Services contemplated under this
Agreement.
13.2 Sponsor represents and warrants to PPD that it is authorized to
enter into this Agreement, and that its execution, delivery and performance of
this Agreement will not conflict with or constitute a default under any other
agreement to which it is a party or by which its assets are bound.
14. INDEPENDENT CONTRACTOR RELATIONSHIP.
------------------------------------
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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The parties hereto are independent contractors and nothing contained in
this Agreement shall be construed to place them in the relationship of partners,
principal and agent, employer/employee or joint venturer. Both parties agree
that neither party (including such party's employees, servants, agents or
independent contractors) shall have power or right to bind or obligate the other
party, nor shall either hold itself out as having such authority.
15. PUBLICITY.
----------
Except as required by law, neither party shall use the name of the other
party nor of any employee of the other party in connection with any publicity
without the prior written approval of the other party.
16. FORCE MAJEURE.
--------------
Both parties to this Agreement shall be excused from the performance of
their obligations under this Agreement if such performance is prevented by force
majeure and the non-performing party promptly provides notice of the prevention
to the other party. Such excuse shall be continued so long as the condition
constituting force majeure continues and the non-performing party takes
reasonable efforts to remove the condition. Any timelines affected by such force
majeure shall be extended for a period equal to that of the delay and any
affected Study Budgets shall be adjusted to reflect costs increases resulting
from force majeure. For purposes of this Agreement, force majeure shall include
conditions which are beyond the reasonable control of a party and which could
not have been avoided by the exercise of reasonable diligence, including without
limitation, an act of God, compliance with any regulation, law or order of any
government, war, civil commotion, epidemic, or failure or default of public
utilities.
17. ACCESS TO SITES AND DATA.
-------------------------
17.1 PPD shall ensure that Sponsor's authorized representatives upon
reasonable notice, and regulatory authorities to the extent permitted by law,
may, during regular business hours, (i) examine and inspect the facilities of
PPD or any Investigator site used in the Project and/or Study, and (ii) inspect
and copy all data, documentation and work products relating to the Project
and/or Study, including, without limitation, the medical records of any patient
participating in the Project and/or Study. Sponsor's right to inspect and copy
all data, documentation, and work products relating to the Project and Study
shall survive any termination of this Agreement or the completion of the Project
and Study for two years after PPD stops providing services hereunder, or such
longer period as shall be required by law.
17.2 Notwithstanding anything else in this Agreement to the contrary, PPD
shall retain and preserve one (1) copy only of all records relating to the
Project and Study for two (2) years after PPD stops providing services
hereunder or such period as shall be required by law (such period being
referred to herein as the "Retention Period"). At the end of such period, PPD
may destroy all such material upon giving Sponsor written notice of its intent
to do so at least sixty (60) days prior to destruction.
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18. REGULATORY COMPLIANCE AND INSPECTIONS.
--------------------------------------
Each party acknowledges that the other party may respond independently
to any regulatory correspondence or inquiry in which such party or its
affiliates is named. Each party, however, shall:
(a) notify the other party promptly of any FDA or other governmental or
regulatory inspection or inquiry concerning any Study or Project of Sponsor in
which PPD is providing Services, including, but not limited to, inspection of
investigational sites or laboratories;
(b) forward to the other party copies of any correspondence from any
regulatory or governmental agency relating to such a Study or Project,
including, but not limited to, Form FD-483 notices, or warning letters, even if
they do not specifically mention the other party; and
(c) obtain the written consent of the other party, which will not
unreasonably be withheld, before referring to the other party or any of its
affiliates in any regulatory correspondence. Where reasonably practicable, each
party will be given the opportunity to have a representative present during an
FDA or regulatory inspection. Each party, however, acknowledges that it may not
direct the manner in which the other party fulfills its obligations to permit
inspection by governmental entities.
Each party agrees that, during an inspection by the FDA or other regulatory
authority concerning any Study or Project of Sponsor in which PPD is providing
Services, it will not disclose information and materials that are not required
to be disclosed to such agency without the prior consent of the other party,
which consent shall not unreasonably be withheld. Such information and materials
include, but are not limited to, the following:
(a) financial data and pricing data (including, but not limited to, the
budget and payment schedule); and
(b) personal data (other than data relating to the qualification of
technical and professional persons performing functions subject to the
regulatory requirements).
19. DEBARMENT.
----------
19.1 PPD hereby certifies that it has not been debarred, and has not been
convicted of a crime which could lead to debarment, under any applicable law,
rule or regulation, as amended. In the event that PPD or any of its officers,
directors, employees or agents under contract to perform services under a
Project Addendum with Sponsor becomes debarred or receives notice of action or
threat of action with respect to its debarment, PPD shall notify Sponsor
immediately, and Sponsor shall have the right to immediately terminate this
Agreement pursuant to Article 4.
19.2 PPD hereby certifies that it has not utilized, and will use its
reasonable best efforts not to utilize, the services of any individual or entity
in the performance of services under this Agreement or any Project Addendum
that has been debarred or that has been convicted of a crime that could lead to
debarment under any applicable law, rule or regulation, as amended. In the
event that PPD receives notice of the debarment or threatened debarment of any
such individual or entity,
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PPD shall notify Sponsor immediately, and Sponsor shall have the right to
immediately terminate this Agreement pursuant to Article 4.
20. NOTICES.
--------
Any notice required or permitted to be given hereunder by either party
hereunder shall be in writing and shall be deemed given on the date received if
delivered personally or five (5) days after the date postmarked if sent by
registered or certified mail, return receipt requested, postage prepaid to the
following address (or such other address or addresses of which a party shall
have given written notice to the other):
If to PPD: PPD Development, LLC
0000 00xx Xxxxxx Xxxxxxxxx
Xxxxxxxxxx, Xxxxx Xxxxxxxx 00000
Attention: CEO
Tel: (000) 000-0000
Fax: (000) 000-0000
If to Sponsor: Introgen Therapeutics, Inc.
000 xx Xxxxxxxx Xxxxxx
Xxxxx 0000
Xxxxxx, Xxxxx 00000
Attention: President
Tel: (000) 000-0000
Fax: (000) 000-0000
21. GOVERNING LAW.
--------------
This Agreement and the rights and obligations of the parties hereunder
shall be governed by the laws of the State of Texas, without regard to
conflict-of-law principles.
22. SEVERANCE.
----------
If any one or more provisions of this Agreement shall be found to be
illegal or unenforceable in any respect from which no appeal can be taken, the
validity, legality and enforceability of the remaining provisions shall not in
any way be affected or impaired thereby. In such case, the parties shall in
good faith modify or substitute such provision consistent with the parties'
original intent.
23. WAIVER.
-------
Waiver or forbearance by either party or the failure by either party to
claim a breach of any provision of this Agreement or exercise any right or
remedy provided by this Agreement or applicable law, shall not be deemed to
constitute a waiver with respect to any subsequent breach of any provision
hereof.
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24. CHANGES AND MODIFICATION.
-------------------------
No changes or modifications of this Agreement or any Project Addendum
shall be deemed effective unless in writing and executed by the parties hereto.
25. ASSIGNMENT.
-----------
This Agreement and any Project Addenda may not be assigned by PPD without
the prior written consent of the Sponsor.
26. ENTIRE AGREEMENT.
-----------------
This Agreement (including the Project Addenda) represents the complete and
entire understanding between the parties regarding the subject matter hereof
and supersedes all prior negotiations, representations or agreements, either
written or oral, regarding this subject matter.
27. COUNTERPARTS.
-------------
This Agreement may be executed in counterparts, each of which shall be
deemed an original and all of which shall constitute one and the same agreement.
IN WITNESS THEREOF, this Agreement has been executed by the parties hereto
through their duly authorized officers as of the date set forth above.
PPD DEVELOPMENT, LLC INTROGEN THERAPEUTICS, INC.
By: /s/ Xxxx X. Xxxxxxxxx, M.D. By: /s/ J. Xxxxx Xxxxx, Xx.
-------------------------------- ------------------------------
Name: Xxxx X. Xxxxxxxxx, M.D. Name: J. Xxxxx Xxxxx, Xx.
------------------------------ ----------------------------
Title: Sr. V.P. Medical Affairs/CSO Title: V.P. Operations
----------------------------- ---------------------------
Approved
MC 12/17/01
PPD CONTACTS
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[*]
PROJECT ADDENDUM
This agreement ("PROJECT AGREEMENT") made this 1st day of September 2001 by
and between Introgen Therapeutics, Inc., with its principal executive offices
located at 301 at Congress Avenue, Suite 1850, Xxxxxx, Xxxxx 00000, XXX
("SPONSOR"), and PPD Development, LLC, a Texas limited liability company with
its principal executive offices located at 0000 00xx Xxxxxx Xxxxxxxxx,
Xxxxxxxxxx, Xxxxx Xxxxxxxx 00000, XXX along with its affiliate PPD Global Ltd
(collectively "PPD").
WHEREAS, a Master Services Agreement ("Agreement") by and between PPD and
Sponsor was executed July 20, 2001; and
WHEREAS, pursuant to Section 1 of the Agreement the parties now enter into
this Project Addendum for the purposes of setting forth the responsibilities and
obligations of the parties in regards to conducting certain clinical research
programs entitled "A Phase III, Multicenter, open-label, randomized study to
compare the overall survival and safety of bi-weekly intratumoral administration
of RPR/INGN 201 vs. weekly methotrexate in patients with refractory squamous
cell carcinoma of the head and neck" and "A Phase III, Multicenter, open-label,
randomized study to compare the effectiveness and safety of intratumoral
administration of RPR/INGN 201 in combination with chemotherapy vs. chemotherapy
alone in patients with recurrent squamous cell carcinoma of the head and neck"
("Study") under Sponsor's protocols #T301 and T302 ("Protocol") which are
incorporated herein by reference.
NOW, THEREFORE, for good and valuable consideration contained herein, the
exchange, receipt and sufficiency of which are acknowledged, the parties agree
as follows:
1. SERVICES.
---------
PPD shall perform services as required in the Protocol and in the Services
section of this Project Addendum attached as Exhibit A.1 through A.5.
----------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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2. COMPENSATION AND PAYMENT.
-------------------------
2.1 - Compensation - For its performance under this Project Addendum, PPD
shall be compensated in the manner and in the amounts set forth on Exhibit B
attached hereto. Costs labeled "fixed" on Exhibit B are fixed costs per unit,
and PPD will be compensated for such costs in the amount of the Cost Per Unit
times the total number units of such item (as described on Exhibit B) actually
used or consumed. Costs labeled "variable" on Exhibit "B" are monthly charges
and will be in the same amount each month throughout the term of the agreement.
Costs labeled "direct" costs on Exhibit "B" represent compensation to PPD for
services of all of its personnel involved in the study and includes all
overhead and other costs and expenses of PPD in connection with the study, such
as, for example, long distance telephone charges photocopying, shipping and
courier charges, and all other expenses whatsoever, except for those
categorized as "pass-through costs" on Exhibit "B", and except that in
connection with services provided outside the United States of America, PPD
will also pass through its out-of-pocket expenses paid to third parties for
such items as long distance telephone, shipping, outside copying, courier
charges, etc.
The costs categorized as "pass-through costs" on Exhibit "B" represent PPD's
estimates of out-of-pocket expenses related to each of the activities set forth
thereon. For items such as travel, transportation, hotel, meals, and other
similar expenses, PPD will be reimbursed for [*] in accordance with PPD's travel
policy attached hereto as Exhibit "D", and in accordance with section 3.3 of the
Agreement. Thus, it is estimated that PPD's aggregate compensation based on the
estimates of fixed and variable costs set forth on Exhibit B, will approximate
[*], of which [*] will be direct costs, and of which [*] will constitute
pass-through costs. Such estimated compensation for direct costs is subject to
performance-based adjustment as provided in Section 2.2 below.
The parties understand and agree that the enrollment rates and the number of
sites to be contracted with herein are good-faith estimates only and PPD shall
exercise all reasonable diligence to meet enrollment and site sign-up
expectations.
Should a change in any of the key study parameters, e.g., number of sites,
number of patients, number of CRF pages, number of statistical tables or
listings, study timeline or protocol design result in an increase or decrease in
the study budget, such financial implications will be summarized in writing and
subject to prior written approval by Sponsor. The parties agree to mutually
review all such estimates at least quarterly during the term of this Agreement,
and to revise the budget set forth on Exhibit "B" in the event of material
changes in such estimates, PPD acknowledges that Introgen is conducting studies
of the identical drugs in other countries using clinical research organizations
other than PPD. The estimates of a number of sites, number of patients, number
of CRF pages, etc. estimated herein is based, in part, upon Introgen's
estimates of such activities in other countries. Should Introgen enroll sites
and/or patients more quickly or in larger numbers in such other countries, the
number of sites and patients needed which are the subject of this Project
Addendum will decrease, which may result in a reduction of direct and
pass-through costs payable to PPD hereunder.
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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The indirect reimbursable costs are estimated and may vary as circumstances
require.
2.2 Performance-based Adjustments
(a) The compensation otherwise payable to PPD hereunder (referred to as
"direct costs" on Exhibit "B"), is subject to adjustment of up to [*]
upwards based upon PPD's performance in meeting [*] pre-determined
milestones described on Exhibit "C" attached hereto. With respect to each
of milestone numbers [*] through [*], PPD's direct costs will be increased
by [*] if the milestone is met. With respect to the [*] milestone, the
fixed direct costs will be increased by [*] if the milestone is met.
(b) In addition, PPD can earn further additional compensation by meeting
[*] or more of [*] additional milestones. PPD will be paid (i) [*] of total
direct costs, not to exceed [*], of additional compensation if at least [*]
patients are enrolled in the T301 study on or before [*], and (ii) another
[*] of total direct costs, not to exceed [*] of additional compensation if
at least [*] patients are enrolled in the T302 study on or before [*], and
(iii) another [*] of total direct costs, not to exceed [*] of additional
compensation if at least [*] patients are enrolled in the T301 study on or
before [*], and (iv) another [*] of total direct costs, not to exceed [*]
of additional compensation if at least [*] patients are enrolled in the
T302 study on or before [*]. To be counted for purposes of these payments,
a patient must be enrolled in the study at a site in the [*] or [*]
contracted with and monitored through the efforts of PPD under this Project
Addendum, and must have received at least [*] treatment of the study drug.
(c) The above notwithstanding, all performance-based compensation
described in Sections 2.2.(a) and (b) will be first allocated and paid
directly to [*] working on this project in an amount up to [*], as
determined by Introgen, in its sole discretion [*]. Upon completion of the
project, [*] will be allocated and paid to [*], and other PPD personnel,
all as mutually determined by Introgen and PPD, as a bonus award for
unusual efforts and success in reaching milestones set out in this Project
Addendum. These payments will constitute compensation to such [*] from PPD.
This provision is solely for the benefit of the parties hereto and is not
enforceable by any [*].
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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Project Addendum
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(d) Failure to meet milestones will not, in itself, constitute default by
PPD under this Project Addendum, but will result in failure to earn
additional compensation described above. Such failure to earn additional
compensation in the event of failure to meet one or more milestones will
apply without regard to whether there is fault of PPD or Introgen or any
other event or occurrence, including force majeure as defined in Paragraph
16 of the Agreement, and without regard to any other defense or excuse on
the part of PPD. The performance-based adjustments are intended to provide
an incentive to PPD and its personnel to go beyond what is normally
expected in attempting to reach the milestone and to provide rewards in the
event milestones are reached. The performance-based adjustments are agreed
to in recognition that the timely completion of the tasks will add value to
Introgen's business, and is not intended as a penalty for non-performance
or default.
2.3 - Payment - Payment for the direct and pass-through costs will be made
according to the budget and payment schedules attached as Exhibit "B". There
will be no increase in direct or pass-through costs over those provided in the
budget set forth on Exhibit B unless those increases are first approved in
writing by an officer of Introgen at the level of Vice President or higher. PPD
shall invoice Introgen monthly for all compensation earned and pass-through
costs incurred for that month. All invoices shall be payable within 30 days of
receipt. Further, PPD shall invoice Introgen for all additional
performance-based compensation earned by meeting one or more milestones
described in Section 2.2 when all of PPD's services under this Project Addendum
are completed or after this Project Addendum is terminated without default by
PPD, which invoices will also be paid within 30 days of receipt.
2.3 - Payments to PPD shall be made to:
FOR [*] FOR [*]
--------------------- ----------
[*] [*]
or if wired: [*]
3. STANDARD OPERATING PROCEDURE
----------------------------
PPD shall conduct the Study according to Section 2.1 of the Agreement.
Upon mutual agreement in writing, the parties may conduct the Study under
Sponsor's standard operating procedures. In such case, Sponsor shall provide
prompt and reasonable training to any PPD personnel subject to such SOPs at
Sponsor's expense.
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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4. TERM AND TERMINATION.
---------------------
The term of this Project Addendum shall commence on the Effective Date and
end upon the completion of Services unless otherwise terminated in accordance
with the Agreement.
5. INCORPORATION BY REFERENCE/CONFLICT OF TERMS.
---------------------------------------------
The terms and conditions of this Project Addendum and Exhibits hereto are
hereby incorporated into and made a part of the Agreement. To the extent any
terms contained in an Exhibit hereto conflict with this Project Addendum, the
terms of this Project Addendum shall control. In the event of any inconsistency
between the Agreement, the Project Addendum and the Protocol, the terms of the
Protocol shall govern first, followed by the Project Addendum and then by the
Agreement unless otherwise specified.
6. MODIFICATIONS.
--------------
Any changes to this Project Addendum or its Exhibits shall be documented
by written Amendments upon approval by both parties and shall be attached
hereto. No Amendment will bind Introgen unless it is signed by an Introgen
officer at the level of vice president or higher.
Remainder of this page intentionally left blank
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7. NOTICES.
--------
Persons set forth below shall have the authority to make executive
decisions regarding this contract. Any notice required or permitted to be given
hereunder by either party hereunder shall be in writing and shall be deemed
given on the date received if delivered personally or by fax or five (5) days
after the date postmarked if sent by registered or certified U.S. mail, return
receipt requested, postage prepaid to the following address:
If to PPD: PPD Development, LLC
0000 00xx Xxxxxx Xxxxxxxxx
Xxxxxxxxxx, Xxxxx Xxxxxxxx 00000
Attention: Dr. Xxxx Xxxxxxxxx
Tel: (000) 000-0000
Fax: (000) 000-0000
If to Sponsor: Introgen Therapeutics, Inc.
0000 Xxxxxxxx Xxxx.
Xxxxxxx, Xxxxx 00000
Attention: Vice President, Operations
Tel: (000) 000-0000
Fax: (000) 000-0000
With copy to:
Introgen Therapeutics, Inc.
000 Xxxxxxxx, Xxxxx 0000
Xxxxxx, XX 00000
Attention: Chief Financial Officer
Tel: (000) 000-0000
Fax: (000) 000-0000
8. PPD GLOBAL LTD.
---------------
It is noted that, although it is named as a party to the Agreement, PPD
Global Ltd. did not sign the Agreement. By signing this Project Addendum, PPD
Global Ltd. and PPD Development LLC ratify the Agreement, acknowledge that all
time since its signature by PPD Development LLC on July 20, 2001, PPD Global
Ltd. has been a party to the Agreement, and confirm that PPD Development LLC
and PPD Global Ltd. are jointly and severally responsible for performance of
all obligations of either of them under the Agreement and this Project Addendum.
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PPD DEVELOPMENT, LLC INTROGEN THERAPEUTICS, INC.
By: /s/ Xxxx X. Xxxxxxxxx, M.D. By: /s/ J. Xxxxx Xxxxx, Xx.
Name: Xxxx X. Xxxxxxxxx, M.D. Name: J. Xxxxx Xxxxx, Xx.
Title: Sr. VP Medical Affairs/CSO Title: Vice President of Operations
Date: 17 December 2001 Date: ____________________________
PPD GLOBAL, LTD.
By: /s/ Xxxx X. Xxxxxxxxx, M.D.
Name: Xxxx X. Xxxxxxxxx, M.D.
Title: Sr. VP Medical Affairs/CSO
Date: 17 December 2001
APPROVED
MC 12/17/01
PPD CONTRACTS
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EXHIBIT A.1
[*] PROJECT CONSIDERATIONS
- PPD Development assumes that this project will be conducted according to PPD
Development's Standard Operating Procedures (SOPs) and Working Practice
Documents (WPDs). If Introgen chooses to use their own SOPs and WPDs,
Introgen will assume responsibility for training the PPD Development team on
all applicable SOPs and WPDs.
- PPD Development has assumed a monitoring frequency of [*] during the
enrollment, treatment and follow-up of this trial. We have assumed
approximately [*] on site for interim monitoring visits at those sites
participating in either the T-301 trial or the T-302 trial. If a site is
participating in both the T-301 and T-302 trials, we have assumed a [*]
monitoring visit.
- PPD Development has assumed that a staff of [*] and a Project Manager (PM)
will be necessary once all sites are open and enrolling until [*], at which
time there will be a staff of [*]. PPD Development anticipates that the
current team of [*] and [*] PM will remain on the trial until the end of [*]
and then an additional [*] will be added to the team once the entire group of
sites is open for enrollment.
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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PROJECT SPECIFICATIONS
PROTOCOL TITLE:
A Phase III, Multicenter, Open-Label, Randomized Study to Compare the Overall
Survival and Safety of Bi-Weekly Intratumoral Administration of RPR/INGN 201
Versus Weekly Methotrexate in Patients with Refractory Squamous Cell Carcinoma
of the Head and Neck.
STUDY SPECIFICATIONS
Protocol Number and Compound T301 and T302
Introgen Contact [*]
PPD Development Contact [*]
Manager, Business Development
Indication Head and Neck Cancer
Program Phase III
Study Design Open-label
Number of Enrolled/Randomized Patients [*] Patients in T301 and [*] Patients in T302
for a Total of [*]
Number of Completed Patients [*]
Number of Investigators [*]
Approximate Number of Patients Per Site [*]
Enrollment Period [*] Months
Enrollment Rate [*] Patients/Site/Month
Type of IRB Local
Duration of Patient Participation [*] Months
Interim Monitoring Frequency Every [*] Months
Time on Site [*] Day
Number of Initiation Visits [*] ([*] for T301 and [*] for T302)
Number of Interim Visits [*] for T301 and [*] for T302
Number of Close-Out Visits [*] ([*] for T301 and [*] for T302)
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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-----------------------------------------------------------------------
Case Report Forms per Patient [*]/Patient -- [*] Total for T301
[*]/Patient -- [*] Total for T302
-----------------------------------------------------------------------
Unique Case Report Form [*] for T301 and T302
-----------------------------------------------------------------------
Deliverable Lockable Database
-----------------------------------------------------------------------
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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PROJECT TIMELINE
Project Milestone Periods
The program timeline is summarized in the table below.
ACTIVITY DURATION*
-------- --------
Enrollment Period [*] Months
Treatment Period [*] Months
Study Close-out [*] Months
Total PPD Development Commitment [*] Months
* Some activities may overlap
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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PROJECT TEAMS
- Clinical Project Team
Upon execution of this Project Addendum, PPD will commit [*] Project Manager
and [*] clinical research Associates on a full time basis for both
studies. Initially, the following individuals will occupy such positions:
Project Manager: [*]
CRA: [*]
CRA: [*]
CRA: [*]
CRA: [*]
CRA: [*]
Effective March 1, 2002, the number of CRAs will be increased to [*]
full time individuals, with the newly added personnel to be subject to
approval in writing by Introgen. The Project Manager and all of the CRAs
will work full time (generally at least [*] hours per day, [*] days
per week) on the Studies which are the subject of this Project Addendum, to
the exclusion of work for any other PPD clients or projects. Any PPD
Development employee will be removed from the project and replaced with a
suitable replacement upon request by Introgen, with or without cause.
Should the proposal assumptions change, staffing will be reviewed and
modified accordingly, after appropriate discussions with Introgen, but only
with Introgen's written consent. Such consent shall not be unreasonably
withheld.
European personnel will not work full time on the studies, but will be
assigned by PPD at a level sufficient to complete the project in a timely
manner.
---------
* Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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DESCRIPTION OF SERVICES
PROTOCOL
- PREPARATION OF PROTOCOL
The final study protocol has been completed for this study. Introgen will
be responsible for the preparation of any amendments to the final study
protocol. Should assistance be required, PPD Development has an experienced
team of individuals who are available to provide protocol
preparation/finalization for Introgen.
- INFORMED CONSENT
A draft Informed Consent form containing all required elements had been
reviewed and approved prior to submission to Ethics Committees by the
Investigator.
CASE REPORT FORMS (CRFs)
- CRF DESIGN
CRFs have been designed and drafted for protocols T301 and T302. The CRFs
are designed to capture all pertinent information in a format that allows
for rapid review and data entry.
- PRINT CRF
The CRFs have been printed on NCR paper and shipped to the investigator
sites prior to initiation of the study.
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SITE/INVESTIGATOR IDENTIFICATION AND QUALIFICATION
SITE/INVESTIGATOR IDENTIFICATION
PPD Development maintains an active Investigator Recruitment Database
(IRDB(TM)) consisting of more than [*] investigators worldwide. The
information collected on each investigator includes: site demographics,
professional profile, specialty certifications, research profile, staff
personnel, facilities on site, data management experience, practice setting,
research experience/interest and previous clinical trial experience. Post study
evaluations are also on file for investigators who have worked with PPD
Development. These evaluations are completed by the study Monitor and the
Project Manager. This is a dynamic database that is continually expanded and
updated. It is from this database, as well as from Introgen Therapeutics, Inc.
lists and other external sources, that PPD Development will derive a list of
potential investigators for any particular study. PPD Development will work
closely with Introgen on all aspects of identifying the most appropriate
investigators.
Some of the areas of physician specialty and the number of investigators in
PPD's database include: Allergy/Immunology [*]; Anesthesiology [*]; Cardiology
[*]; Dermatology [*]; Endocrinology [*]; Family Practice [*]; Gastroenterology
[*]; Geriatric Medicine [*]; Infectious Disease [*]; Internal Medicine [*];
Medical Oncology [*]; Neurology [*]; OB/GYN [*]; Orthopedic Surgery [*];
Pediatrics [*]; Psychiatry [*]; Surgery [*]; and Urology [*].
The type and number of practice settings include: University Hospital [*];
Other Hospital [*]; Private, Solo, Group and Multi-Specialty combined [*];
Nursing Home [*]; VA/Military [*]; TMO [*]; Study Health Center [*]; Urgent Care
Center [*]; Rehabilitation Hospital/Clinic [*]; Mental Health Retardation [*];
Managed Health Care [*]; and Surgical Care [*].
PPD Development will assist in identifying investigators with a proven clinical
study record in managing and overseeing this type of clinical trial.
Investigators will be chosen on their ability to produce both the necessary
patient population and the appropriate study staffing. Upon Introgen's
approval, PPD Development will select [*] sites to participate in the study.
Each site will recruit approximately [*] patients during the [*] months of
anticipated enrollment, an average of [*] patients per site per month. These
sites will be located in USA and ceratin European countries; however, no
estimation of site distribution has been determined at this time.
---------
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the Commission. Confidential treatment has been requested with respect to
the omitted portions.
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-- SELECT STUDY SITE/INVESTIGATORS
Clinical Research Associates on the project team will conduct
comprehensive, on-site visits to further evaluate the investigative site,
meet with the study personnel, review the protocol, develop the patient
recruitment plan, visit all the facilities required by the protocol and
review any other site qualifications deemed critical to the successful
completion of the study. The evaluator will then make final recommendations
to the project team.
The success of most programs is dependent upon the ability to identify the
most qualified investigators who will be able to enroll a sufficient number
of patients who meet criteria as specified by the study protocol and to
provide quality data. PPD Development, in collaboration with Introgen, will
use reasonable efforts and due diligence to ensure that each investigator
selected is qualified to perform the services required.
-- SITE QUALIFICATION VISITS
When the list of potential investigators has been compiled and passed
through appropriate review by project management and Introgen, PPD
Development Clinical Research Associates will begin the process of
recruiting the investigators. Rigorous telephone screening of potential
investigators is performed by Clinical Research Associates prior to the
on-site evaluation visits to determine their interest in, and suitability
for, performing the study. These telephone calls to prospective sites will
allow an initial screening via assessment of critical factors such as
availability, staff, facilities, patient population and clinical trial
experience in the appropriate therapeutic area.
PPD Development will perform the site qualification visits. The purpose of
each visit is to assess the study facilities, the staff and the Principal
Investigator for actual protocol competency. During the visit, the PPD
Development project team will ensure the following:
-- The Principal Investigator's expertise
-- The availability of knowledgeable support staff
-- The adequacy of the facility to conduct a clinical trial
-- The availability of the appropriate subject population
-- The Principal Investigator's understanding of the regulatory
obligations as outlined on the FDA form 1572 or equivalent and
specified by Introgen and PPD Development
Additional site qualification visits necessary to reach the project of a
total of 100 active sites will be conducted by PPD Development. Written
trip reports will be prepared and submitted to Introgen within two weeks of
each visit.
-- INVESTIGATOR GRANTS COORDINATION
PPD Development will, in accordance with the investigator contract
previously approved by Introgen, make all necessary payments to the
investigators. Prior to payment, the Project
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Manager will verify the patient enrollment status at the site to ensure all
payments are accurate and reflective of study site activity.
PRE-STUDY ACTIVITIES
- REGULATORY DOCUMENT COLLECTION
PPD Development will collect, review and approve all regulatory documents
required under the United States Code of Federal Regulations (CFR) or
equivalent laws and regulations of each non-U.S. country for each
participating investigator. Critical documents for each site include the
following:
- Protocol agreement page
- IRB or equivalent approval letter together with a list of IRB or
equivalent members
- Copy of the IRB or equivalent approved informed consent form to be
used in the study
- Signed FDA Form 1572 or equivalent
- Curriculum vitae for the principal and sub-investigators
- Laboratory certification and normal values
- Financial Disclosure Agreements
- Other documents required by the laws and regulations of the relevant
country.
Regulatory packets will be assembled and delivered to Introgen. Introgen
shall submit all regulatory packets to the FDA or equivalent. Once the
appropriate regulatory documents have been submitted to the FDA or
equivalent, then Introgen will authorize shipment of the study drug to
each individual site.
- CENTRAL LABORATORY COORDINATION
If a central laboratory is necessary for this study, it will be selected
by Introgen.
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*STUDY DRUG MANAGEMENT
Introgen will design and print labels, label and secondary package, distribute,
store, perform analytical services. PPD Development will perform return
accountability and destroy the study drug or return the study drug to Introgen.
At the conclusion of the study or as requested, a complete accountability
report will be provided to Introgen. The accountability report will contain
at least the following information:
Site # and investigator name
Patient # and initials
Date dispensed, quantity dispensed
Initials of person dispensing study drug
*SPONSOR MEETINGS
PPD Development anticipates a total of 18 Introgen Therapeutics, Inc. meetings
will be held throughout this study. It is estimated that approximately three
PPD Development project team members will attend these meetings. Travel costs
for these meetings will be billed as Pass-through Indirect Costs. Such travel
shall be conducted in accordance with PPD Development travel policy.
STUDY INITIATION
*SITE INITIATION VISITS
PPD Development will perform an initiation visit at each site. The following
areas will be reviewed with site personnel during the initiation visit:
*Background information, including the Investigator Brochure for the study
drug and/or the product package insert(s)
*Protocol, study procedures and associated forms
*Interim monitoring visit schedule
*Regulatory requirements
*Planned enrollment rates, initiation dates and completion dates
*CRF and source documentation
*CRF completion instructions
*Adverse event reporting
*Study drug accountability
Training of all relevant site personnel will occur at this visit and on an
ongoing basis throughout the trial. Introgen agrees that training shall be the
primary responsibility of PPD Development.
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A total of 111 (60+51) initiation visits will be conducted for these
studies. Trip reports will be prepared within two weeks after each visit
and sent to Introgen.
PROJECT MANAGEMENT
- PROJECT MANAGEMENT
The Project Manager's responsibilities will include managing the technical
and administrative aspects of the study as defined by Introgen. The Project
Manager will coordinate the organization, implementation and management of
the study. In addition, the Project Manager will interact directly with the
Clinical Project Director, Medical Director, Project CRAs, Compliance
personnel, Data Management personnel and Biostatistics personnel (all of
whom are PPD employees) to ensure the effective and timely completion of
the study.
The Project Manager will also perform the following project-specific
activities:
- Project planning
- Preparation of the Study Operations Manual
- Coordination and assistance with personnel training
- Coordination of the investigators' meeting, to include travel and
agenda planning
- Provision of monthly status reports to include:
- Regulatory document collection
- Site start-up status
- Enrollment status
- Monitor visit reports
- Site drug inventories
- Serious Adverse Events (SAEs)
- Number of CRFs retrieved
- Review and sign timesheets, expense reports and travel authorizations
- Review project staffing and utilization, travel itinerary, trip
reports, external correspondence and telephone reports, internal
correspondence, follow-up letters and monthly travel calendars/plans
- Assure all tracking logs are updated weekly by the CRAs
- Facilitate all financial and contractual matters between Introgen and
PPD Development (i.e., prepare study-specific invoices for payment at
milestones met by PPD Development)
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ON-SITE MONITORING
- ON-SITE MONITORING
PPD Development will perform all interim monitoring visits for this study,
with the exception of [*], which will be monitored by Introgen. Given the
anticipated study length of [*] months per patient, an enrollment period of
[*] months and a monitoring frequency of every [*] months, PPD Development
will be required to perform approximately [*] interim monitoring visits of
[*] duration per site. The CRA will perform the following tasks during each
interim visit:
- Compare 100% of the CRFs to the source documents
- Review the CRFs and source documents for serious adverse events
- Resolve queries
- Perform drug accountability
- Ensure appropriate signed informed consent exists for each study
participant
- Review investigator study files for completeness
- Ensure investigator compliance to the study protocol
A total of [*] interim monitoring visits will be conducted. Trip reports will
be prepared and provided periodically to Introgen as agreed.
- CLOSE-OUT VISITS
A final close-out visit will be conducted after all subjects have completed
or have been discontinued from the study and after all queries have been
resolved. Each visit will include:
- Review and retrieval of all outstanding CRFs
- Study drug accountability and preparation for the shipment of study drug
to Introgen
- Review of investigator's study file for completeness
- Review of record retention per FDA or other regulatory requirements
A total of [*] close-out visits will be performed for these studies.
Close-out visit reports will be prepared within two weeks after each visit
and sent to Introgen.
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- TOTAL NUMBER OF SITE VISITS T301
SITE VISIT NUMBER PER SITE TOTAL
Qualification [*] [*]
Initiation [*] [*]
Interim Monitoring [*] [*]
Close-Out [*] [*]
TOTAL [*] [*]
- TOTAL NUMBER OF SITE VISITS T302
SITE VISIT NUMBER PER SITE TOTAL
Qualification [*] [*]
Initiation [*] [*]
Interim Monitoring [*] [*]
Close-Out [*] [*]
TOTAL [*] [*]
SITE MANAGEMENT
- IN-HOUSE SITE MANAGEMENT BY CLINICAL PROJECT TEAM
Between monitoring visits, investigators will be called weekly to verify
patient enrollment status, review study progress, answer protocol questions,
discuss CRF completion and ensure the study proceeds in a timely manner. Site
contact reports will become part of the investigator file located at PPD
Development. Additionally the PPD Development CRAs will be responsible for:
- Tracking and ordering study drug and other supplies
- Tracking regulatory document revisions
- Writing trip reports
- Writing follow-up letters
- Providing query resolution
- Performing in-house second review of CRFs
- Participating in scheduled conference calls with Introgen
- Tracking protocol violations, CRF progression at site and PPD Development
and tracking of query resolution
- Conducting audit of investigator files at PPD Development
- Developing newsletter materials and distributing newsletter to sites
PPD Development will be responsible for all follow-up on action items
identified during the monitoring visits.
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- CLINICAL REVIEW OF CRFs AND QUERY RESOLUTION
The CRF will be forwarded to the Clinical Project Manager who will evaluate
the following elements:
- Accurate and appropriate documentation of adverse events ("AEs")
- Overall subject study drug and protocol compliance
- Proper identification and documentation of potential protocol deviations
or violations
- Accurate completion of inclusion/exclusion criteria
- Accurate transcription of CRF data
- Appropriate use of medical terminology
- Correlation of all clinical information
- Accuracy of any medication dosages
DATA MANAGEMENT
- DATA MANAGEMENT PLAN
The PPD Clinical Data Management (CDM) Project Leader/Manager will compile
a Data Management Plan that describes the processes and specifications to
be used in the project. This includes documentation on the data
dictionaries to be used; the logic and processes for data review and
validation; critical timelines and milestones; and timing and types of
management reports. This Plan will be reviewed and finalized and will be
updated during the course of the project.
- DATABASE DEVELOPMENT
The project database will be set up using PPD Development's established
data management systems. PPD Development will develop the specifications
for this database following a review of the protocol, CRFs and PPD
Development's previous experience with the Introgen studies. Database
specifications will be independently reviewed by PPD Development prior to
installation. PPD Development will submit the database specifications to
Introgen for approval if requested.
- DOCUMENT MANAGEMENT
CRFs will be forwarded from each investigational site or by the study
monitors to the PPD Development Document Management team. Each CRF will be
entered into a tracking system and followed throughout the entire process.
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- DATA ENTRY
Data entry screens will be developed based on the study CRF and database
requirements. The entry of the data from each CRF into the database will
take place as CRFs are retrieved, to keep the database as current as
possible. All data entry discrepancies will be resolved by PPD Development
Data Management staff. Reports regarding data entry status and the database
will be available as needed.
- DATA VALIDATION
Validation (edit) checks and derivation procedures will be developed by PPD
Development using PL/SQL, SQL, RPL or SAS procedures. The validation
specifications will be developed taking into account the requirements of
the analysis plan, a review of the protocol and general experience. The
validation specifications will be forwarded to Introgen for review and
approval. The results from the validation process will be reviewed and
queries will be generated for resolution.
- IMPORTING ELECTRONIC DATA
Electronic data from central laboratories and any associated ranges will be
imported and integrated into the study database. PPD Development will
provide validation checks as required and issue queries as part of the data
review and validation process.
- CODING OF DRUGS AND DISEASES
Unless otherwise requested by Introgen, PPD Development will provide the
coding dictionaries required for coding adverse events and concomitant
medications. WHOART and COSTART will be used to code adverse events and
WHODRUG will be used to code concomitant medications. If necessary,
Introgen coding dictionaries can also be used.
PPD Development will use its ORACLE-based auto-encoding system to identify
appropriate codes and insert them into the appropriate tables. The PPD
Development auto-encoding system maintains a synonym dictionary so as not
to compromise Introgen dictionaries. This synonym dictionary also contains
multi-lingual coding translations. Efficient support of international and
cross-national coding schemes is provided. Validation checks on the synonym
code lists can be imposed to ensure that coding meets Introgen criteria.
Coded terms can be sent to Introgen for routine review. A final clinical
review by PPD Development will be conducted of all codes to ensure accuracy
and consistency.
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- DATA QUERY RESOLUTION
Queries arising from data entry, validation and dictionary coding will be
reviewed and, if possible, resolved by Data Management personnel, according to
the rules documented in the Data Management Plan. Where necessary, queries
will be passed to CRAs for resolution or forwarded to the investigator. Review
and correction of data will occur on an ongoing basis. Queries and corrections
will be tracked electronically for each CRF.
- STATUS REPORTS
PPD will provide Introgen with standard monthly status reports indicating the
progress made on the project. This report can be customized to meet Introgen
specifications. The report will include such information as number of patients
entered, number of completed patients, number of ongoing patients and metrics
on key processes.
- SPONSOR ACCESS TO DATABASE
At Introgen's option, PPD Development will set up a link to allow Introgen
browsing access to the clinical data at additional mutually agreeable costs.
This access will be accomplished using secure telecommunications with specific
software. This option will allow browsing of the clinical database and
creation of ad hoc data reports. PPD Development will work with Introgen to
set up a study specific process for the access so that the material being
reviewed by Introgen is well defined.
- DATA MANAGEMENT QUALITY CONTROL
To ensure accuracy, PPD Development will conduct a [*] verification of the
CRF against the database for randomly selected [*] sample of the patients
through the study. In addition, various patient listings will also be produced
and reviewed to assure data quality and consistency.
- DATABASE FINALIZATION
As required by the study and identified in the Data Management Plan, key
safety and efficacy variables will be [*] reviewed. A final quality control
check will be performed on [*] of the patients on the final database after all
data has been entered and all queries resolved. A written report of this check
will be prepared and sent to Introgen reporting discrepancies that are found.
PPD Development will return to Introgen the database in a SAS format. The
program code for data validations will remain with PPD at the conclusion of
the study. CRFs and supporting documentation will be returned to Introgen at
the conclusion of the project.
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- QUALITY ASSURANCE
PPD Development's Quality Assurance (QA) department will be informed when a
database lock has occurred. In such event, QA will perform an audit to
review the Quality Control (QC) procedures used during the conduct of the
study to ensure that SOPs, Working Practices and project specific plans
have been followed. The database error rates will be reviewed to ensure
that acceptable quality as defined in the study plan have been achieved.
- DATA TRANSFERS
FORMAT AND TEST. PPD Development will require data transfer specifications
(i.e., file layouts, formats) before initiating program development for
data transfers. We recommend at least [*] preliminary transfer to test the
transfer mechanism prior to the final database transfer. PPD Development
will be required to transfer the study database [*] times for each project.
On protocol T301, this will include [*] test transfer, [*] interim data
transfer after the first [*] patients have completed [*] months on study,
[*] DSMB transfer, and [*] final transfer. The interim transfers will have
clean safety and efficacy data. Clean is defined as all first round queries
run and updated and data is coded.
On Protocol T302, the transfers will include [*] test transfer, [*] interim
transfer after the first [*] patients have completed [*] months of
treatment, [*] DSMB transfers and [*] final transfer. The interim transfers
will have clean safety and efficacy data. Clean is defined as all first
round queries run and updated and data is coded.
PPD Development will provide Introgen with SAS files containing the project
database along with complete documentation.
- ALTERNATIVE TECHNOLOGIES
PPD Development has experience with a variety of alternative technologies,
(e.g., remote data capture, imaging). PPD Development welcomes further
discussion of data management operational strategy to meet the needs of
Introgen.
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DATA MANAGEMENT WORK FLOW
Data Management
Set-Up
CRF's Received
CRF's Tracked
Pre-Entry Review
Independent Dual Entry
Edit
Verification
Execute Tag Listings
Resolve Discrepancies
Remove Flags
QC Validate
Manual Link Lab Data
Review
Resolve Outstanding
Queries
Code Drugs and Diseases
Merge Data Table
Final QC
DBA Revokes Privileges
(Locked Database)
Deliver Final Database
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STATEMENT OF SERVICES
T301/T302
The following lists the specific responsibilities assigned to Introgen (x) or
PPD Development (x).
PPD
TASK LIST INTROGEN DEVELOPMENT
A. PROTOCOL
1. Design study [*] [*]
2. Write protocol [*] [*]
3. Approve protocol [*] [*]
4. Prepare template informed consent [*] [*]
B. CASE REPORT FORM (CRF)
1. Design and draft CRFs [*] [*]
2. Finalize CRFs [*] [*]
3. Print and bind CRFs [*] [*]
4. Distribute CRFs to sites [*] [*]
5. Write CRF instruction guide [*] [*]
C. SITE/INVESTIGATOR IDENTIFICATION AND QUALIFICATIONS
1. Develop list of potential sites [*] [*]
2. Select study sites/investigators [*] [*]
3. Conduct site qualification visits [*] [*]
4. Provide written site evaluation reports [*] [*]
5. Discuss grant payments and contract with sites [*] [*]
6. Negotiate investigator grants, LOA, LOI [*] [*]
7. Prepare investigator contract [*] [*]
8. Prepare indemnification/liability statement [*] [*]
D. PRE-STUDY ACTIVITIES
1. Collect regulatory documents (CVs, IRB approval, [*] [*]
FDA 1572)
2. Obtain IRB approval [*] [*]
3. Review and evaluate for completeness all elements [*] [*]
of informed consents for all sites
4. Contract with central laboratory [*] [*]
5. Set up project tracking system via RTMS(TM) [*] [*]
E. TEST ARTICLE MANAGEMENT
1. Supply study drug/device [*] [*]
2. Package study drug/device [*] [*]
3. Label study drug/device [*] [*]
4. Distribute study drug/device to site [*] [*]
5. Store study drug/device [*] [*]
6. Develop drug/device accountability log [*] [*]
7. Manage drug/device accountability records [*] [*]
8. Perform post-study study drug/device accountability [*] [*]
9. Return unused supplies/study drug/device to Introgen [*] [*]
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PPD
TASK LIST INTROGEN DEVELOPMENT
F. RANDOMIZATION SERVICES
1. Provide randomization scheme [*] [*]
2. Provide central computerized
randomization (IVR--touch-tone system) [*] [*]
3. Provide central attended randomization [*] [*]
4. Provide at-site randomization envelopes [*] [*]
G. COMMUNICATIONS MANAGEMENT
1. Attend project meetings [*] [*]
H. INVESTIGATORS' MEETING(S)
1. Plan investigators' meeting(s) [*] [*]
2. Prepare start-up information binders [*] [*]
3. Approve start-up information binders [*] [*]
4. Conduct investigators' meeting(s) [*] [*]
5. Present at investigators' meeting(s) [*] [*]
I. STUDY INITIATION
1. Conduct site initiation visits [*] [*]
2. Provide and maintain training of
site personnel [*] [*]
3. Review source documents--CRFs,
drug records, etc. [*] [*]
J. PATIENT RECRUITMENT
1. Develop and execute advertising plan [*] [*]
2. Refer potential patients to sites [*] [*]
K. PROJECT MANAGEMENT
1. provide weekly updates via RTMS(TM) [*] [*]
2. Contribute study information for
monthly newsletter [*] [*]
3. Select central laboratory [*] [*]
4. Coordinate with central laboratory [*] [*]
5. Establish and maintain 24 hour SAE
phone line [*] [*]
6. Administer investigator payments [*] [*]
7. Develop/maintain protocol deviation
database [*] [*]
8. Train the project team [*] [*]
L. ON-SITE MONITORING
1. Conduct interim on site monitoring visits [*] [*]
2. Review and verify 100% of available source
documentation on all CRFs [*] [*]
3. Obtain corrections to CRFs/query
resolution [*] [*]
4. Review drug records [*] [*]
5. Verify investigators' compliance with
protocol and regulatory requirements [*] [*]
6. Maintain site training of personnel [*] [*]
7. Conduct study close-out visits [*] [*]
8. Provide written site monitoring reports [*] [*]
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PPD
TASK LIST INTROGEN DEVELOPMENT
M. SITE MANAGEMENT
1. Maintain phone log of clinical questions [*] [*]
2. Maintain phone log of questions regarding CRFs/logistics [*] [*]
3. Participate in scheduled conference calls [*] [*]
4. Provide document control of CRFs - log, track, archive [*] [*]
5. Perform clinical review of CRFs [*] [*]
6. Perform records management [*] [*]
7. Enter and verify data [*] [*]
N. DATA MANAGEMENT SET-UP
1. Design data collection system [*] [*]
2. Develop data collection system [*] [*]
3. Validate data collection system [*] [*]
4. Design data cleaning system [*] [*]
5. Develop data cleaning system [*] [*]
6. Validate data cleaning system [*] [*]
7. Provide drug dictionary [*] [*]
8. Provide adverse event dictionary [*] [*]
O. DATA ENTRY
1. Initial review of CRFs [*] [*]
2. Document management of CRFs - log, track, archive [*] [*]
3. Enter and verify data [*] [*]
P. DATA MANAGEMENT
1. Run data cleaning system [*] [*]
2. Resolve queries generated [*] [*]
3. Document corrections to CRFs [*] [*]
4. Perform data management audits [*] [*]
5. Code concomitant drugs [*] [*]
6. Code adverse events [*] [*]
7. Integrate/merge electronic data [*] [*]
Q. DATA TRANSFERS
1. Format data according to Introgen format (SAS datasets) [*] [*]
2. Test data transfer [*] [*]
3. Interim analysis data transfer(s) Number: 1 [*] [*]
4. Final data transfer [*] [*]
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[*]
PROJECT SPECIFICATIONS FOR T-301 & T-302
The following key assumptions have been used to provide costs for Introgen.
These are based on the previous communication with PPD Development and Introgen,
our experience with the studies PPD Development is performing in [*] and our
best estimates based on our extensive experience in performing and managing
clinical studies.
Should any details change then PPD Development will review and amend these
budgets as appropriate.
GENERAL ASSUMPTIONS
STUDY X-000 X-000
Number of Screened Patients [*] [*]
Number of Patients Entering trial [*] [*]
Number of Evaluable Patients [*] [*]
Participating Countries/Sites
[*] [*]
This is just a basic assumption at [*] [*]
present and will be updated when [*] [*]
information is available [*] [*]
Number of CRF pages per Enrolled
Patient* [*] [*]
Number of CRF pages per Screened
Patient [*] [*]
Investigators' Meeting [*] [*]
Enrolment Period [*] [*]
Treatment Period [*] [*]
Number of Patient visits [*] [*]
Number of Client Meetings
Includes pre June tel conf and [*] [*]
hand over meeting
Number of Project Team Meetings
Include 2 day monitors meeting [*] [*]
Number of Conference Calls [*] [*]
* PPD Development understand that total number of CRF pages is [*]
has been used to account for the high patient death rate that will affect
the patient completion rate.
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CLINICAL/MEDICAL ASSUMPTIONS
We have assumed that all sites will require either a hand-over site visit with
the Introgen CRA and in some cases this will be the site initiation visit. PPD
Development will be negotiating and coordinating Investigator payments. No
investigator meetings will be required for either study for the purpose of this
costing. PPD Development would be happy to provide costs for investigator
meetings later should Introgen wish to hold further meetings.
STUDY X-000 X-000
Number of protocol
summaries/ICON Translations [*] [*]
Number of Sites Identified [*] [*]
Number of Pre-study evaluation
visits [*] [*]
Number of Initiation/Hand-Over
Visits [*] [*]
Interim Monitoring Frequency [*] [*]
Total Number of Interim Visits/
site [*] [*]
Duration of Monitoring visit (Av.) [*] [*]
Number of Close-Out Visits [*] [*]
% Source Data Verification [*] [*]
Number of QA Site Audits [*] [*]
Anticipated Number of SAEs [*] [*]
Frequency of Investigator
Payments [*] [*]
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PROJECT TIMELINE
The program timeline is summarized in the table below;
ACTIVITY TIMETABLE TIMETABLE
X-000 X-000
Start of PPD Activity [*] [*]
Study Hand Over Meeting [*] [*]
Enrollment Period [*] [*]
[*]
Treatment/Follow-up [*] [*]
Period
Site Close-Out Visits [*] [*]
TOTAL PPD DEVELOPMENT
COMMITMENT [*] [*]
These timelines are subject to:
- Introgen providing all the necessary documentation and information in
sufficient time for the hand-over process to begin [*].
- Patient recruitment rates correspond with Introgen's expectations as per
the study designs.
PPD Development will review all timelines during the study and should any
situation arise that may compromise these timelines, PPD Development, with
Introgen's consent, may revise them or take further actions as necessary to
successfully complete the study to Introgen's satisfaction.
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STATEMENT OF SERVICES
The following lists the specific responsibilities assigned to Introgen (x) or
PPD (x).
ACTIVITY INTROGEN PPD
DEVELOPMENT
STUDY SET-UP
A. REGULATORY AFFAIRS
1. Prepare Core Dossier [*] [*]
[*] [*]
2. Prepare, review and submit appropriate country [*] [*]
specific filings [*] [*]
3. Prepare Investigator Brochure [*] [*]
B. STUDY DOCUMENTS
1. Write and Approve Protocol [*] [*]
2. Translate Protocol into appropriate languages [*] [*]
when necessary [*] [*]
3. Prepare template informed consent [*] [*]
4. Translate informed consent into appropriate
local languages [*] [*]
5. Provide specifications for CRF design [*] [*]
6. Design CRF [*] [*]
7. Review CRF [*] [*]
8. Print and bind CRF [*] [*]
9. Write CRF instruction guide [*] [*]
10. Distribute CRF to sites [*] [*]
C. SITE IDENTIFICATION AND QUALIFICATION
1. Develop list of additional potential sites [*] [*]
[*] [*]
2. Conduct pre-study qualification visits [*] [*]
3. Negotiate investigator grants [*] [*]
4. Administer investigator payments [*] [*]
5. Prepare indemnity/liability statement [*] [*]
D. RANDOMISATION
1. Provide randomisation schedule [*] [*]
2. Arrange for provision of randomisation materials [*] [*]
E. CENTRAL LABORATORY
1. Identify central laboratory if applicable [*] [*]
2. Contract with central laboratory [*] [*]
3. Resolve issues with central laboratory [*] [*]
4. Administer payments to central laboratory [*] [*]
F. CLINICAL TRIAL SUPPLY MANAGEMENT
1. Supply, package and label study drug [*] [*]
2. Secondary labeling [*] [*]
3. Distribute study drug to sites [*] [*]
4. Perform post-study drug accountability [*] [*]
5. Return unused study drug to sponsor [*] [*]
6. Distribute miscellaneous clinical supplies to site [*] [*]
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G. INVESTIGATOR MEETING
1. Organise and conduct investigator meeting [*] [*]
2. Prepare start-up information binders [*] [*]
3. Approve start-up information binders [*] [*]
4. Attend investigator meeting [*] [*]
5. Present at investigator meeting [*] [*]
H. ETHICS COMMITTEE APPROVAL AND SITE INITIATION
1 . Collect essential documents [*] [*]
2. Obtain IEC approval [*] [*]
[*] [*]
3. Conduct site initiation/hand-over visits [*] [*]
4. Provide training of site personnel [*] [*]
STUDY CONDUCT
I. ON-SITE MONITORING
1. Conduct interim on-site visits [*] [*]
2. Review and verify available source documentation
on all CRFs [*] [*]
3. Obtain corrections to all CRFs/query resolution [*] [*]
4. Review drug records [*] [*]
5. Verify investigators compliance with protocol
and regulatory requirements [*] [*]
6. Maintain training of personnel at study sites [*] [*]
J. SITE MANAGEMENT
1. Maintain phone log of clinical questions [*] [*]
2. Maintain phone log of questions regarding
CRFs/logistics [*] [*]
3. Control of CRFs - log, track and archive [*] [*]
4. Make regular contact with site between visits [*] [*]
K. PROJECT MANAGEMENT
1. Provide regular updates to Sponsor via RTMS [*] [*]
2. Develop/maintain protocol deviation database [*] [*]
3. Provide on-going project team training [*] [*]
4. Review investigator payments [*] [*]
5. Administer investigator payments [*] [*]
6. Participate in client meetings [*] [*]
7. Participate in team meetings [*] [*]
8. Participate in conference calls [*] [*]
L. MEDICAL MONITORING AND PHARMACOVIGILANCE
1. Conduct all Pharmacovigilance* [*] [*]
2. Perform serious adverse event investigation [*] [*]
3. Write SAE patient narratives [*] [*]
M. SITE CLOSE-OUT
1. Conduct study close-out visits [*] [*]
QUALITY ASSURANCE
1. In-house file audits [*] [*]
2. Study site audits [*] [*]
* - Time and material rates are included in the grids below but will be
discussed in the Consulting Agreement.
** - Full specifications to follow in a contract modification.
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EXHIBIT A.2
[*] REGULATORY
Personnel. The Services shall be performed by PPD under the direction of
[*] and [*] or such other employee acceptable to Introgen as PPD may from time
to time designate.
This service will be performed on a Time and Materials basis.
STATEMENT OF SEVICES
STUDY SET-UP INTROGEN PPD
REGULATORY AFFAIRS
1. Prepare Core Dossier [*] [*]
2. Prepare, review and submit appropriate
country specific filings [*] [*]
3. Prepare Investigator Brochure [*] [*]
ETHICS COMMITTEE APPROVAL AND SITE INITIATION
1. Collect essential documents [*] [*]
2. Obtain IEC approval [*] [*]
4. Conduct hand-over visits at Introgen
affiliate HQ [*] [*]
5. Conduct additional set up visits to ensure
maximized recruitment at site.* [*] [*]
*Additional visits should be approved by
Introgen in advance
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EXHIBIT A.3
[*] REGULATORY
Introgen agrees to engage PPD to provide consulting services as described
in the Scope of Work listed below, and PPD agrees to provide such services.
PPD agrees to comply with all regulations, laws and Introgen policies
applicable to the services to be performed under this Agreement, including
without limitation Introgen's Business Conduct Policy, which is enclosed for
reference. Further, PPD shall inform any of its employees providing services to
or on behalf of Introgen that they must abide by such regulations, laws and
policies and PPD shall obtain their written agreement to comply.
This Regulatory component shall commence as of [*], and shall continue
through [*], unless further extended in writing.
Introgen shall pay PPD as follows for professional fees:
Regulatory Administrative Assistant [*]
Regulatory Affairs Specialist [*]
Manager, Regulatory Affairs [*]
Associate Director, Regulatory [*]
Director, Regulatory Affairs [*]
Said billing rates of PPD shall be in effect for the [*] first set forth
herein and shall be subject to change on a [*] basis.
Fees for services for the duration of this agreement will be billed on a
time and materials basis and are not expected to exceed [*] (based on original
contract of [*] plus an additional [*] covered in an amendment with an effective
date of [*].
In addition, Introgen shall reimburse PPD for actual expenses of pre
approved air travel (not in excess of the fares for air journeys reimbursed to
employees of Introgen), car fare (if for a personal car, not in excess of the
per mile rate reimbursed to employees of Introgen), and living expenses
reasonably incurred for travel necessary in connection with the performance of
the PPD's services and for reasonable out-of-pocket expenses such as telephone,
facsimile and reproduction expenses. Any expenses other than nominal out-of-
pocket expenses must be approved in advance by Introgen. At the end of [*]
during the existence of this Agreement, PPD shall submit an itemized list of his
expenses, if any, for the month, together with adequate documentation, and the
Introgen shall remit his fee and reimbursed expenses within [*] days thereafter.
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Scope of Work
Under this agreement, PPD will act as the official correspondent to the FDA for
BB-IND 6165 and BB-IND 6026, and perform IND maintenance for these INDs
including those activities under 21 CFR 312.30, 312.31, 312.32, 312.33, 312.40,
312.47, and 312.50. Both paper and electronic copies of all regulatory
correspondence and submissions to the FDA will be provided to Introgen. PPD will
attend team meetings and may perform additional tasks, at the written request
of Introgen, on an as needed basis.
In addition, PPD will prepare and submit site documents and report serious
adverse events to the NIH. Other submissions to the NIH, including points-to-
consider document's, and annual reports will also be prepared by Introgen. Both
paper and electronic copies of all correspondence and submissions to the NIH
will be provided to Introgen.
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EXHIBIT A.4
IVRS PROJECT SPECIFICATIONS
The following are assumptions that PPD has used to calculate our cost proposal.
Should any of these assumptions change, PPD reserve the right to review the
budget and make any relevant amendments if appropriate.
Protocol Number [*] [*]
Number of Randomized Patients [*] [*]
Participating Countries/Sites [*] [*]
Language of Script and Prompt [*] [*]
Language of IVRS system [*] [*]
& Randomization Notification
Number of Users [*] [*]
Enrolment Period [*] [*]
Number of Treatment Groups [*] [*]
Level of Support [*] [*]
[*]
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EXHIBIT A.5
* MEDICAL AFFAIRS AND PHARMACOVIGILANCE (MA/PVG)
The following PPD Medical Affairs/Pharmacovigilance (MA/PVG) services and costs
are based on the information available to date. We have assumed additional
discussions may be required to finalize the specific activities needed for this
project.
Investigator sites will report serious adverse events (SAEs) to PPD's MA/PVG
group. Introgen's physician will be responsible for medical review of SAEs and
consulting with investigator sites and project team members. PPD will notify
Introgen of SAE's within one business day of receipt of SAE report. Introgen
will be responsible for providing the final causality/reportability assessment.
The MA/PVG group will obtain requested SAE follow-up information from
investigator sites, and will work in concert with the clinical project team to
resolve SAE related queries prior to the final clinical database lock.
Each SAE will be billed on a per event basis of [*] per SAE (subject to a [*]
inflation increase each year). SAE's which are reported to PPD, processed, and
subsequently downgraded to "not serious" will be included in the total number
of SAEs and billed accordingly.
Costs associated with narrative production, the set-up and maintenance of a SAE
database utilizing Clintrace(TM) software, the participation of a PPD
Development physician in an investigator meeting, MA/PVG review of lab data, or
AE listing and coding review are not included in this proposal. If Introgen
request PPD manage these tasks, cost can be provided under separate cover.
The MA/PVG group will submit to Introgen on a routine basis a SAE tracking
report which contains a listing of all SAEs received and the current status of
those SAEs. Upon request, any additional reports will be discussed with
Introgen and the costs for those reports submitted under separate cover.
PPD will be responsible for the submission of expedited safety reports to the
appropriate regulatory agencies. Each submission will be billed at [*] for
submission to the first country and [*] for each subsequent country.
All translation expenses (verbal or written) will be considered pass through
costs and billed accordingly.
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Actual costs to provide MA/PVG services will depend upon the nature, extent and
frequency of FDA inquiries regarding the safety reports as well as the extent
and frequency of document revisions requested by Introgen. For this reason,
MA/PVG costs provided within this budget may need to be negotiated on an annual
basis. Additionally, extensive follow-up requested by the Introgen or regulatory
agencies beyond that included in this proposal will be billed at time and
materials.
TASK LIST INTROGEN PPD
V. SAFETY (MEDICAL AFFAIRS/PHARMACOVIGILANCE)
1. Receive and process SAEs from investigator sites. [*] [*]
2. Medically review SAE reports and final preliminary [*] [*]
causality assessment statements/reportability
3. Maintain 24-hour Phone Line for reporting SAEs [*] [*]
4. Provide medical consultation to investigator sites [*] [*]
and project team (24-hour Medical coverage)
5. Write SAE narratives [*] [*]
6. Submit expedited safety reports to appropriate [*] [*]
regulatory agencies.
7. Maintain SAE database [*] [*]
ALL TRAVEL IS PASS-THROUGH
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EXHIBIT B
[*] COSTS
T301
ASSUMPTIONS UNIT COST PER UNIT COST TYPE ESTIMATED SUB-TOTAL
UNIT# UNIT LABEL TOTAL UNITS
[*]
[*] [*] [*] [*] [*] [*] [*]
ASSUMPTIONS UNIT COST PER UNIT COST TYPE ESTIMATED SUB-TOTAL
UNIT# UNIT LABEL TOTAL UNITS
[*] [*] [*] [*] [*] [*] [*]
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[*]
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[*]
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[*] COSTS
T302
ASSUMPTIONS UNIT COST PER UNIT COST TYPE ESTIMATED SUB-TOTAL
UNIT# UNIT LABEL TOTAL UNITS
[*]
[*] [*] [*] [*] [*] [*]
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[*]
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[*]
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[*] COSTS
T301
ASSUMPTIONS UNIT COST PER UNIT COST TYPE ESTIMATED SUB-TOTAL
UNIT# UNIT LABEL TOTAL UNITS
[*] [*] [*] [*] [*] [*] [*]
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Unit # UNIT LABEL
[*]
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[*] COSTS
T302
ASSUMPTIONS UNIT COST PER UNIT COST TYPE ESTIMATED SUB-TOTAL
UNIT# UNIT LABEL TOTAL UNITS
[*] [*] [*] [*] [*] [*] [*]
TOTAL CLINICAL DIRECT COSTS
UNIT# UNIT LABEL
[*] [*] [*] [*] [*] [*] [*]
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UNIT LABEL
[*]
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EXHIBIT C
Milestone Descriptions:
[*]
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EXHIBIT D
[*]
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[*]
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[*]
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[*]
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[*]
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[*]
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[*]
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[*]
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[*]
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