Work Order - Cubist Pharmaceuticals Inc. and Quintiles Inc.
CONFIDENTIAL TREATMENT
WORK ORDER 1
This Work Order ("Work Order") is between Cubist Pharmaceuticals, Inc.
("Sponsor") and Quintiles, Inc. ("Quintiles") and relates to the Master Services
Agreement dated April 25, 2001 (the "Master Agreement"), Pursuant to the Master
Agreement, Quintiles has agreed to perform certain services in accordance with
written work orders, such as this one, entered into from time-to-time.
The parties hereby agree as follows:
1. Work Order. This document constitutes a "Work Order" under the
Master Agreement, and this Work Order and the services contemplated herein are
subject to the terms and provisions of the Master Agreement.
2. Services and Payment of Fees and Expenses. The specific services
contemplated by this Work Order (the "Services") and the related payment terms
and obligations are set forth on the following attachments, which are
incorporated herein by reference:
SCOPE OF WORK ATTACHMENT 1
PROJECT BUDGET ATTACHMENT 2
PAYMENT SCHEDULE ATTACHMENT 3
TRANSFER OF OBLIGATION ATTACHMENT 4
LOCAL REPRESENTATIVE DUTIES ATTACHMENT 5
3. Term. The term of this Work Order shall commence on the date of
execution and shall continue until the services described in Attachment I are
completed, unless this Work Order is terminated in accordance with the Master
Agreement.
4. Affiliates and Subcontractors. Sponsor agrees that Quintiles may use
the services of its corporate affiliates to fulfill Quintiles' obligations under
this Work Order. Any such affiliates shall be bound by all the terms and
conditions of, and be entitled to all rights and protections afforded under, the
Master Agreement and this Work Order. Any subcontractors or consultants (other
than Quintiles' affiliates) that will be used by Quintiles in performing the
Services are listed below:
None
5. Amendments. No modification, amendment, or waiver of this Work Order
shall be effective unless in writing and duly executed and delivered by each
party to the other.
6. Currency Exchange. The currency to be used for invoice and payment
shall be U.S. Dollars. If Quintiles incurs expenses or pass-through costs in a
foreign currency, then
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Sponsor shall reimburse Quintiles for Quintiles' actual costs, in U.S. dollars,
to pay those expenses and pass-through costs. Sponsor acknowledges that, due to
fluctuations in currency exchange rates, Quintiles' actual costs for such
expenses and pass-through costs may be greater or lesser than the budgeted or
estimated amounts contained in this Agreement. In addition, if this Agreement
involves performance of Services in countries other than the United States,
Quintiles' Budget for those Services will be based on the local rates in the
local currency of those countries, as converted to U.S. Dollars. If payments for
Services in & foreign currency exceed $1,000,000, and the currency in which the
payment is to be made has fluctuated more than 2%, plus or minus, since the
Budget was prepared, Quintiles will calculate a foreign currency exchange
adjustment for those Services. The adjustment will be calculated by comparing
the Wall Street Journal ("WST') foreign currency exchange spot rate on the last
business Friday before the Budget was finalized to the WSJ spot rate on the last
business Friday before each invoice is issued. Any resulting decrease in costs
will be credited to Sponsor and any resulting increase in costs will be invoiced
to Sponsor.
ACKNOWLEDGED, ACCEPTED AND AGREED TO:
QUINTILES, INC. CUBIST PHARMACEUTICALS, INC. By:
By: /s/ Michael P. Arlotto By: /s/ Michael DeBruin
-------------------------------- -------------------------------
Name: Michael P. Arlotto, Ph.D. Name: Michael DeBruin
Title: Vice President Title: Vice President, Clinical
Date: 6/4/01 Date: 6/7/01
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 1
SCOPE OF WORK
PROJECT ASSUMPTIONS
A RANDOMIZED, DOUBLE-BLIND, PHASE III, COMPARATIVE STUDY OF CIDECIN(TM)
(DAPTOMYCIN) TO ROCEPHIN(R) (CEFTRIAXONE) IN THE TREATMENT OF MODERATE
TO SEVERE COMMUNITY-ACQUIRED ACUTE BACTERIAL PNEUMONIA DUE TO S. PNEUMONIAE
STUDY SITES LATIN AMERICA
[*] [*]
[*] [*]
[*] [*]
[*] [*]
[*] [*]
[*] [*]
--------------------------------------------------------------------------------
PATIENTS
Screened [*]
Enrolled [*]
Evaluable (completed) [*]
--------------------------------------------------------------------------------
IVRS
--------------------------------------------------------------------------------
Number of Reports [*]
Languages Required
Number of IVRS Languages [*]
Number of Quick Reference Guide Languages [*]
Number of IVRS Calls per Subject [*]
Number of IVRS Database Transfers [*]
--------------------------------------------------------------------------------
MONITORITNG
Frequency [*]
Average Time on Site/Travel/In-House
Source Document Review (%) o [*]
o [*]
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 1
SCOPE OF WORK
--------------------------------------------------------------------------------
VISITS
Total # of Pre-Study Site Visits [*]
Total # of Initiation Visits [*]
Total # of Interim Monitoring Visits/site [*]
Total # of Close-out Visits [*]
Total # of Interim Monitoring Visits All Site [*]
Total # of Site Visits [*]
--------------------------------------------------------------------------------
ESTIMATED SAES [*]
--------------------------------------------------------------------------------
TIMELINE
Pre-study - Start-Up Period [*]
Enrollment Period [*]
Treatment Period - Follow-up [*]
Site Close-Out [*]
--------------------------------------------------------------------------------
TOTAL PROJECT DURATION [*]
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*Any deviations from the assumptions herein may require a modification to the
budget.
FIXED-PRICED BUDGET EXPLANATION
Quintiles' proposed approach draws on our infectious disease experience,
feasibility interviews, expected seasonality and an expected recruitment period.
Quintiles recognizes the study objective is to recruit and screen [*] patients
to yield [*] patients for complete study evaluation. The clear study objective
is for Quintiles to obtain these patients from the sites identified, screened
and included in the proposal. Quintiles expects to recruit these patients in the
countries and sites identified using the Quintiles resources as described, and
the assumptions stated above form the basis for the current fixed-priced budget.
CUBIST's and Quintiles' objective is to complete patient recruitment in the [*]
calendar year. CUBIST and Quintiles recognize that scheduling changes have
already forced revisions to the initial budget and scope of work. These scope
changes were have been made to maintain the patient recruitment and [*]
completion objectives. If unforeseen events occur, both Cubist and Quintiles can
expect to revisit the scope of work to make additional changes.
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
A. PROJECT INITIATION
SELECTION OF CLINICAL STUDY TEAM AND PROJECT MANAGER
1. Unless otherwise stated in this Scope of Work, Quintiles' Standard
Operating Procedures (SOPS) will be used.
2. Quintiles will assign a Project Manager (PM), a Project Medical Officer
(PMO), a Lead Clinical Research Associate (LCRA), nine (9) Clinical
Research Associates (CRAB), and staff from Quintiles Interactive Voice
Response System (IVRS) for this study. The PM will serve as Cubist's
primary contact within Quintiles. Rene Martinet, M.D. will act as the
Cubist Daptomycin PM
3. Quintiles will provide Interactive Voice Response System (IVRS)
randomization services for DAP-CAP-00-08.
B. STUDY DOCUMENT PREPARATION
PROTOCOL DEVELOPMENT
4. Cubist will be responsible for the development of the Protocol and any
revisions thereto.
5. Quintiles will be responsible for printing and distributing copies of
the Protocol to the Investigative Sites.
CASE REPORT FORM DEVELOPMENT
6. Cubist will be responsible for developing and finalizing the Case
Report Form (CRF). Quintiles will review the CRF (included in the scope
and budget for Work Order 2 for Data Management).
7. Quintiles will be responsible for the printing and shipping of the
CRF. [*].
STUDY SITE REFERENCE MANUAL
8. Quintiles will prepare the Study Site Reference Manual.
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
STUDY MATERIAL REVIEW AND TRANSLATION
9. Quintiles will review and assess core study materials required for
regulatory submission. These include CRFs, Clinical Investigator's
Brochure (M), and Patient Written Inform Consent Form (ICF). Quintiles
will provide certified translations of these materials into Spanish and
Portuguese.
10. Cubist will be responsible for preparing and finalizing the
Investigator Brochure.
11. Quintiles will also translate and review corollary materials including
the Study Manual.
CLINICAL MONITORING PLAN
12. Quintiles will propose a clinical monitoring plan for all [*]
countries. The specifics of that plan will be detailed by the PM and
clinical study team as part of study activities.
ETHICS COMMITTEE
13. [*].
PREPARATION OF REGULATORY BINDER AND SUBMISSION OF DOCUMENTS TO LOCAL HEALTH
AUTHORITIES
14. Quintiles will collect and prepare the documentation for regulatory
submissions to each country's regulatory agencies (outside the United
States). Local health officials require National Submission Binders
that include specific sets of information presented in specified
formats.
15. Quintiles will prepare these binders, translating required information
as necessary to satisfy each national regulatory agency. Those
documents may include [*], and others as required by the local
legislation. Quintiles will gather all of the above-named documents
together and file far the study approval. This process must be
fulfilled in order to file for Import Permits of the Investigational
drug (ID).
DRUG IMPORTATION/CLINICAL TRIAL MATERIAL/DRUG DISTRIBUTION
16. Cubist will review and approve all regulatory documents from each site
prior to study drug shipment. After regulatory document approval,
Cubist will contact Quintiles and request drug shipment to the site.
17. Drugs to be used in this study include:
o [*]
o [*]
o [*]
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
18. Cubist will ship the study drug to Quintiles' facilities in [*].
Quintiles will store the study drug in Quintiles' facilities and ship
the drug to the sites. Customs approvals are required to import CTM in
each of the study countries. Quintiles will prepare the local
documentation required to obtain export licenses from the country of
origin, as well as the Import Permit for each of the designated
countries.
19. After filing the regulatory submission and receiving regulatory
approval, Quintiles will assume responsibility to receive the CTM from
national customs in each country. After receiving and documenting the
CTM, Quintiles will store and deliver CTM to Investigative sites
according to study specifications.
20. Quintiles will purchase the ceftriaxone and the aztreonam. Costs for
purchase and distribution of the drugs will be passed through to
Cubist.
21. Quintiles will label the [*]. Cubist will provide labels in [*].
22. [*]shipments of the Investigational drug will be required for each
country. Each site will require [*] additional shipments of the drug.
23. At the end of the study, CRAs will ship unused study supplies and study
drug back to Quintiles facilities in [*]. Quintiles will verify that
the medication is destroyed and will provide notice of that destruction
to Cubist. A third-party vendor, approved by Cubist, will perform the
drug destruction. Costs for this task are not included in the budget,
and will be passed through to Cubist.
C. INVESTIGATOR SELECTION
IDENTIFICATION, SELECTION, AND EVALUATION OF INVESTIGATORS
24. Quintiles will screen potential Investigators and make initial contact
with each site to determine the Investigators' interest and abilities
to conduct this clinical trial. Before the site inspection, Quintiles'
CRAB will:
|X| Contact each site and screen for:
|X| Qualifications and experience
|X| Time and interest
|X| Patient population
|X| Adequate facilities
|X| Number of ongoing trials at each site
o Send appropriate documentation to each potential Investigator, e.g.:
|X| Confidential Disclosure Agreement
|X| Protocol or Protocol Synopsis
|X| Investigators' Brochure
|X| A sample of the written Informed Consent
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
o Discuss briefly with each potential Investigator:
|X| An overview of Cubist and Quintiles
|X| The Investigational drug
|X| The study procedures/ assessments
|X| The number and availability of patients to be recruited
|X| The study duration, protocol highlights, and Investigator's
clinical workload
|X| The patient inclusion/exclusion criteria |X| The study budget
(i.e., laboratory fees, Investigator honorarium, and other as
applicable)
PRE-STUDY SITE VISIT
25. Quintiles will perform a pre-study assessment visit at each site to
o Discuss the study, obligations, and responsibilities of both
the Investigator and patients
o Assess facilities (including laboratory, as applicable)
o Confirm Investigator's interest
o Assess Investigational drug's safety and depot at the site
o Determine whether suitable population exists
o Assess Investigator's willingness to comply with local
regulations and Good Clinical practice (GCP) requirements
o Obtain pre-study documentation (e.g. curriculum vitae [CV],
infrastructure specifications, etc.)
o Complete a pre-study report for each site visited summarizing
discussions and resulting agreements.
o Follow-up of pre-study visits with:
|X| Summary of discussions, action items, request for
outstanding documentation, etc., for suitable
Investigators
|X| Remove study material from sites not selected
26. Each pre-study site visit is estimated to consist of [*] on-site, [*]
travel time, and [*] in-house time.
27. Quintiles will provide to Cubist written visit reports according to
Quintiles' SOPS. Completed visit reports will be delivered to Cubist
within [*] days of the visit.
D. INVESTIGATOR GRANTS NEGOTIATION AND PAYMENT ADMINISTRATION
28. Quintiles will sign pre-negotiated (with Cubist) Clinical Trial
Agreements with each of the Principal Investigators/sites selected to
participate in the study. The Clinical Trial Agreements will include an
Investigator grant and payment schedule.
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
29. Quintiles will track patient enrollment, discontinuation and
completion. This data will be combined in a Patient Status Report that
will become the basis o(pound) subsequent financial administration.
30. Investigators will receive compensation for patients who satisfy all
inclusion and exclusion criteria of the Protocol or as stated in the
Clinical Trial Agreements.
31. Periodically Quintiles will draw on the Patient Status Report to
produce a list that tracks disbursements to each Investigator and
moneys owed. Quintiles will prepare checks for each Principal
Investigator/site according to the signed Clinical Trial Agreements and
the Patient Status Report.
32. Quintiles will disburse periodic payments per agreements with the
Investigators and sites. Quintiles will provide regular disbursement
reports to Cubist.
33. Quintiles will provide written notification to Cubist each time a
payment is due. Cubist will pay such payment by wire transfer to
Quintiles within [*] business days of the date of such notification.
Quintiles will make such Investigator payment within [*] days of
receipt from Sponsor.
E. FINANCIAL DISCLOSURE
34. Quintiles will collect all initial documentation (including all updates
throughout the life of the study), and at final study closeout for
financial disclosure information for all sites as required in 21 CFR
Part 54. Cubist will supply Quintiles with a follow-up financial
disclosure. form to be distributed to Investigators at the close-out
visit. Investigators will contact Cubist-directly with any financial
disclosure inquiries after the close-out visit has occurred.
F. INVESTIGATOR MEETINGS
35. Quintiles will arrange, attend and participate in [*] Investigator
Meetings, [*] (for Investigators in [*], Cubist and Quintiles staff)
and [*], Cubist and Quintiles staff). The meeting objectives will be to
maximize consistency in the study process by ensuring a uniform
interpretation of the study protocol, CRF, and all study procedures.
36. The Investigator meetings will be arranged by Quintiles. Meeting
coordination costs (estimated at [*] dollars per participant) and
meeting attendance costs (estimated at [*] per participant) are
included in the budget and will be passed through to Cubist.
37. [*] members of the Quintiles project team will attend the first
Investigator Meeting, in [*]. Attendees to this meeting will include
the PM, PMO, the IVRS PM, the Inntrax manager, two (2) LCRAs the PA and
nine (9) CRAs. Attendees to the second meeting in [*], will include the
PM, PMO, IVRS PM, LCRA, PA and four (4) CRAB.
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
G. CLINICAL DRUG SUPPLIES
LABELING, PACKAGING, AND STORAGE OF STUDY DRUG
38. Aver filing the regulatory submission and receiving regulatory
approval, Quintiles will assume responsibility to receive the CTM from
national customs in each country. After receiving and documenting the
CTM, Quintiles will store and eventually deliver CTM to investigative
sites according to study specifications.
39. Once imported, Quintiles will:
o Monitor to verify that full and proper drug accountability
records are maintained at each site. This includes documenting
shipments to and from the sites as well as reconciling missing
and damaged supplies.
o Distribute, store (and/or arrange for storage as necessary) of
CRFs and other study supplies as directed by Cubist.
40. Quintiles will maintain full documentation concerning delivery and
receipt of the Investigational Product. Quintiles will oversee the
storage and distribution of these materials to each of the study sites.
Quintiles' management and distribution of the CTM will fully comply
with local regulatory guidelines.
H. SITE INITIATION
SITE PREPARATION AND INITIATION
41. Prior to site initiation Quintiles' CRAB will collect all regulatory
documents, including:
o Written IRB/IEC approval o IRB/IEC approved Informed
Consent letter
o Laboratory Certification and laboratory reference ranges (if
applicable)
o Investigator Statement to conduct the Protocol Signed, updated
Investigator and co-Investigator CVs
o Signed Financial Agreement o Financial Disclosure Agreement
42. Quintiles' CRAB will perform a comprehensive site initiation visit at
each study site. The CRA will meet with the Investigator and site staff
to review the Protocol, CRF completion and verification procedures, and
other clinical issues.
43. Each site initiation visit is estimated to consist of [*] on-site, [*],
and [*] in-house-time:
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
44. Quintiles will provide to Cubist written visit reports according to
Quintiles' SOPs. Completed visit reports will be delivered to Cubist
within [*] days of the visit.
45. Quintiles will provide to Cubist written visit reports according to
Quintiles' SOPS. completed visit reports will be delivered to Cubist
within [*] days of the visit.
46. Drug shipment will be coordinated with the initiation visit so that the
drug accountability procedures required by the Protocol can also be
reviewed with the site personnel. The monitor will review the site's
regulatory file completely. The aim of this visit is to be certain that
the study site staff understands all project regulations and
documentation as well as procedures to fill out all forms.
47. Quintiles will maintain all original study documents until the end of
the study, unless specified otherwise by Cubist. Prior to shipment of
the Investigational drug, copies of all documents will be sent to
Cubist for review or submission to third party.
48. Quintiles will train the Investigators and Study Coordinators in the
understanding of the Study Manual. This will include (but is not
limited to): Investigator responsibilities, Protocol amendments to IRB,
CRF handling and transmission of data, drug shipment checklist,
maintenance of study files, study medication storage and handling,
specimen handling, adverse events (AE) and Serious Adverse Event (SAES)
reporting, preparation for regulatory inspections and general
assistance.
49. For each initiation visit performed, Quintiles will complete a Study
Initiation Visit Report according to Quintiles SOPS. A detailed
follow-up report will be sent to the Investigator, outlining the
pertinent points for each visit and the agreed-upon actions.
I. INTERACTIVE VOICE RESPONSE SYSTEM DESIGN AND DEVELOPMENT
50. Quintiles will provide WAS randomization services for DAP-CAP-00-08
51. Project Team Members include Quintiles staff from IVR Services.
PROJECT MEETINGS
52. The Quintiles IVR Services Project Manager and Technical Lead will
participate in [*] teleconference with project representatives from
Cubist to discuss PROJECT start-up activities.
53. The Quintiles IVR Services Project Manager and Technical Lead will
participate in [*] analysis and design meetings, via teleconference,
with Cubist to discuss the IVRS design and functions.
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
54. The Quintiles IVR Services Project Manager will attend [*] Investigator
Meeting in [*] and [*] Investigator Meeting in [*] to demonstrate the
IVRS and provide training to site users.
DEVELOP IVRS SPECIFICATIONS
55. The Quintiles IVR Services Project Team, in conjunction with team
members from Cubist, will create a Software Requirements Specification
(SRS)/Functional Design Specification (FDS) document. The SRS defines
the scope of the software, the users of the software, and the
requirements of the software. The FDS defines bow the software will
meet the requirements from the users' perspective, defines the messages
the software will use to interact with the users, and provides details
on information exchanged between the Quintiles IVR System and other
systems. Cubist will be responsible for approving the SRS/FDS document.
56. Quintiles and Cubist will also develop IVRS Message Dialog Flows and
Message Lists, which define the flow of the dialogs between the system
and the users.
57. Quintiles will provide the IVRS in [*].
58. The system will be available to unblinded site staff as follows: [*]
toll-free number for each country participating in the study [*] will
be established for access to the IVRS. These lines will be set to
connect to a bank o(pound) lines terminating at Quintiles IVRS
facility.
59. Quintiles will create a Physical Design Specification (PDS) to assist
them in designing the I;VR System. The PDS is an internal document that
identifies how the software will meet the requirements from the
programmers' perspective and the hardware and software specifications
on which the software is implemented. The PDS will identify the modules
used to implement the software, the functions and/or procedures within
each module, the interaction between modules, and the database
structure.
60. Quintiles will create IVR, database, and reporting modules, create and
execute unitlintegration tests, create and execute functional tests,
perform code review of modules, and install code into the version
management system_
61. Quintiles will develop a demonstration system which will provide the
primary user with a "hands on" demonstration of the IVRS. Primary users
will have an opportunity to hear how tbc system functions and receive
training on the software.
62. Quintiles will create a Quick Reference Cruide for site users. The
Quick Reference Guide is a one (1)-page reference sheet to assist the
unblinded site staff in using the IVRS. The reference guide includes
phone numbers for the IVRS and Helpline, helpful tips for using the
IVRS, and the system menu hierarchy.
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
63. Quintiles will create a user manual/demonstration guide which functions
as a detailed reference guide on the IVRS, in addition to providing the
users with instructions to operate the demonstration portion of the
IVRS.
64. Cubist will be responsible for approving the Quick Reference Guide and
User Manual/Demonstration Guide.
IVRS VALIDATION
65. A validation package is created for each IVR application. The
validation package includes documents such as the SRS/FDS, traceability
matrix, executed test plans, test plan summary, and acceptance
certificate.
66. Quintiles will develop a Computer System Validation plan to define the
validation process. Quintiles will also create test plans/cases to
describe how the software will be tested based on gathered and approved
requirements.
67. Quintiles will develop a Unit Test Plan, which provides a written
record of the actual test inputs and expected/actual results and
provides instructions to permit execution of the test by the
appropriate personnel. The Unit Test Plan will define in detail
precisely what constitutes an acceptable product by establishing
specific tests that demonstrate that the applications performed as
expected.
68. Quintiles will develop the Integration Test Plan that defines how the
software will be tested to ensure that it meets the primary user's
requirements. The Executed Integration Test Plan demonstrates the
functionality of the application, determines successful implementation
of requirements and design elements for the software, and along with
the Test Summary, provides a tool to explain any deficiencies found in
the software during execution OF the Executed Integration Test Plan.
69. After successful execution of the test plans, Quintiles will offer
Cubist a window of time in which to perform user acceptance testing_
The software will be put into production after Cubist performs user
acceptance testing or uses Quintiles IVRS testing as their acceptance.
70. Any changes to the IVRS subsequent to production implementation are
handled with Quintiles TVRS change control process to assure continuous
validation.
J. IVRS SERVICES
RANDOMIZATION SERVICES
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
71. The IVRS will provide centralized randomization services for [*]
subjects located at [*] sites in [*]. The system will be programmed in
[*].
72. The IVRS will support one (1) call per subject to announce treatment
arm assignment. The TVRS will not announce treatment kit numbers.
73. The IVRS will randomize subjects into one (1) of two (2) treatment
arms [*].
74. The IVRS will support a simple randomization schedule with no
stratification variables or minimization algorithms.
75. The IVRS will not have functionality to discontinue subjects.
76. The IVRS will be in operation for [*] months to support the [*] month
enrollment period.
STUDY DRUG MANAGEMENT SERVICES
77. Quintiles will be responsible for monitoring study drug inventory at
the sites and requesting re-supply drug orders from the distribution
centers.
TRANSLATION SERVICES
78. The IVRS and Quick Reference Guide will be translated into [*]. The
User Manual/Demonstration Guide will be provided in English only.
HELPLINE SUPPORT SERVICES
79. Helpline staff will be available 24 hours a day, seven (7) days a week
to assist Quintiles IVRS site users who have questions or experience
difficulty with the IVRS. The Helpline is designed to assist monitors,
Investigators, and study coordinators who require assistance with the
IVRS. The Helpline is always staffed with [*] speaking associates, and
in addition, some Helpline staff do speak [*], although these
individuals may not be available for a given call. To accommodate [*]
speaking sites; Quintiles can use Language Line Services in a
conference call manner. Costs associated with Language Line Services
will be passed through to Cubist at cost. These costs are not estimated
in Quintiles budget.
80. The Helpline is involved throughout the life cycle of the IVRS. During
the start-up phase of the study, the Project Manager collaborates with
the Helpline Lead to write procedures to be used by the Helpline staff:
The Helpline Lead sets-up issue tracking tools and trains staff members
on protocol specific details such as randomization and system set-up,
as appropriate. During the maintenance phase of the IVRS life cycle,
the Helpline is responsible for assisting sites in using the IVRS,
disclosing lost or forgotten User IDs and Personal Identification
Numbers (PINs), monitoring system availability, performing certain data
edits, following-up with programmers on outstanding data edits, and
identifying system problems to the Project Manager
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WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
81. Quintiles will direct inquiries of a medical, monitoring, or
protocol-related nature to appropriate medical personnel designated in
advance by Cubist.
STATUS REPORTS AND DATABASE TRANSFER
82. The IVRS will automatically send faxes and reports to the sites and
Cubist. The IVRS will produce the following three (3) reports for use
throughout this study:
o Randomization
o Weekly site enrollment
o On Hold (Site did not confirm subject's treatment via IVRS)
MAINTENANCE ACTIVITIES
83. The IVRS will support [*] manual database edits (MDEs); [*] routine
edits (i.e., change in fax number) and [*] non-routine edit (i.e., to
correct site user errors), per site over the course of this study.
ELECTRONIC DATABASE TRANSFER
84. Before the first database transfer, Quintiles will conduct a test
transfer at an interval predetermined jointly by Cubist and Quintiles.
The test transfer will verify compatibility with relevant existing
Cubist databases. Following verification, Quintiles will transfer the
database. Test transfers will occur until Cubist and Quintiles agree
that the database files meet the specifications.
85. Quintiles has budgeted for [*] IVRS database transfer.
OTHER NOTES
86 Quintiles will generate [*] PINS per site.
87. Quintiles has not included costs for providing real time access to data
via a web interface.
K. INTERIM MONITORING VISITS
STUDY MONITORING VISITS/SITE MANAGEMENT
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
88. CRAB will be assigned monitoring responsibilities according to their
experience, availability, and geographic proximity to a site. To
facilitate communication within the monitoring team, CRAB will conduct
periodic calls to sites. The telephone calls provide a forum in which
issues are identified, examined, and resolved, and relevant information
is distributed and discussed.
89. The PM will use weekly project calls with project CRAs to focus and
organize the ongoing study. The PM will coordinate monitoring efforts
to communicate important study updates across all regions/offices.
The PM will provide periodic reports to Cubist.
90. Quintiles' CRAB will prepare for periodic site visits by reviewing
relevant information from the study, by scheduling the visit, and by
preparing the agenda. Key objectives of the monitoring visit are
anticipated to include the following:
o Ascertain that the study staff is adhering to Protocol
o Review Protocol updates, amendments, and revisions as
applicable
o Check regulatory file maintenance
o Assess the progress of the study
o Verify adequacy of enrollment per Protocol
o Review CRFs for completeness and legibility
o Compare CRY with source documents to assess consistency,
accuracy, and completeness
o Collect CRF pages for completed patients and unused medication
o Resolve outstanding data clarification forms (DCFs) from
Cubist
o Assess patient enrollment and discuss scheduling of future
visits based on enrollment rates
o Review to verify that Informed Consents and IRB procedures are
being followed
o Monitor to verify SAES reporting according to Cubist's SOPS
o Review facilities and staff for consistency across the study
o Perform drug inventory, monitor drug distribution, and check
storage procedures
o Ascertain that GCPs are followed
o Discuss questions regarding the study procedures
91. Key efficacy and safety data will be verified at each monitoring visit.
Quintiles will perform 100% Source Data Verification (SDV) for all data
including key efficacy parameters, safety data and inclusion/exclusion
criteria. At the completion of each site visit, Quintiles' CRAB will
meet with study staff to review what was been accomplished during the
visit, to document any issues requiring further action by either the
study or Quintiles' staff and to consider recommendations for future
visits.
92. Each monitoring visit includes [*] hours on-site, [*] hours travel, and
[*] in house time. Time on-site for monitoring visits will be increased
or decreased proportionately based on patient enrollment. Additional
on-site monitoring time has been included in the budget to cover
additional days on site.
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
93. Each site will receive [*] interim monitoring visits.
94. Quintiles will provide to Cubist written visit reports according to
Quintiles' SOPS. Completed visit reports will be delivered to Cubist
within [*] days of the visit.
IN-HOUSE ACTIVITIES
95. In-house monitoring activities will include reports of every visit
performed, follow-up with sites for data resolutions, telephone
monitoring between visits, correspondence with the sites and Cubist,
and periodic telephone monitoring. Quintiles' CRAB will make frequent
telephone contact with sites throughout the patient enrollment and
treatment period, including communications with each study site
regarding protocol issues or DCFs. The in-house activities also include
the generation of periodic study status reports and monitoring reports.
Those reports will include, but are not limited to:
o Listing of corrected discrepancies
o Patient accurate Status report
o Number of patients entered into the study
o Number of patients dropped from the study
o Number of patients who have completed the study
o Progress report of patients in the study
o Issues related to patient recruitment and active evaluation
o Issues related to patient safety
o Tracking of CRFs
o Status of regulatory documents
o Status of drug accountability
96. Quintiles will provide read-only access of the Inntrax!* project
management tracking system to CUBIST during the enrollment and
treatment portion of the study_ Costs for this service are included as
a pass-through in the budget.
97. A detailed follow-up report will be sent to the investigator, outlining
the pertinent points from each visit and the agreed-upon actions.
Quintiles will consolidate and update the patient status report
monthly.
98. The Quintiles' CRAB will communicate with each clinical site on a
routine basis, at least every two (2) weeks, documenting all
communication in a telephone log. Quintiles will forward telephone logs
to Cubist on a monthly basis. The CRAs will resolve data discrepancies
as they are identified by internal review or via data management
procedures.
L. SAFETY REPORTING
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
ADVERSE EVENT (AE) HANDLING AND REPORTING
99. Quintiles will prepare SAE reports. for all SAES. All reports will be
submitted to Cubist for approval. Cubist will be responsible for
submitting SAE reports to the FDA. Quintiles will be responsible for
submitting all required reports to Latin American
governments/regulatory authorities after Cubist has reviewed and
approved them.
100. Investigators will be directed to contact the PMO at Quintiles' Mexico
facility to report all SAES. The PMO will collect all AE and SAES
reported during the trial. Local and national AE and SAE reports (e.g.
ANMAT 'reports in Argentina) will be prepared and submitted by the
Quintiles local office.
101. The PMO will be available to respond to patient (treatment, selection,
concomitant drug, etc), Protocol, and drug use questions.
102. Quintiles will prepare patient SAE narratives. Quintiles will submit
narratives directly to Latin American authorities after each narrative
has approval from Cubist.
103. Full details of all AEs that occur during the study will be recorded in
the CRF. These will be reviewed by the CRA during monitoring visits,
and any queries will be clarified at that time. If the CRA finds any
potential SAES that have not been reported, the CRA will report them
immediately to Quintiles.
Quintiles assumes that for this study, [*] SAEs will be processed
104. Quintiles will be responsible for notifying the sites and local
regulatory authorities of any Daptomycin related serious or unexpected
adverse event that is deemed reportable to FDA. The documents will be
provided to Quintiles by Cubist for distribution to the sites and local
authorities.
M. CLOSE-OUT VISITS
105. Quintiles will perform a close-out visit at each site following
notification from Cubist that database lock has occurred. The close-out
visit will include the following:
o Collection of all outstanding CRFs
o Resolution of missing and questionable data
o Review of the Investigator's regulatory binder for completion
and regulatory compliance
o Management of final drug accountability
o Record retention
o Any pending issues that might have accumulated throughout the
study
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT I
SCOPE OF WORK
106. Quintiles will remove all appropriate study documentation, CRFs, drug
supplies, etc, from each investigative site. These documents may
include:
o Copies of the signed IRB-Approved Informed Consent Forms
o Laboratory Certification and Laboratory Reference Ranges
o Copies of all CRFs
o Patients' Master Files
o Investigator File
o Copies of all data queries
o Copies of all communications (e.g., with Cubist, IRB, etc.)
107. Each site close-out visit is estimated to consist of [*] hours on-site,
[*] hours travel, and [*] hours in-house-time.
108. Quintiles will conduct follow-up visits to sites (after site close
out), if requested by Cubist, to inform the Investigator of any
remaining regulatory responsibilities and to reconcile missing or
questionable data. Costs for these visits are not included in the
budget and will be invoiced to Cubist on a fee-for-service basis.
109. After completing the close out visit and any requested follow-up
visits, Quintiles will complete a suitable visit report and send a
close-out letter to the Investigator, outlining the pertinent points
from the visit(s). A copy of this letter, as well as a copy of the
Investigator's letter to the IRB closing the site, will be forwarded to
Cubist.
110. Quintiles will provide to Cubist written visit reports according to
Quintiles' SOPS. Completed visit reports will be delivered to Cubist
within [*] days of the visit.
N. CONTRACT MODIFICATIONS
111. Modifications to the contract will be handled as follows:
o Requests for services beyond this scope of work will be
requested by Cubist to the PM
o The PM will submit a Change Notification Form (CNk) to Cubist
o Upon signed approval of the CNF, a formal contract modification
will be sent to Cubist
o Upon Cubist's approval, the additional services will be
performed as specified in the contract modification, and at the
agreed cost
o If required, the payment schedule will be modified to reflect
adjustment in costs, subject to the approval of Cubist and
Quintiles.
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 2
PROJECT BUDGET
PROJECT BUDGET
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 2
PROJECT BUDGET
[*]
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 2
PROJECT BUDGET
IVRS BUDGET
[*]
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 2
PROJECT BUDGET
[*]
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 2
PROJECT BUDGET
BUDGET NOTES
[*]
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 3
PAYMENT SCHEDULE
[*]
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 3
PAYMENT SCHEDULE
[*]
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<PAGE>
WORK ORDER l
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 3
PAYMENT SCHEDULE
[*]
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<PAGE>
WORK ORDER 1
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 4
TRANSFER OF OBLIGATIONS
TRANSFER OF OBLIGATIONS
[*]
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<PAGE>
WORK ORDER
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 5
LOCAL REPRESENTATION
LOCAL REPRESENTATIVE DUTIES
WHEREAS, pursuant to the attached Work Order (the "Work Order') Cubist
Pharmaceuticals, Inc. ("Sponsor") desires to conduct clinical trials in one or
more countries that require a local sponsor or representative, but Sponsor does
not have offices in such countries; and,
WHEREAS Quintiles, Inc. and/or its affiliates (hereinafter, jointly,
"Quintiles") has offices in such countries, and Sponsor has requested
that Quintiles act as its local sponsor or representative ("Local
Representative") in such countries in conducting the clinical trials
referenced in, or covered by, the attached Work Order (the "Clinical
Trials");
NOW THEREFORE, as part of the attached Work Order, the parties hereby agree as
follows:
1) Quintiles agrees that it will act as Sponsor's Local Representative
for the Clinical Trials in the following countries that require a Local
Representative: [*], Sponsor agrees that Quintiles will be Sponsor's authorized
agent solely for the purpose of performing the duties and obligations required
of a Local Representative in the above-listed countries. If a local governmental
authority instructs Quintiles, in its capacity as Local Representative, to
fulfill duties or tasks that Sponsor has not delegated to Quintiles, then
Quintiles shall inform Sponsor of the instructions, and either Sponsor shall
perform the required duties or tasks, or Quintiles shall perform the required
duties and tasks, and Sponsor shall pay for Quintiles' time (at its standard
daily rates) and expenses in performing such duties and tasks. In addition to
any other indemnification provided by Sponsor, Sponsor hereby expressly agrees
to defend, indemnify and hold harmless Quintiles and its affiliates, and
Quintiles' and its affiliates' directors, officers, employees, subcontractors
and agents from and against any and all claims, damages, costs, liabilities and
expenses (including reasonable attorney's fees and court costs) of any type
("Losses") arising from or in connection with Quintiles' services as Local
Representative for the Clinical Trials, including, but not limited to, any and
all Losses incurred due to any indemnifications entered into by Quintiles
pursuant to Section 2 below.
2) In certain countries (currently [*], certain governmental
authorities, local ethics committees and/or and investigative sites require that
the Local Representative must enter into indemnifications that involve promises
to pay for any damages or harm caused by the drug, product or device being
tested (hereafter, the "Study Drug"). Although such indemnifications frequently
are provided during clinical trials by the owner of the Study Drug, they involve
significant legal risks and responsibilities that are not normally assumed by
companies such as Quintiles. If Sponsor has requested in Section 1 above, or
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<PAGE>
WORK ORDER
CUBIST PHARMACEUTICALS, INC.
DAP-CAP-00-08
ATTACHMENT 5
LOCAL REPRESENTATION
LOCAL REPRESENTATIVE DUTIES
requests in the future as part of an expansion of the Clinical Trials, that
Quintiles serve as the Local Representative in any country with such
indemnification requirements, then Quintiles will serve as the Local
Representative for those countries only if the following special requirements
are met.
a) Sponsor shall make Quintiles and its affiliates an
additional insured on insurance policies covering the Clinical Trials
that are valid in each such country and that contain, at a minimum, the
following types and amounts of insurance: Commercial general liability
coverage, including products liability insurance, and professional
liability insurance, with an insurance company that is rated at least
A, XIII by A.M. Best (or of an analogous rating by a similar
organization if Sponsor is not a United States company) having an
aggregate coverage and per occurrence limit of not less than [*] with,
terms reasonably acceptable to Quintiles. Such insurance will remain in
effect during the entire period of the Clinical Trials and for six
months thereafter and will not be canceled or otherwise materially
changed during that period without thirty (30) days prior written
notice to Quintiles. Sponsor agrees to provide a certificate of
insurance for the above-referenced insurance within 10 days of the
execution of the Work Order to the Quintiles Project Manager far the
Clinical Trials, with a copy to the following address: Quintiles
Transnational Risk Management, 4709 Creekstone Drive, Durham, North
Carolina, 27703, Attention, Barbara Allen,
b) Quintiles shall perform all the monitoring in countries
with such indemnification requirements, and Sponsor shall not use any
other contract research organization in those countries to perform any
duties or tasks for which Quintiles may be held responsible as Local
Representative.
3) If the attached Work Order is terminated, then Quintiles will cease
acting as Local Representative, will terminate any indemnifications it has
entered into as Local Representative, and will assign to Sponsor or Sponsor's
designate any investigator agreements relating to the Clinical Trials that have
been executed by Quintiles. In addition, regarding the countries referenced in
Section 2, Quintiles may cease acting as Local Representative and terminate any
existing indemnifications if a) Sponsor fails to maintain the insurance required
in Section 2; b) Quintiles is no longer providing all the monitoring due to a
modification of the attached Work Order; or, c) one or more serious adverse
events occur such Quintiles reasonably believe that subjects or patients will be
subjected to unacceptable safety risks. Sponsor agrees that Quintiles shall have
no liability to Sponsor for any cessation of its Local Representative Duties or
termination of indemnifications pursuant to this Section.
4) If Sponsor requests that Quintiles act as its Local Representative
in any additional country NOT currently listed herein, and Quintiles agrees in
writing to act as the Local Representative in such country, then the terms of
this Attachment shall apply to Quintiles' services as Local Representative in
that country; provided, however, that Quintiles may refuse to serve as Local
Sponsor in the countries requiring the indemnifications referenced in Section 2
until and unless all the requirements of Section 2 are satisfied
5) The terms of this attachment shall form an integral part of, and are
incorporated into, the attached Work Order.
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the Commission.