Exhibit 10.01
Confidential treatment has been requested for portions of this exhibit.
The confidential portions are designated by brackets [ ].
CLINICAL DEVELOPMENT AGREEMENT
(this "Agreement")
between
VION PHARMACEUTICALS INC.("The Sponsor")
XXXX XXXXXXX XXXX
XXX XXXXX
XX 00000
XXX
and
Covance Clinical Research Unit Ltd ("Covance")
Phase II, Xxxxxxxxxxx Xxxxx
Xxxx Xxxxxx
Xxxxx
XX0 0XX
UK
and
Covance Inc D/B/A Covance Clinical and Periapproval Services ("Covance")
000 Xxxxxxxx Xxxxxx
Xxxxxxxxx
Xxx Xxxxxx 00000
XXX
PREAMBLE
The Sponsor is a pharmaceutical manufacturer which is currently considering the
evaluation of the safety and efficacy of a medicinal product known as
Porfiromycin (the "Drug").
Covance is a Contract Research Organisation ("CRO") primarily engaged in the
business of managing and reporting of clinical trials of medical and related
products.
It is the intention of the Sponsor to contract to Covance the preparation of
clinical trial reports arising from clinical trials performed by Covance for the
inclusion in a regulatory submission dossier.
1. STUDIES (Programme)
The Sponsor hereby requests from Covance and Covance agrees to perform
the responsibilities specified in (a) Section 2 of this agreement, (b)
the Time and Cost Estimate, as may be amended or modified from time to
time (the "TCE") and attached hereto as Exhibit A and (c) the Protocol
as may hereinafter be provided and amended from time to time
(hereinafter, (a)-(c) collectively known as the "Studies") and Covance
agrees to furnish to the Sponsor the final product resulting from the
Studies.
With the Sponsor's prior written consent, Covance shall be authorized
to subcontract parts of the Studies to other companies affiliated with
it. Covance shall not be authorized to conduct any Studies concerning
the Drug beyond those specifically agreed to hereunder unless there is
a written approved modification to this agreement from the Sponsor.
2. OBLIGATIONS OF COVANCE
Covance shall
a) take over the responsibilities as set forth in the TCE and
adhere to the procedures agreed to in Exhibit A;
b) recruit clinical investigators for the practical performance
of the Studies having the necessary training, professional
qualification, experience, licenses to practice medicine at
the location where the Studies will be performed (the
"Investigators") and providing for appropriate and available
Studies site and facilities;
c) provide all Investigators with all information on the Drug and
the Studies available to Covance and make all possible efforts
to assure the Investigators' performance of their work in
accordance with Exhibit A and any and all applicable laws and
regulations, including, but not limited to, generally accepted
principles of Good Clinical Practice, which include the
Declaration of Helsinki and the ICH -Note for Guidance on Good
Clinical Practice and the United States Food and Drug
Administration ("FDA") requirements.
d) instruct Investigators orally and in writing to ensure that
written informed consent is obtained from all trial subjects
and properly signed with the exceptions described in the
national regulations applicable to
2
the conduct of the Studies;
e) have clinical laboratory tests conducted only at laboratories
having the required licences or approvals;
f) require the Investigators to notify Covance promptly of any
SAE (defined below) occurring to a trial subject during the
Studies. Assuming the Investigators have satisfied their
reporting obligations to Covance, Covance shall inform the
Sponsor within the time frames required by the respective
authorities as stated in the Adverse Event Reporting Plan,
specified in Exhibit B, attached hereto;
g) upon prior notification by the Sponsor, assist the Sponsor in
co-monitoring Investigator sites and in conducting its audits;
h) notify the Sponsor and supply all pertinent information in
case any government or regulatory authority conducts an
inspection of any investigational site or takes any other
regulatory action affecting the Studies and grant the Sponsor
the right to be present at any such inspection or regulatory
action;
i) regularly inform designated personnel of the Sponsor on the
progress of the Studies by furnishing status reports including
in particular the number of patients/subjects entered,
withdrawn and completed and information on visits to the
Studies sites;
j) Covance shall instruct the study sites to destroy all unused
clinical supplies upon completion of the Studies;
k) disclose promptly to the Sponsor or its nominee any and all
patentable inventions, discoveries and improvements concerning
the Drug or its use made while performing the tasks for the
Studies and assign all its interests therein to the Sponsor at
the Sponsor's first request and do all such acts which may be
necessary for patent application and registration in any
country, provided that the Sponsor shall fully compensate
Covance for all time and money spent, and these obligations
shall continue beyond the termination of this agreement with
respect to patentable inventions, discoveries and improvements
conceived or made by Covance while providing services to the
Sponsor pursuant to this agreement, and shall be binding upon
Covance's assignees, administrators and other legal
representatives;
3
l) shall indemnify the Sponsor and its officers, directors,
employees and agents from any loss, damage, cost or expense
(including reasonable attorney's fees) (a "Loss") arising from
any claim, demand, assessment, action, suit or proceeding (a
"Claim") for personal injury to study participants or personal
injury to any employee of the Sponsor or property damage
arising or occurring during the conduct of the studies as a
result of Covance's gross negligence or intentional misconduct
or inaction; provided that if such Loss or Claim arises in
whole or in part from the Sponsors gross negligence or
intentional misconduct or inaction, then the amount of the
Loss that Covance shall indemnify the Sponsor for, pursuant to
this agreement, shall be reduced by an amount in proportion to
the percentage of the Sponsor's responsibilities for such
Loss.
m) document all data received in the course of the Studies and
store such data and related records until completion of the
Studies unless otherwise required by applicable laws and
regulations.
3. OBLIGATIONS OF THE SPONSOR
The Sponsor shall cooperate with and support Covance in order
that the Studies be completed in a timely manner and perform
the tasks specified in the TCE, which are allocated to the
Sponsor as specified therein. In addition, the Sponsor shall
a) provide Covance promptly with all information on the
Drug relevant to the Studies including an
Investigational Drug Brochure and any new information
concerning the Drug, which becomes available in the
course of the Studies, specifically, any information
which may require a change in the design of the
Studies or its conduct; especially, any information
that may indicate changes to the risk or health of
trial subjects in the Studies;
b) submit in a timely manner required information and
documents to relevant authorities and ethics
committees, including required updates and obtain
necessary licenses and approvals, or enable Covance
to make such submissions, if applicable;
c) keep adequate records of the clinical supplies made,
and keep such information available for Covance's use
and provide suitable information to Covance to enable
Covance to instruct Investigators how
4
to properly record, safely handle, store and use such clinical
supplies;
d) appoint a properly qualified person to liaise with Covance
concerning the conduct of the Studies;
e) In the event that the TCE specifies that Covance takes
responsibilty for the reporting of the SAEs, Covance will be
available 24 hours a day to deal with all SAEs and to take any
and all appropriate measures with respect to SAEs required by
any laws, statutes, ordinances and regulations. For purposes
of this Agreement an"SAE"is as described in the Serious
Adverse Event Reporting Plan (Exhibit B attached).
f) promptly provide full compensation and adequate treatment for
trial subjects in the event of Studies related injury or death
according to national laws, and provide indemnity (legal and
financial cover) for the Investigators except for claims
resulting from malpractice and/or gross negligence;
g) promptly analyse any reports received from Covance and notify
Covance of any apparent inconsistencies or suspected errors,
mistakes or risks;
h) shall indemnify Covance, formerly Corning Besselaar, Inc. and
their respective affiliates and their respective officers,
directors, employees and agents from any CLAIM or LOSS arising
from or related to;
(i) personal injury directly or indirectly caused by the Drug
or related to the Drug's harmful or otherwise unsafe effects, including a claim,
based on the use, consumption, sale or marketing of the Drug,
(ii) Covance's performance of the Studies or its obligations
under this agreement, the Studies or any aspect thereof set
forth in the PROTOCOL that violates any applicable law, rule,
regulation or ordinance or
(iii) the negligence, gross negligence of intentional
misconduct or inaction of the Sponsor; provided that if such LOSS or CLAIM
hereof arises in whole or in part from Covance's gross negligence or intentional
misconduct or inaction, then the amount of such LOSS that the Sponsor shall
indemnify Covance for pursuant to this agreement shall be reduced by an amount
in proportion to the percentage of Covance's responsibilities for such LOSS.
Under no circumstances shall the Sponsor be entitled to
incidental, indirect, consequential or special damages in connection with a
default
5
or breach of Covance's obligations under this agreement or any documents related
hereto.
i) notify Covance and supply all pertinent information in case
any government or regulatory authorities conduct an inspection
of any investigational site or take any other regulatory
action affecting the Studies and permit Covance to be present
at any such inspection or regulatory action;
j) retain on file and archive all records and items relating
specifically to the Studies for the time period and manner
required by applicable law and regulations upon completion
thereof (e.g., complete case report forms, other test data,
project management and investigator's files, data tapes,
reports, etc.). The Sponsor will make said records and items
available to Covance at no cost to enable Covance to comply
with any and all regulatory requests, inspections or audits,
even after expiry of this agreement;
k) comply with all obligations of the Sponsor under ICH-Note for
Guidance of Good Clinical Practice and FDA requirements not
specifically transferred to Covance by this agreement and its
Exhibit(s).
4. CLINICAL SUPPLIES
a) After necessary ethics committees approvals have been obtained
and all regulatory requirements for starting the Studies have
been met, the Sponsor shall, at its expense, supply the Drug
and other clinical supplies required for the Studies at the
time and to the location indicated by Covance.
b) The Sponsor warrants that such clinical supplies will have
been manufactured in sufficient quantities and in accordance
with applicable Good Manufacturing Practice, and that they are
suitably packed and labelled in such a way that any blinding
procedure is ensured. In the event that the TCE specifies that
Covance arrange the clinical packaging with a sub-contractor,
the Sponsor shall provide Covance the necessary instructions
to package and label the clinical supplies.
c) The Sponsor shall supply Covance with the necessary
documentation to import the Drug into the countries where the
Studies will be conducted.
6
5 CONFIDENTIAL INFORMATION
a) All information transmitted in conjunction with the
implementation of the Studies, whether prior to or subsequent
to the execution of this agreement, concerning the Drug
furnished to Covance or its affiliates, employees or agents by
the Sponsor for the purpose of preparing the Studies and the
data generated for and incorporated in the Studies by Covance
shall belong exclusively to the Sponsor and be held in
confidence by Covance (the "Confidential Information") during
the Studies hereunder and for ten (10) years after termination
of this agreement for whatever reason. Covance will neither
use the Confidential Information for its own benefit nor the
benefit of others.
b) Disclosure will only be made by Covance to its employees,
affiliates, agents or sub-contractors who have a need to know
the Confidential Information and to hospital authorities,
Investigators, their staff, ethics committees and others who
are involved in the Studies;
c) Upon termination of this agreement all Confidential
Information shall be returned to the Sponsor;
d) The obligation of confidentially hereunder shall not apply to
information that is or becomes publicly available through no
fault of Covance, is disclosed to Covance by a third party
entitled to disclose it, is already known to Covance as shown
by its prior written records or is required by law or order of
an authority to be disclosed;
e) Any publication allowing identification of the Sponsor or the
Drug shall be made by Covance only with the prior written
consent of the Sponsor. Any publication by the Sponsor
containing data generated by Covance, the sponsor shall inform
Covance and state that the data was generated by Covance.
6. TIME SCHEDULE
Covance shall use its best efforts to perform the tasks for the Studies
within the time frame as estimated in the TCE. The TCE assumes,
however, the full cooperation of the Sponsor, regulatory authorities,
ethics committees and Investigators, and shall be subject to amendment
from time to time (including as to costs) if the work for the Studies
is delayed due to circumstances not
7
attributable to Covance, which include, but are not limited to, the
following:
a) failure of the Sponsor to deliver the medical supplies or
Studies related information in due time, or
b) amendments to previously agreed upon protocols, procedures or
documents required for the Studies at the request of the
Sponsor, or
c) significant delays in pre-Study meetings or in other tasks to
be performed by Covance caused by the Sponsor, or
d) delays in obtaining or subsequent withdrawal of regulatory
approvals concerning the Studies, or delays in receiving
ethics committees' opinions, or
e) death or disability of any Investigator or other research
specialist to continue his or her work for the Studies, or
f) higher ratio of drop-outs among trial subjects than
anticipated in the TCE (Exhibit A), or
g) lower enrolment rates than expected and agreed to by the
Sponsor and Covance, or
h) unforeseen changes in the relevant medical practice,
regulations, or
i) any other event or circumstance outside of Covance's control.
Data management and statistical analysis timelines are based upon [ ]
([ ]) from the end of monitoring to the production of the final report.
Within the stated [] weeks, [] has been allocated for client review.
The actual dates are also dependant upon but are not limited to the
above listed a) - i)
7. COMPENSATION (FIXED PRICE)
a) The total price for the Studies is described in the TCE, which
specifies Covance's fixed fees and out-of-pocket expenses in
addition to fees and other disbursements to be paid to
Investigator's, subcontractor's and trial subjects (if any),
relating to the Studies on a pass-through basis.
8
b) The cost of deviations in the Studies outside of Covance's
control or changes in the scope of the Studies will be
discussed with the Sponsor and additional work in connection
with the Studies will not be performed by Covance without the
signature of the Sponsor on the respective Charge Order Form.
Covance shall not be obliged to perform any work for the
Studies without proper compensation by the Sponsor.
c) The fees shall be invoiced by Covance in accordance with the
scheduled milestones contained in the TCE. All invoices shall
be payable net without deduction within 30 days after the date
of invoice. Covance, at its discretion, may charge a 3%
reminder fee per month for invoices delayed by more than 30
days.
d) This agreement is denominated in UK sterling (pound). Any
exchange differences arising from fluctuation in exchange
rates will accrue to the Sponsor and will be the subject of a
separate quarterly credit note or invoice.
e) The calculation of costs in the TCE incorporates an annual
inflation rate of 5% as it relates to the pharmaceutical
industry. Any inflation rate beyond [] will result in separate
quarterly invoice.
8. TERMS AND TERMINATION
This agreement shall become effective upon the execution by both
parties and shall continue until the Studies under this agreement has
been completed unless this agreement is terminated earlier as proved
hereinafter.
The Sponsor may terminate this agreement prematurely as follows:
a) If Covance fails to perform or performs negligently any
material work in accordance with this agreement, which
continues uncured for 30 days after receipt of written notice
from the Sponsor;
b) if the Sponsor and/or any regulatory authority recognizes that
any adverse drug reactions necessitate discontinuation of the
work for the Studies;
c) if continuation of the work for the Studies becomes
commercially unfeasible, by giving Covance [] prior written
notice;
9
d) if the Sponsor licenses the Drug to a third party who wishes
to conduct the remaining part of the Studies themselves, by
giving Covance [] prior written notice.
In the event of termination under item a), Covance shall be paid only
for work properly completed and costs to which it is actually obligated
such as Investigators fees, etc.
In all other cases Covance shall be fully paid for all the work
performed and all expenses incurred until termination becomes effective
and all costs relating to severance of subcontracts or service
agreements as a result of such termination. In addition, the Sponsor
shall pay Covance [].
In all cases of termination hereunder, the parties shall cooperate in
order to ensure patient safety, continuity of treatment, delivery of
the works and compliance with all applicable regulations.
9. FORCE MAJEURE
No party shall be liable for any delay in performance or failure to
perform this agreement, if due to an act of God or any other occurrence
beyond the control of the respective party; provided, however, that
performance is resumed promptly following the end of the occurrence
causing delay or failure.
10. MISCELLANEOUS PROVISIONS
a) Any amendment or modification to this agreement and its
Exhibit(s) shall be effective only if made in writing and
signed by both parties.
b) Except as expressly provided herein, neither this agreement
nor any rights arising thereunder shall be assigned to any
third parties, except affiliates of the Sponsor and Covance,
without the prior written consent of the other party which
consent shall not be unreasonably withheld.
c) This agreement, together with the attached Exhibits, is the
entire understanding between the parties hereto with regard to
the subject matter covered hereby and supersedes any and all
prior agreements or understandings between the parties whether
written or oral.
10
d) Covance's relationship with the Sponsor under this agreement
shall be that of an independent contractor and nothing
contained herein or considered hereby shall constitute Covance
or any of its subcontractors, auxiliaries or employees as the
Sponsor or as employees, joint venture, or partner of the
Sponsor.
e) Neither party shall during the term of this agreement and for
one year thereafter solicit for employment either directly or
indirectly any employees of the other or its affiliates, who
became familiar with it as the result of the work for the
Studies.
In case of breach of this provision by one party the other
party shall, in addition to other remedies, be entitled to
specific performance and enforcement thereof by judicial
injunction.
f) Should any of the provisions hereof be held invalid or
unenforceable, the validity and effect of the other provisions
of this agreement shall not be affected thereby.
g) The waiver or the failure to claim a breach of any provision
of this agreement by either party shall not constitute a
waiver or estoppel with respect to any subsequent breach or
with respect to any other provision thereof.
h) Any notices given or required to be given hereunder shall be
effective if delivered personally or mailed by certified or
registered mail to the other party at the address first given
above or such other address or addresses of which such party
shall have given notice.
11. GOVERNING LAW
This agreement shall be governed by UK substantive law.
11
IN WITNESS WHEREOF, the parties have caused this agreement to be executed by
their duly authorized officers.
/s/ Xxxxxx Xxxxxxx
------------------- -----------------------------
SIGNATURE on behalf of Vion Pharmaceuticals Inc.
Xxxxxx Xxxxxxx
------------------- -----------------------------
PRINT NAME
Vice President Operations
------------------- -----------------------------
TITLE
6/25/97
------------------- -----------------------------
DATE
/s/ Xx X X Xxxxx
------------------- -----------------------------
SIGNATURE on behalf of Covance Clinical and
Periapproval Services Ltd
Xx X X Xxxxx
------------------- -----------------------------
PRINT NAME
Senior Vice President, Europe
------------------- -----------------------------
TITLE
18th June 97
------------------- -----------------------------
DATE
/s/ Xxxxx Xxxxxxx
------------------- -----------------------------
SIGNATURE on behalf of Covance CRU Ltd.
Xx Xxxxx Xxxxxxx
------------------- -----------------------------
PRINT NAME
Managing Director
------------------- -----------------------------
TITLE
------------------- -----------------------------
DATE
12
TIME AND COST ESTIMATION
FOR
VION PHARMACEUTICALS INC.
XXXX XXXXXXX XXXX
XXX XXXXX
XX 00000
XXX
=================================================================
PORFIROMYCIN IN HEAD & NECK CANCER
=================================================================
This estimation is valid for 30 days for the clinical trial in accordance with
the assumptions that have been listed within. Materials contained within this
proposal are confidential and except for data provided by Vion Pharmaceuticals
Inc are the property of Covance.
Dated: 23rd June 1997
TABLE OF CONTENTS
-----------------
I. INTRODUCTION................................................................3
II. BACKGROUND AND RATIONALE...................................................3
(I) PHASE II TEAM ONCOLOGY EXPERIENCE..........................................4
(II) EXAMPLES OF PERSONNEL PROFILES............................................5
III. STUDY DESIGN SUMMARY......................................................7
IV COVANCE TASKS...............................................................7
(A) OVERALL PROJECT MANAGEMENT.................................................7
(B) REGULATORY SUBMISSIONS.....................................................8
(C) PROTOCOL REVIEW............................................................8
(D) CASE REPORT FORM (CRF) AND MONITORING CONVENTIONS DEVELOPMENT..............8
(E) LABORATORY SELECTION.......................................................8
(F) INVESTIGATOR SELECTION.....................................................9
(G) PRE-STUDY SITE VISITS......................................................9
(H) INVESTIGATOR BUDGET MANAGEMENT.............................................9
(I) INVESTIGATOR PACKAGE......................................................10
(J) TRANSLATIONS..............................................................10
(K) INVESTIGATOR MEETINGS.....................................................11
(L) DRUG SUPPLY MANAGEMENT....................................................11
(M) INTERACTIVE VOICE RESPONSE SYSTEM (IVRS)..................................12
(N) INITIATION, MONITORING AND CLOSE OUT VISITS...............................12
(O) STATUS REPORTING..........................................................13
(P) ICH GCP SITE AUDITS.......................................................13
(Q) ADVERSE EXPERIENCE REPORTING..............................................14
(R) CLINICAL DATA MANAGEMENT AND BIOSTATISTICS................................15
o Data Entry...............................................................15
o Data Review and Clean-Up.................................................15
o Programming..............................................................16
o Preparation of the Interim Analyses......................................16
o Statistical Analysis.....................................................16
o Preparation of the Statistical and Clinical Trial Reports................17
(S) CONTRACT MANAGEMENT.......................................................17
(T) DEVELOPMENT AND MAINTENANCE OF AN E-MAIL SYSTEM...........................17
V STUDY SYNOPSIS AND TIMELINES................................................19
VI PROJECT RESPONSIBILITIES ASSESSMENT........................................20
VII. GLOBAL COST ESTIMATION...................................................21
VIII. CLINICAL AND BIOSTATISTICAL ASSUMPTIONS.................................22
IX. OUT OF POCKET STUDY COSTS.................................................23
X. PAYMENT SCHEDULE...........................................................24
XI. TOTAL ESTIMATED COSTS (EXCLUDING OUT-OF-POCKET EXPENSES)..................25
XII. SUMMARY AND CONCLUSIONS..................................................25
ATTACHMENT I.
ORGANOGRAM................................................................25
2
INTRODUCTION AND BACKGROUND
---------------------------
I. INTRODUCTION
Vion Pharmaceuticals have asked Covance CRU Ltd (Covance) to provide a
Time and Cost Estimate (TCE) for providing Clinical and Biostatistical
services for a Phase III, double-blind, randomised, placebo-controlled
study of porfiromycin when used as an adjuvant to radiation therapy in
patients with Head and Neck Cancer
This proposal provides a description of the tasks Covance will perform,
as discussed with Vion Pharmaceuticals to complete this program. The
proposal also provides an operational plan describing the
implementation and management of the program, including communication
channels between Vion Pharmaceuticals and Covance world-wide. Timelines
and costs associated with this program have been developed and outlined
herewith in detail, including the assumptions that Covance has used for
generation of this proposal. Changes to these assumptions may have an
impact on the timelines and costs provided herein.
II. BACKGROUND AND RATIONALE
Covance's European Phase II Clinical group was created in December
1994. Based in the Maidenhead office the group is comprised of ten
Clinical Research Associates (CRAs), who are supported by 2 Clinical
Studies Assistants and a Project Secretary. The clinical team has
experience of managing projects in a number of therapeutic areas and
six of the ten CRAs have experience of monitoring in Europe.
Covance's European Phase II Biostatistics group was created in 1995 to
provide data management, statistical analysis and report writing
services for Phase II European-based clinical trials, conducted by
Covance. In addition to this, the group is ideally suited to
stand-alone analysis and reporting of smaller trials from all phases of
clinical research.
Covance will be responsible for []
The success of the Vion program will depend upon many factors, which
include: clarity of program goals and complexity, and the establishment
of an enthusiastic and well-integrated Vion Pharmaceuticals and Covance
project team with well-defined
3
roles and responsibilities for team members. A Covance team has been
actively working on the Vion Pharmaceuticals program with Vion
Pharmaceuticals since [].
The productive relationship Vion Pharmaceuticals and Covance have
shared will help to minimise the time spent on administrative issues
such as establishing acceptable billing procedures, standard operating
procedures, and reporting of project information. Experienced personnel
will be placed in key positions to ensure that Covance meets its
responsibilities for the program. The below table provides a summary of
the Phase II personnel's specific oncology experience. Also, examples
of personnel profile for clinical and biostatistical staff are
enclosed. An organogram of specific personnel is illustrated in
Attachment II.
(I) PHASE II TEAM ONCOLOGY EXPERIENCE
------------------ -------------------- ----------- --------------- ======================================
INDICATION DRUG PHASE PATIENTS CENTRES
------------------ -------------------- ----------- --------------- ======================================
NSCLC [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
NSCLC [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
NSCLC [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
NSCLC [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
NSCLC [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
Breast Cancer [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
Pancreatic Cancer [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
Pancreatic Cancer [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
Pancreatic [ ] [ ] [ ] [ ]
Cancer
ongoing
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
Gastric Cancer [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
Breast Cancer [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
Ovarian Cancer [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
All Solid Tumours [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
NSCLC [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
AML [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
4
------------------ -------------------- ----------- --------------- ======================================
SCLC [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
Breast Cancer [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
------------------ -------------------- ----------- --------------- ======================================
CML [ ] [ ] [ ] [ ]
------------------ -------------------- ----------- --------------- ======================================
In addition to the above experience we have also written a PK study
protocol of []
(II) EXAMPLES OF PERSONNEL PROFILES
EXAMPLE OF PERSONNEL PROFILE - CLINICAL
---------------------------------------
This study will be managed by 1 Principal Clinical Research Associate,
4 Clinical Research Associates (based in the UK, Spain and Germany) and
assisted by 1 Clinical Studies Assistant. The team may draw upon CRAs
in other European offices as required.
Project Director is a Principal Clinical Research Associate (PCRA). The
PCRA has [] years monitoring experience throughout Europe and has
experience of monitoring and managing oncology studies.
Project Physician is a Medical Oncologist who also has several years
experience in Medical Oncology within the Pharmaceuticals and CRO
industry.
Monitors are [] Clinical Research Associate (CRA). The CRAs have at
least [] years monitoring experience throughout Europe and will have
experience of monitoring and managing oncology studies.
The US study will be managed by an RMS Project Leader and assisted by
[] RMS Associates.
Regional Monitoring Services Project Leader (RMS PL). The Project
Leader has [] years experience in monitoring and managing clinical
trials.
Regional Monitoring Services Monitoring Associate (RMS Assoc.). The RMS
Assoc.'s have at least [] years monitoring experience throughout the
US.
Clinical Studies Assistant (CSA) would provide Administrative support
to the study.
5
EXAMPLE OF PERSONNEL PROFILE - BIOSTATISTICS
--------------------------------------------
The biostatistical function of the study will be managed by a
Biometrics Manager and assisted by data entry, data management and
statistical programming personnel.
Project Coordinator is a Biometrics Manager within Phase II
Biostatistics with appropriate data management and programming and
statistical experience, in a Clinical Research Organisation (CRO)
environment and pharmaceutical company. The PC has a post-graduate
qualification in statistics and has worked in a variety of therapeutic
areas.
Statistical Programmer will provide statistical programming support for
production of Tables, Figures and Listings. The statistical programmer
has a first degree in a statistical subject.
Data Coordinator will carry out data management of Case Report Forms to
provide the statistician with a clean database. The data coordinator
has a first degree in a life science.
Data Entry Operators will carry out data entry of Case Report Forms.
The data entry supervisor has [] years experience of working within a
Clinical Research Organisation.
The PC and project team are focused by the needs of the customer and
are responsible for ensuring that the project meets all the objectives
against the agreed specifications.
6
III. STUDY DESIGN SUMMARY
The Vion Pharmaceuticals Phase III trial for the treatment of Head &
Neck cancer will be conducted in the UK, France, Spain, Germany and the
U.S. The trial is a double-blind, randomised, placebo-controlled study
of porfiromycin when used as an adjuvant to radiation therapy. The
primary endpoint is the time to treatment failure over a two year
follow-up. In addition, secondary endpoints are tumour recurrence rate,
disease free survival time and overall survival.
The statistical analysis will be carried out on an intent-to-treat
basis. Patients must have received radiation therapy and at least one
dose of study medication.
[] will be performed unblinded by an independent Covance Statistician.
[]
[]
[]
[]
Statistical analysis will be performed using SAS. Tables, figures and
listings will be produced by SAS and stored in ASCII output files for
inclusion in the clinical trial report.
IV COVANCE TASKS
(A) OVERALL PROJECT MANAGEMENT
Overall responsibility for this study lies with the Global
Project Director, as shown on the organogram, Attachment X.
Xxxx Pharmaceuticals and Covance will discuss on an ongoing
basis any modification to the project team that is required to
expedite the program.
7
(B) REGULATORY SUBMISSIONS
Covance will prepare the regulatory submissions for Europe
(France, UK, Spain and Germany) and the USA. Covance European
Regulatory group have a separate agreement directly with Vion
Pharmaceuticals.
(C) PROTOCOL REVIEW
Vion Pharmaceuticals has prepared the head and neck cancer
trial protocol, no. PORF-96-001. Covance will review the
protocol extensively in preparation for investigator selection
and pre-study visits.
(D) CASE REPORT FORM (CRF) AND MONITORING CONVENTIONS DEVELOPMENT
Covance will develop a CRF. The CRF will be reviewed and
approved according to the Covance CRF review process. The CRF
will be designed to capture all pertinent information in a
format that allows for rapid review and data entry.
The same CRF will be utilised for Europe and the USA. Covance
will produce monitoring conventions.
The final size of the CRF is 176 pages, this is the assumption
used in the cost estimation.
Covance will be responsible for managing the printing and
shipping of the CRFs, monitoring conventions and other
ancillary forms to the investigational sites.
All CRFs will be printed in the UK. Covance will monitor
investigational site's needs requesting shipment of additional
supplies and verifying shipment of supplies (ie; CRFs and
accompanying forms) to the sites.
(E) LABORATORY SELECTION
The hospital laboratory at each investigational centre will be
used for routine clinical chemistry, haematology and urinary
evaluations.
8
(F) INVESTIGATOR SELECTION
Covance in collaboration with Vion Pharmaceuticals will
identify an adequate number of potential investigators to
yield a total of [] qualified investigators.
The physicians that Covance recruit for this trial will have
the relevant and necessary oncology experience required for
the purpose of this program.
Covance anticipates that [] will be located in the USA and []
will be located in Europe.
For purposes of this Time and Cost Estimate, Covance has
assumed that the total number of investigational sites is [].
(G) PRE-STUDY SITE VISITS
Covance has assumed that its monitors will conduct a total of
[] pre-study site visits in order that a selection of [] sites
may be determined to conduct this program.
During each pre-study site visit, the Covance monitor will
evaluate the investigator in detail for professional
experience and training, prior experience in conducting
clinical drug trials, access to an adequate number of
appropriate patients, an adequate interest in and
understanding of the protocol, a required level of staffing
(preferably including the availability of a study
co-ordinator), adequacy of facilities, current workload and an
understanding of regulatory requirements.
Vion Pharmaceuticals and Covance will agree on the final
selection of investigators.
(H) INVESTIGATOR BUDGET MANAGEMENT
Covance will be responsible for negotiation, maintenance, and
payment of investigator budgets for all investigational sites
in liaison with Vion Pharmaceuticals. Vion Pharmaceuticals has
provided Covance with guidelines for negotiating all
investigator budgets. Investigator costs are pass-through
costs (out-of-pocket expenses) to Vion Pharmaceuticals.
9
(I) INVESTIGATOR PACKAGE
An Investigator package is a collection of documents including
Regulatory Authority and Ethical Committee approval for a
study and individual sites. The purpose of the investigator
package is to ensure that all necessary documentation is in
place for a study and a site before study drug is released.
Covance Regulatory Affairs and Clinical Research Departments
will prepare an investigator package plan describing the
requirements and general procedures regarding the content,
review and approval of the investigator package necessary for
the release of study medication to clinical study sites. This
approval is called the "regulatory green light". Covance will
verify the completeness and accuracy of the first package for
each country before approving shipment of study medication.
Covance will be responsible for approving shipment of study
medication for subsequent shipments within each country.
Covance will prepare and submit local clinical trial
applications where appropriate in European countries.
Additionally, Covance will be responsible for ensuring that
the Principal Investigator maintains and updates an
Investigator/Regulatory Documents file at each site. The file
will include but not be limited to: the protocol and
amendments, Investigators' Drug Brochure, IRB or Ethics
Committee approval letters, FDA 1572 form, consent forms,
safety updates, correspondence, and other regulatory
documents.
(J) TRANSLATIONS
Covance will be responsible for ensuring accurate and complete
translation of informed consent forms, IRB or Ethics Committee
approval letters, and significant regulatory correspondence
upon request. Costs have not been included for translation of
investigator CVs. Covance will use translators located in
Covance's European offices or will contract with outside
translators for translation into 3 languages (ie; Spanish,
French and German). Covance will be responsible for
back-translation to English.
Covance will be responsible for the translation and drafting
of country specific labels. Covance will be responsible for
back-translation certification of the final labels.
10
(K) INVESTIGATOR MEETINGS
Covance will organise and conduct two Investigators' Meetings
for the Vion Pharmaceuticals program. One meeting will be
conducted in Europe for the European investigational sites and
one meeting will be conducted in the U.S. for North American
sites. Each meeting will gather investigators and study
co-ordinators participating in the trial.
Covance will work to produce the meeting agenda and be
responsible for the organisation of the meetings. Each meeting
will be conducted in English. In Europe, local Covance
representatives will assist with translation in case of
English translation difficulties. If necessary, data flow and
management operations will be highlighted. Expeditable Adverse
Experience reporting processes will be emphasised as well as
ICH-GCP guidelines. Procedures for screening patients will be
reviewed in detail.
(L) DRUG SUPPLY MANAGEMENT
Covance will be responsible for managing all packaging and
primary labelling of clinical drug supplies for the trial. For
Europe, Covance will be responsible for the translation and
drafting of country specific labels, including national
regulatory requirements. Covance will be responsible for
back-translation certification of the final labels.
Covance will be responsible for shipment of clinical drug
supplies to investigational sites in North America. Covance
Packaging will be responsible for shipment of clinical drug
supplies to investigational sites in Europe. Covance will be
responsible for obtaining import licenses where it is a local
requirement.
Covance Packaging will be responsible for affixing secondary
labels to the clinical drug supplies at the time of shipment
to an investigational site in Europe. These secondary labels
will include the investigators name, address, telephone
number, and site number.
Covance will have procedures in place to allow for shipment of
clinical drug supplies to an investigational site when Covance
has authorised the regulatory package approval for the site.
Vion Pharmaceuticals will be responsible for ensuring that
ample supply of study medication is available for the duration
of the program for re-supply of clinical drug supplies to
investigational sites.
11
At the investigational level, Covance will be responsible for
drug management, inventory, and resupply through the
Interactive Voice Response System (IVRS). Covance will be
responsible for monitoring of drug accountability
documentation and destruction of clinical supplies, as
requested, either centrally at a subcontractor or locally.
(M) INTERACTIVE VOICE RESPONSE SYSTEM (IVRS)
Covance's IVRS will be utilised for this trial. The IVRS will
provide computerised patient randomisation and patient
assignment using touch-tone telephone input and computerised
voice output. The system will be multi-lingual and provide an
option for randomisation in either English, French, Spanish or
German. Accessibility will be provided via toll-free telephone
numbers for all countries and the system will be available 24
hours a day for patient assignment.
(N) INITIATION, MONITORING AND CLOSE OUT VISITS
INITIATION VISITS:
------------------
Investigational sites will be initiated by a member of the
Covance project team. Prior to each Investigators' Meeting,
Covance will conduct a training session for all CRAs that will
be conducting initiation visits. Covance will schedule the
initiation visit once Covance Regulatory Department have
approved the package of investigators' regulatory documents
that Covance has compiled and authorised shipment of clinical
drug supply. The visit will involve all appropriate members of
the investigators' team. The Covance monitor will conduct a
thorough review of the protocol, CRF, regulatory requirements,
inventory and storage of clinical drug supplies, and any other
study specific issues.
MONITORING & CLOSE-OUT VISITS:
-----------------------------
Covance has assumed that the initial monitoring of each
investigational site will occur shortly after the study staff
has enrolled its first patient at the site. Covance will
conduct subsequent routine monitoring visits []. If necessary,
Covance will monitor sites more frequently. However, costs
have not been included in this proposal for []. The actual
monitoring frequency of a site will depend upon the site
meeting its enrolment goals and the number of studies the site
is conducting. Covance will review the monitoring needs of the
project regularly. Covance has assumed a total of []
12
routine monitoring visits for Europe and [] routine monitoring
visits for the USA in this Time and Cost Estimate.
Covance believes that on-site monitoring is the most important
step in the data quality assurance process. Thus, our field
monitoring is intense and includes verification of source
documents against CRF entries. Covance monitors verify
information recorded in a CRF for completeness and
transcription accuracy against the information included in the
patient's medical chart. Documentation required in the medical
charts and other sources include inclusion and exclusion
criteria, primary efficacy endpoints, adverse experiences, and
concomitant medications. Covance will develop monitoring
conventions specific to this trial.
As part of routine monitoring, Covance monitors will review
the Study File Notebook and pharmacy drug dispensing records,
inspect drug supplies, and ensure appropriate drug storage.
Covance will produce monitoring trip reports for each
monitoring visit within [] working days of the monitoring
visit. This will be available to Vion Pharmaceuticals on
request. Covance anticipates that these reports will provide
detailed information about patient accrual, adverse
experiences, regulatory compliance, and study conduct. Between
monitoring visits, Covance will maintain frequent telephone
contact with each investigational site to discuss patient
accrual activity, adverse experiences, and any other study
related issues.
Covance will close out each investigational site at the time
of the final monitoring visit. Covance monitors will ensure
that all site documentation is complete and accessible for
future audits, that the investigator is aware of his/her
responsibilities, and that all remaining clinical trial
materials to be returned to Vion Pharmaceuticals or Covance
Packaging are removed from the investigational site. Covance
will provide a final visit report to Vion Pharmaceuticals for
each site.
(O) STATUS REPORTING
Covance will provide monthly project status reports to Vion
Pharmaceuticals.
(P) ICH GCP SITE AUDITS
Covance will conduct ICH GCP field audits for this study. The
field audits will include sites audited on a random basis or
for-cause. Random audits will involve visits to an adequate
number of investigational sites to ensure that the
13
investigator is conducting the study according to the protocol
and applicable regulations. Covance has estimated a total of
[] site audits to be conducted ([] in Europe and [] in USA)
for the purpose of this cost estimate. Covance has assumed
that [], this depends on the number of patients recruited at
each investigational site.
(Q) ADVERSE EXPERIENCE REPORTING
Up to [] all adverse experiences will be collected on the case
report form and all expeditable adverse experiences (serious
adverse experience, unexpected adverse experience or
withdrawals due to adverse experiences) will be collected
using the Covance SWAER form.
After [] and until the patient withdraws from the study, all
serious adverse experiences will continue to be collected on
the case report form. The Covance SWAER form will be used to
collect all deaths, all unexpected adverse experiences and any
adverse experiences that are related to the study drug.
Once the Covance SWAER form is completed it will be sent to
Drug Safety Co-ordination, Europe for all European adverse
experiences and to the Clinical Project Team for all US
adverse experiences. Once in Covance the expeditable adverse
experience will have a narrative written (if one is not
already available), be medically reviewed and entered into
Clintrace. Printed Covance SWAER forms will be generated and
sent to Vion Pharmaceuticals with a copy to the Global Project
Director, the Project Physician, the US Project Manager (for
US adverse experiences only) and the site monitor.
Drug Safety Co-ordination, Europe or Princeton (depending upon
the Regulatory Authority) will make the submission to the
Regulatory Authorities on behalf of Vion Pharmaceuticals.
24 HOUR MEDICAL COVER
In order to comply with the guidelines applicable to the UK,
it is necessary to provide 24hr medical cover for this trial.
This service will be extended to all sites in all countries.
The patient will be advised to contact his/her investigator
should they have any concerns or experience any adverse event.
They will be issued a patient alert card for this purpose.
The investigator will be able to contact the site monitor,
Project Director, medical monitor or other Covance on-call
medic.
14
Work performed by the Global Medic will be accrued on an
hourly basis and invoiced periodically.
(R) CLINICAL DATA MANAGEMENT AND BIOSTATISTICS
Covance will be responsible for data management activities
through provision of a Clinical Trial Report.
Covance will conduct all data management, statistical
programming and statistical analysis activities at Maidenhead,
UK.
For the purposes of this Time and Cost Estimate, Covance has
assumed that the CRF for this trial be 176 pages in length.
o DATA ENTRY
Covance will design the database structure.
The Case Report Forms (CRFs) will be returned by Covance
monitors from the sites to, Maidenhead, where they will be
inventoried, and logged into the CRF Tracking System.
Following the logging process, CRFs will be prepared for entry
into the computer. Data Processing personnel create and test
the data entry screens corresponding to the Case Report Forms.
Entry of the data will be performed on an ongoing basis by two
independent operators; one operator performs the entry step
and the second operator performs the double-key, verification
step. No CRF is released from Data Entry unless all data have
been verified.
o DATA REVIEW AND CLEAN-UP
The data validation process will begin with the preparation of
a Data Handling Manual (DHM) that specifies the computerised
validation checks, table specifications, query conventions,
data dictionary, and coding plan. The DHM will be developed at
the time the CRF Monitoring Conventions (i.e., rules for
completing the CRF) are developed to assure consistency and
appropriateness in approach to data collection and handling.
Medications mapping will be provided by Covance. Data element
mapping will use the following coding dictionaries unless
otherwise indicated by Vion Pharmaceuticals:
- Adverse Events will use the COSTART mapping terms
15
- Concomitant Medication will use the WHO mapping terms
To assure data quality, Covance will conduct a database audit
(a sampling of the database verified with the hard copy CRF,
item by item). Data Co-ordination personnel will conduct the
random sample audit of datapoints against the Case Report Form
to quantify the keying error rate of the files. In addition, a
[] of complete CRFs and a [] (as agreed with Vion
Pharmaceuticals) will be checked against the database. If the
error rate is 0.5% or less, Covance accepts the file. [].
o PROGRAMMING
Covance will be responsible for all the programming tasks to
include programming for computerised diagnostics, Tables,
Figures and Listings, Final analyses and data transfers to
Vion Pharmaceuticals as necessary.
All programs used will be documented and validated using
standard programming conventions established in the Covance
Statistical Programming Guidelines.
o PREPARATION OF THE INTERIM ANALYSES
Covance will prepare an [] (as detailed in the protocol) after
[]. Covance will perform the analysis and generate summary
tables. The [] will be performed on "clean" (i.e., reviewed
and corrected) data for the above mentioned data parameters.
An independent statistician from Covance will perform this
analysis and will be identified to serve as a liaison with
Vion Pharmaceuticals. To maintain the integrity of the study,
results will remain blinded except to the liaison from Covance
and Vion Pharmaceuticals.
o STATISTICAL ANALYSIS
Covance will be responsible for development of a Statistical
Analysis Plan (SAP) which details the way in which the data
will be presented and analysed. The SAP will include a written
section followed by mock-ups of the Tables, Figures and
Listings.
16
Covance will be responsible for the final statistical analysis
and the Clinical Trial Report. The SAP will be sent to Vion
Pharmaceuticals for review and approval.
o Preparation of the Statistical and Clinical Trial
Reports
Covance will be responsible for generation of Clinical Trial
Reports. The Clinical Trial Report will be based on the
standard Covance Clinical Trial Report unless otherwise
stipulated by Vion Pharmaceuticals. A skeleton Clinical Trial
Report will be sent to Vion Pharmaceuticals for approval of
style and contents.
(S) CONTRACT MANAGEMENT
The contract with Vion will be held by the Phase II group
based in Maidenhead, UK. The Phase II group issues its
contracts in the name of Covance Clinical Research Unit,
Leeds.
The Time and Cost Estimate will be denominated in English
pounds sterling ((pound)) and will be fixed price for Covance
fees with out-of-pockets and Investigator payments being first
estimated and later invoiced to the client on a monthly basis.
Any exchange differences arising from fluctuation in exchange
rates will accrue to Vion Pharmaceuticals and will be the
subject of a separate quarterly credit note or invoice.
Covance Phase II business development staff will be
responsible for the issue of any Change Order due to changed
assumptions which has an impact on the costing. The Time and
Cost Estimate will be reviewed every two months until such a
time as Covance and Vion Pharmaceuticals agree a different
frequency.
It is the intention of the Covance Phase II group to obtain a
signed contract (Clinical Development Agreement) before
enrolling patients into the trial.
(T) DEVELOPMENT AND MAINTENANCE OF AN E-MAIL SYSTEM
Covance will develop and maintain an E-mail system that will
allow communication between Vion Pharmaceuticals and Covance
offices world-wide for exchange of messages and documents.
Covance currently has an E-Mail system that is operational
within Vion Pharmaceuticals. The existing E-mail connection
between Vion Pharmaceuticals and Covance will be used to
17
transfer messages between organisations. Vion Pharmaceuticals
and Covance will develop a list of project team members
needing E-mail access.
18
ESTIMATION FOR CLINICAL STUDY MANAGEMENT
The estimated cost described below specifies Covance's fixed fees and out of
pocket expenses. Any deviations in the assumptions described in this Time and
Cost Estimation, which are out of Covance's control, or changes in the scope of
the study will be discussed with Vion Pharmaceuticals Inc and any required
additional work for this study will not be performed by Covance without the
signature of Vion Pharmaceuticals Inc on the respective change order.
V STUDY SYNOPSIS AND TIMELINES
---------------------------- ========================================================================
Sponsor Vion Pharmaceuticals Inc
---------------------------- ========================================================================
Drug Porfiromycin
---------------------------- ========================================================================
Indication Head and Neck Cancer
---------------------------- ========================================================================
Design Phase III, Double-blind, Randomised, Placebo-controlled
---------------------------- ========================================================================
Sites [] []
---------------------------- ==================================== ===================================
Countries UK, France, Belgium, Germany, North America
Spain
---------------------------- ==================================== ===================================
Recruited Patients [] []
---------------------------- ==================================== ===================================
------------------------------------- --------------------------- ===================================
TASK EUROPE NORTH AMERICA
------------------------------------- --------------------------- ===================================
Agreement Reached [] []
------------------------------------- --------------------------- ===================================
Final Protocol Available [] []
------------------------------------- --------------------------- ===================================
Site Initiations Commence [] []
------------------------------------- --------------------------- ===================================
First Patient In [] []
------------------------------------- --------------------------- ===================================
Last Patient In [] []
------------------------------------- --------------------------- ===================================
Last Patient Out [] []
------------------------------------- --------------------------- ===================================
Clinical Trial Report To [] []
Vion Pharmaceuticals Inc
------------------------------------- --------------------------- ===================================
* Patient Recruitment will commence when the signed Clinical Development
Agreement is received in-house at Covance.
** These timelines are assuming that there is one Ethical Committee Review and
that all other regulatory requirements have not been delayed.
19
VI PROJECT RESPONSIBILITIES ASSESSMENT
-------------------------------------------- --------- ===================
TASK COVANCE VION
PHARMACEUTICALS INC
-------------------------------------------- --------- ===================
Overall Project Management [] []
Regulatory Submissions [] []
Protocol Review [] []
CRF Development [] []
Monitoring Conventions [] []
Laboratory Selection [] []
Investigator Selection [] []
Pre-Study Site Visits [] []
Investigator Budget Management [] []
Ethics Committee Submissions [] []
Drug Supply Management [] []
Translations [] []
Investigator Meeting [] []
Initiation, Monitoring & Close-Out Visits [] []
Site Audits [] []
Adverse Experience Reporting [] []
CRF Review and Correction (in-house) [] []
Status Reports [] []
Data Management [] []
Statistical Analysis [] []
Preparation of CTR [] []
Contract Management [] []
============================================ --------- ===================
Please note that some of the expenses involved in the above tasks are accounted
for as out-of-pocket expenses, please see page 22
20
VII. GLOBAL COST ESTIMATION
The following estimation is for the clinical trial with study drug: Porfiromycin
in the treatment of Head and Neck Cancer. The study will be conducted according
to ICH GCP Guidelines and FDA requirements as appropriate.
-------------- -------------------------------------------------- ==============
ACTIVITY ESTIMATED COST
((pound))
-------------- -------------------------------------------------- ==============
PRE STUDY IND Preparation / Maintenance / Updates []
Protocol and CRF Design []
Protocol Amendments (x []) []
Pre-Study Activities, including ethics submissions []
CLINICAL PHASE Initiation Visits []
On-site Monitoring and Project Support Services []
Project Management []
Site Audits []
Expeditable Adverse Experience Reporting []
Site Management []
Drug Supply Management * []
IVRS []
POST STUDY In-house Data Query Resolution []
Data Management []
Statistical Analysis & Programming []
QA & Medical Writing []
Contract Management []
============== ================================================== ==============
TOTAL []
============== ================================================== ==============
Exchange Rate: [] ($ to (pound))
* Drug Supply Management, excluding packaging and distribution (Allentown,
Horsham, Tailleur ) will be regarded as Out of Pocket costs directly passed
through to the client.
21
GLOBAL VION PROGRAMME
VIII. CLINICAL AND BIOSTATISTICAL ASSUMPTIONS
====================================== -------------- xxxxxxxxxxxxxxxxxxxxx
XXXXXX XXXXX XXXXXXX
-------------- =====================
No. of Patients [ ] [ ]
No. of Sites [ ] [ ]
Countries [ ] [ ]
No. of CRF Pages [ ] [ ]
No. of Pre-Study Visits [ ] [ ]
No. of Initiation Visits [ ] [ ]
Monitoring Frequency [ ] [ ]
[ ] [ ]
[ ] [ ]
[ ]
No. of Routine Monitoring Visits [ ] [ ]
Frequency of SAEs / patient [ ] [ ]
No. of Covance QA Field Audits [ ] [ ]
Number of clinical personnel [ ] [ ]
involved [ ] [ ]
[ ]
[ ]
Number of biostatistical [ ]
personnel involved [ ]
[ ]
[ ]
[ ]
====================================== -------------- =====================
The costs that are illustrated in the Global Cost Estimation (Section VII) for
this frequency of Expeditable Adverse Experiences per patient is the maximum
cost that could be incurred for this particular task in this trial. Any changes
that are made in the assumptions above along with any alterations in the
timelines during the course of the trial once a clinical development agreement
has been signed, may result in the production of a change order form.
22
IX. OUT OF POCKET STUDY COSTS
For the purpose of an estimated Total Budget figure and from experience, Covance
estimates that the total study Out of Pocket costs will summate to a figure that
is [ ]. This is based on the assumption that the following tasks may be included
in the Out of Pocket costs:
o Investigator Fees
o Investigator Meeting Costs
o Ethics Committee Meeting Costs
o Global Team Meetings
o Patient Travel Costs
o Travel Costs
o Accommodation Costs
o Clinical Personnel Daily Subsistence
o Central Laboratory Costs
o CRF Printing Costs
o Courier Charges
o Drug packaging & distribution (Horsham, Allentown and Tailleur)
It is important to note that this estimate is based on a "rule of thumb" but may
vary considerably from study to study.
Detailed estimates of expected out-of-pocket costs will be provided as soon as
these can be determined
23
X. PAYMENT SCHEDULE
[ ]
24
XI. TOTAL ESTIMATED COSTS (EXCLUDING OUT-OF-POCKET EXPENSES)
================================================================================
ESTIMATED TOTAL COSTS
VION PORF-96-001 PROGRAM
================================================================================
---------------------------------------------------- ===========================
Category Cost ((pound))
---------------------------------------------------- ===========================
Covance Clinical Fees [ ]
---------------------------------------------------- ===========================
---------------------------------------------------- ===========================
Covance Biostatistical and Report Writing Fees [ ]
---------------------------------------------------- ===========================
---------------------------------------------------- ===========================
Covance Regulatory Fees [ ]
---------------------------------------------------- ===========================
---------------------------------------------------- ===========================
Total [ ]
---------------------------------------------------- ===========================
---------------------------------------------------- ===========================
OUT-OF POCKETS To be Advised
---------------------------------------------------- ===========================
XII. SUMMARY AND CONCLUSIONS
o Time and Cost Estimates for the conduct of this program have been
presented.
o Many aspects of the tasks and responsibilities are undergoing
discussion and finalisation (e.g., Investigator Selection, etc.). As
with other projects Covance encourages frequent and open communication
with Vion Pharmaceuticals during the planning process and throughout
the conduct of this study.
25
ATTACHMENT I
[ ]
26
