Protocol AN01.01.0012 Change Order no. 2, 8th June 2006
Exhibit 4.57
| Amarin 694/005 | ||
| Protocol AN01.01.0012 |
Change Order
no. 2, 8th June 2006
|
Change
Order
|
DATED
|
the
8th day of June 2006.
|
|
BETWEEN
|
Amarin
Neuroscience Limited of King’s Park House, Laurelhill Business Park,
Stirling, UK FK7 9PQ (‘Amarin’)
|
|
AND
|
ICON
Clinical Research Limited of South County Business Park, Leopardstown,
Dublin 18 (‘ICON’)
|
WHEREAS:
|
A.
|
The
parties entered into an Agreement for Services on 30th June 2005,
concerning Study known as Protocol AN01.01.0012A Multi-centre,
double-blind, randomized, parallel group, placebo-controlled trial of
ethylepa (Ethyl-Icosapent) in patients with Huntington’s
Disease. This is a Europe only
study.
|
|
B.
|
The
main changes to the project specifications are to the study timelines, the
site and patient distribution and the CRF page numbers. The
revised specifications are detailed in Appendix 1
attached.
|
IT
IS AGREED BY THE PARTIES AS FOLLOWS:
|
|
1.
|
The
parties agree to amend the Agreement to reflect changes set out in the
‘European Revised Project Specifications and Cost Document’ which is
attached hereto and incorporated
hereby.
|
|
|
2.
|
Save
as otherwise provided in this Change Order, all the terms and conditions
of the Agreement dated the 30th June 2005 shall remain in full force and
effect.
|
|
|
3.
|
The
value of this Change Order shall be £382,057 in direct fees and £1,385,655
in pass through costs. The direct fees shall be paid in an
initial fee of 10% at signature of this agreement and monthly fees
thereafter as outlined below:
|
| Change Order Direct Fee Value: | £382,057 |
|
Initial
Payment 10% on siqnature of Change Order (June 06)
|
£38,205
|
|
Monthly
Payments x 12 months (June’06 to May’07)
|
£28,654.33
|
| Amarin 694/005 | ||
| Protocol AN01.01.0012 |
Change Order
no. 2, 8th June 2006
|
IN WITNESS WHEREOF, the
parties hereto have executed this Change Order by their duly authorised
representatives on the date(s) written below.
|
Amarin
Neuroscience Limited
|
ICON
Clinical Research Limited
|
|
King’s
Park House
|
South
County Business Park
|
|
Laurelhill
Business Park
|
Leopardstown
|
|
UKFK7
9PQ
|
Dublin
18
|
|
United
Kingdom
|
Ireland
|
| 30 June 2006 | 29 September 2006 | |
|
DATE
|
DATE
|
|
| /s/ Xxxxxxx Xxxxxx | /s/ Xxxx Xxxxx | |
|
SIGNED
|
SIGNED
|
|
| X. XXXXXX | XXXX XXXXX | |
|
NAME
|
NAME
|
|
|
V.P.
CLINICAL DEVELOPMENT
|
EXEC. VP COMMERCIAL AND ORGANISATIONAL DEVELOPMENT | |
|
TITLE
|
TITLE
|
| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
Appendix
1
Change
Order No. 2
Europe
Revised Project Specifications and Cost
Document
Version
4, Submitted 7th June 2006
A
MULTICENTRE, MULTINATIONAL, DOUBLE-BLIND, RANDOMISED,
PARALLEL
GROUP, PLACEBO CONTROLLED TRIAL OF ETHYL-EPA
(ETHYL-ICOSAPENT)
IN PATIENTS WITH HUNTINGTON’S DISEASE
Protocol
Number: AN01.01.0012
Page 1 of
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| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
1. Introduction
|
This
document includes revised specifications to the Clinical Research Proposal
Version 5 Submitted 17 May 2005 and the Change Order #1 document (Version 2,
Dated 15 Nov 2005) and associated costs for the clinical conduct of study
AN01.01.0012 in Europe. The main changes to the project
specifications are to the study timelines, the site and patient distribution and
the CRF page numbers. For Biometrics, we have removed the costs for
the US study and the synergies for managing both studies in
parallel.
The study
set-up was delayed primarily due to the late delivery of the final signed
protocol to ICON on the 9th of August. Study set-up was also delayed
due to the delay in providing details of the required number of pre-selected
sites. Details of the xxxxx 0 sites were provided to ICON on the
14th
of September 2005.
Consequently
the selection of study sites was delayed as well as EC and regulatory
submissions. The other study timelines will also be affected
accordingly.
It is now
planned to conduct this study in 6 countries. Austria, Italy and
Portugal have been added to the countries originally selected (other countries
previously agreed are: Germany, Spain, UK and Netherlands, however
Netherlands has now been excluded).
Allowing
for staggered site initiations, we estimate that the total number of monitoring
visits for each site will vary from 7 to 9 visits. We propose that
the monitoring frequency from April to August 2006 be every 5
weeks. This will have an impact on CRA and CPM allocation and these
allocations have been increased accordingly (CPM = 0.8 FTE, CRA = 4.6
FTE). The increase in CRA allocation has also been due to an increase
in the number of CRF pages from 60 pages to 96 pages. We have been
able to reduce the planned number of CRAb allocated after study set-up from a
total of 3 FTEs to 2.8 FTEs (January 2006 to March 2006).
In order
to effectively manage the study we have extended the Project Manager to 0.8 FTEs
from the original 1-month after the planned FPI (1st September 2005) until 15
days after, the revised planned FPI (15th December 2005).
Following
the meeting with Amarin on 7th November 2005, it was agreed that as the clinical
resource required will be heavily dependent on enrolment and site activity, and
as the CRF has increased to a 96-page CRF (from 60 pages) ICON will actively
evaluate the clinical resource on an ongoing basis and provide 3-monthly reports
to Amarin of the same. Where required, ICON will adjust the clinical
resource, following written approval from Amarin.
During a
subsequent meeting with Amarin on 16th February 2006 it was agreed that
additional changes in specifications would be included in Change Order No:
1.
Page 2 of
18
| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
2. Revised
Clinical project Specifications
|
(1) Project
Timelines:
The table
below summarizes the original and revised projected timelines for the conduct of
this study.
|
Milestone
|
Original
Date
|
Revised
Date
|
|
ICON
involvement begins
|
1st
April 2005
|
1st April
2005
|
|
Final
Protocol Available*
|
1st
June 2005
|
9th
August 2005
|
|
First
patient in
|
1st
September 2005
|
15th
December 2005
|
|
Last
patient screened
|
Not
specified
|
June
2006
|
|
Last
patient in
|
1st
March 2006
|
July
2006
|
The
proposed revised dates for LPO, Database lock and ICON end will be according to
previously agreed intervals.
The
revised timelines include the following revisions:
|
·
|
A
delay of 2.5 months to study
set-up.
|
|
·
|
The
inclusion of the 1-month follow-up period (i.e. patients will be in the
study for 6 months plus 1 month
follow-up)
|
|
·
|
The
inclusion of an additional 2 weeks period (It was planned to screen the
first patient in December 2005; in the project meeting in November it was
decided that the last patient in date would be June 2006, in total 6.5
months).
|
|
·
|
Last
patient in date means date last patient randomised to
medication
|
|
·
|
Last
patient out date is 1 month/35 days after last patient off
treatment.
|
(2) Site
and Patient Distribution
Approximately
37 sites will be contacted and surveyed to establish their interest and
suitability for participating in this study (originally 38
planned). It is planned to conduct a total of 37 pre-study visits
(originally 33 planned) and to initiate 30 sites (originally 30
planned).
Page 3 of
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| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
The
tables below show the site and patient distribution per the original contract as
well as the current site and patient distribution.
Original
Site and Patient Distribution
|
Country
|
Number
of
screened
sites
|
Number
of
initiated
sites
|
Number
of
randomized
patients
|
|
Germany
|
14
|
12
|
96
|
|
Netherlands
|
|||
|
UK
|
24
|
18
|
144
|
|
Spain
|
|||
|
TOTAL
|
38
|
30
|
240
|
Revised
Site and Patient Distribution
|
Country
|
Number
of
screened
sites
|
Number
of
initiated
sites
|
Number
of
randomized
patients
|
|
Austria
|
2
|
2
|
24
|
|
Germany
|
9
|
9
|
80
|
|
Italy
|
4
|
4
|
30
|
|
Netherlands
|
1
|
0
|
0
|
|
Portugal
|
3
|
2
|
8
|
|
Spain
|
5
|
4
|
28
|
|
Switerland
|
1
|
0
|
0
|
|
UK
|
12
|
9
|
70
|
|
TOTAL
|
37
|
30
|
240
|
Page 4 of
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| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
(3) Staff
Allocation
Based on
the revised study timelines and the current site and patient distribution the
clinical study team allocation has been revised as follows:
|
FTE
|
Staff
|
Time
Allocation
|
|
0.4
|
Project
Manager
|
Allocated
in April 2005
|
|
0.8
|
Project
Manager
|
Allocated
from 1st of
May 2005 through 31st of December 2005
|
|
0.6
|
Project
Manager
|
Allocated
from 1st of January 2006 through 31st of March 2006
|
|
0.8
|
Project
Manager
|
Allocated
from 1st of April 2006 through 31st of August 2006
|
|
0.6
|
Project
Manager
|
Allocated
from 1st of September 2006 through 31st of January 2007
|
|
0.8
|
Project
Manager
|
Allocated
from 1st
of February 2007 through 31st of May 2007
|
|
1.5
|
Clinical
Research Associate(s)
|
Allocated
in April 2005
|
|
3.0
|
Clinical
Research Associate(s)
|
Allocated
from 1st of May 2005 through 31st of December 2005
|
|
2.8
|
Clinical
Research Associate(s)
|
Allocated
from 1st of January 2006 through 31st of March 2006
|
|
4.6
|
Clinical
Research Associate(s)
|
Allocated
from 1st of April 2006 through 31st of August 2006
|
|
3.4
|
Clinical
Research Associate(s)
|
Allocated
from 1st of September 2006 through 31st of May 2007
|
|
0.7
|
Clinical
Research Assistant(s)
|
Allocated
in April 2005
|
|
1.4
|
Clinical
Research Assistant(s)
|
Allocated
from 1st of May 2005 through 31st of December 2005
|
|
1.2
|
Clinical
Research Assistant(s)
|
Allocated
from 1st of January 2006 through 31st of March 2006
|
|
1.4
|
Clinical
Research Assistant(s)
|
Allocation
from 1st of April 2006 through 31st of August 2006
|
|
1.2
|
Clinical
Research Assistant(s)
|
Allocation
from 1st of September 2006 through 31st of May 2007
|
|
Therapeutic
Director
|
Allocated
for 5 days for study duration
|
|
|
Clinical
Regulatory Compliance Associate
|
Allocated
for 17 days for study duration
|
|
|
Accounting
Administrator
|
Allocated
for 69 days for study duration
|
Page 5 of
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| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
The above
allocations are also based on the participation of 30 sites in the project,
96 CRF pages per patient and on a
5-weekly monitoring
visit frequency from April 2006 to August 2006 and 7-weekly thereafter
(previously 6 weekly) for a total of 7-9 visits per site
(previously 8). Based on the recruitment rates expected at EU sites,
on-site monitoring activities and the revised number of CRF pages will take
approximately 10 hours
to perform.
ICON will
actively evaluate the clinical resource on an ongoing basis and provide
3-monthly reports to Amarin of the same. Where required, ICON will
adjust the clinical resource, following written approval from
Amarin.
(4) Clinical
Documentation
The
following changes in project specifications have been made in respect to study
documentation:
|
·
|
ICON
will write the Austrian Protocol Amendment required for EC and regulatory
submissions.
|
|
·
|
ICON
will organise for the translation of medication instructions through a
third party vendor.
|
|
·
|
ICON
will organise for the translation of the study protocol into Spanish
through a third party vendor.
|
|
·
|
ICON
will organise for the translation of regulatory documentation through a
third party vendor.
|
(5) Clinical
Activities
(a) Administration
of Investigator Payments
ICON will
be responsible for the administration of investigator payments and hospital and
pharmacy fees, where necessary. Payments will be made by ICON on a
3-monthly basis. All payments, which will be agreed in advance, will
be charged to Amarin as “pass-through”. In addition Amarin will
provide ICON with a float of 30% of the total budget of
investigator fees for the payment of investigator fees to support the agreed up
front payments to sites.
(b) Regulatory
Submissions
ICON will
be responsible for any follow-up or re-submission of regulatory clinical trial
submissions to the relevant authorities in Germany, Spain and the
UK. Any future request will be documented in a change notification
before documented in a change order. (Amarin has requested ICON to be
responsible for any new submission or follow-up).
ICON will
complete the AMG form for the German submission and will make the local
regulatory notifications. ICON has also provided advice to Xxxxxx
Xxxxxx (Sub-contractor of Amarin) regarding regulatory submissions for a total
of 8 hours.
Page 6 of
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| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
ICON will
be responsible for making regulatory clinical trial submissions to the relevant
authorities in Austria, Italy (including the Osservatorio web site) and
Portugal. Amarin will provide draft documentation for the Austrian
and Portuguese submissions.
ICON will
be responsible for any additional notification or submission.
Amarin
will be responsible for responding in a timely way to questions from regulatory
agencies to affect a final outcome. ICON will assist, as
appropriate
(c) Ethics
Committee Submissions
ICON will
be responsible for preparing 27 local and 6 central ethics committee submissions
in Austria, Germany, Italy, Portugal, Spain and in the UK. Both
Amarin and ICON will be responsible for responding in a timely manner to
questions raised by ethics committees to affect a final outcome.
Page 7 of
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| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
3. Revised
Biometrics Project Specifications
|
The
following changes have been made to the Biometrics costs and
specifications:
|
Data
Management
|
Contract
|
CO#1
|
Comments
|
|
US
Study and Synergies:
|
-
|
-
|
Both
the costs for the US study and the synergies (for managing both studies in
parallel) have been removed.
|
|
Timelines
(EU study):
|
21
|
28
|
The
original contract specifications were based on 21 months (from 1 Apr 05 to
1 Jan 07). The date for database lock has been moved so the
timelines have been extended by 5 months thus increasing the costs for the
following activities: Project Management, teleconferences and
the review of monthly central laboratory and ECG transfers. The
date for Database lock is estimated to be 4-6 weeks post Last Patient Last
Visit (LPLV) date. ICON will make all possible efforts to
achieve Database Lock as early as possible.
|
|
Status
Reports (EU study):
|
21
|
76
|
The
original contract specifications were based on monthly status reports over
21 months. From April 2006 status reports will be provided on a
weekly basis, thus the number of reports has increased to
76.
|
|
Face-to-face
Meetings (EU study):
|
2
|
6
|
The
original contract specifications were based on attendance at two
face-to-face meetings. Four additional meetings have been
included (including travel costs) as the Data Management group has already
attended two meetings to date and it is expected that there will be
quarterly meetings on an ongoing basis.
|
|
Pages
(EU Study):
|
13,680
|
21,816
|
The
original contract specifications were based on 13,680 (24 drop-outs x 30
pages plus 216 completers x 60 pages) pages. The number of CRF
pages has now increased to 21,816 pages (24 drop-outs x 45 pages plus 216
completers x 96 pages), thus increasing the costs for data and query
processing (10%).
|
|
CRF
Design (EU study):
|
60
|
96
|
The
original contract was based on 30 unique/30 replicate CRF
pages. This has now increased to 30 unique/66 replicate pages
thus increasing the costs for CRF
design.
|
Note: No changes have
been applied to the Biostatistics costs and specifications as the Statistical
Analysis Plan(s) has yet to be finalised.
Page 8 of
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| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
4. Revised
Pass-through Costs
|
The
following changes have been made to the cost estimates of pass-through
costs.
|
Activity
|
Description
|
|
Travel
Costs
|
Cost
estimates for site visits have been increased from an average of £210 to
£300 due to the revised site allocation. It is estimated that
there will be an additional 26 visits conducted.
|
|
Translations
|
Translation
costs for the following have been included in the
budget:
|
|
Translation
of patient cards into 7 languages.
|
|
|
Translation
of medication instructions into 7 languages.
|
|
|
Translation
of the study protocol into Spanish.
|
|
|
Translation
of the study synopsis into 3 additional languages.
|
|
|
Translation
of the informed consent form into 4 additional
languages.
|
|
|
Translation
of additional EC documentation for 6 additional
submissions.
|
|
|
Translation
of regulatory documents from three languages into
English.
|
|
|
Translation
of investigator contracts.
|
|
|
Regulatory
Agency Fees
|
Regulatory
fees for 3 clinical trial submissions have been included in the revised
pass-through budget.
|
|
Ethics
Committee Fees
|
EC
fees for one less EC submission have been deduced from the revised
pass-through budget.
|
|
Investigator
Fees
|
Cost
estimates for investigators fees including hospital overheads and pharmacy
fees have been included in the revised past-through
budget.
|
Page 9 of
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| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
5. Revised
Cost Estimates (Clinical)5. Revised Cost Estimates
(Clinical)
|
Cost
estimates for ICON services and associated “pass-through” costs are presented in
this section. These cost estimates reflect the changes in cost
associated with the revised project specifications presented in sections
1-3. Should these or other project specifications change the cost
estimate provided herein may require modification.
|
Clinical
Research Management
|
Units
|
Number
of
Units
|
Price
per unit*
|
Revised
Cost
(STG£)
|
Contract
(STG£)
|
Change
Order (STG£)
|
|
Therapeutic
Director
|
Days
|
5
|
1,330
|
6,651
|
6,651
|
0
|
|
Project
Manager
|
Days
|
357
|
922
|
329,143
|
252,780
|
76,363
|
|
Clinical
Research Associate
|
Days
|
1663
|
497
|
827,105
|
580,952
|
246,153
|
|
Clinical
Research Assistant
|
Days
|
633
|
390
|
246,579
|
197,766
|
48,813
|
|
Clinical
Regulatory Compliance
|
Days
|
17
|
511
|
8,692
|
6,977
|
1,715
|
|
Account
Administrator
|
Days
|
69
|
494
|
34,076
|
34,076
|
0
|
|
CLINICAL
RESEARCH MANAGEMENT SUB-TOTAL
|
£1,452,246
|
£1,079,202
|
£373,044
|
|||
*Figures
in the “Price per unit” column have been rounded, figures in the “Total” column
are correct.
Page 10
of 18
| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
Support
Services
|
Units
|
Number
of
Units |
Price
per
unit* |
Revised
Cost
(STG£) |
Contract
(STG£) |
Change
Order (STG£)
|
|
Local
Ethics Committee Submissions
|
Sites
|
27
|
552
|
14,905
|
16,562
|
-1,657
|
|
Central
Ethics Committee Submission
|
Sites
|
6
|
828
|
4,968
|
3,312
|
1,656
|
|
Regulatory
Submission
|
Submission
|
3
|
3,005
|
9,015
|
0
|
9,015
|
|
ICOTrack
Set-up
|
System
Set-
|
1
|
2,795
|
2,795
|
2,795
|
0
|
|
ICOTrackMaintenance
|
Months
|
26
|
177
|
4,612
|
4,612
|
0
|
|
SUPPORT
SERVICES SUB-TOTAL
|
£36,295
|
£27,281
|
£9,013
|
|||
*Figures
in the “Price per unit” column have been rounded, figures in the “Total” column
are correct.
|
ICON
CLINICAL RESEARCH
|
£1,488,541
|
£1,106,484
|
£382,057
|
Page 11
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Change Order
No. 2
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|
|
Version 4, 7th
of June 2006
|
|
Estimated
pass-through costs
|
Units
|
Number
of
Units
|
Price
per unit
|
Revised
Cost (STG£)
|
Contract
(STG£)
|
Change
Order
(STGE)
|
|
Travel
|
||||||
|
Site
Visit Adjustment
|
Visits
|
333
|
300
|
99,900
|
69,810
|
30,090
|
|
Additional
Site visits
|
Visit
|
26
|
300
|
7,800
|
0
|
7,800
|
|
Team
Meetings
|
Meetings
|
7
|
629
|
4,402
|
4,402
|
0
|
|
Sponsor
Meetings
|
Meetings
|
7
|
1,118
|
7,827
|
7,827
|
0
|
|
Investigator
Fees
|
||||||
|
Investigator
Fees
|
Patient
|
240
|
4,900
|
1,176,000
|
0
|
1,176,000
|
|
Pharmacy
Fees
|
site
|
30
|
340
|
10,200
|
0
|
10,200
|
|
Hospital
Overheads
|
10%
per
|
000
|
000
|
000,600
|
0
|
117,600
|
|
Investigator
Meetings
|
||||||
|
Travel
|
Attendees
|
69
|
1,747
|
120,543
|
120,543
|
0
|
|
Administrative
Fee - 10%
|
12,054
|
12,054
|
0
|
|||
|
Translations
|
||||||
|
Protocol
synopsis (1,000 words)
|
Language
|
6
|
391
|
2,348
|
1,174
|
1,174
|
|
Protocol
|
Language
|
1
|
3,000
|
3,000
|
0
|
3,000
|
|
Informed
consent document
|
Language
|
7
|
783
|
5,479
|
2,348
|
3,131
|
|
EC
documents
|
Submission
|
33
|
433
|
14,297
|
11,265
|
3,033
|
|
Medication
Instructions
|
Language
|
7
|
120
|
840
|
0
|
840
|
|
Regulatory
documents
|
Submission
|
3
|
866
|
2,598
|
0
|
2,598
|
|
Patient
Cards
|
Language
|
7
|
53
|
371
|
0
|
371
|
|
Investigator
Contracts
|
Site
|
23
|
800
|
18,400
|
0
|
18,400
|
|
Other
|
||||||
|
Teleconferencing
(3 lines)
|
Meetings
|
65
|
84
|
5,451
|
5,451
|
0
|
|
Ethics
Committee Fees
|
Sites
|
33
|
559
|
18,448
|
19,007
|
-559
|
|
Regulatory
Fees
|
Submission
|
3
|
800
|
2,400
|
0
|
2,400
|
|
Courier
|
per
site/month
|
120
|
71
|
33,258
|
24,710
|
8,548
|
|
Mobile
phones
|
per
CRA per
|
25
|
42
|
3,675
|
2,646
|
1,029
|
|
£1,666,891
|
£281,237
|
£1,385,655
|
||||
|
CLINICAL
RESEARCH TOTAL
|
£1,488,541
|
£1,106,484
|
£382,057
|
|||
|
ESTIMATED
PASS THROUGH COSTS
|
£1,666,891
|
£281,237
|
£1,385,655
|
|||
|
OVERALL
TOTAL
|
£3,155,432
|
£1,387,720
|
£1,763,512
|
|||
Page 12
of 18
| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
Revised
cost Estimates (Biometrics)
|
|
Data
Management
|
Contract
Costs
|
Removal
of US
Study
Costs and
Synergies
|
EU
Study Cost
(No
Synergy)
|
New
Costs
(CO#1)
|
Change
in
Specifications
|
Cost
Reduction
|
|
1.
Project Management
|
£30,677
|
£17,367
|
£13,310
|
£29,951
|
£16,641
|
-£726
|
|
Planning
|
£9,409
|
£6,914
|
£2,495
|
£3,327
|
£832
|
-£6,082
|
|
Communications
|
£9,409
|
£6,914
|
£2,495
|
£3,327
|
£832
|
-£6,082
|
|
Set-up
of Status Reports
|
£992
|
£22
|
£969
|
£969
|
£0
|
-£22
|
|
Ongoing
Status Reports
|
£1,884
|
£637
|
£1,248
|
£4,515
|
£3,267
|
£2,631
|
|
2.
Meetings
|
||||||
|
Teleconference
with Sponsor
|
£7,651
|
£3,612
|
£4,039
|
£5,385
|
£1,346
|
-£2,265
|
|
Kick-off
Meeting
|
£3,328
|
£75
|
£3,253
|
£3,253
|
£0
|
-£75
|
|
Face-to-face
Meetings
|
£3,948
|
£1,997
|
£1,952
|
£16,263
|
£14,312
|
£12,315
|
|
3.
Project Set-up
|
||||||
|
Data
Management Plan
|
£4,225
|
£1,492
|
£2,733
|
£2,733
|
£0
|
-£1,492
|
|
Study
Specific Procedures
|
£5,147
|
£1,104
|
£4,042
|
£4,042
|
£0
|
-£1,104
|
Page 13
of 18
| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
Data
Management
|
Contract
Costs
|
Removal
of US Study Costs and Synergies |
EU
Study Cost
(No
Synergy)
|
New
Costs
(CO#1)
|
Change
in
Specifications
|
Cost
Reduction
|
|
Edit
Check Document
|
£6,659
|
£1,906
|
£4,753
|
£4,753
|
£0
|
-£1,906
|
|
Data
Management Report
|
£3,026
|
£649
|
£2,376
|
£2,376
|
£0
|
-£649
|
|
Database
Setup
|
£14,839
|
£1,628
|
£13,211
|
£13,211
|
£0
|
-£1,628
|
|
Edit
Programming
|
£28,107
|
£8,046
|
£20,061
|
£20,061
|
£0
|
-£8,046
|
|
Data
Listings - Programming
|
£3,026
|
£649
|
£2,376
|
£2,376
|
£0
|
-£649
|
|
Central
Laboratory - Programming
|
£4,886
|
£1,678
|
£3,208
|
£3,208
|
£0
|
-£1,678
|
|
ECG
- Programming
|
£6,491
|
£3,282
|
£3,208
|
£3,208
|
£0
|
-£3,282
|
|
4.
Review External Data
|
||||||
|
Central
Laboratory - Data
Reconciliation
|
£11,745
|
£7,067
|
£4,679
|
£6,238
|
£1,560
|
-£5,507
|
|
ECG
- data Reconciliation
|
£5,873
|
£3,533
|
£2,339
|
£3,119
|
£780
|
-£2,754
|
|
5.
Data Processing
|
||||||
|
CRF
Scanning
|
£20,269
|
£11,264
|
£9,005
|
£13,772
|
£4,766
|
-£6,498
|
|
Data
Entry
|
£58,239
|
£32,685
|
£25,555
|
£40,753
|
£15,198
|
-£17,486
|
|
Obvious
Corrections
|
£42,736
|
£23,984
|
£18,752
|
£29,905
|
£11,153
|
-£12,831
|
|
Data
Listings - Review
|
£5,001
|
£2,807
|
£2,194
|
£3,499
|
£1,305
|
-£1,502
|
|
Validation
|
£60,777
|
£34,109
|
£26,668
|
£42,529
|
£15,861
|
-£18,248
|
Page 14
of 18
| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
|
Data
Management
|
Contract
Costs
|
Removal of US
Study Costs and Synergies |
EU
Study Cost
(No
Synergy)
|
New
Costs
(CO#1)
|
Change
in
Specifications
|
Cost
Reduction
|
|
6.
Coding
|
||||||
|
Data
Coding (60% autoencode)
|
£9,228
|
£5,179
|
£4,049
|
£4,049
|
£0
|
-£5,179
|
|
7.
Query Processing
|
||||||
|
Query
Resolution
|
£28,864
|
£16,199
|
£12,665
|
£20,198
|
£7,532
|
-£8,666
|
|
8.
Data Transfers to Sponsor
|
||||||
|
Test
Transfer
|
£2,449
|
£1,176
|
£1,274
|
£1,274
|
£0
|
-£1,176
|
|
Final
Database Transfer
|
£12,625
|
£5,981
|
£6,644
|
£6,644
|
£0
|
-£5,981
|
|
9.
Closeout Activities
|
||||||
|
CRF
Quality Control Reviews (SQRT n+1) Enrolled Patients
|
£1,483
|
£791
|
£692
|
£692
|
£0
|
-£791
|
|
Critical
Item Reviews 100% Enrolled Patients
|
£12,796
|
£8,411
|
£4,384
|
£4,384
|
£0
|
-£8,411
|
|
Closeout
& Archive
|
£4,893
|
£2,648
|
£2,246
|
£2,246
|
£0
|
-£2,648
|
|
10.
SAE Reconciliation
|
||||||
|
SAE
Reconciliation
|
£5,741
|
£3,313
|
£2,428
|
£2,428
|
£0
|
-£3,313
|
|
DATA
MANAGEMENT*
|
£426,423
|
£217,119
|
£209,304
|
£304,688
|
£95,384
|
-£121,734
|
*NOTE: No costs have
been included for the merging of data between the EU and US studies, which, if
requested, may incur an additional cost.
|
CFR
DESIGN
|
£16,393
|
£3,279
|
£13,114
|
£15,906
|
£2,791
|
-£487
|
|
BIOSTATISTICS
|
£163,451
|
-
|
-
|
£163,451
|
-
|
-
|
|
PASS-THROUGH
COSTS
|
£50,742
|
£26,972
|
£23,770
|
£34,019
|
£10,249
|
£16,723
|
Page 15
of 18
| Amarin Neuroscience |
CONFIDENTIAL
|
Change Order
No. 2
|
||
|
|
Version 4, 7th
of June 2006
|
The table
below summarizes the revised, original and change order cost.
|
Overall
costs
|
Revised
Cost
(STG£) |
Contract
Costs
(STG£) |
Change
Order
(STG£) |
|
CLINICAL
RESEARCH TOTAL
|
1,488,541
|
1,106,484
|
382,057
|
|
ESTIMATED
PASS THROUGH COSTS
|
1,666,891
|
281,237
|
1,385,655
|
|
OVERALL
CLINICAL TOTAL
|
£3,155,432
|
£1,387,720
|
£1,763,512
|
|
DATA
MANAGEMENT
|
304,688
|
426,423
|
-121,734
|
|
CRF
DESIGN
|
15,906
|
16,393
|
-487
|
|
BIOSTATISTICS
|
163,451
|
163,451
|
0
|
|
DM
and BIOSTAT PASS-THROUGH Costs
|
34,019
|
50,742
|
-16,723
|
|
OVERALL
DM and BIOSTAT TOTAL
|
£518,064
|
£657,009
|
-£138,944
|
|
OVERALL
TOTAL
|
£3,673,496
|
£2,044,729
|
£1,624,568
|
Page 16
of 18
| Amarin 694/005 |
|
|
||
| Protocol AN01.01.0012 |
Change Order No.
2 Version 4, 7th
of June 2006
|
|||
|
|
Payment
Schedule
|
Payment
Schedule
|
Summary
of Costs (CO#2)
|
|
Change
Order Direct Fee Value: £382,057
|
|
|
Initial
Payment 10% on signature of Change Order (June 06)
|
£38,205
|
|
Monthly
Payments x 12 months (June ’06 to May ’07)
£28,654.33
per month
|
£343,852
|
|
Change
Order Direct Fee Value: -£122,221
|
|
|
Initial
Payment 10% on signature of Change Order (June 06)
|
-£12,222
|
|
Monthly
Payments x 12 months (June ’06 to May ’07) -
£1,018.51
per month
|
£109,999
|
|
SUMMARY: Change
Order 2 Payment Schedule
|
|
|
Change
Order Direct Fee Value: Clinical
|
£382,057
|
|
Change
Order Direct Fee Value: Data Management
|
-£122,221
|
|
£259,836
|
|
|
Summary
of Costs (CO#2)
|
|
10%
upon signature
|
£25,984
|
|
Monthly
Payments x 12 months (June ’06 to May ’07)
|
|
|
£19,487.70
per month
|
£233,852
|
|
£259,836
|
|
|
REVISED
ICON EU PAYMENT SCHEDULED (CHANGE ORDER #2)U PAYMENT SCHEDULED (CHANGE
ORDER #2)
|
|
|
Milestone
Payments
|
|
|
Task
Completed
|
Contract
Value
|
|
Contract
Signed
|
342,550
|
|
All
sites initiated
|
192,684
|
|
50%
of patients enrolled
|
192,684
|
|
Initial
Payment 10% on signature of C/O#2
|
25,984
|
|
100%
of patients enrolled
|
192,684
|
|
Mid-point
of treatment phase
|
192,684
|
|
All
patients completed and data at DM
|
192,684
|
|
All
sites closed
|
38,537
|
|
Final
Tables & Listings
|
25,691
|
|
Total
Milestones payments
|
£1,396,185
|
|||
|
Monthly
Payments contract
|
April
’05 - June ‘07
|
22
|
15,570
|
342,550
|
|
Monthly
Payments change order #2*
|
Jun
’06 - May ‘07
|
12
|
19,488
|
233,852
|
|
Total
Monthly payments
|
£576,403
|
|
Total
payments
|
£1,972,587
|
*Change
Order #2: monthly payment have been adjusted to include the increase
of the clinical direct cost and decrease the data management cost
Page 17
of 18
| Amarin 694/005 |
|
|
||
| Protocol AN01.01.0012 |
Change Order No.
2 Version 4, 7th
of June 2006
|
|||
|
|
Payment
Schedule
|
IN WITNESS WHEREOF, the
parties hereto have executed this Change Order by their duly authorised
representatives on the date(s) written below.
|
Amarin
Neuroscience Limited
|
ICON
Clinical Research Limited
|
|
King’s
Park House
|
South
County Business Park
|
|
Laurelhill
Business Park
|
Leopardstown
|
|
UKFK7
9PQ
|
Dublin
18
|
|
United
Kingdom
|
Ireland
|
| 16 October 2006 | 29 September 2006 | |
|
DATE
|
DATE
|
|
| /s/ Xxxxxxx Xxxxxx | /s/ Xxxx Xxxxx | |
|
SIGNED
|
SIGNED
|
|
| X. XXXXXX | XXXX XXXXX | |
|
NAME
|
NAME
|
|
|
VP CLINICAL DEVELOPMENT
|
EXEC. VP COMMERCIAL AND ORGANISATIONAL DEVELOPMENT | |
|
TITLE
|
TITLE
|
Page 18 of 18
