EX-4.57 2 ex4_57.htm EXHIBIT 4.57 ex4_57.htm
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 AN01.01.0012A 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/ Anthony Clarke    /s/ Sean Leech
SIGNED
  
SIGNED
     
 A. CLARKE    SEAN LEECH
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 18
 

 
 
 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 final 5 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 18
 
 
 
 
 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 18
 
 
 
 
 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 18
 

 
 
 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 Alison Bannon (Sub-contractor of Amarin) regarding regulatory submissions for a total of 8 hours.
 

 
Page 6 of 18
 

 
 
 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 18
 
 
 
 
 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 18
 
 
 
 
 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 18
 
 
 
 
 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 of 18
 
 
 
 Amarin Neuroscience  
 CONFIDENTIAL
  
 Change Order No. 2
 
      
 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
240
490
117,600
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/ Anthony Clarke    /s/ Sean Leech
SIGNED
  
SIGNED
     
 A. CLARKE    SEAN LEECH
NAME
  
NAME
     
 
VP CLINICAL DEVELOPMENT
    EXEC. VP COMMERCIAL AND ORGANISATIONAL DEVELOPMENT
TITLE
  
TITLE
 
 
 
 
Page 18 of 18