ex4_81.htm


    

      Ex.
4.81

       

      


        
          	
                  Aramin
      694/005 & 006

                	 
      
	 	 
	
                  Protocol
      AN01.01.0012 & AN01.01.0011

                	
                  28th
      May 2008

                


        



      Change
Order for Additional Biostatistics & Medical Writing Work

       

      
        	
                DATED

              	
                the
      28th
      May 2008

              


      

       

      
        	
                BETWEEN

              	
                Amarin
      Neuroscience Limited of Magdalen Centre North, Oxford Science Park, Oxford
      OX4 4GA UK ('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 &
      AN01.01.0011 - A Multi-centre, double-blind, randomized, parallel group,
      placebo-controlled trial of ethyl-epa (Ethyl-Icosapent) in patients with
      Huntington's Disease (the "Agreement"). This Agreement was further amended
      by various Change Order for both the US and
EU.

              


      

       

      
        	
                B.

              	
                The
      parties have agreed to certain changes to the services to be provided and
      the associated cost as set out
herein.

              


      

       

      IT
IS AGREED BY THE PARTIES AS FOLLOWS:

       

      
        	
                 
      

              	
                1.

              	
                The
      parties agree to amend the Agreement to reflect changes set out in the
      Appendix 1 which is attached hereto and incorporated
    hereby.

              


      

       

      
        	
                 
      

              	
                2

              	
                The
      activities and associated costs in this Change Order relate to both
      protocols AN01.01.0011 (694/006) and AN01.01.0012
    (694/005).

              


      

       

      
        	
                 
      

              	
                3.

              	
                Save
      as otherwise provided in this Change Order, all the terms and conditions
      of the Agreement dated the 30th
      June 2005 and subsequent change orders shall remain in full force and
      effect.

              


      

       

      
        	
                 
      

              	
                4.

              	
                The
      value for completion of these activities shall be £91,818 in direct fees.
      Additional tasks, including the CSR addendum for the AN01.01.0012 study,
      of which an estimate is included in this cost, and any additional work on
      patient narratives for both studies and any additional biostatistics work
      requested will be charged on a time and materials basis as per the hourly
      rates in Appendix 1. All costs will be invoiced upon completion of the
      work.

              


      

       


      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

       

       

      

        
          	
                  Aramin
      694/005 & 006

                	 
      
	 	 
	
                  Protocol
      AN01.01.0012 & AN01.01.0011

                	
                  28th
      May 2008

                


        



      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

              
	 	 
	 	 
	
                NAME___________________

              	
                Ms.
      Seána Hopkins

              
	 	 
	
                TITLE
      ___________________

              	
                TITLE:  VP
      Commercial Affairs

              
	 	 
	
                DATE____________________

              	
                DATE_________________

              
	 	 
	
                SIGNED_________________

              	
                SIGNED______________

              


      


      
        
           


        

        
          -2-

          
            

          

        

        
           


        

      

       

       

       

      

        
          	
                  Aramin
      694/005 & 006

                	 
      
	 	 
	
                  Protocol
      AN01.01.0012 & AN01.01.0011

                	
                  28th
      May 2008

                


        



      Appendix
I

       

      
         

         

        Section
1. Change Order Specifications

         

         

        


      

      
        	
                Item

              	
                Amarin
      694005/694006

              	
                CO
      Value (£)

              	
                Comments
      /timelines

              
	
                Date:

              	
                May-07

              	 
      	 
      
	 
      	
                694005
      extension phase efficacy analysis

              	 
      	 
      
	
                Management

              	
                3hrslwk

              	
                £615

              	
                2
      weeks

              
	
                SAP

              	
                10
      hours

              	
                £1,026

              	
                SAP
      Includes all time from Jan08 to 01May08 (synergy
  applied)

              
	
                TFLs

              	
                5
      Unique Tables

              	
                £2,165

              	
                Unique
      TFLs absorbs dataset programming and validation cost (visit excel
      spreadsheet, last dose updates, revisit of LOCF for assessment dates,
      etc.)

              
	 
      	
                16
      Replicate Tables

              	
                £1,728

              	 
      
	 
      	
                3
      Unique Listings

              	
                £648

              	 
      
	 
      	
                4
      Repeat Listings

              	
                £324

              	 
      
	
                Total

              	 
      	
                £6,506

              	 
      
	 
      	
                694005
      extension phase safety analysis

              	 
      	 
      
	
                Management

              	
                3hrs/wk

              	
                £615

              	
                2
      weeks

              
	
                SAP

              	
                10
      hours

              	
                £1,026

              	
                SAP
      includes all time from Jan08 to 01 May08 (synergy
  applied)

              
	
                TFLs

              	
                8
      Unique Tables

              	
                £
      3,464

              	 
      
	 
      	
                11
      Replicate Tables

              	
                £1,188

              	 
      
	 
      	
                1
      Unique Listing

              	
                £216

              	 
      
	 
      	
                22
      Replicate Listings

              	
                £1,782

              	 
      
	
                Total

              	 
      	
                £8,291

              	 
      
	 
      	
                694006
      extension phase efficacy analysis

              	 
      	 
      
	
                Management

              	
                3
      hrslwk

              	
                £615

              	
                2
      weeks

              
	
                SAP

              	
                10
      hours

              	
                £1,026

              	
                SAP
      includes all time from Jan08 to 01May08 (synergy
  applied)

              
	
                TFLs
      - 1

                parameter

              	
                5
      Unique Tables

              	
                £2,165

              	 
      
	 
      	
                22
      Replicate Tables

              	
                £2,376

              	 
      
	 
      	
                6
      Repeat Listings

              	
                £486

              	 
      
	
                Total

              	 
      	
                £6,668

              	 
      
	 
      	
                694006
      extension phase safety analysis

              	 
      	 
      
	
                Management

              	
                3hrs/wk

              	
                £615

              	
                2
      weeks

              


      


      
        
           


        

        
          -3-

          
            

          

        

        
           


        

      

       

       

      

        
          	
                  Aramin
      694/005 & 006

                	 
      
	 	 
	
                  Protocol
      AN01.01.0012 & AN01.01.0011

                	
                  28th
      May 2008

                


        

      

      
 

      


      
        	
                SAP

              	
                10
      hours

              	
                £1,026

              	
                SAP
      Includes all time from Jan08 to 01 May08 (synergy
  applied)

              
	
                TFLs

              	
                9
      Unique Tables

              	
                £3,897

              	 
      
	 
      	
                17
      Replicate Tables

              	
                £1,836

              	 
      
	 
      	
                3
      Unique Listings

              	
                £648

              	 
      
	 
      	
                23
      Replicate Listings

              	
                £1,863

              	 
      
	
                Total

              	 
      	
                £9,885

              	 
      
	 
      	
                694006
      main phase rerun safety

              	 
      	 
      
	
                Management

              	
                3
      hrs/wk

              	
                £308

              	 
      
	
                Dry
      Run

              	
                1
      dry run

              	
                £5,103

              	 
      
	
                Total

              	 
      	
                £5,411

              	 
      
	 
      	
                694006
      main phase rerun efficacy

              	 
      	 
      
	
                Management

              	
                3
      hrs/wk

              	
                £308

              	 
      
	
                Dry
      Run

              	
                1
      dry run

              	
                £5,103

              	 
      
	
                Total

              	 
      	
                £5,411

              	 
      
	 
      	
                STATS TOTAL

              	 
      	
                £           42,172

              


      

      


      
         
Medical
Writing

      

       

      
         
Clinical
Study Report:

      

       

      The costs
for the Clinical Study Report (CSR) for the AN01.01.0011 study are based on the
following assumptions, with any deviations from these assumptions requiring a
further recost:

       

      
        	
                ·  

              	
                Amarin
      want the existing CSR for the double-blind phase (dated 01 June 2007) to
      be updated to include the OLE study methods and results, a brief summary
      of the EFA laboratory data (maximum one days work), and a revision of the
      double-blind data. It has been assumed that any changes to the
      double-blind data will not change the message of the existing CSR dated 01
      June 2007.

              


      

       

      
        	
                ·  

              	
                The
      cost includes the provision of a mock report including shell results
      tables for client review.

              


      

       

      
        	
                ·  

              	
                Two
      sets of consolidated client comments after the provision of Draft 1. Any
      additional revisions will be charged on a timesheet
  basis.

              


      

       

      
        	
                ·  

              	
                ICON
      has provided a separate unit cost for narrative writing and updates as
      required.

              


      

       

      
        	
                ·  

              	
                ICON
      Medical Writing will not be compiling the
  appendices.

              


      

       

      The costs
for this are £25,844

       

      The costs
for the open-label extension CSR addendum for the AN.01.01.0012 study will be
charged on a timesheet basis using the hourly rates in section 3 below. It is
estimated that the cost will be £23,802, which includes revisions based on two
sets of consolidated client comments, but excludes an estimate for narratives
(for which unit costs are presented below).

       


      
        
           


        

        
          -4-

          
            

          

        

        
           


        

      


      

        
          	
                  Aramin
      694/005 & 006

                	 
      
	 	 
	
                  Protocol
      AN01.01.0012 & AN01.01.0011

                	
                  28th
      May 2008

                


        



       

      
        	
                 
      

              	
                Patient
      Narratives:

              


      

       

      Various
different complexities of work will need to be done to the patient narratives
for both studies. These will be charges on a unit basis as detailed
below:

       

      
        	
                ·  

              	
                A
      new narrative written from scratch -* £204.05 per
  narrative

              


      

       

      
        	
                ·  

              	
                An
      existing narrative QC'd against listings and SAE reports/CIOMS, and
      updated à
      £153.04

              


      

       

      
        	
                ·  

              	
                An
      existing narrative QC'd against listings only, and updated à
      £102.02

              


      

       

      (Exchange
rate used = €1 =£0.6988, as per contract)


      
        
           


        

        
          -5-

          
            

          

        

        
           


        

      

       

      

        
          	
                  Aramin
      694/005 & 006

                	 
      
	 	 
	
                  Protocol
      AN01.01.0012 & AN01.01.0011

                	
                  28th
      May 2008

                


        



      
        


        Section
2. Summary of Costs

        


      

      


      
        	
                Biostatistics

              	 
      	 
      
	
                AN01.01.0011

              	 
      	 
      
	
                Extension
      Phase Efficacy Analysis

              	
                £

              	
                6,668

              
	
                Extension
      Phase Safety Analysis

              	
                £

              	
                9,885

              
	
                Main
      Phase Rerun Safety

              	
                £

              	
                5,411

              
	
                Main
      Phase Rerun Efficacy

              	
                £

              	
                5,411

              
	
                AN01.01.0012

              	 
      	 
      
	
                Extension
      Phase Efficacy Analysis

              	
                £

              	
                6,506

              
	
                Extension
      Phase Safety Analysis

              	
                £

              	
                8,291

              
	
                Total
      Biostatistics

              	
                £

              	
                42,172

              
	
                Medical
      Writing

              	 
      	 
      
	
                AN01.01.0011
      CSR

              	
                £

              	
                25,844

              
	
                AN.01.01.0012
      Open-Label Extension CSR addendum

              	
                £

              	
                23,802

              
	
                Patient
      Narratives

              	
                Unit
      Costs

              
	
                Total
      Medical Writing

              	
                £

              	
                49,646

              
	
                TOTAL

              	
                £

              	
                91,818

              


      

      


       

      
        


        Section
3. Hourly Rates to be used for any additional Work Requested by
Amarin

        


      

      


      The
following hourly rates will be applied for any additional work required by
Amarin.

       

      
        	
                 
      

              	
                Biostatistics

              


      

       

      
        	
                ·  

              	
                Senior
      Statistician à
      £102.58

              


      

       

      
        	
                 
      

              	
                Medical

              


      

       

      
        	
                ·  

              	
                Medical
      Writing - à
      £127.62

              


      

       

      
        	
                ·  

              	
                QA
      à
      £111.72

              


      

       

      


      

-6-