EX-4.13 2 exh_413.htm EXHIBIT 4.13 exh_413.htm
Exhibit 4.13
 
THE SYMBOL “[****]” DENOTES PLACES WHERE PORTIONS OF THIS DOCUMENT HAVE BEEN OMITTED PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT. SUCH MATERIAL HAS BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION.


Amendment 2 to Clinical Services Agreement

Sponsor’s study drug RHB-104


THIS AMENDMENT #2 (“Amendment”) to the Clinical Services Agreement signed 15 June 2011 (“Clinical Services Agreement”), is by and among:
 
 
(1) (1) RedHill Biopharma Ltd., having its principle place of business at 21 Ha’arba’a St., Tel Aviv 64739, Israel (hereafter “SPONSOR”);
  
     
 
(2) 7810962 Canada Inc., a Canadian corporation, having its principal office at 245 Victoria Ave, Suite 100, Montreal, Quebec, H3Z 2M6, Canada (hereinafter "MANAGER");
  

 
Is hereby made effective as of December 11, 2013 (“Effective Date”) and the parties hereby agree as follows:
 
 
1.
Amendment 2 to Clinical Services Agreement.

This Change Order constitutes an amendment to the Clinical Services Agreement pursuant to section 3.0 therein.  As such, this Change Order is subject in all respects to the terms and provisions of the Clinical Services Agreement.

 
2.
Scope of Work

In addition to the Services to be provided in the above-referenced Clinical Services Agreement, Manager will cause inVentiv Health Clinical to perform additional Services for Sponsor’s study drug RHB-104, in accordance with the Summary of Changes attached hereto and incorporated herein as Exhibit A. The EU trial is removed from the contract in this amendment to the trial agreement.
 
 
3.
Compensation

Under this Change Order, inVentiv Health Clinical’s Professional Fees have decreased by the discounted amount of USD [****], the pass-through costs have increased by USD [****] and the investigator’s grants costs have Increased by USD [****]. The total cost of the Clinical Services Agreement have increased to USD 10,540,751.

 
 
 
Exhibit 4.13
 
Payment due to Manager for the Services provided under this Change Order shall be made pursuant to the Agreement and the revised unit Payment Schedule attached hereto and incorporated herein as Exhibit B.

 
4.
Project Period

The term of this Change Order shall commence on the date of its execution and shall continue until the Services as described in the Clinical Services Agreement are completed, unless this Change Order or corresponding Clinical Services Agreement are terminated early in accordance with the Clinical Services Agreement.


By their signatures below, the parties hereto agree to the terms of this Change Order and represent that they are authorized to enter into this Change Order on behalf of their respective companies.


ACCEPTED AND AGREED TO:

RedHill Biopharma Ltd.
For 7810962 Canada Inc
       
       
/s/ Dror Ben-Asher
   /s/ Alain Guimond  
    Name: Alain Guimond
Name: Dror Ben-Asher Title: Sr Director of R&D
       
Title: CEO      
    Date: January 10, 2014
       
Date: January 19, 2014
    
       
       
       
RedHill Biopharma Ltd.    
       
/s/ Ori Shilo      
Name: Ori Shilo      
       
       
Title: Deputy CEO Finance and Operations    
       
       
Date: January 19, 2014
    
 
 
 
 
Exhibit 4.13
 
Exhibit A: Summary of Changes
 
Study Assumption Changes
 
Changes to the parameters and assumptions for the study are defined below. Unless otherwise noted, activities will be performed according to the original contract. EU trial is removed from the study agreement
 
Amendment #2 RedHill Biopharma
 
Overview of major level changes

Category
Contract
Change Order –
NA Project
Rationale for change
Study Start- Up period
[****]
[****]
Work on global project began mid-July2011, with kick-off meeting August 10, 2011. Final protocol for NA expected early September, and then delayed until December 2011. [****]. On Mar. 1, 2012, the project was put on hold with an agreed upon charge of $[****]K/month; a contract amendment was put in place. The hold lasted [****] months, at which time inVentiv Health Clinical was instructed to restart start-up activities in full. Start-up activities continue.
Enrolment period
[****]
[****]
Per client
Stats Timeline
[****]
[****]
  
# of countries
[****]
[****]
EU sites are removed from the study agreement. [****].
# of sites
[****]
[****]
Per client
# of subjects
[****]
[****]
Per client
# of CRF pages/book
[****]
[****]
Number of visits in NA study has [****][****]
# of unique CRF pages
[****]
[****]
CRFs are complete [****].
# RMVs per site
[****]
[****]
Calculated based on total number of CRF pages. [****]
# of PSVs
[****]
[****]
Additional sites, therefore additional PSVs
# of SIVs
[****]
[****]
Additional sites, therefore additional SIVs
# of RMVs
[****]
[****]
Additional CRF pages to be monitored (as detailed above), therefore additional RMVs required
# of COVs
[****]
[****]
Additional sites, therefore additional COVs
# of internal meetings
[****]
[****]
Dependent upon duration of trial: meetings typically held weekly during start-up and enrolment, then monthly thereafter
# of client telecons
[****]
[****]
Dependent upon duration of trial: meetings typically held weekly during start-up and enrolment, then monthly thereafter
 
 
3
 
 
Category
Contract
Change Order –
NA Project
Rationale for change
Investigator Meeting
[****]
[****]
Per client
# of vendors
[****]
[****]
[****]
# of edit checks
[****]
[****]
[****]: have 2 unique databases now, and larger CRF for each
# of imports
[****]
[****]
[****]: imports occur monthly from FPI to LPO plus one month, plus 1 test and 1 final
# of SAEs
[****]
[****]
Increased because # of subjects has increased. Assume 5% SAE rate in each study.
# of SAE Narratives
[****]
[****]
As above. Require 1 narrative for each SAE.
IVRS
[****]
[****]
Client request to include IVRS for randomization with 1 drug assignment/site, and unblinding capability
eCRF Changes
[****]
[****]
Amended protocol required changes to the previously finalized eCRF


 
 
 
 
 
 
4
 
Confidential
 
 
1.1
Revised Costs
 
Costs for this study are presented below in two categories, pass-through costs and professional fees.
 
1.1.1
Pass-Through Costs
 
Pass-through costs are in US dollars and include, but are not limited to, those expenses listed below. Manager will invoice Sponsor for actual costs in these areas. Actual costs will be kept to reasonable levels through adherence to inVentiv Health Clinical’s travel policy and prudent negotiation with outside providers. Pass-through costs are presented in the table below:
 
Task
Original
(USD)
New NA
(USD)
Assumption
Changes
influencing the
change in the
budget
Additional
comments
         
Site Visit Travel
[****]
[****]
Original contract has a total of [****] site visits. [****]
  
Investigators' Meeting Organisation
[****]
[****]
WebEx costs included in original budget. Investigator meetings have been changed to F2F.
  
Kick-off Meeting Travel/Attendance
[****]
[****]
Originally assumed [****] cover study globally, as studies and timelines were the same. Now assume [****] for each study, since timelines are vastly different and study teams not identical.
  
Shipping/Photocopying
[****]
[****]
Original contract assumes [****]. New NA budget assumes [****].
  
Translation
[****]
[****]
Original contract [****]. New NA budget [****];
Costs for translating patient recruitment materials have been removed as this service is not included in updated budgets.
Regulatory Fees
[****]
[****]
assumed [****].
Current costing tool separates out
 
 
 
 
Confidential
 
 
Task
Original
(USD)
New NA
(USD)
Assumption
Changes
influencing the
change in the
budget
Additional
comments
[****] (& Regulatory) Fees
[****]
 [****] New NA costing assumes [****]. Regulatory Fees and [****] fees, as seen in EU costing. For original costing and new NA costing, these fees remain combined.
EDC Studies/3G Cards
[****]
[****]
[****]
  
[****]
[****]
[****]
  
[****]
EDC Fees ([****])
[****]
[****]
  
EDC Fees were included in Professional Fees in initial bid
 Pass Through Costs
[****]
[****]
    

 
 
 
 

 
 
 
 
Confidential
 
 
1.1.2
Investigator Grants Costs
 
Investigator
Grants
Original
(USD)
NA
(USD)
Assumption Changes
influencing the
change in the budget
Additional
Comments
 
[****]
$4,800,000
Original contract assumed [****] patients. New NA costing assumed [****] patients
Estimate only. Will be paid based on actual costs as approved by the Client.
 
 
 
1.1.3
Professional Fees
 
Based on the parameters and assumptions outlined in the original proposal, inVentiv Health Clinical fees are categorised by major activity in the table below and in USD:
 
 
Task
Original
(US Dollars)
New NA
(US Dollars)
Assumption Changes
influencing the change in
the budget
Additional comments
Pre-study Activities
        
Case Report Form Preparation/Review
[****]
[****]
[****]
Original costs were to prepare one CRF that would be utilized by both studies; with different study designs now we are preparing two different CRFs but are able to take efficiencies on pages that will be the same in both studies. Additionally, number of visits in NA study has [****] since details provided in protocol synopsis in April 2011
Data Management Plan Preparation/Review
[****]
[****]
[****]
Originally cost allocation was to prepare one plan to be utilized by both studies; with different study designs now we are preparing two different DM plans.  We are able to copy some aspects/pages of the DM plan from the NA study to the EU study, and where there are not similarities we have allocated cost for new pages/edit specs.
Informed Consent Preparation/Review
 
[****]
[****]
[****]
  
[****]
 
[****]
[****]
[****]
  
Investigators' Meetings
 
[****]
[****]
[****]
  
 
 
 
 
 
Confidential
 
 
Task
Original
(US Dollars)
New NA
(US Dollars)
Assumption Changes
influencing the change in
the budget
Additional comments
Investigator Site Contract
 
[****]
[****]
[****]
  
Investigator Recruitment
 
[****]
[****]
[****]
[****]
Project Plan Preparation/Review
[****]
[****]
[****]
[****]Assumed that there are efficiencies in the preparation of the EU plan based on finalization of the plan in NA due to similar process where applicable.  EU IPP plan will be different based on countries included outside NA and Israeli.
Protocol Preparation/Review
[****]
[****]
[****]
Assumes a separate CRA team is reviewing/reading protocol due to countries not being the same.  With the start of the EU study subsequent to the NA, there is also a separate team in many functional areas, i.e., separate DM team, biostats, medical writing, and safety.
Randomization Schedule Preparation
[****]
[****]
Originally allocated cost for
[****]and now doing [****]
  
Study-Specific Form Preparation
[****]
[****]
Originally allocated cost for [****]Now [****]
Efficiencies will be applied in EU study: assume use NA forms modified to suit EU study
Training - Project-Specific
[****]
[****]
Originally allocated cost for [****]
Training two separate teams w larger EU team.  Assumed NA training would be modified for EU training, but protocol designs are different so training different.
Translations
[****]
[****]
[****]
Fewer languages in NA study than EU
PROMIS
[****]
[****]
[****]
Two separate databases; one for each study.
Monitoring/Site Management
        
Data Clean-up
[****]
[****]
  
Increased number of eCRF pages.
Investigator Grant Administration
 
[****]
[****]
[****]
[****]
Laboratory Report Review
[****]
[****]
Decrease in total number of patients
Originally allocated cost for [****]
Serious/Significant Adverse Event Management
[****]
[****]
Decreased number of SAEs due to decreased number of subjects
Originally allocated cost for [****]
 
 
 
 
 
Confidential
 
Task Original
(US Dollars)
 New NA
(US Dollars)
 Assumption Changes
influencing the change in
the budget
Additional comments
Site Management
[****]
[****]
Decreased number of sites and  increased months
Originally allocated cost for the management  [****]
Site Visits - Pre-study Visits
[****]
[****]
Decreased number of sites
Originally cost allocation was for [****]
Site Visits - Initiation Visits
[****]
[****]
Decreased number of sites
Originally cost allocation was for [****]
Site Visits - Routine Visits
[****]
[****]
Increased number of visits due to increased number of CRF pages to monitor
Originally cost allocation was for [****]
Site Visits - Close-out Visits
[****]
[****]
Decreased number of sites
Originally cost allocation was for [****]
Study Master File/Project File Set-up and Maintenance
[****]
[****]
Decreased number of sites and  increased months
Originally allocated cost for the management  [****]
Patient/Site Recruitment
[****]
[****]
    
Regulatory
        
Regulatory Documentation Preparation/Review
[****]
[****]
Decreased number of sites
Originally cost allocation was  [****]
Project Management/Project Tracking
        
Financial Project Management
[****]
[****]
Increased study durations; 2 separate studies vs. 1
Originally cost allocation was  [****]
Project Management
[****]
[****]
Increased study durations; 2 separate studies vs. 1
Originally cost allocation was  [****]
Project Tracking/Communications
[****]
[****]
Increased study durations; 2 separate studies vs. 1
Originally cost allocation was  [****]
Vendor Management
[****]
[****]
Added [****] contract payment management
[****]
Data Management
        
Database Archiving
[****]
[****]
    
Data Cleanup (DM)
[****]
[****]
[****].
  
Data Management: Database Quality Control Inspection
[****]
[****]
[****]
  
Database Design
[****]
[****]
[****]
Assume NA DB designed first with efficiencies taken for similar eCRF pages/edit specs in both studies.  We will reconsider upon receipt of synopsis with final assumptions. Assumed one data base originally and now two
Dictionary Coding
[****]
[****]
Increased number of subjects, therefore increased number of terms overall
  
 
 
 
 
 
Confidential
 
Task Original
(US Dollars)
 New NA
(US Dollars)
 Assumption Changes
influencing the change in
the budget
Additional comments
Edit Check Programming
[****]
[****]
Increased number of edit checks due to increased CRF size
Assume NA DB designed first with efficiencies taken for similar eCRF pages/edit specs in both studies.  We will reconsider upon receipt of synopsis with final assumptions.
Electronic Data Import
[****]
[****]
  
[****]
Case Report Form Data/Document Transfers
[****]
[****]
  
[****]
EDC Fees
[****]
[****]
  
[****]
Statistical Analysis and Table Generation
        
Electronic Data Transfer
[****]
[****]
[****]
  
Interim Analysis/Report Preparation and Review
[****]
[****]
[****]
  
Statistical Analysis Plan Preparation/Review
[****]
[****]
[****]
Originally cost allocation was to [****]
Table Generation
[****]
[****]
[****]
Originally preparing [****]
Table/Listings Review
[****]
[****]
[****]
Reviewing [****]separate sets of T&Ls.
Clinical Study Report
        
Clinical Study Report Preparation/Review
[****]
[****]
  
Assumes [****]separate study reports, originally assumed one.
Team Meetings
        
Project Team Meetings - Internal Meetings
[****]
[****]
[****]
  
Project Team Meetings - Client Teleconferences
[****]
[****]
[****]
  
Project Team Meetings - Kick-off Meeting
[****]
[****]
[****]
  
Total Direct Costs
[****]
[****]
    

 
Total Costs
 
 
Total Costs($)
Category
Current Contract
Change in Scope #1
Revised Total
 
(USD)
(USD)
(USD)
[****]
[****]
[****]
[****]
Investigator Grants Costs
[****]
[****]
$4,800,000
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
 
 
 
 
 
Confidential
 
 
 
Total Costs($)
Category
Current Contract
Change in Scope #1
Revised Total
 
(USD)
(USD)
(USD)
Revised Professional Fees
[****]
[****]
$4,995,243
Grand Total
$8,142,331
$2,398,420
$10,540,751
 
 
 
 
 
 

 
 
 
 
Confidential
 
Exhibit B Payment Schedule
 
 
 
Milestone Payment Schedule
7810962 Canada Inc (11ISB001)

 
Milestone
Total
(USD)
[****]
CO#1 [****]
Total
(USD)
[****]
[****]
[****]
[****]
[****]
[****]
  
[****]
[****]
[****]
[****]
[****]
    
[****]
      
[****]
    
[****]
      
[****]
    
[****]
      
[****]
    
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
[****]
      
[****]
  
[****]
[****]
[****]
[****]
  
[****]
  
[****]
[****]
      
 
[****]
[****]
[****]
      
[****]
    
[****]
      
[****]
  
[****]
[****]
      
[****]
    
[****]
      
[****]
    
[****]
      
[****]
    
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
[****]
      
 
[****]
[****]
[****]
      
[****]
    
[****]
      
[****]
  
[****]
[****]
      
[****]
    
[****]
      
[****]
    
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
        
[****]
  
[****]
[****]
      
[****]
    
[****]
      
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
      
 
[****]
[****]
[****]
      
Total Milestones
3,987,715
-1,708,011,
2,279,866
  
[****]
[****]
 
 
 
Page 12 of 14
 
Confidential
 
 
Milestone
Total
(USD)
[****]
CO#1 [****]
Total
(USD)
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
[****]
  
[****]
[****]
[****]
[****]
[****]
[****]
  
[****]
[****]
      
             
Total Milestone Payments[****]
[****]
[****]
4,995,243
  
[****]
[****]
             
[****]
            
             
             
[****]
            
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
             
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
[****]
      
[****]
[****]
[****]
         
[****]
[****]

 
Pass Through Costs:
 
 
(a)
[****] percent ([****]%) of the average estimated pass through costs equaling $[****] (exclusive of funds for investigator grants); will be due and payable upon execution of this Agreement. These funds will be drawn down as necessary to pay incurred pass through costs and will be replenished to the full [****]% once the amounts held are [****]% depleted.  This process to continue until the end of the study.
 
 
(b)
The pass-through costs above will be as provided in the expenses estimate and any additional costs will be pre-approved by the Company. The pass-through costs will be billed as incurred by inVentiv Health Clinical.
 
 
(c)
Any unused funds held for pass through costs will be returned within ninety (90) days from the date of the final reconciliation.
 
 
3.
Investigator Grants:
 
 
(a)
[****] percent ([****]%) of the estimated grant payments for the study, equaling $[****], will be invoiced upon commencement of services. These funds will be drawn down as the Investigator Grants are paid and the full [****]% will be replenished once the amounts held are [****]% depleted). This process to continue until the end of the study.
 
 
Page 13 of 14
 
Confidential
 
 
(b)
inVentiv Health Clinical will submit invoices for the amounts paid to investigators during the previous month. Any amount exceeding the estimate investigator grant payments will be pre-approved by the Company.
 
 
(c)
inVentiv Health Clinical will not make payments to investigators without having sufficient funds available in advance.
 
 
(d)
Any unused funds will be returned within ninety (90) days from the date of the final reconciliation
 
 
4.
Payment Conditions:

 
(a)
For all Services, pass through expenses and investigator grants invoiced, payments are due net thirty (30) days from invoice date as set forth in Terms, Item 2 of the Agreement.  In the event of a dispute, all undisputed portions of the invoice(s) are due within the above stated terms
 
 
(b)
Payments shall be made in the currency identified above and shall be made free of any applicable local withholding taxes, charges or remittance fees.  Invoices will be inclusive of applicable taxes as determined by local laws and regulations
 
 
(c)
InVentiv Health Clinical reserves the right to charge interest against any unpaid overdue balance at the rate of [****] percent ([****]%) per month
 
 
(d)
All services and pass-through payments should be sent via wire or ACH
 
 
 
 
Page 14 of 14