EX-10.3 3 filename3.htm

 

Exhibit 10.3

 

Master Services Agreement Dated

Between Kitov Pharmaceuticals Limited (Kitov)

and

Java Clincial Research Ltd ( JAVA)

 

CHANGE ORDER FORM (1)

 

PROTOCOL NUMBER:

 

 K-302-03-01

Kitov CONTACT:

 

 Mr Simcha Rock

SUPPLIER CONTACT:

 

 Ms Ruth Nallen

DATE OF REQUEST:

 

 26 03 2014

BRIEFLY DESCRIBE ORIGINAL ASSUMPTION AND NEW REQUEST:

 

The Original MSA dated 04 February refers only to Java Professional and Pass through Fees.

This change order reflects total agree PI Fees for both Republic of Ireland and Northern Ireland.

  • ROI fees which will be paid in euro to Java Clinical Research ltd who will then pass it on to the PIs upon receipt of invoices.
  • NI fees will be paid in sterling directly to the single Investigator site at Celerion.
  • A detailed service agreement will be exchanged directly between Kitov Pharmaceuticals and Celerion.

 

IMPACT (estimated effort and/or timeline):

 

This change order has no impact on effort or timelines.

COST:

Total additional cost: €669,989.60

 

Payment Terms: Payment details and schedules are detailed in Appendix 1 & 2

 

Amendment:  This Change Order Form shall constitute a Contract Amendment to the MSA dated 04 February 2014 between Kitov and Java and shall apply only to the revision of PIs fees attached hereto.  In all other respects the terms and conditions of the MSA shall remain in full force and effect and shall be applied to this Contract Amendment.

Kitov Pharmaceuticals Ltd

 

 

 

/s/ Simcha Rock                             

(Signature)

 

26/3/2014                                         

(Date)

 

 

 

Java

 

 

 

/s/ Ruth Nallen                               

(Signature)

 

26/03/2014                                  

(Date)

 

 

Change order no 1

Kitov/ Java MSA

        

 

Page 1 of 3

 

 

 

Appendix 1

 

PI Fees Republic of Ireland

Fees payable to Java Clinical Research Ltd

 

 

Study Reference K-03-01       
Estimate ROI  Investigator   Costs (Euro)       
Investigator fees   72,000.00   Cost per screen failure: €720 x 100 subjects
    257,500.00   Cost per randomised subject: €2575 x 100 subjects
Total   329,500.00    
Other Investigator Pass through costs        
GP Patient Referral Fee   7,500.00   Estimate: 100 patients x €100 per patient
Community Screening Clinics   7,500.00   Estimate: €1000 per site x 10 sites
ABPM subject lifestyle inconvenience reimbursement   25,000.00   Screen failures: 100 x 1 x €50; Randomised subjects: 100 x 4 x €50
Estimated receipted subject travel expenses   60,000.00   Screen failures:100 x 3 visits  x €50; Randomised subjects:100 x 9 visitsx €50
Total   100,000.00    
Proposed  payment of PI fees      Estimate Invoice  Date 
Upfront payment of  25%   82,375.00   Apr-14
Payments every 2 months thereafter based on subject visits        
    82,375.00   Jul-04
    82,375.00   Sep-14
    82,375.00   Nov-14
    329,500.00  
Pass through Fees        
Upfront 25%   25,000.00   Apr-14
 Following SIV completion   25,000.00   Jun-14
Payments every 2 months thereafter based on exepditure   25,000.00   Aug-14
Payments every 2 months thereafter based on exepditure   25,000.00   Oct-14
    100,000.00  

 

 

 

Change order no 1

Kitov/ Java MSA     

 

Page 2 of 3             

 

 

 

Appendix 2

 

PI Fees Northern Ireland

Paid and contracted directly to Celerion

 

MSA Kitov/ Celerion  Euro   Sterling 
           
Patient Management /PI Fees  €217,166.40   £180,972.00 
           
Pass through costs  €6,000.00   £5,000.00 
           
PK sampling  €17,323.20   £14,436.00 
           
Total  €240,489.60   £200,408.00 

 

 

Change order no 1

Kitov/ Java MSA

 

Page 3 of 3

 

 

 

Master Services Agreement Dated

Between Kitov Pharmaceuticals Limited (Kitov)

and

Java Clinical Research Ltd ( JAVA)

 

CHANGE ORDER FORM (2)

 

PROTOCOL NUMBER:

 

 KIT-302-03-01

Kitov CONTACT:

 

 Mr Simcha Rock

SUPPLIER CONTACT:

 

 Ms Ruth Nallen

DATE OF REQUEST:

 

 22 09 2014

BRIEFLY DESCRIBE ORIGINAL ASSUMPTION AND NEW REQUEST:

 

  • Project timelines have extended as the study will now be conducted in the UK as opposed to the Republic of Ireland as stated in the original MSA. The movement of the study to the UK necessitated additional feasibility assessments which resulted in the selection of 4 additional UK sites and a central laboratory in the UK. Kitov Pharmaceuticals will contract directly with ACM laboratories so this service is now excluded from the MSA. Kitov will also manage PI fees directly with UK sites, so the PI fees itemised in CO 1 will no longer be applicable to this MSA.

 

  • Multiple protocol amendments were issued to facilitate recruitment. This resulted in the submission of multiple substantial amendment to the UK REC and MHRA. It also resulted in modifications to the eCRF and data management plan. Additionally REC approval, by means of submission of a substantial amendment to the REC, was required for each of the additional UK sites.

 

 

IMPACT (estimated effort and/or timeline):

 

  • Project preparation timelines extended by 4 weeks
  • Study conduct time has extended by 20 weeks
  • Milestone payments have been restructured as detailed below in payment terms

 

 

COST:

Total additional cost:

 

€ 96,716.34 Professional Fees

€ 9,968 Pass through Fees

 

Revised budget break down is included in Appendix 1.

Costs will be revisited if recruitment is completed earlier than 27 March 2015 as detailed in the attached Appendix 1.

 

GRAND  REVISED TOTAL  PROFESSIONAL FEES    664,799.58 
less received to date   204,657.98 
      
Balance    460,141.60 
      
20% following 10 subjects randomised   92,028.32 
10 % following 30  subjects randomised   46,014.16 
10 % following 50 subjects randomised   46,014.16 
10 % following 75 subjects randomised   46,014.16 
10 % following 100 subjects randomised   46,014.16 
10 % following 125 subjects randomised   46,014.16 
10 % following 150 subjects randomised   46,014.16 
10%  following LPLV   46,014.16 
5% following DB lock   23,007.08 
5% following final study Report   23,007.08 
    460,141.60 

 

Amendment:  This Change Order Form shall constitute a Contract Amendment to the MSA dated 04 February 2014 and Change Order No 1 dated 26 March 2014 between Kitov and Java. In all respects the terms and conditions of the MSA shall remain in full force and effect and shall be applied to this Contract Amendment No 2

Kitov Pharmaceuticals Ltd

 

 

 

/s/ Simcha Rock                             

(Signature)

 

September 23, 2014                       

(Date)

 

 

 

Java Clinical Research ltd

 

 

 

/s/                                                    

(Signature)

 

_________________________

(Date)

 

Change order no 1

Kitov/ Java MSA

 Page 1 of 5

 

 

Appendix 1

Revised Professional & Pass through fees

 

Study Reference K-03-01          
           
Projected Timelines:          
Project Preparation 14 weeks 18 weeks    January 2014 – Mid-May 2014
Study Recruitment and Conduct Period 22 weeks 42 weeks   22 June 2014 - 27 March 2015
Close out period 12 weeks      30 March 2015 - 19 June 2015
           
Indication: Hypertension         
           
Key Assumptions:          
Number of patients to be screened 300        
Number of patients to be randomised 150        
Sites 1 site NI 4 sites UK       
Number of monitoring visits Estimated pool of 45 monitoring site visits  
Total CRF pages per patient TBC        

                   
ACTIVITY  RATE   UNIT  EST. REQ.   ESTIMATED CHARGE   Comments
   €      Range   Range €    
Project Preparation                  
PM project training   110.00   hour   16    1,760.00   To include protocol, CRF and SOP training
CRA project training   85.00   hour   16    1,360.00   To include protocol, CRF and SOP training
PM project preparation time   1,760.00   week   22    38,720.00   Includes site contacts/feasibility assessments to ensure all required systems are in place for study initiation, assistance with eCRF development to include advice on required CRF data fields, communication with Kitov Ltd on project related progress/issue
PM Feasibility & Preparation UK sites   880.00   day   12    10,560.00   Site & laboratory feasibility and selection activities including  budget and contract negotiations
CRA project preparation time   1,360.00   week   14    19,040.00   Includes site contacts/feasibility, communication with Kitov Ltd, collating all study related materials required for initiation, addressing site queries and issues, preparation/customisation of Investigator Study Files and Forms, collection of essential d
CTA project preparation time   400.00   week   18    7,200.00    
                      
Preparation total                78,640.00    
Regulatory and Ethics                     
Review and submission of CTA to IMB (including submission of responses to any queries raised during review period)   3,840.00   submission   1    3,840.00    
Review and submission of CTA to MHRA (including submission of responses to any queries raised during review period)   3,840.00   submission   1    3,840.00    
Submission of  Substantial Amendment  to MHRA   120.00   hour   38    4,560.00   12 hours Amen1: 8 hours Ament 2 ;                                            16 hours Amen 3 :12 hours amendment 4
Submission to National Ethics Committee in Northern Ireland  (including submission of responses to any queries raised during review period)   2,040.00   submission   1    2,040.00    
Submission to National Ethics Committee in Northern Ireland (including submission of responses to any queries   2,720.00   submission   1    2,720.00    
Preparation and submission of substantial amendments to National Ethics Committee in Northern Ireland   880.00   submission   7    6,160.00    
Management of R&D Office Approval, including budget negotiation   1,760.00   site   1    1,760.00    

 

Change order no 1

Kitov/ Java MSA

 Page 2 of 5

 

 

Regulatory total                24,920.00   Estimate  13 Belfast visits; 32 UK visits
Clinical Operations                    Assuming 1 Belfast  Centre:  4  UK Regional Centres  -  estimated Monitoring Visit Pool of 45 visits ( 12 visits Belfast : 32UK)) 
Site Qualification Visits   680.00   site   10    6,800.00   Site Visit preparation time for pre study visits  -  2 hours. Site Visit preparation time for SIV and close out visit - 4 hours.  Site Qualification and Pre study visit duration - 4 hours. SIV and close out visit duration - 8 hours. Monitoring Visits  pre
Travel time   400.00   site   6    2,400.00    
Site Qualification Visits UK   680.00   site   4    2,720.00    
Travel time UK   600.00   site   4    2,400.00    
Pre-Study Visits   850.00   site   5    4,250.00    
Travel time Belfast   200.00   visit   1    200.00    
Travel time UK   600.00   visit   4    2,400.00    
Site Initiation Visits   1,360.00   site   5    6,800.00    
Travel time Belfast   200.00   visit   1    200.00    
travel time UK   600.00   visit   4    2,400.00    
                      
Study Monitoring Visits   2,040.00   site   45    91,800.00    
Travel time Belfast   200.00   visit   13    2,600.00    
Travel time UK   600.00   visit   32    19,200.00    
Study Close-Out Visits   1,360.00   site   5    6,800.00    
Travel time Belfast   200.00   visit   1    200.00    
Travel time UK   600.00   visit   4    2,400.00    
CRA Site Management   340.00   week   18    6,120.00   June - Sept 2014
CRA Site Management   850.00   week   24    20,400.00   Oct - March 2015
CRA Site Management   850.00   week   12    10,200.00   Close out period
Project Management   2,200.00   week   52    114,400.00   Internal management of CRAs including advice on recruitment strategies, site related issues, contingency measurement implementation etc; Communication with Kitov Ltd on project progress/study related issues; Management of Third Party Vendors; Management o
CTA study conduct   320.00   week   52    16,640.00   Assistance with compilation of return of essential dcoument for TMF, CRA travel arrangements, collation of all pass through costs and study related invoices.

 

Change order no 1

Kitov/ Java MSA

 Page3 of 5

 

 

Clinical Operations   321,330.00    
Other Services        
Clinical Laboratory Services (Estimate)        
Central Laboratory set up  Fee   5,874.00   ACM laboratory contracted directly with Kitov
Data Management and Statistics        
Biometrics Management   11,172.00    
Data Management   42,873.50    
Amendment 1-3   5,133.50    
Amendment 4   27,522.00    
eCRF management and hosting   64,189.25    
Statistics   37,225.75    
    188,116.00    
         
Pharmacovigilance        
Safety Database Maintenance   4,000.00    
PhV Specifications   2,910.00    
SAE Initial/Follow-up Report Processing   3,600.00    
Expedite SUSARs reporting   108.00    
Line Listing production   2,440.00    
Responsible Person - Eudravigilance   6712.5    
Pharmacovigilance Subtotal   19,770.50    
         
Medical Writing        
Clinical Study Report   14,252.00    
         
Other Services Subtotal   222,138.50    
8% overhead   17,771.08    
 Preparation Regulatory & Clinops Subtotals   424,890.00    
         
GRAND TOTAL  PROFESSIONAL FEES   664,799.58    

 

         
Other study conduct  costs        
IMB CTA   1,443.00    
MHRA CTA + amendments   5,000.00    
Ethics Committe Fees   3,500.00    
CRA Travel   28,200.00   Belfast  site: 1 sites x 4 visits x €300 = €1200 (SQV/PS/SIV/C0)
        Belfast site: 1 x 13 visits x €300 = 3900
        UK sites: 4 sites x 4 visits  €500 =€8000 (SQV/PS/SIV/C0)
        UK sites: 32 x €500 = €16000
Courier Costs - as per receipted expenses   8,000.00   Estimate
Stationary, Printing, Photocopying for TMF, Investigator Site Files and Ethics Applications ; other   10,000.00    
Management of PI fees   9,885.00    
Estimate other pass through costs   66,028.00    

 

Change order no 1

Kitov/ Java MSA

 Page 4 of 5

 

      
GRAND TOTAL  PROFESSIONAL FEES   664,799.58 
less received to date   204,657.98 
      
Balance   460,141.60 
      
20% following 10 subjects randomised   92,028.32 
10 % following 30  subjects randomised   46,014.16 
10 % following 50 subjects randomised   46,014.16 
10 % following 75 subjects randomised   46,014.16 
10 % following 100 subjects randomised   46,014.16 
10 % following 125 subjects randomised   46,014.16 
10 % following 150 subjects randomised   46,014.16 
10%  following LPLV   46,014.16 
5% following DB lock   23,007.08 
5% following final study Report   23,007.08 
    460,141.60 

 

Change order no 1

Kitov/ Java MSA

 Page 5 of 5

 

 

Master Services Agreement Dated

2nd April 2015

 

Between Kitov Pharmaceuticals Limited (Kitov)

and

Java Clinical Research Ltd ( JAVA)

 

CHANGE ORDER FORM (3)

 

PROTOCOL NUMBER:

 

 KIT-302-03-01

Kitov CONTACT:

 

 Mr Simcha Rock

SUPPLIER CONTACT:

 

 Ms Ruth Nallen

DATE OF REQUEST:

 

 2nd April 2015

 

BRIEFLY DESCRIBE ORIGINAL ASSUMPTION AND NEW REQUEST:

 


·      Project timelines have been extended as follows: 8 additional weeks in the study conduct 8 weeks interim analysis

 

·The budget is now reflective of up to 30 additional patients.  

 

·The Monitoring visit schedule has been restructured. The total monitoring visits have increased from 45 to 56; 40 of which are two day visits and 16 are one day visits.

·3 additional sites in the UK have been included; the budget reflects additional site feasibility assessments and initiation and close out visits allocated to these new sites.

 

·Protocol amendments were issued to facilitate recruitment. This resulted in the submission of multiple substantial amendment to the UK REC and MHRA. It also resulted in modifications to the eCRF and data management plan. Additionally REC approval, by means of submission of a substantial amendment to the REC, was required for each of the additional UK sites.

 

IMPACT (estimated effort and/or timeline):

As stated above

 

COST:

Total additional cost:

 

€116,238.18

 

Revised budget break down is included in Appendix 1.

 

Page 1 of 5

 

 

GRAND TOTAL  PROFESSIONAL FEES    781,037.76 
Less received to date    388,714.62 
Invoice due for payment 30 March 2015   46,014.16 
    434,728.78 
Balance Due    346,308.98 
Revised Payment schedule ( based on montly resources)     
30-Apr-15   76,957.50 
30-Jun-15   76,957.50 
30-Aug-15   76,957.50 
30-Oct-15   76,957.50 
30-Dec-15   38,478.98 
    346,308.98 
      
      

 

Amendment:  This Change Order Form shall constitute a Contract Amendment to the MSA dated 04 February 2014, Change Order No 1 dated 26 March 2014 and Change Order 2 dated 22 September 2014 between Kitov and Java. In all respects the terms and conditions of the MSA shall remain in full force and effect and shall be applied to this Change Order  No 3.

Kitov Pharmaceuticals Ltd

 

 

 

/s/ Simcha Rock                             

(Signature)

 

April 2, 2015                                    

(Date)

 

 

 

Java Clinical Research ltd

 

 

 

/s/ Ruth Nallen                      

(Signature)

 

02 April 2015                          

(Date)

   

 

Change order no 1

Kitov/ Java MSA

 

Page 2 of 5

 

 

Appendix 1

Revised Professional fees

 

Study Reference K-03-01          
  Agreed V8  Revised V9      
Projected Timelines:          
Project Preparation 18 weeks     January 2014 – Mid-May 2014
Study Recruitment and Conduct Period 42 weeks 50 weeks   22 June 2014 - 05 June  2015
Interim Analysis Recruitment and Conduct Period   8   08 June - 03 AUG
Close out period 12 weeks  12 weeks   03 AUG - 2 Nov  
           
Indication: Hypertension         
           
Key Assumptions:          
Number of patients to be screened 300 400      
Number of patients to be randomised  150 150      
Number of patients randomised  during interim analysis   30      
Sites 5 sites 8 Sites      
Number of monitoring visits (180 patients) Estimated pool of 56 monitoring site visits  
     
Total CRF pages per patient TBC        

 

Change order no 1

Kitov/ Java MSA

 

Page 3 of 5

 

                   
ACTIVITY  RATE   UNIT  EST. REQ.   ESTIMATED CHARGE   Comments
   €      Range   Range €    
Project Preparation                  
PM project training   110.00   hour   16    1,760.00   To include protocol, CRF and SOP training
CRA project training   85.00   hour   16    1,360.00   To include protocol, CRF and SOP training
PM project preparation time   1,760.00   week   22    38,720.00   Includes site contacts/feasibility assessments to ensure all required systems are in place for study initiation, assistance with eCRF development to include advice on required CRF data fields, communication with Kitov Ltd on project related progress/issue
PM Feasibility & Preparation UK sites   880.00   day   12    10,560.00   Site & laboratory feasibility and selection activities including  budget and contract negotiations
CRA project preparation time   1,360.00   week   14    19,040.00   Includes site contacts/feasibility, communication with Kitov Ltd, collating all study related materials required for initiation, addressing site queries and issues, preparation/customisation of Investigator Study Files and Forms, collection of essential d
CRA project preparation time   2,040.00   site   3    6,120.00   additional 3 sites
CTA project preparation time   400.00   week   18    7,200.00    
Preparation total                84,760.00    
Regulatory and Ethics                     
Review and submission of CTA to IMB (including submission of responses to any queries raised during review period)   3,840.00   submission   1    3,840.00    
Review and submission of CTA to MHRA (including submission of responses to any queries raised during review period)   3,840.00   submission   1    3,840.00    
Submission of  Substantial Amendment  to MHRA   120.00   hour   38    4,560.00   12 hours Amen1: 8 hours Ament 2 ; 16 hours Amen 3 :12 hours amendment 4
Submission to National Ethics Committee in Northern Ireland  (including submission of responses to any queries raised during review period)   2,040.00   submission   1    2,040.00    
Submission to National Ethics Committee in Northern Ireland (including submission of responses to any queries   2,720.00   submission   1    2,720.00    
Preparation and submission of substantial amendments to National Ethics Committee in Northern Ireland   880.00   submission   12    10,560.00    
Preparation and submission of non substantial amendments to National Ethics Committee in Northern Ireland   220.00   submission   25    5,500.00    
Management of R&D Office Approval, including budget negotiation   1,760.00   site   1    1,760.00    
Submission fo R&D Office Amendment including revised budget negotiaition for QMUH   880.00   site   1    880.00    
Regulatory total                35,700.00    
Clinical Operations                     
Site Qualification Visits   680.00   site   10    6,800.00   Site Visit preparation time for pre study visits  -  2 hours. Site Visit preparation time for SIV and close out visit - 4 hours. Site Qualification and Pre study visit duration - 4 hours. SIV and close out visit duration - 8 hours. Monitoring Visits  prep
Travel time   400.00   site   6    2,400.00    
Site Qualification Visits UK   680.00   site   4    2,720.00    
Travel time UK   600.00   site   4    2,400.00    
Pre-Study Visits   850.00   site   8    6,800.00    
Travel time Belfast   200.00   visit   1    200.00    
Travel time UK   200.00   visit   4    800.00    
Site Initiation Visits   1,360.00   site   8    10,880.00    
Travel time Belfast   200.00   visit   1    200.00    
travel time UK   200.00   visit   7    1,400.00    
                      
Study Monitoring Visits (2 day visits)   2,040.00   site   40    81,600.00    
Study Monitoring Visits (1 day visits)   1,360.00   site   16    21,760.00    
Travel time Belfast   200.00   visit   7    1,400.00    
Travel time UK   200.00   visit   49    9,800.00    
Study Close-Out Visits   1,360.00   site   8    10,880.00    
Travel time Belfast   200.00   visit   1    200.00    
Travel time UK   200.00   visit   7    1,400.00    
CRA Site Management   340.00   week   18    6,120.00   June - Sept 2014 (2 sites)
CRA Site Management   510.00   week   12    6,120.00   Oct - Dec 2014 (5 sites)
CRA Site Management   680.00   week   28    19,040.00   Jan - Aug 2015(8 sites) 1 hour per site per week
CRA Site Management   1,360.00   week   12    16,320.00   Close out period  2 hours per site per week
Project Management   2,200.00   week   70    154,000.00   Internal management of CRAs including advice on recruitment strategies, site related issues, contingency measurement implementation etc.; Communication with Kitov Ltd on project progress/study related issues; Management of Third Party Vendors; Management
CTA study conduct   320.00   week   70    22,400.00   Assistance with compilation of return of essential document for TMF, CRA travel arrangements, collation of all pass through costs and study related invoices.

 

Change order no 1

Kitov/ Java MSA

Page 4 of 5

 

 

Clinical Operations   385,640.00    
Other Services        
Clinical Laboratory Services (Estimate)        
Central Laboratory set up  Fee   5,874.00   ACM laboratory contracted directly with Kitov
Clinical Laboratory Services (Estimate) total   5,874.00    
         
Data Management and Statistics        
Biometrics Management   15,361.00    
Data Management   52,313.50    
Statistics   37,225.75    
Amendment 1-3   5,133.50    
Amendment 4   27,522.00    
eCRF management and hosting   82,148.75    
Data Management and Statistics total   219,704.50    
         
Pharmacovigilance        
Safety Database Maintenance   6,857.50    
PhV Specifications   2,910.00    
SAE Initial/Follow-up Report Processing       3600  only if  SAE
Expedite SUSARs reporting   108.00    
Line Listing production   2,440.00    
Responsible Person - Eudravigilance   8,300.00    
Pharmacovigilance total   20,615.50    
         
Medical Writing        
Clinical Study Report   14,252.00    
Medical Writing total   14,252.00    
Other Services Subtotal        
Summary        
Preparation total   84,760.00    
Regulatory total   35,700.00    
Clinical Operations total   385,640.00    
Other Services total   254,572.00    
8% overhead   20,365.76    
         
GRAND TOTAL  PROFESSIONAL FEES   781,037.76    

 

Change order no 1

Kitov/ Java MSA

 

Page 5 of 5