Exhibit 4.12
Confidential
THE SYMBOL "[****]" DENOTES PLACES WHERE PORTIONS OF THIS DOCUMENT HAVE BEEN OMIITTED PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT. SUCH MATERIAL HAS BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION
Change Order 6.1 to Clinical Services Agreement
Client’s study drug RHB-104
This Change Order 6.1 (“Change Order”) to the Clinical Services Agreement signed 15 June 2011 (“Clinical Services Agreement”), is by and among:
(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 5320 13th Avenue, Montreal, Quebec, H1X 2X8, Canada ((hereinafter "MANAGER");
WHEREAS, “SPONSOR” mandated "MANAGER" to enter into a subcontract with inVentiv Health Clinical to act as a CRO for its Study (as defined in the Clinical Services Agreement);
Is hereby made effective as of July 28, 2016 (“Effective Date”) and the parties hereby agree as follows:
1. Change Order 6.1 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, inVentiv Health Clinical will perform additional Services for Client’s study drug RHB-104, in accordance with the Summary of Changes attached hereto and incorporated herein as Exhibit A.
3. Compensation
Under this Change Order, inVentiv Health Clinical’s Professional Fees have increased by the amount of USD [****]. The total costs of the Clinical Services Agreement have increased to USD [****].
Payment due to inVentiv Health Clinical 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.
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ACCEPTED AND AGREED TO: | | |
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RedHill Biopharma Ltd. | | For 7810962 Canada |
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/s/ Dror Ben-Asher | /s/ Micha Ben Chorin | | /s/ Alain Guimond |
Name: Dror Ben-Asher | Micha Ben Chorin | | Name: Alain Guimond |
Title: CEO | CFO | | Title: V-P R&D |
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Date: August 31, 2016__________________ | | Date: 30-August-2016 |
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| Confidential | inVentivHealthclinical.com |
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.
Change Order 6.1 for 7810962 Canada Inc. /Red Hill Biopharma Ltd.
Overview of major level changes
| · | | The fee to add [****]to the DCRA team is $[****]- There are [****]hrs in the [****]month period from [****] through to [****]. The hourly rate is $[****]/hr. |
| · | | Number of DCRAs changed from [****] to [****]. |
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 those expenses listed below. inVentiv Health Clinical will invoice Client for actual costs in these areas, it being understood that any pass-through costs in excess of the amounts set out below will require the Client’s prior written approval. inVentiv Health Clinical will use its best efforts to keep actual costs 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:
11ISB001 7810962 Canada Inc., /RedHill Biopharma Ltd. 28 July 2016 | |
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| © inVentiv Health. All Rights Reserved. |
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Task | Current
(USD) | Change
Order #6.1 | Assumption Changes
influencing the
change in the budget | Additional
comments |
Site Visit Travel | $[****] | $[****] | No change | |
Investigators' Meeting Organization | $[****] | $[****] | No change | |
Kick-off Meeting Travel/Attendance | $[****] | $[****] | No change | |
Shipping/Photocopying | $[****] | $[****] | No change | |
Translation | $[****] | $[****] | No change | |
Regulatory Fees | $[****] | $[****] | No change | |
Ethics Committee Fees | $[****] | $[****] | No change | |
EDC Studies/3G Cards | $[****] | $[****] | No change | |
DSMB member fees | $[****] | $[****] | No change | |
EDC Fees (Oracle) | $[****] | $[****] | No change | |
CRA Face to Face Meeting Travel expenses | $[****] | $[****] | No change | |
Pass Through Costs | $[****] | $[****] | | |
11ISB001 7810962 Canada Inc., /RedHill Biopharma Ltd. 28 July 2016 | |
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| © inVentiv Health. All Rights Reserved. |
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| Confidential | inVentivHealthclinical.com |
1.1.2 Investigator Grants Costs
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Investigator
Grants | Current
(USD) | Change
Order #6.1 | Assumption
Changes
influencing the
change in the
budget | Additional
Comments |
| $[****] | $[****] | No Change | 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 | Current
(US Dollars) | Change
Order #6.1 | Assumption
Changes
influencing the
change in the
budget | Additional comments |
Pre-study Activities | | | | |
Case Report Form Preparation/Review | $[****] | $[****] | No change | No change |
Data Management Plan Preparation/Review | $[****] | $[****] | No change | No change |
Informed Consent Preparation/Review | $[****] | $[****] | No change | No change |
IRB/Ethics Committee Interactions | $[****] | $[****] | No change | No change |
Investigators' Meetings | $[****] | $[****] | No change | No change |
Investigator Site Contract | $[****] | $[****] | No change | No change |
Investigator Recruitment | $[****] | $[****] | No change | No change |
Project Feasibility | $[****] | $[****] | No change | No change |
Project Plan Preparation/Review | $[****] | $[****] | No Change | No change |
11ISB001 7810962 Canada Inc., /RedHill Biopharma Ltd. 28 July 2016 | |
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| © inVentiv Health. All Rights Reserved. |
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| Confidential | inVentivHealthclinical.com |
Task | Current
(US Dollars) | Change
Order #6.1 | Assumption
Changes
influencing the
change in the
budget | Additional comments |
Protocol Preparation/Review | $[****] | $[****] | No change | No change |
Randomization Schedule Preparation | $[****] | $[****] | No change | No change |
Study-Specific Form Preparation | $[****] | $[****] | No change | No change |
Training - Project-Specific | $[****] | $[****] | No change | No change |
Translations | $[****] | $[****] | No change | No change |
PROMIS | $[****] | $[****] | No change | No change |
Monitoring/Site Management | | | | |
Data Clean-up | $[****] | $[****] | No change | No change |
Investigator Grant Administration | $[****] | $[****] | No change | No change |
Laboratory Report Review | $[****] | $[****] | No change | No change |
Serious/Significant Adverse Event Management | $[****] | $[****] | No change | No change |
Site Management | $[****] | $[****] | No change | No change |
Remote Monitoring of Site Data | $[****] | $[****] | No change | No change |
Site Visits - Pre-study Visits | $[****] | $[****] | No change | No change |
Site Visits - Initiation Visits | $[****] | $[****] | No change | No change |
Site Visits - Routine Visits conducted on site | $[****] | $[****] | No change | No change |
Site Visits - Routine Visits conducted on site – Dedicated NA CRA Program-[****]CRAs | $[****] | $[****] | No change | No change |
Site Visits - Routine Visits conducted on site-Dedicated NA CRA Program-[****] CRA | $[****] | $[****] | Dedicated NA CRA Program | Adding [****] Dedicated Sr. CRA- $[****]/hr X [****]hrs ([****] hrs over a year X [****] months) |
Site Visits - Close-out Visits at each site at Study End | $[****] | $[****] | No change | No change |
Study Master File/Project File Set-up and Maintenance | $[****] | $[****] | No change | No change |
11ISB001 7810962 Canada Inc., /RedHill Biopharma Ltd. 28 July 2016 | |
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| © inVentiv Health. All Rights Reserved. |
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| Confidential | inVentivHealthclinical.com |
Task | Current
(US Dollars) | Change
Order #6.1 | Assumption
Changes
influencing the
change in the
budget | Additional comments |
Patient/Site Recruitment | $[****] | $[****] | No change | No change |
Client/CRO meeting | $[****] | $[****] | No change | No change |
Regulatory | | | | |
Regulatory Documentation Preparation/Review | $[****] | $[****] | No change | No change |
Project Management /Project Tracking | | | | |
Financial Project Management | $[****] | $[****] | No change | No change |
Project Management | $ [****] | $ [****] | No change | No change |
Project Tracking / Communications | $[****] | $[****] | No change | No change |
Vendor Management | $[****] | $[****] | No change | No change |
Data Management | | | | |
Database Archiving | $[****] | $[****] | No change | No change |
Data Cleanup (DM) | $[****] | $[****] | No change | No change |
Data Management: Database Quality Control Inspection | $[****] | $[****] | No change | No change |
Database Design | $[****] | $[****] | No change | No change |
Dictionary Coding | $[****] | $[****] | No change | No change |
Edit Check Programming | $[****] | $[****] | No change | No change |
Electronic Data Import | $[****] | $[****] | No change | No change |
Case Report Form Data/Document Transfers | $[****] | $[****] | No change | No change |
EDC Fees | $[****] | $[****] | No change | No change |
Statistical Analysis and Table Generation | | | | |
Electronic Data Transfer | $[****] | $[****] | No change | No change |
11ISB001 7810962 Canada Inc., /RedHill Biopharma Ltd. 28 July 2016 | |
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| © inVentiv Health. All Rights Reserved. |
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| Confidential | inVentivHealthclinical.com |
Task | Current
(US Dollars) | Change
Order #6.1 | Assumption
Changes
influencing the
change in the
budget | Additional comments |
Interim Analysis/Report Preparation and Review | $[****] | $[****] | No change | No change |
Statistical Analysis Plan Preparation/Review | $[****] | $[****] | No change | No change |
Table Generation | $[****] | $[****] | No change | No change |
Table/Listings Review | $[****] | $[****] | No change | No change |
Clinical Study Report | | | | |
Clinical Study Report Preparation/Review | $[****] | $[****] | No change | No change |
Team Meetings | | | | |
Project Team Meetings - Internal Meetings | $ [****] | $ [****] | No change | No change |
Project Team Meetings - Client Teleconferences | $[****] | $[****] | No change | No change |
Project Team Meetings - Kick-off Meeting | $[****] | $[****] | No change | No change |
Total Direct Costs | $[****] | $[****] | | |
Total Costs
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Category | Total Costs($) |
Current Contract
(USD) | Change in Scope # 6.1
(USD) | Revised Total
(USD) |
Pass-Through Costs | $[****] | $[****] | $[****] |
Investigator Grants Costs | $[****] | $[****] | $[****] |
Professional Fees | $[****] | $[****] | $ |
Discount | -$[****] | $[****] | -$[****] |
Revised Professional Fees | $[****] | $[****] | $[****] |
Grand Total | $[****] | $[****] | $[****] |
11ISB001 7810962 Canada Inc., /RedHill Biopharma Ltd. 28 July 2016 | |
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| © inVentiv Health. All Rights Reserved. |
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| Confidential | inVentivHealthclinical.com |
Exhibit B Payment Schedule
1. PAYMENT TERMS
A. Service Fees:
Exhibit B
inVentiv Health Clinical
Milestone Payment Schedule
7810962 Canada Inc. (11ISB001)
Milestone | Original
Agreement | CO#2 with
Discount | CO#3 with
Discount | CO#4 with
Discount | CO#5 | CO#6 | CO#6.1 | Total (USD)
with Discount | Invoice # | Invoice
Amount | Paid Amount |
Upon Execution of Contract | 250,249 | | | | | | | 250,249 | 11ISB001-001 | 250,249 | 250,249 |
Upon Execution of CO#3 | | | 904,042 | | | | | 904,042 | 11ISB001-064 | 904,042 | 904,042 |
Upon Execution of CO#4 | | | | 119,480 | | | | 119,480 | 11ISB001-065 | 119,480 | 119,480 |
Upon Execution of CO#5 | | | | | 349,419 | | | 349,419 | 0030018998 | 349,419 | 349,419 |
Upon Execution of CO#6 | | | | | | 424,093 | | 424,093 | | | |
Completion of Investigator Meeting | | | | | | | | 0 | | | |
50% of Site Initiation Visits completed | | | | | | | | 0 | | | |
Last Site Initiation Visits completed | | | | | | | | 0 | | | |
Database Release (eCRF release) to Production | | | | | | | | 0 | | | |
First Patient In US Trial | 250,249 | -250,249 | | | | | | 0 | | | |
First Patient In European Trial | 250,249 | -250,249 | | | | | | 0 | | | |
Last Patient In US Trial | 344,865 | -344,865 | | | | | | 0 | | | |
Last Patient In European Trial | 344,865 | -344,865 | | | | | | 0 | | | |
First Patient In | | 421,712 | | | | | | 421,712 | 11ISB001-034/11ISB001-042 | 421,712 | 421,712 |
Last Patient in | | 576,327 | 300,000 | | | | | 876,327 | | | |
| 1,440,477 | -192,189 | 1,204,042 | 119,480 | 349,419 | 424,093 | 0 | 3,345,322 | | | |
26-week Subject Treatment Period Ends: | | | | | | | | 0 | | | |
DBL for all patients completing 26-weeks completed | | 412,620 | 280,000 | | | | | 692,620 | | | |
Study Unblinded after analysis of efficacy part completed | | | | | | | | 0 | | | |
Delivery of Draft Tables, Listings and Graphs | | | | | | | | 0 | | | |
Delivery of Final Tables, Listings and Graphs | | | | | | | | 0 | | | |
Delivery of Final 26 CSR US Trial | 750,746 | -750,746 | | | | | | 0 | | | |
Delivery of Final 26 CSR European Trial | 750,746 | -750,746 | | | | | | 0 | | | |
| 1,501,492 | -1,088,872 | 280,000 | | | | | 692,620 | | | |
52-week Subject Treatment Period ends: | | | | | | | | 0 | | | |
DBL for all patients completed | | 232,364 | 200,000 | | | | | 432,364 | | | |
Delivery of Draft Tables, Listings and Graphs | | | | | | | | 0 | | | |
Delivery of Final Tables, Listings and Graphs | | | | | | | | 0 | | | |
Delivery of Final 52 CSR US Trial | 261,441 | -261,441 | | | | | | 0 | | | |
Delivery of Final 52 CSR European Trial | 261,442 | -261,441 | | | | | | 1 | | | |
Delivery of Final CSR | | 124,981 | | | | | | 124,981 | | | |
Database Lock | | | | | | | | 0 | | | |
Delivery of Draft CRF US Trial | 261,432 | 0 | | | | | | 261,432 | 11ISB001-023 | 261,432 | 261,432 |
Delivery of Draft CRF European Trial | 261,432 | -261,432 | | | | | | 0 | | | |
| 1,045,747 | -426,969 | 200,000 | 0 | 0 | 0 | 0 | 818,778 | | | |
Total Milestones | 3,987,716 | -1,708,030 | 1,684,042 | 119,480 | 349,419 | 424,093 | 0 | 4,856,720 | | 2,306,334 | 2,306,334 |
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| Confidential | inVentivHealthclinical.com |
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Quarterly Project Management Fee (10 Quarters starting June 16, 2011, ending December 15, 2013: 183,590 USD per quarter) Only Invoiced for 7 quarters | 1,835,894 | -598,157 | | | | | | 1,237,737 | See below | 1,237,737 | 1,237,737 |
Monthly Fees for Hold Period: (9 Monthlies starting April 2012, ending December 2012: 15,000 USD per month) Only Invoiced for 6 months | | 90,000 | | | | | | 90,000 | 11ISB001-017 | 90,000 | 90,000 |
Quarterly Project Management Fee: (8 Quarterly Payments starting January 2014: $173,477.50 USD per quarter) Only invoiced for 4 quarters | | 1,387,820 | -693,909 | | | | | 693,911 | See below | 693,911 | 693,911 |
Quarterly Project Management Fee: (4 Quarterly Payments starting January 2015: $244,147.50 USD per quarter) | | | 976,590 | | | | | 976,590 | See below | 976,590 | 976,590 |
Quarterly Fees for Dedicated CRA Program (4 Quarters Starting July 2016: $141,364.29 USD per quarter) | | | | | | 565,457 | | 565,457 | | | |
Quarterly Fees for Dedicated CRA Program (3 Quarters Starting July 2016: $59,985 USD per quarter) | | | | | | | 179,955 | 179,955 | | | |
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Total Milestone Payments1 | 5,823,610 | -828,367 | 1,966,723 | 119,480 | 349,419 | 989,550 | 179,955 | 8,600,370 | | 5,304,572 | 5,304,572 |
1 - Professional fees are net of the 5% discount applied to Original Agreement and CO#1-#4
Quarterly Payments | | | |
3rd Quarter 2011 | 11ISB001-002 | 183,590.00 | 183,590 |
4th Quarter 2011 | 11ISB001-006 | 183,590.00 | 183,590 |
1st Quarter 2012 | 11ISB001-008 | 183,590.00 | 183,590 |
1st Quarter 2012 (Reconciled for Amendment #1) | 11ISB001-017 & 19 | (47,393.00) | (47,393) |
1st Quarter 2013 | 11ISB001-022 | 183,590.00 | 183,590 |
2nd Quarter 2013 | 11ISB001-027 | 183,590.00 | 183,590 |
3rd Quarter 2013 | 11ISB001-032 | 183,590.00 | 183,590 |
4th Quarter 2013 | 11ISB001-032 | 183,590.00 | 183,590 |
1st Quarter 2014 | 11ISB001-042 | 173,477.50 | 173,478 |
2nd Quarter 2014 | 11ISB001-045 | 173,477.50 | 173,478 |
3rd Quarter 2014 | 11ISB001-053 | 173,477.50 | 173,478 |
4th Quarter 2014 | 11ISB001-058 | 173,478.00 | 173,478 |
1st Quarter 2015 | 11ISB001-064 | 244,147.50 | 244,148 |
2nd Quarter 2015 | 0030014002 | 244,147.50 | 244,148 |
3rd Quarter 2015 | 0030017725 | 244,147.50 | 244,148 |
4th Quarter 2015 | 0030017726 | 244,147.50 | 244,148 |
3rd Quarter 2016 | | 141,364.29 | |
4rd Quarter 2016 | | 201,349.29 | |
1st Quarter 2017 | | 201,349.29 | |
2nd Quarter 2017 | | 201,349.29 | |
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2. Pass Through Costs:
| (a) | | CO#2: Twenty percent (20%) of the average estimated expenses as set forth in the Expenses Estimate (exclusive of funds for investigator grants), totaling $[****], was invoiced upon execution of this Agreement. Prepayment for Out of Pocket Expenses (to be drawn down once paid and replenished once 75% depleted). This process to continue until the end of the study. |
| (b) | | CO#3: Twenty percent (20%) of the average estimated expenses as set forth in the Expenses Estimate (exclusive of funds for investigator grants), totaling $[****], was invoiced upon execution of this Agreement. Prepayment for Out of Pocket Expenses (to be drawn down once paid and replenished once 75% depleted). This process to continue until the end of the study. |
| (c) | | CO#4: This is a one-time payment of $[****] (exclusive of funds for investigator grants), that was invoiced upon execution of this Agreement. |
| (d) | | CO#5: This is a one-time payment of $[****] (exclusive of funds for investigator grants), that was invoiced upon execution of this Agreement. |
| (e) | | CO#6: This is a quarterly payment of [****]for ([****]) Quarters beginning with 1st payment invoiced on or after [****]. First payment invoiced on [****]. |
| (f) | | CO#6.1: This is a Quarterly payment of [****]for ([****]) Quarters beginning with 1st payment to be invoiced on [****]or upon execution of this Agreement if the executed date is later than [****]. |
| (g) | | Actual pass-through expenses, as provided in the expenses estimate, will be billed as incurred by inVentiv Health Clinical |
| (h) | | Any unused funds will be returned within ninety (90) days from the date of the final reconciliation |
3. Investigator Grants:
| (a) | | Twenty percent (20%) of the estimated total of the grant payments of the study, totaling $[****], was invoiced upon commencement of services. Prepayment for Investigator Grants (to be drawn down once paid and replenished once 75% depleted). This process to continue until the end of the study. |
| (b) | | inVentiv Health Clinical will submit invoices in advance for estimated amounts to be paid to investigators during the next quarter to ensure that adequate funds are available to pay investigator grants |
| (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 one and a half percent (1.5%) per month |
(d)All services and pass-through payments should be sent via wire or ACH
