EX-4.28 8 exhibit_4-28.htm EXHIBIT 4.28 exhibit_4-28.htm


Exhibit 4.28
 
(inc research logo)
Prana Biotechnology Limited
 
WORK AUTHORISATION
Reference: WA002 (PBT2-204)
 
This Work Authorisation is between Prana Biotechnology Limited of Level 2, 369 Royal Parade, Parkville, VIC 3052, Australia (hereinafter “Customer”) and INCResearch Australia Pty Limited ACN 080 425 387 & ABN 67 080 425 387, 124 Lipson Street, Port Adelaide 5015 SA (hereinafter “INC”) and relates to the Master Services Agreement dated 28th September 2011, (the “Master Agreement”). Pursuant to the Master Agreement, INC has agreed to provide certain services in accordance with written work authorisations, such as this one, entered into from time-to-time describing such services.
 
Study Title:
Randomised, Double-blind, Placebo-controlled, Parallel-group, Phase 2 Study to Evaluate the Effect of One Dose of PBT2 (250mg daily) for 52 Weeks on Aβ Deposition in the Brains of Patients with Mild Alzheimer’s Disease Compared to Placebo and to Evaluate the Safety and Tolerability of PBT2 (250mg daily) for 52 Weeks in Patients with Mild Alzheimer’s Disease
 
The parties hereby agree as follows:
 
1. Work Authorisation. This document constitutes a “Work Authorisation” under the Master Agreement and this Work Authorisation and the services contemplated herein are subject to the terms and provisions of the Master Agreement.
 
2. Services and Payment of Fees and Expenses. The specific services contemplated by this Work Authorisation (the “Services”) and the related payment terms and obligations are set forth in the following attachments, which are incorporated herein by reference:
 
SCOPE OF WORK
ATTACHMENT 1
PROJECT BUDGET & SCHEDULE OF PAYMENT
ATTACHMENT 2
 
3. Term. The term of this Work Authorisation shall commence on the 28th September 2011 and shall continue until 31st December 2013, unless this Work Authorisation is terminated in accordance with the Master Agreement or extended by written agreement.
 
4. Amendments. No modification, amendment, or waiver of this Work Authorisation shall be effective unless in writing and duly executed and delivered by each party to the other.
 
5. Currency Exchange. All amounts are stated in Australian Dollars (AUD). This will also be the prime currency for invoicing and payment on this project.
 
ACKNOWLEDGED, ACCEPTED AND AGREED TO:
         
Prana Biotechnology Limited
 
INCResearch Australia Limited
     
By:
-s- dianne angus  
By:
-s- garth tierney
         
Name:
Dianne Angus
 
Name:
Garth Tierney
         
Title:
Chief Operating Officer
 
Title:
General Manager
         
Date:
2 April 2012
 
Date:
18 April 2012

WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 1 of 17

 
 
Prana Biotechnology Limited
 
Attachment 1:
SCOPE OF WORK
 
1.
ASSUMPTIONS-SERVICES
   
1.1
General Assumptions

GENERAL
   
Phase
 
II
Number of Study Sites + Location
 
3 sites in Melbourne
Number of Subjects Screened
 
Not Specified
Number of Subjects Randomised
 
40
Local Study Sponsor - Australia
 
Prana
SOPs to be Used
 
INC
CLINICAL
   
Site Identification
 
Sites have been identified by Prana
Investigator Meeting (length, location)
 
1 day meeting in Melbourne
Monitoring Frequency or Total No.
 
13 one-day visits per site
Visits/Site
   
Paper or eCRF
 
Paper
No. CRF pages/Subject
 
80 pages
% SDV
 
100
Monitor Location
 
Melbourne
Project Manager
 
Prana
SAFETY REPORTING and MEDICAL MONITORING
No. (%) of SAEs Expected
 
Assume 1
SAEs Initially Reported to...
 
INC
SAE Reporting to Local Regulatory Authority
 
INC
Medical Monitor
 
Prana (INC as back up)
BIOMETRICS
   
CRF Design
 
INC
Medical Coding of Adverse Events
 
MedDra
Medical Coding Medications
 
WHO Drug
Data Entry
 
Double DE
Number of Datasets
 
25
No. of Check Programs per panel
 
7
Expected Query rate
 
7 queries per 100 pages
Laboratory data
 
Central labs: Safety data (electronic) Local labs: None
Exports
 
2 (draft and final)
Frequency of Reporting
 
Monthly Data Management Metrics
DSMC requirements
 
3 (10%, 40%, 70%)
Statistics tasks
 
Input to Protocol, Randomisation, Statistical Analysis Plan, Statistical Analyses, DSMB, Statistical Text for CSR
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 2 of 17

 
 
Prana Biotechnology Limited
 
1.2
Timelines Assumptions

Timelines
 
Start
 
End
Start-up
 
1-Oct-11
 
10-Oct-11
Recruitment
 
11-Oct-11
 
10-Jun-12
Treatment
 
11-Jun-12
 
10-Jul-13
Follow-up
 
11-Jul-13
 
10-Aug-13
Study Conduct
 
11-Oct-11
 
10-Jul-13
Close-out
 
10-Aug-13
 
10-Oct-13
Total Duration
 
1-Oct-11
 
10-Oct-13
 
In the event that any of these tasks cannot be completed by the End dates above, INC will notify the Customer immediately, providing:
 
reasons for the delay;
revised End dates;
any impact on costs; and
where any delay is caused by INC due to factors within their control, the Customer requires INC to show how any lost time can be made up.
 
The Customer acknowledges that, subject to clause 33, INC and the Customer will meet to agree any additional costs for any delays that INC can establish to, the Customer’s reasonable satisfaction are outside of the control of INC.
   
1.3
Detailed Transfer of Responsibilities

ACTIVITY
 
Customer/ Third
Party
 
INC
Study Start-up Activities
       
Study Sponsorship – Australia
 
ü
   
Protocol Development
 
ü
   
Approval and Authorisation of Final Protocol
 
ü
   
Patient Information Sheet & Consent Template Development
 
ü
   
Creation of Study Manual/Monitoring Guidelines
     
ü
List Trial on Public Register e.g. ANZCTR, Clinicaltrials.gov
 
ü
   
Conduct Internal Team Kick-Off Meeting
     
ü
Investigator/Site Identification
 
ü
   
Approval of Final Investigator’s/Sites
 
ü
   
Finalise Clinical Trial Agreements
 
ü
   
Creation and Collection of Essential Documents
     
ü
Conduct Pre-study/Site Qualification Visits
 
NA
 
NA
Complete Ethics Submissions and Follow-up
 
ü
   
Respond to Issues Raised by the Ethics Committee
 
ü
   
Regulatory Submissions (CTN)
 
ü
   
Import/Export Permit Handling
 
ü
   
Investigator’s Meeting
       
Attend Investigator’s Meeting
 
ü
 
ü
Present at Investigator’s Meeting
 
ü
 
ü
Organise Investigator’s Meeting
 
ü
   

WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 3 of 17

 
 
Prana Biotechnology Limited
 
ACTIVITY
 
Customer/ Third
Party
 
INC
Investigational Product (IP)
       
IP Packaging and Labelling
 
ü
   
IP Storage
 
ü
   
IP Distribution
 
ü
   
IP Accountability
     
ü
IP Destruction
 
ü
   
Site Visits
       
Site Initiation Visits
 
 
 
ü
Monitoring Visits
 
 
 
ü
Unblinded Monitoring Visits
 
NA
 
NA
Close-out Visits
 
 
 
ü
Completion of Visit Reports
 
 
 
ü
Site Management
       
Site Management
 
 
 
ü
Project Management
 
 
   
Project Management (Local)
 
ü
   
Project Tool Development
 
ü
   
Create Master Study Files
 
ü
   
Maintenance of Master Study Files During Study
 
ü
   
Create Investigator In-house and Site Study Files
 
ü
   
Maintain In-house Investigator Study Files During Study
 
ü
   
Manage and Make Payments to Investigators/Sites
 
ü
   
Produce/Distribute Newsletters
 
ü
   
Archiving of Study Files Post-study
 
ü
   
Safety Reporting & Medical Monitoring
       
Initial Receipt and Handling of SAEs
     
ü
Medical Review of SAEs & Narrative Creation
     
ü
Reporting to Local Regulatory Authority
     
ü
Follow-up of SAEs
     
ü
Creation and Distribution of Investigator Notification Letters
     
ü
Six-monthly SUSAR Line Listings
     
ü
Annual Update of IB or Annual Safety Report (EU
 
ü
   
Medical Monitoring
 
ü
 
ü (back up)
Biometrics
       
Data Mgt – CRF Design and Development
 
ü
 
ü
Data Mgt – CRF Approval
 
ü
   
Data Mgt – Database Design and Build
     
ü
Data Mgt – Database Consistency Check Programming
     
ü
Data Mgt – Data Validation Manual/Data Management Plan
     
ü
Data Mgt – Data Entry
     
ü
Data Mgt – Medical Coding
     
ü
Data Mgt – Quality Control
     
ü
Data Mgt – Generation of Data Queries
     
ü
Data Mgt – Delivery of Clean Verified CRFs to Customer
     
ü
Statistics – Sample Size Determination
 
ü
   

WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 4 of 17

 
 
Prana Biotechnology Limited

ACTIVITY
 
Customer/ Third
Party
 
INC
Statistics – Input to Protocol
 
ü
   
Statistics – Generation of Randomisation Schedule and Provision of Randomisation Envelopes.
     
ü
Statistics – Statistical Analysis Plan
     
ü
Statistics – Produce Tables, Figures and Listings
     
ü
Statistics – Interim Analysis
     
ü
Statistics – Analysis and Reporting
     
ü
Medical Writing
       
Provision of Top Line Data/results 4 weeks post database lock
     
ü
Provision of draft Clinical Study Report 7 weeks post database lock
     
ü
Provision of final Clinical Study Report 10 weeks post database lock
     
ü
 
Service & Expense Assumptions are as per agreed Proposal and Cost Estimate, version 5, dated 15th September 2011.
 
Study Start up and Document Management
     
Study training/kick-off/familiarisation is included to train the project team on the following:-
 
Protocol
 
Investigators’ Brochure
 
Therapeutic Area Training (by INC’s Chief Medical Officer whose time is a value add service not charged to our Customers)
 
SOPs
  CRF
 
Monitoring Guidelines
 
An internal INC kick-off meeting will be held via teleconference at the beginning of the project for all members of the INC study team.
   
Customer kick-off meeting: The Customer will provide training for the CRA(s)/study team on the following;
Study protocol
Investigational product
CTMS (if applicable)
Relevant client procedures or plans
 
(Amount of time to be discussed and agreed between INC and the Customer).
   
A Study Manual/Monitoring Manual will be produced for this study. This may include explanations of the following, but will vary depending on the Customer’s and the study requirements; applicable SOPs, communication procedures, initiation and monitoring visit procedures and reporting, source document verification (SDV) guidelines, protocol violation procedures, AE and SAE recording, concomitant medication recording, screen failures, withdrawals and early termination visits, investigational product (IP) handling, query resolution.
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 5 of 17

 

Prana Biotechnology Limited
   
Clinical Trial Notification (CTN) Handling – Prana will complete all forms and arrange submission of the regulatory applications to the relevant health authorities Therapeutic Goods Administration.
   
Ethics committee submissions includes Pl/consent customisation, completion of application, coordination of copies, coordination of any follow up required. Prana will be responsible for this task.
   
A 1.5 day Investigator’s meeting is scheduled in 2011, which will be organised by Prana. This will include a session for training the INC team.
   
Limited time has been allocated for the preparation of presentations. This will be a shared responsibility between the Customer and INC. Additional time may be required depending on the nature of the presentations that INC is required to develop.
   
Study Conduct and Monitoring
   
Study initiation visits include visit preparation, time on site, report completion after visits, follow-up correspondence with sites, post visit document handling and issue resolution.
   
Monitoring Visits
 
It has been calculated that 39 monitoring days onsite will be required. This calculation is based on 40 patients, 100% SDV and an 80 page CRF. This assumes that it is possible to monitor an average of 85 CRF pages/day. It has been assumed that monitoring visits includes visit preparation, time on site, report completion after visits, follow-up correspondence with sites, post visit document handling and issue resolution.
   
Due to the varying rates of enrolment across sites, the INC Project Manager will have the discretion to reallocate monitoring visits across and between all sites as required. The number of monitoring visits will be assessed on an ongoing basis to determine if more or less monitoring visits are required. This will be discussed and agreed with the Customer on an ongoing basis.
   
Close-out visits includes visit preparation, time on site, report completion after visits, follow-up correspondence with sites, post visit document handling and issue resolution.
   
CRA site management includes: ongoing communications with study sites, regular contacts with site between visits, communications with the Project Manager and the Customer, issue resolution between visits, management of study files and liaison with data management.
   
Project Management
   
Project Management will be handled by Prana.
   
Teleconferences - It has been assumed that there will be monthly teleconferences for the project team for the period (October 2011 – October 2013).
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
 
Page 6 of 17

 
 
Prana Biotechnology Limited
 
Safety Reporting and Medical Monitoring (Optional Service)
   
SAE reporting process (To be confirmed).
 
SAEs will be reported directly to INC. INC will then conduct a medical review of the SAE and provide a final report to Prana. INC will be responsible for reporting the SAE to the local regulatory authorities.
   
For the purposes of this proposal, it has been assumed there will be a total of 1 SAE during the course of the trial which is reportable event. There will be 1 SAE Follow up. This provides a unit cost, in the case that there are more SAEs/reportable events and/or follow-ups these will be billed to Prana.
   
The INC Safety Officer will be responsible for the development of a study specific SAE Flow Chart. This will involve liaison with Prana’s Safety Officer or Department.
   
Safety administration – includes familiarisation, set-up, correspondence, tracking, customer liaison, filing, study completion and archiving and has been estimated from October 2011 – July 2013.
   
Investigator notification letters – Includes preparation and oversight
   
The Medical Monitor will be provided by Prana. If required INC can provide a Medical Monitor on a retainer for an additional monthly fee, this will include professional advice in relation to inclusion/exclusion criteria, therapeutic area and review and narrative creation of SAEs.
 
Data Management
 
CRF Design
INC will design the CRF using the final protocol and its associated schedules and employing INC’s set of standard pages combined with any example CRF pages provided by the client. Modules of the CRF will be drafted and once agreed will be replicated according to the study visit schedule to form the complete book. When the complete book is assembled navigation prompts will be added to form the final CRF.
 
The CRFs will be printed as 3 part NCR to provide for original, data management and site copies.
 
Database Design and Build
A database will be designed employing an annotated CRF which will detail on a blank CRF all database fields, code lists and database structures. This will be presented to the client in PDF format for approval prior to commencement of database build. The design of the database will be to INC internal database standards or CDISC (conversion to be costed).
 
INC will perform all necessary programming tasks, including developing and testing the database modules, data entry screens and code lists. The database will be maintained until conclusion and archive of the study.
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 7 of 17

 
 
Prana Biotechnology Limited
 
Data Validation Manual (DVM)
INC will prepare a Data Validation Manual. This will include detailed descriptions in the following categories, as applicable for the project:
   
CRF tracking and filing guidelines
Data entry guidelines
Pre-review guidelines
List of electronic edit checks to be performed
List of self-evident corrections and abbreviations
Electronic data integration plan
Local safety laboratory data handling procedures
Medical coding guidelines
Serious adverse event reconciliation guidelines
Quality control plan
Query reconciliation plan
 
The Data Validation Manual will be forwarded to the Customer for authorization prior to the commencement of data processing for the study.
 
Consistency Check Programming
After the Data Validation Manual has been authorized INC will develop the consistency check programs. Programs will check for problems with structural integrity, missing data, the logical consistency of data and the reasonability of data against set upper and lower ranges. In addition, listings will arrange data in convenient order so that cross checks of adverse events and other study data can be conducted as a back up to the CRA’s manual review.
 
Approximately 140 electronic CRF consistency checks as agreed with the Customer will be programmed. In addition 35 structural checks and manual listings will be programmed as required.
 
For appropriate checks (specified in the Data Validation Manual), output will be produced in the form of data query forms ready for review by the Clinical Data Associate. For others the output will be in the form of discrepancy listings which will be reviewed in full by the Clinical Data Associate.
 
All programming will be fully QC’d and validated using data entered into a test database prior to the programs being applied to the production databases.
 
Data Entry
Prior to data entry the completed CRF pages will be pre-coded (as defined in the data validation guidelines) by INC to allow efficient and timely entry of the data. The data will then be entered into the project database using validated data entry guidelines. The data entry will be via the entry and verification technique. This will involve entry by two independent data entry clerks.
 
Electronic Data
Electronic data for the study will be identified. For this project safety data is expected.
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 8 of 17

 
 
Prana Biotechnology Limited
 
During the database setup process a data transfer specification will be prepared for each electronic source of data. This will describe the agreed format of the data to be transferred, the frequency, the data structure and whether partial or cumulative transfers are expected. The transfer plan will be signed off by INC and the third party supplier. INC will seek one test transfer of data from the supplier and confirm that the data is being transferred in the agreed format prior to production transfers being received.
 
Upon receipt of electronic data INC will check the file for structural integrity and cross check it with relevant CRF data. Any discrepancies found will be queried for resolution with the supplier and/or the investigator.
 
Query Management
Upon successful entry of the data consistency checks will be run regularly across the database. We will review the data for completeness, logical consistency and reasonability of numeric values. We will also perform a manual review of key safety data – particularly adverse events and medications. Any discrepancies found will assessed and where necessary data queries issued. All queries will be provided to clinical operations for resolution with the study site.
 
All queries will be uniquely numbered and tracked electronically. On receipt of resolved queries, the Clinical Data Associate will update the query log, then, edit the database and CRF as appropriate.
 
Computer generated query resolution is an ongoing process that begins when the first CRF is received and processed, and continues through to study completion.
 
Medical Coding
Medical coding of adverse events will be conducted employing the MedDRA 14.0 coding dictionary. Coding of medications will be conducted using the WHO drug dictionary Q2, 2010.
 
Auto-encoders will be created for the study to code all unique adverse event terms and medications. This means that common terms are coded directly from the dictionary and repetitive terms only need to be coded once. Coding commences with the clarification of any unclear adverse event or medication terms. This may involve the use of data queries. When all terms are clear the medical coder will undertake the medical coding utilizing the auto-encoder. After events and medications are coded listings of coded items are submitted for medical review and any miscoding updated. Clients may also be involved in this review process according to their preference.
 
Quality Control
Patient’s data will be checked according to the QC plan which will be fully detailed in the Data Validation Manual. For this study it is proposed that 100% of CRF pages be compared to the database for 10% of the patients. In addition a 100% QC of all critically defined data will be conducted as patients become frozen awaiting lock.
 
Database Lock
At the end of data processing, when all queries have been resolved and SAE reconciliation completed the database will be frozen. Before the database lock a final error rate will be calculated. If above 0.1% then an additional 10% of data will be QC’d and the error rate recalculated. If the error rate is still above 0.1 then 100% of the data is QC’d. When the QC has been satisfactorily completed and authorization has been received from the Customer, the database will be locked.
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 9 of 17

 
 
Prana Biotechnology Limited
 
Statistics
 
A randomization schedule will be generated programmatically and provided as a master list to authorized personnel. Individual subjects’ blind break envelopes will be provided to the PI.
 
A draft Statistical Analysis Plan (SAP) will be prepared in accordance with SOPs and will include specifications for all tables, listings and figures to be produced. This will also detail how the study population will be defined for the study and how key efficacy and safety data will be analysed.
 
The Customer will review the draft SAP and any feedback/review will be incorporated into the final analysis plan, which will be approved by the Customer prior to the statistical analysis.
 
After the SAP is finalized the analysis datasets will be defined and programmed.
 
After database lock a review of the data and protocol violations will be conducted and patients allocated to the study populations applicable for the study.
 
The study blind will be broken and we will perform the SAS programming and QC processes and produce the agreed tables, listings and figures.
 
The statistician will analyse the data using the methods agreed in the SAP; determine the statistical results for the study, and provide text for inclusion in the study report.
 
A maximum of 35 tables (15 unique and 20 repeat formatted tables), 35 associated listings, 0 figures and 10 analysis endpoints are budgeted using SAS V9.2.
 
A Data Safety Monitoring Committee will meet after approximately 10%, 40% and 70% of total study treatment has occurred. It is anticipated that listings as described in the SAP for the final analysis will be able to be produced for these meetings. However extra programmed listings can be provided (as required) according to the unit cost of listings in the study budget.
 
At the end of the study INC will prepare a final statistical package including:
   
Final Statistical Analysis Plan
Tables, figure, and listings, in an industry-common electronic format, such as SAS, Adobe PDF or Microsoft Word, that will be mutually agreed upon prior to the transfer.
A summary and list of protocol deviations and other anomalies known to INC staff.
 
INC will provide the transfer on CD-R media
 
Medical Writing (Optional Service)
   
The final Clinical Study Report (CSR) for this study will be to International Conference on Harmonisation (ICH) format taking into account any relevant guidelines. The expected length of the report is 30-40 pages of prepared text plus tables and listings as appendices.
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
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Prana Biotechnology Limited
 
We assume one review cycle (i.e., an initial draft report is prepared for client review and following receipt of Customer comments a final report can be issued).
   
We assume that the final report is delivered to the customer in an electronic format.
   
Prana may wish to include an optional of 8 hours QA review. A quality control check is automatically incorporated.
   
Additional services (e.g., full electronic compilation) can be provided at additional cost
 
It is only possible to provide estimates for Medical Writing services at this stage. We will discuss specific requirements with Prana so that we can that we can tailor our services to meet the Prana’s needs. Due to the nature of Medical Writing the time required to complete a project depends on a number of factors including the CSR template to be used, the length of a document, the complexity of the study, the nature of the study results and the amount of supporting literature provided by the Customer.
 
The CSR can be developed using a client-provided CSR template if requested by the client but the use of INC’s CSR template has been costed in this proposal.
 
Expense Assumptions
 
INC will always obtain the best possible prices to minimise expenditure. Expenses are invoiced separately on a pass through basis and relevant receipt copies are always included, except for general expenses, as outlined below. All amounts specified are in Australian dollars.
 
Customer Project Team Meeting
   
INC assumes that the Customer Project Kick-off meeting will be held in Melbourne, and therefore, there will be no travel expenses.
   
Investigator’s Meeting Expenses
   
An Australian investigator meeting will be held in Melbourne.
   
Travel Related Expenses (Airfares/Accommodation/Taxis)
   
As all monitoring will be regionalised there are no travel related expenses for site visits.
   
Site Visit Expenses (Parking/Meals/Tolls/Incidentals)
   
An allowance of $50 per day has been estimated for site visits.
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
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Prana Biotechnology Limited
 
General Expenses/Other
   
Costs related to couriers, and teleconference call will be passed though at cost.
   
A general expense has been calculated to include photocopying (excluding ethics submission copying), stationery (files), express post costs, standard postage and communications (excluding teleconferences). This will be billed at a set rate for the duration of the study.
   
CRF printing – this has been estimated at $2,500, assuming this will be on 3 part no-carbon required (NCR) paper.

WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 12 of 17

 


Prana Biotechnology Limited
 
Attachment 2:
 
PROJECT BUDGET & PAYMENT SCHEDULE
 
1. 
PAYMENT SCHEDULE AND INVOICING
 
Goods and Services Tax (GST)
In Australia all goods and services are subject to GST of 10%. Unless otherwise specified, fees are expressed as exclusive of Goods and Services Tax (GST). Where fees are GST exclusive and INC is liable to pay GST in respect of any Services provided pursuant to this Agreement, INC may add the GST amount to invoices provided to Customer for the Services. Provided that the relevant invoice complies with the requirements of a tax invoice to enable Customer to claim a credit or refund of GST, Customer shall pay the GST amount at the same time and in the same manner as other amounts invoiced under this Agreement.
 
Where the services are directly contracted by an overseas Customer GST will not be applicable.
 
All Clinical Services will be on a unit basis comprising of fixed units (e.g. File Management, Site Management and Management/Supervision) which will be invoiced monthly at the fixed cost as per the Cost Sheet and variable units (e.g. Site Visits), which will be invoiced according to actual number of units incurred each month.
 
Data Management/Statistics and Medical Writing will be invoiced on a milestone basis.
 
A percentage of the contract value will be payable upfront upon execution of the Work Authorisation.
 
If services requirements exceeding those specified in the cost estimate are required then written approval will be obtained from the Customer before conducting the additional services.
 
INC will invoice the Customer for Data Management/Statistics/Medical Writing according to the following schedule:
 
 
Execution of agreement
20%
 
Database Complete
20%
 
100% data entered
20%
 
Data base Lock
20%
 
1st Draft Study Report
10%
 
Final Study Report
10%
 
INC will invoice the Customer for provision of services on a monthly basis. This will include any service units incurred during the previous month.
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
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Prana Biotechnology Limited
 
All Professional Services have been adjusted to take into account standard fee reviews that would occur over the period of the trial. If the timelines extend beyond the period estimated then INC may increase fees beyond the period stated and any additional costs will be prior approved in writing by the Customer.
 
Disbursements will be invoiced separately on a monthly basis and will include copies of receipts where relevant.
 
Payment will be due within 30 days of date of invoices.
Invoices will be submitted to the following E mail address:
 
Email:
krowe@pranabio.com
Cc:
Peneamor@bigpond.net.au and dangus@pranabio.com
 
Attention:    Kerry Rowe
 
Payment will be made by electronic transfer as follows:
 
Bank Name: Bank of South Australia (A Division of St George Bank Limited)
 
Swift Code:
 
BSB (Routing Number):
 
Account Number:
 
Account Name: INCResearch Australia Pty Limited
 
2. 
CONTACTS & COMMUNICATION
 
The key Customer contact person for project related issues, contract and financial issues is Pene Amor. The key contact for INC for project related matters is Belinda Fricke. The key contact for contract related matters is Garth Tierney.
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
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Prana Biotechnology Limited
 
4.1    Budget- Services

Service/Item
 
Comments
 
Responsibility
 
Unit
 
Unit Cost
 
Number
of Units
 
Item Cost
 
AUD$
Study Start Up Activities
                           
Study Training/ Internal Kick Off Meeting
 
Familiarisation, Protocol. IB, CRF, procedures etc.
 
CRA
 
per CRA
 
1080
 
1.00
 
1,080
 
Essential document collection
 
Creation, Collection and tracking
 
CRA
 
per site
 
1350
 
3.00
 
4,050
   
Study Manual/Monitoring Manual Development
     
Med Writer / PM
 
per manual
 
3100
 
1
 
3,100
   
Study Files
 
Set up of study master files and Investigator site files
 
PA
 
per study
 
720
 
1.00
 
720
   
File Management
 
per month
 
PA
 
per month
 
283
 
24.00
 
6,787
   
                       
Subtotal
 
$15,737
Customer Project Team Meetings
                           
Teleconference participation
 
25 x 1 hour Telecon, 1 CRAs
 
CRA
 
per telecon
 
138
 
25.00
 
3.450
   
                       
Subtotal
 
$3,450
Investigator’s/Monitor’s Meeting
                           
Preparation of Presentations
 
Trident & Customer shared responsibility
 
CRA
 
per meeting
 
1620
 
1.00
 
1.620
   
Attendance
 
assume 1 day meeting, 1 CRA
 
CRA
 
per CRA
 
1080
 
1.00
 
1,080
   
                       
Subtotal
 
$2,700
Site Visits
                           
Study Initiation
 
Incl. prep, travel, on-site, reporting & follow-up
 
CRA
 
per visit
 
1620
 
3.00
 
4,860
   
Monitoring Visits (1 Day visits)
 
Incl. prep, travel, 1 day on-site, reporting & follow-up 13 visits/site
 
CRA
 
per visit
 
1932
 
39.00
 
75,348
   
Closeout visits
 
Incl. prep, travel, on-site, reporting & follow-up
 
CRA
 
per visit
 
2070
 
3.00
 
6,210
   
                       
Subtotal
 
$86,418
Site Management
                           
Site Management (October 2011 - July 2013)
 
per month
 
CRA
 
per month
 
1780
 
22.00
 
39,164
   
Site Management (August 2013 - September 2013)
 
per month
 
CRA
 
per month
 
828
 
2.00
 
1,656
   
Management/Supervision
 
per month
 
Management
 
per month
 
340
 
24.00
 
8,160
   
                       
Subtotal
 
$48,980
Safety Monitoring
                           
Safety Administration
 
Incl. set up, maintenance and completion activities
 
Safety Officer
     
3979
 
1.00
 
3,979
   
Initial Receipt and handling SAEs
 
All events - assume 1 SAE
 
Safety Officer
 
per SAE
 
330
 
1.00
 
330
   
Medical Review of SAEs and Narrative creation
 
Optional - as required
 
Medical Monitor
 
per SAE
 
838
 
0,00
 
0
   
Reporting to local Authorities
 
Assume 1 Reportable events
 
Safety Officer
 
per SAE
 
660
 
1.00
 
660
   
Follow up of SAEs
 
Assume 2 hours/Follow-up/SAE, 1 Follow-ups
 
Safety Officer
 
per follow-up
 
330
 
1.00
 
330
   
Investigator Notification Letters
 
preparation and oversight
 
Safety Officer
 
per letter
 
165
 
1.00
 
165
   
Med Monitor Retainer (June 12 - Oct 13)
     
Medical Monitor
 
per month
 
419
 
16.00
 
6,704
   
                       
Subtotal
 
$12,167
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 15 of 17

 
 
Prana Biotechnology Limited
 
 Service/Item  
Comments
 
Responsibility
 
Unit
 
Unit Cost
 
Number
of Units
 
Item Cost
 
AUD$
Data Management & Statistics
                           
CRF Design
 
25 unique pages. 80 pages of CRF and 11 pages of questionnaire. 91 Total pages.   One print run.
 
Data Operations Assoc Manager
 
1 study
 
14520
 
1.00
 
14,520
   
Database design and build
     
DBA/CDA
 
1 Data set
 
463
 
25.00
 
11,563
   
Database / Consistency Check programming
     
DBA/CDA
 
1 Check
 
53
 
208.25
 
11,114
   
Data Validation Manual / Data Management Plan
     
CDA
 
1 DVM/DMP
 
3400
 
1.00
 
3.400
   
Data entry
 
Double Data Entry 40 patients × 80 CRF pages plus 40 × 11 questionaires=3640 total pages. Cost per extra page=5.87
 
DE
 
1 page
 
6
 
3640.00
 
21,385
   
Medical Coding
 
MedDRA - AE, WHO - Drug
 
DBA/CDA
 
1 Coded term
 
6
 
800.00
 
5,036
   
Data Cleaning / Monitoring
 
3200 CRF pages. Cost per extra page=$5.10                  224 Queries.
Cost per extra query=$42.50
 
CDA
 
1 study
 
29617
 
1.00
 
29,617
   
Quality Control
 
10% of all patients, 100% of all critical data   (15% critical / 85% non critical)
 
CDA
 
1 page
 
3
 
811.40
 
2,391
   
Import laboratory data
 
1 central lab
 
DBA/CDA
 
1  study
 
3680
 
1.00
 
3,680
   
Data exports
 
Assume 2 exports
 
DBA
 
1  export
 
360
 
2.00
 
720
   
Database maintenance
 
Study Duration = 18 months
 
DBA
 
1  month
 
0
 
18.00
 
4,320
   
DM & Statistics - Project Management
 
Client meetings & corresp, DM metrics. 1hrs/month x 18 months
 
DM
 
1 month
 
120
 
18.00
 
1,530
   
Input to protocol
 
Text and sample size calcualtion / power
 
Statistician
 
1 hour
 
200
 
4,00
 
800
   
Generation of Randomisation schedule
 
1 Schedule.     40 Envelopes. Cost per
 
Statistician
 
1
 
1175
 
1.00
 
1,175
   
Statistical Analysis Plan
 
Includes text and table and Isting shells
 
Statistician
 
1 Statistical
 
5840
 
1.00
 
5,840
   
Identify Protocol Deviations and define Analysis
 
Unblinding, Protocol deviations and
 
Statistician
 
1 study
 
1600
 
1.00
 
1,600
   
Analysis Datasets
 
Specification, Programming   & QC
 
SAS Programmer
 
1 study
 
4800
 
1.00
 
4,800
   
Production of Tables & Listings
 
15 Unique tables.   Cost per extra $720 20 Repeat tables. Cost per extra $240 0 Figures. Cost per extra S420 35 Listings. Cost per extra S300
 
SAS Programmer
 
1 study
 
26100
 
1.00
 
26,100
   
Statistical Analysis
 
10 analysis endpoints. Cost per extra $400
 
Statistician
 
1 analysis endpoint
 
400
 
10.00
 
4,000
   
Provision of data to DSMB
 
Assumes interim running and QC of  6 TFLs in row ‘Programming Tables and listings.
 
Statistician
 
1  meeting
 
960
 
3.00
 
2,880
   
Input to Final report
 
Text for inclusion in study report.
 
Statistician
 
1  hour
 
2400
 
1.00
 
2,400
   
                       
Subtotal
 
$158,869
Medical Writing (Optional)
                           
Clinical study report (CSR)
     
Medical Writer
 
per CSR
 
22497
 
1.00
 
22,497
   
QA review of CSR
 
Optional for Client
 
Medical Writer
 
per CSR
 
2769
 
1.00
 
2,769
   
                       
Subtotal
 
$25,266
                             
                       
TOTAL
 
$353,588
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 16 of 17

 
 
Prana Biotechnology Limited
 
4.2    Budget- Expenses

Expense/Item
 
Comments
 
Unit Cost
 
Number
of Units
 
Item Cost
AUD$
 
AUD$
Site Visits
                   
Other Site visit Costs
 
Parking/tolls/meals and incidentals for site visits
 
$50/day
 
45.00
 
2,250
   
               
Subtotal
 
$2,250
General Expenses
                   
General Expenses - Couriers, Postage, Telecommunications, Copying, stationery (files)
 
$70/site/month, 3 sites for 25 months
 
$210/month
 
25
 
5,250
   

CRF Printing
     
$2,500
 
1
 
2,500
   
               
Subtotal
 
$7,750
                     
               
TOTAL
 
$10,000
 
WA002 PBT2-204 (800089) V4, 2nd April 2012
 
 
 
Page 17 of 17

 
 
27 June 2012
 
(inc research logo)
 
  
1st Amendment to Work Order # 800089 (PBT2-204)
 
This 1st Amendment to Work Order (hereinafter Work Order) is between Prana Biotechnology Limited (hereinafter Sponsor) with principal offices located at Level 2, 369 Royal Parade, Parkville, VIC 3052, Australia and INCResearch Australia Pty Limited, together with its parent company, subsidiaries and legal affiliates (hereinafter INC Research) with offices located at 124 Lipson Street, Port Adelaide SA 5015 Australia and relates to the Master Services Agreement effectively dated 28th September 2011 which expressly incorporates this Work Order hereto by reference into the Master Services Agreement. Pursuant to the Master Services Agreement, INC Research has agreed to perform certain services in accordance with written work orders, such as this one, entered into from time to time describing such services.
 
Study Title:
Randomised, Double-blind, Placebo-controlled, Parallel-group, Phase 2 Study to Evaluate the Effect of One Dose of PBT2 (250mg daily) for 52 weeks on Ab Deposition in the Brains of Patients with Mild Alzheimer’s Disease Compared to Placebo and to Evaluate the Safety and Tolerability of PBT2 (250mg daily) for 52 weeks in Patients with Mild Alzheimer’s Disease
 
The parties hereby agree as follows:
 
Amendment Summary:
 
Agreement
 
Details
Original Agreement
 
WA002
Date of Original Agreement
 
Version 4, doted 2nd April 2012
Amendment number
 
Amendment #1
Version & Date of Amendment
 
Version 2, doted 27th June 2012
Project ID (INC internal code)
 
800089
Client
 
Prono Biotechnology Limited
Client Project Code
 
PBT2-204
Description of Amendment
   
Additional 2 sites – RMH and Geelong Private
     
1 additional CRA
     
Reduction in 1 day Monitoring visits
     
Addition of 2 day Monitoring visits
     
Deletion of Medical Monitor retainer
     
Site Management adjustment
 
Prana 800089 (PBT2-204) version 2, 27th June 2012 
 
 
 
Page 1 of 6

 
 
Costs Implication for Amendment
 
Direct Costs (Services)
     
Study Training for additional 1 CRA @  $540/CRA = $540.00
     
Additional 2 Sites Essential Document Collection @ $1350/site = $2,700.00
     
Additional 14 months File Management  for 2 new sites @ $283/month = $3,959.00
     
16 x 1 hour Teleconference participation  for additional 1 CRA @ $138/telecom = $2,208.00
     
2 additional Study Initiation Visits @ $1620/visit = $3,240.00
     
Reduction of 19 x 1 day monitoring visits @ $1932/visit = -$36,708.00
     
15 x 2 day monitoring visits @ $3174/visit = $47,610.00
     
2 additional Close out Visits @ $2070/visit = $4,140.00
     
Addition of 2 months of Site Management for 1 site @ $593.50/month = $1,187.00
     
Addition of 6 months of Site Management for 2 sites @ $1187/month = $7,121.00
     
Reduction in 8 months of Site Management of 3 sites @ $1780/month = -$14,240.00
     
12 months Site Management for 2 new sites @ $1187/month = $14,242.00
     
2 months Site Management for 2 new sites @ $552/month = $1,104.00
     
Deletion of Medical Monitor retainer =  -$6,704.00
        -    Total Cost $30,398.00
   
Indirect Costs (Expenses)
     
15 days of additional Other Site Visit costs @ $50/day = $750.00
     
Additional General Expenses for 2 new sites for 16 months @ $140/month = $2,240.00
        -    Total Cost = $2,990.00
Total Cost Implication for Amendment
 
$33,388.00
 
Prana 800089 (PBT2-204) version 2, 27th June 2012 
 
 
 
Page 2 of 6

 
 
Budget Summary:
 
Work Order
 
Services
 
Expenses
 
Total
Contract
Original Work Order
 
$353,588.00
 
$10,000.00
 
$363,588.00
Amendment #1
 
$30,398.00
 
$2,990.00
 
$33,388.00
Revised Contract Value
 
$383,986.00
 
$12,990.00
 
$396,976.00
 
Details of Amendment 1
 
Assumption - General Services
 
GENERAL
Phase
II
Number of Study Sites + Location
5 sites in Melbourne
Number of Subjects Screened
Not Specified
Number of Subjects Randomised
40
Local Study Sponsor Australia
Prana
SOPs to be Used
INC
CLINICAL
Site Identification
Sites have been identified by Prana
Investigator Meeting (length, location)
1 day meeting in Melbourne
Monitoring Frequency or Total No. Visits/Site
4 x 1 day visits and 3 x 2 day visit per site
Paper or eCRF
Paper
No. CRF pages/Subject
80 pages
% SDV
100
Monitor Location
Melbourne x 2
Project Manager
Prana
SAFETY REPORTING and MEDICAL MONITORING
No. (%) of SAEs Expected
Assume 1
SAEs Initially Reported to...
INC
SAE Reporting to Local Regulatory Authority
INC
Medical Monitor
Prana (INC as back up)
BIOMETRICS
CRF Design
INC
Medical Coding of Adverse Events
MedDra
Medical Coding Medications
WHO Drug
Data Entry
Double DE
Number of Datasets
25
No. of Check Programs per panel
7
 
Prana 800089 (PBT2-204) version 2, 27th June 2012 
 
 
 
Page 3 of 6

 

Expected Query rate
7 queries per 100 pages
Laboratory data
Central labs: Safety data (electronic)
Local labs: None
Exports
2 (draft and final)
Frequency of Reporting
Monthly Data Management Metrics
DSMC requirements
3 (10%, 40%, 70%)
Statistics tasks
Input to Protocol, Randomisation, Statistical Analysis Plan, Statistical Analyses, DSMB, Statistical Text for CSR
 
Amendment 1 to Budget Services
 
Service/Item
 
Comments
 
Responsibility
 
Unit
 
Unit Cost
 
Number of Units
 
Item Cost
 
AUD$
Study Start Up Activities
 
 
                       
Study Training/ Internal Kick Off Meeting
 
Familiarisation, Protocol, IB, CRF, procedures etc.
 
CRA
 
per CRA
 
1080
 
1.00
 
1,080
   
Study Training
 
Familiarisation etc.
 
CRA
 
per CRA
 
540
 
1.00
 
540
   
Essential document collection
 
Creation, Collection and tracking
 
CRA
 
per site
 
1350
 
5.00
 
6,750
   
Study Manual/Monitoring Manual Development
 
 
 
Med Writer / PM
 
per manual
 
3100
 
1
 
3,100
   
Study Files
 
Set up of study master files and Investigator site files
 
PA
 
per study
 
720
 
1.00
 
720
   
File Management
 
per month
 
PA
 
per month
 
283
 
24.00
 
6,787
   
File Management - 2 new sites
 
per month from August 2012
 
PA
 
per month
 
283
 
14.00
 
3,959
   
 
 
 
                 
Subtotal
 
$22.937
Customer Project Team Meetings
 
 
                       
Teleconference participation
 
25 x 1 hour Telecon, 1 CRAs
 
CRA
 
per telecon
 
138
 
25.00
 
3,450
   
Teleconference participation
 
16 x monthly hour Telecon, 1 CRA
 
CRA
 
per telecon
 
138
 
16.00
 
2,208
   
 
 
 
                 
Subtotal
 
$5,658
Investigators Monitor’s Meeting
 
 
                       
Preparation of Presentations
 
Trident & Customer shared responsibility
 
CRA
 
per meeting
 
1620
 
1.00
 
1,620
   
Attendance
 
assume 1 day meeting, 1 CRA
 
CRA
 
per CRA
 
1080
 
1.00
 
1,080
   
 
 
 
                 
Subtotal
 
$2,700
Site Visits
 
 
                       
Study Initiation
 
Incl. prep, travel, on-site, reporting & follow-up
 
CRA
 
per visit
 
1620
 
5.00
 
8,100
   
Monitoring Visits (1 Day visits)
 
Incl. prep, travel, 1 day on-site, reporting & follow-up 4 visits/site
 
CRA
 
per visit
 
1932
 
20.00
 
38,640
   
Monitoring Visits (2 Day visits)
 
Incl. prep, travel, 2 days on-site, reporting & follow-up 3 visits/site
 
CRA
 
per visit
 
3174
 
15.00
 
47,610
   
Closeout visits
 
Incl. prep, travel, on-site, reporting & follow-up
 
CRA
 
Per visit
 
2070
 
5.00
 
10,350
   
 
 
 
                 
Subtotal
 
$104,700
Site Management
 
 
                       
Site Management (October 2011 - Nov 2011)
 
1 site
 
CRA
 
per month
 
593
 
2.00
 
1,187
   
Site Management (Dec 2011 - May 2012)
 
2 sites
 
CRA
 
per month
 
1187
 
6.00
 
7,121
   
Site Management (June 2012 - July 2013)
 
3 sites
 
CRA
 
per month
 
1780
 
14.00
 
24,923
   
Site Management (August 2012 - July 2013)
 
per month - 2 new sites
 
CRA
 
per month
 
1187
 
12.00
 
14,242
   
Site Management (August 2013 - September 2013)
 
3 sites
 
CRA
 
per month
 
828
 
2.00
 
1,656
   
Site Management (August 2013 - September 2013)
 
per month - 2 new sites
 
CRA
 
per month
 
552
 
2.00
 
1,104
   
Management/Supervision
 
per month
 
Management
 
per month
 
340
 
24.00
 
8,160
   
 
 
 
                 
Subtotal
 
$58,392
Safety Monitoring
 
 
                       
Safety Administration
 
Incl. set up, maintenance and completion activities
 
Safety Officer
     
3979
 
1.00
 
3,979
   
Initial Receipt and handling SAEs
 
All events - assume 1 SAE
 
Safety Officer
 
per SAE
 
330
 
1.00
 
330
   
Medical Review of SAEs and Narrative creation
 
Optional - as required
 
Medical Monitor
 
per SAE
 
838
 
0.00
 
0
   
Reporting to local Authorities
 
Assume 1 Reportable events
 
Safety Officer
 
per SAE
 
660
 
1.00
 
660
   
Follow up of SAEs
 
Assume 2 hours/Follow-up/SAE, 1 Follow ups
 
Safety Officer
 
per follow-up
 
330
 
1.00
 
330
   
Investigator Notification Letters
 
preparation and oversight
 
Safety Officer
 
per letter
 
165
 
1.00
 
165
   
 
 
 
                 
Subtotal
 
$5,464
 
Prana 800089 (PBT2-204) version 2, 27th June 2012  
 
 
Page 4 of 6

 
 
  Service/Item  
Comments
 
Responsibility
 
Unit
 
Unit Cost
 
Number of Units
 
Item Cost
 
AUD$
Data Management & Statistics
 
 
                       
CRF Design
 
25 unique pages. 80 pages of CRF and 11 pages of questionnaire. 91 Total pages.   One print run.
 
Data Operations Assoc Manager
 
1 study
 
14520
 
1.00
 
14,520
   
Database design and build
 
 
 
DBA/CDA
 
1 Data set
 
463
 
25.00
 
11,563
   
Database / Consistency Check programming
 
 
 
OBA/CDA
 
1 Check
 
53
 
208.25
 
11,114
   
Data Validation Manual / Data Management Plan
 
 
 
CDA
 
1 DVM/DMP
 
3400
 
1.00
 
3,400
   
Data entry
 
Double Data Entry 40 patients x 80 CRF pages plus 40 x 11 questionaires=3640 total pages. Cost per extra page=5.87
 
DE
 
1 page
 
6
 
3640.00
 
21,385
   
Medical Coding
 
MedDRA - AE, WHO - Drug
 
DBA/CDA
 
1 Coded term
 
6
 
800.00
 
5,036
   
Data Cleaning / Monitoring
 
3200 CRF pages. Cost per extra page=$5.10         224 Queries.
Cost per extra query=$42.50
 
CDA
 
1 study
 
29617
 
1.00
 
29,617
   
Quality Control
 
10% of all patients, 100% of all critical data (15% critical / 85% non critical)
 
CDA
 
1 page
 
3
 
811.40
 
2,391
   
Impart laboratory data
 
1 central lab.
 
DBA/CDA
 
1 study
 
3680
 
1.00
 
3,680
   
Data exports
 
Assume 2 exports
 
DBA
 
1 export
 
360
 
2.00
 
720
   
Database maintenance
 
Study Duration = 18 months
 
DBA
 
1 month
 
0
 
18.00
 
4,320
   
DM & Statistics - Project Management
 
Client meetings & corresp, DM metrics. 1hrs/month x 18 months
 
DM
 
1 month
 
120
 
18.00
 
1,530
   
Input to protocol
 
Text and sample size calcualtion / power
 
Statistician
 
1 hour
 
200
 
4.00
 
800
   
Generation of Randomisation schedule
 
1 Schedule.   40 Envelopes. Cost per
 
Statistician
 
1
 
1175
 
1.00
 
1,175
   
Statistical Analysis Plan
 
Includes text and table and Isting shells
 
Statistician
 
1 Statistical
 
5840
 
1.00
 
5,840
   
Identify Protocol Deviations and define Analysis
 
Unblinding. Protocol deviations and
 
Statistician
 
1 study
 
1600
 
1.00
 
1,600
   
Analysis Datasets
 
Specification, Programming  & QC
 
SAS Programmer
 
1 study
 
4800
 
1.00
 
4,800
   
Production of Tables 4 Listings
 
15 Unique tables. Cost per extra $720
20 Repeat tables. Cost per extra $240 0 Figures. Cost per extra $420
35 Listings, Cost per extra $300
 
SAS Programmer
 
1 study
 
26100
 
1.00
 
26,100
   
Statistical Analysis
 
10 analysis endpoints. Cost per extra $400
 
Statistician
 
1 analysis endpoint
 
400
 
10.00
 
4,000
   
Provision of data to DSMB
 
Assumes interim running and QC of 6 TFLs in row Programming Tables and listings.
 
Statistician
 
1 meeting
 
960
 
3.00
 
2,880
   
Input to Final report
 
Text for inclusion in study report.
 
Statistician
 
1 hour
 
2400
 
1.00
 
2,400
   
 
 
 
                 
Subtotal
 
$158,869
Medical Writing (Optional)
 
 
                       
Clinical study report (CSR)
 
 
 
Medical Writer
 
per CSR
 
22497
 
1.00
 
22,497
   
QA review of CSR
 
Optional for Client
 
Medical Writer
 
per CSR
 
2769
 
1.00
 
2,769
   
 
 
 
                 
Subtotal
 
$25,266
 
 
 
                       
 
 
 
                 
TOTAL
 
$383,986
 
Amendment 1 to Budget Expenses
 
Expense/Item
 
Comments
 
Unit Cost
 
Number
of Units
 
Item Cost
AUD$
 
AUD$
Site Visits
 
 
               
Other Site visit Costs
 
Parking/tolls/meals and incidentals for site visits
 
$50/day
 
60.00
 
3,000
   
 
 
 
         
Subtotal
 
$3,000
General Expenses
 
 
               
General Expenses - Couriers, Postage, Telecommunications, Copying, stationery (files)
 
$70/site/month, 3 sites for 25 months
 
$210/month
 
25
 
5,250
   
General Expenses - Couriers. Postage, Telecommunications, Copying, stationery (files)
 
$70/site/month, 2 new sites for 16 months
 
$140/month
 
16
 
2,240
   
                     
CRF Printing
 
 
 
$2,500
 
1
 
2,500
   
 
 
 
         
Subtotal
 
$9,990
 
 
 
               
 
 
 
         
TOTAL
 
$12,990
 
Prana 800089 (PBT2-204) version 2, 27th June 2012  
 
 
Page 5 of 6

 
 
IN WITNESS WHEREOF, the undersigned have caused this Work Order to be executed by a duly authorized individual on behalf of each requisite party effective as of the day and year last written below. In the event that the parties execute this Work Order by exchange of electronically signed copies or facsimile signed copies, the parties agree that, upon being signed by both parties, this Work Order shall become effective and binding and that facsimile copies and/or electronic signatures will constitute evidence of the existence of this Work Order with the expectation that original documents may later be exchanged in good faith. Thereafter, the parties agree that in connection with request for information that either party may need from the other related to the Services provided hereunder, both parties expressly permit communication via facsimile to the extent allowed by applicable laws and regulations to be disseminated in that manner.
 
Prana Biotechnology Limited  
     
By:
-s- diawne angels
 
     
Name:
Dianne Angus
 
     
Title:
Chief Operating Officer
 
     
Date:
13 July 2012
 
 
INCResearch Australia Pty Limited  
     
By:
-s- garth tierney
 
     
Name:
Garth Tierney
 
     
Title:
Regional General Manager, Australia and South East Asia
 
     
Date:
19 July 2012
 
 
Prana 800089 (PBT2-204) version 2, 27th June 2012  
 
 
Page 6 of 6

 
 

 
(INC RESEARCH LOGO)
 
CHANGE ORDER N°1 to Work Order #1000504
 
This Change Order number 1 to Work Order #1000504 (hereinafter “Change Order”) is made and entered into as of the date of last signature (hereinafter “Effective Date”) by and between Prana Biotechnology Limited (hereinafter “Sponsor”) with an office located at Level 2, 369 Royal Parade, Parkville VIC 3052, Australia and INCResearch Australia Pty Limited, together with its parent company, subsidiaries and legal affiliates (hereinafter “INC Research”) with principal offices located at 124 Lipson Street, Port Adelaide SA 5015, Australia.
 
RECITALS
 
WHEREAS, Sponsor and INC Research have entered into Work Order #1000504 (hereinafter “Agreement”) to perform Services for Protocol # PBT2-203 for study entitled: A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Tolerability, and Efficacy of PBT2 in Patients with Early to Mid-stage Huntington Disease (hereinafter “Study”), which was signed by Sponsor and INC Research on 14th August 2012, and
 
WHEREAS, during the course of the performance of the Study, Sponsor and INC Research have identified changes in assumptions; and
 
WHEREAS, Sponsor desires to retain additional services from INC Research and INC Research desires to supply such services to Sponsor under the terms and conditions set forth herein; and
 
WHEREAS, Sponsor and INC Research agree that all other terms and conditions of the Agreement shall remain in full force and effect, unless specifically agreed otherwise in this Change Order; and
 
WHEREAS, Sponsor and INC Research agree that the services and costs covered by this Change Order are additional to the services and costs covered by the Agreement;
 
NOW THEREFORE, subject to the terms, conditions and covenants hereinafter set forth, INC Research and Sponsor agree as follows:
 
SECTION l: CHANGES IN SCOPE
 
This section contains an overview of the changes in assumptions, timelines, and revision in Scope of services. In summary, this Change Order mainly reflects the following changes:
 
Direct Costs
Addition of seven (7) x One Day Monitoring Visits, to be invoiced only if required.
Addition of eight (8) x Two Day Monitoring Visits, to be invoiced only if required.
Addition of one (1) x Four Day Monitoring Visit.
Addition of nine (9) x Serious Adverse Events (SAE) Notifications, to be invoiced only if required.
Addition of four (4) x Reporting to Local Authorities of SAEs, to be invoiced only if required.
Addition of 6 Monthly Suspected Unexpected Serious Adverse Reaction (SUSAR) Line Listings time
for Safety Officer, to be invoiced only if required.
 
INC Research, LLC – CONFIDENTIAL
 
INCResearch Australia Pty Limited - 1000504 
Prana Change Order #1, v2, l0th April 2013 
 
 
Page 1 of 8

 

 
(INC RESEARCH LOGO)
 
INC Research, LLC Change Order Form
 
Indirect Costs
    Addition of twenty-seven (27) x Other Site Visit Costs.
 
The parties hereby agree the total cost associated with this Change Order is AUD $48,505.00.
 
SECTION II: COSTS OVERVIEW
 
The additional deliverables and tasks performed by INC Research are specified in Attachment A. This Attachment includes an overview of the total prices of deliverables in the original agreement and previous change orders, and an overview of the additional total prices of the new deliverables and services. The total amount of all contracted deliverables (original agreement including all change orders) is shown in Attachment A.
 
A summary of both direct and indirect costs related to the original agreement and all changes in scope as occurred is provided in the table below:
 
   
Effective Date
 
Direct Costs
AUD$
 
Indirect Costs
AUD$
 
Grand Total
AUD$
Original Contract
 
14th August 2012
 
$263,821.00
 
$17,100.00
 
$280,921.00
Change Order # 1
 
Upon Execution
 
$47,155.00
 
$1,350.00
 
$48,505.00
Total Contract Value
     
$310,976.00
 
$18,450.00
 
$329,426.00
 
INC Research, LLC – CONFIDENTIAL
 
INCResearch Australia Pty Limited - 1000504 
Prana Change Order #1, v2, l0th April 2013 
 
 
Page 2 of 8

 

(INC RESEARCH LOGO)
 
Revised Direct Costs
 
Service/Item
 
Comments
 
Responsibility
 
Unit
 
Unit
Cost
(AUD)
 
Original
Number
of Units
 
CO#1 Number
of Units
 
Original Item
Cost (AUD$)
 
CO#1
Item
Cost (AUD$)
 
TOTAL COST AUD$
Study Start Up Activities
                                   
Study Training/Internal Kick Off Meeting
 
Familiarisation, Protocol, IB
 
CRA
 
per
CRA
 
1123
 
3
 
0
 
3,370
   
0
   
Study Training/Internal Kick Off Meeting
 
Familiarisation, Protocol, IB
 
PM
 
per PM
 
1290
 
1
 
0
 
1,290
 
0
   
Essential Document Collection
 
Creation, Collection and Tracking
 
CRA
 
per
site
 
1123
 
5
 
0
 
5,616
 
0
   
Study Files
 
Set-up of Study Master Files and Investigator Site Files
 
PA
 
per
study
 
749
 
1
 
0
 
749
 
0
   
CRA Administration (March 2012 -May 2012)
 
Communications -
Customer, Site, Project Manager
 
CRA
 
per
month
 
3019
 
3
 
0
 
9,056
 
0
   
                       
Subtotal
 
20,080
 
0
 
$20,080  
Customer Project Team Meetings
                                   
Customer Kick-off Meeting
 
Teleconference
 
PM
 
per PM
 
322
 
1
 
0
 
322
 
0
   
Sponsor Teleconference Participation
 
21 x 1 hour Telecon
 
PM
 
per
telecon
 
165
 
21
 
0
 
3,456
 
0
   
                       
Subtotal
 
3,778
 
0
 
$3,778  
Investigator’s/Monitor’s meeting
                                   
Travel Time
 
4 hours Return
 
PM
 
per PM
 
645
 
1
 
0
 
645
 
0
   
Travel Time
 
8 hours Return
 
CRA
 
per
CRA
 
1123
 
1
 
0
 
1,123
 
0
   
 
INC Research, LLC – CONFIDENTIAL
 
INCResearch Australia Pty Limited - 1000504 
Prana Change Order #1, v2, 10th April 2013 
 
 
Page 3 of 8

 
 
(INC RESEARCH LOGO)
 
INC Research, LLC Change Order Form
Service/Item
 
Comments
 
Responsibility
 
Unit
 
Unit
Cost
(AUD)
 
Original
Number
of Units
 
CO#1
Number
of Units
 
Original Item
Cost (AUD$)
 
CO#1
Item
Cost (AUD$)
 
TOTAL
COST
AUD$
Attendance
 
Assume 1.5 day Meeting, 1 PM
 
PM
 
per PM
 
1934
 
1
 
0
 
1,934
 
0
   
Attendance
 
Assume 1.5 day Meeting, 2 CRAs
 
CRA
 
per
CRA
 
1685
 
2
 
0
 
3,370
 
0
   
                       
Subtotal
 
7,072
 
0
 
$7,072  
Site Visits
                                   
Study Initiation
 
Includes Preparation, Travel, Time On-site, Reporting and Follow-up
 
CRA
 
Per
visit
 
1404
 
5
 
0
 
7,020
 
0
   
Monitoring Visits (1 Day Visits)
 
Including Preparation, Travel, 1 day On-site, Reporting and Follow-up - only if required
 
CRA
 
Per
 visit
 
1579
 
25
 
7
 
39,478
 
11,054
   
Monitoring Visits (2 Day Visits)
 
Including Preparation, Travel, 2 days On-site, Reporting and Follow-up - only if required
 
CRA
 
Per
visit
 
3015
 
0
 
8
 
0
 
24,117
   
Monitoring Visits (4 Day Visits)
 
Including Preparation, Travel, 4 days On-site, Reporting and Follow-up
 
CRA
 
per
visit
 
5886
 
0
 
1
 
0
 
5,886
   
Closeout Visits
 
Includes Preparation, Travel, Time On-site, Reporting and Follow-up
 
CRA
 
per
visit
 
1752
 
5
 
0
 
8,761
 
0
   
       
-
         
-
 
Subtotal
 
55,258
 
41,057
 
$96,315
Site Management
                                   
Site Management (June 2012 -September 2013)
 
per Month
 
CRA
 
per
month
 
3086
 
16
 
0
 
49,383
 
0
   
                                     
Site Management (October 2013 - November 2013)
 
per Month
 
CRA
 
Per
month
 
1460
 
2
 
0
 
2,920
 
0
   
                       
Subtotal
 
52,303
 
0
 
$52,303
 
INC Research, LLC – CONFIDENTIAL
 
INCResearch Australia Pty Limited - 1000504
Prana Change Order #1, v2, l0th April 2013
 
 
Page 4 of 8

 
 
(INC RESEARCH LOGO)
 
INC Research, LLC Change Order Form
 
Service/Item
 
Comments
 
Responsibility
 
Unit
 
Unit
Cost (AUD)
 
Original Number of Units
 
CO#1 Number of Units
 
Original Item Cost (AUD$)
 
CO#1 Item Cost (AUD$)
 
TOTAL COST
AUDS
Project Management
                                   
Local Coordination/Supervision (March 2012 - May 2012)
 
per Month
 
PM
 
per
month
 
5158
 
3
 
0
 
15,475
 
0
   
Local Coordination/Supervision (June 2012 - September 2013)
 
per Month
 
PM
 
per
month
 
3296
 
16
 
0
 
52,743
 
0
   
Local Coordination/Supervision (October 2013 - November 2013)
 
per Month
 
PM
 
per
month
 
3353
 
2
 
0
 
6,706
 
0
   
                                     
Project Assistance (March 2012 - November 2013)
 
per Month
 
PA
 
per
month
 
2054
 
21
 
0
 
43,144
 
0
   
                       
Subtotal
 
118,068
 
0
 
$118,068  
Safety Monitoring
                                   
Safety Administration
 
Includes Set-up, Maintenance and Completion Activities
 
Safety Officer
 
per
study
 
4597
 
1
 
0
 
4,597
 
0
   
Handling of SAEs (Notifications)
 
All Events - Assume 10
 
Safety Officer
 
per
SAE
 
330
 
1
 
9
 
330
 
2,967
   
Medical Review of SAEs and Narrative Creation
 
All Events - Assume 1 SAE
 
Medical Monitor
 
per
SAE
 
851
 
1
 
0
 
851
 
0
   
Reporting to Local Authorities
 
All Events - Assume 5
 
Safety Officer
 
per
SAE
 
659
 
1
 
4
 
659
 
2,637
   
6-Monthly SUSAR Line Listing
 
Preparation, distribute and tracking
 
Safety Officer
 
per
study
 
494
 
0
 
1
 
0
 
494
   
Safety Management Plan (review)
     
Safety Officer
 
per
study
 
659
 
1
 
0
 
659
 
0
   
 
INC Research, LLC – CONFIDENTIAL
 
INCResearch Australia Pty Limited - 1000504
Prana Change Order #1, v2, l0th April 2013
 
 
Page 5 of 8

 

(INC RESEARCH LOGO)
 
INC Research, LLC Change Order Form
Service/Item
 
Comments
 
Responsibility
 
Unit
 
Unit
Cost
(AUD)
 
Original Number
of Units
 
CO#1 Number
of Units
 
Original Item
Cost (AUD$)
 
CO#1
Item
Cost (AUD$)
 
TOTAL COST AUD$
Teleconference
 
Assume 1 hour teleconference
 
Safety Officer
 
per
telecon
 
165
 
1
 
0
 
165
 
0
   
                       
Subtotal
 
7,261
 
6,098
 
$13,360  
               
 
                   
   
 
                 
TOTAL
 
263,821
 
47,155
 
$310,976 
 
Revised Indirect Costs

Expense/Item
 
Comments
 
Unit Cost
 
Original Number
of Units
 
CO#1
Number
of Units
 
Original
Item
Cost
AUD$
 
CO#1
Item
Cost
AUD$
 
TOTAL
COST
AUD$
Investigator’s/Monitor’s Meeting Attendance
                           
   
Airfares, accommodation &
                       
Travel/Attendance Costs
 
meals provided by Client, $500 - taxis, currency exchange, meals in transit, phone
 
$500/person
 
2
 
0
 
1,000
 
0
   
               
Subtotal
 
1,000
 
0
 
$1,000  
Site Visits
                           
Other Site visit Costs
 
Parking/tolls/meals and incidentals for site visits
 
$50/day
 
35
 
27
 
1,750
 
1,350
   
               
Subtotal
 
1,750
 
1,350
 
$3,100  
General Expenses
                           
Couriers, Express Post,
Teleconferences
     
$7,000
 
1
 
0
 
7,000
 
0
   
 
INC Research, LLC – CONFIDENTIAL
 
INCResearch Australia Pty Limited - 1000504
Prana Change Order #1, v2, l0th April 2013
 
 
Page 6 of 8

 
 
(INC RESEARCH LOGO)
 
INC Research, LLC Change Order Form
 
Copying (Excluding ethics submissions), postage, telecommunications (excluding teleconferences), stationery (files)
 
$70/site/month, 5 sites for 21 months
 
$350/month
 
21
 
0
 
7,350
 
0
   
               
Subtotal
 
14,350
 
0
 
$14,350   
                TOTAL   17,100   1,350   $18,450 
 
INC Research, LLC CONFIDENTIAL
 
INCResearch Australia Pty Limited - 1000504
Prana Change Order #1, v2, l0th April 2013
 
 
Page 7 of 8

 
 
(INC RESEARCH LOGO)
 
SIGNATURE
 
COUNTERPARTS. This Change Order may be signed in counterparts and said counterparts shall be treated as though signed as one document. The parties acknowledge legal validity of facsimile, portable document format or other commercially acceptable electronic exchange of copies of the documents, which are essential for Change Order execution. A party which uses a facsimile, portable document format or other commercially acceptable electronic exchange copy of an authorized person’s signature in the documents guaranties its authenticity.
 
IN WITNESS WHEREOF, the undersigned have caused this Change Order to be executed by a duly authorized individual on behalf of each requisite party effective as of the day and year last written below.
     
Prana Biotechnology Limited
 
INCResearch Australia Pty Limited
     
-s- diawne angels    -s- garth tierney
Signature By:
 
Signature By:
DIANNE ANGUS      Garth Tierney
Name (print)
 
Name (print)      
C.O.O
 
Executive Vice President, Asia/Pacific
Title
 
Title
16/April/2013
 
24/04/2013
Date
 
Date
 
INC Research, LLC – CONFIDENTIAL
 
INCResearch Australia Pty Limited - 1000504
Prana Change Order #1, v2, l0th April 2013
 
Page 8 of 8