Exhibit 10.21
 
Project Agreement Number: 1 Aptiv Project Number: ACTI-1903
 
This Project Agreement is made and entered into on September 30, 2011, the Effective Date, by and between Actinium Pharmaceuticals, Inc., with offices at 391 Lafayette Street, Newark, NJ 07105 (hereinafter referred to as "Client") and Aptiv Solutions, Inc., together with its Affiliates, with offices at 1925 Isaac Newton Square, Suite 100, Reston, Virginia 20190 (hereinafter referred to as "Aptiv").
 
WHEREAS, Client and Aptiv have entered into that certain Master Services Agreement for dated September 30, 2011(hereinafter referred to as the "Agreement"); and
 
WHEREAS, pursuant to the Agreement, Aptiv has agreed to perform certain Services in accordance with Project Agreements from time to time entered into by the Parties, as more fully provided in Section 2 of the Agreement, and Client and Aptiv now desire to enter into such a Project Agreement.
 
WHEREAS, Aptiv and Client desire that Aptiv provide certain Services with respect to a Phase I/II Advanced Myeloid Malignancy study, (the "Study") for the study of the drug 225AC-HuM195 ("Study Drug") as set out in the Protocol titled: A Phase I/II Study on the Safety and Efficacy of 25AC-HuM195 in Patients with Advanced Myeloid Malignancies, which is incorporated herein by reference.
 
NOW, THEREFORE, in consideration of the mutual covenants contained herein, the parties hereby agree as follows:
 
1.      Project Specifications. Aptiv will perform the services described in the Project Specifications, attached hereto as Appendix A, in accordance with the Project Schedule, attached hereto as Appendix B and any other documents attached to this Project Agreement ("Services").
 
2.      Compensation. For performance of these Services, Client will pay to Aptiv the amounts described in the Budget for Services and Pass-Through Budget set forth in Appendix C, which amounts will be payable pursuant to the Payment Schedule set forth in Appendix D.
 
 
2.1.
A payment plan inclusive of a down payment element of twelve and a half percent (12.5%) of the total budget estimate, inclusive of Pass Through Expenses will be included in the Payment Schedule. The down payment is considered as an advance payment and shall be taken into account with the final payment(s) upon completion of the Services.
     
 
2.2.
Down payment invoices are due immediately upon signature of this Project Agreement. All payments are to be made in accordance with the Agreement and due within thirty (30) days of invoice date.
 
 
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3.       Designated Contact Person (pending assignment of project team) For Aptiv Solutions:
 
Philip Dehazya, PhD
Program Director, Oncology Business Unit
Aptiv Solutions
800 Westchester Avenue
Rye Brook, New York 10573
Direct: +1 914.733.3445
Cell: +1 516.851.2329
 
For Client:
 
Dragan Cicic, MD
CEO
Actinium Pharmaceuticals, Inc.
Tel: 718 369 7089
Cell: 917 575 2057
E-mail: dcicic@actiniumpharmaceuticals.com
 
4.       Term and Termination. The term of this Project Agreement will commence upon its execution by Aptiv and Client and will continue until completion of the Services Aptiv Solutions involvement with this project. Aptiv anticipates starting work in May, 2011 and expects to end in December 2014, as more fully described in Appendix B, provided, however, that either Party may terminate this Project Agreement in accordance with Section 4, Term and Termination, of the Agreement.
 
5.       Incorporation by Reference; Conflict. The provisions of the Agreement are hereby expressly incorporated by reference into and made a part of this Project Agreement. In the event of a conflict between the terms and conditions of this Project Agreement and those of the Agreement, the terms of the Agreement will take precedence and control; provided however, in event of conflicts between the Project Agreement and the Agreement, Sections 3.0 Payment, 4.0 Term and Termination, the Project Agreement shall control.
 
 
2
 
 
 
IN WITNESS WHEREOF, the parties have hereunto signed this Project Agreement effective as of the day and year first written above.
 
APTIV SOLUTIONS, INC.   ACTINIUM PHARMACEUTICALS, INC.  
       
   
Authorized Signature
  
Authorized Signature
  
       
Evp Business Developement   CEO  
Title
  
Title
  
       
Nov 14, 2011   October 26, 2011  
Date   Date  
 
List of Appendices
 
Appendix A:       Project Specifications
Appendix B:        Project Schedule
Appendix C:        Budget for Services and Pass-Through Budget
Appendix D:        Payment Schedule
 
 
3
 
 
Appendix A: Project Specifications
The Project Manager will:
 
               
 
1.
Create a Project Management Plan (PMP) based on the study deliverables and timelines, implements an action plan.
               
       
The PMP will Include:
       
●
Detailed individual roles and responsibilities
       
●
Communication plan
       
●
Agreed timelines and milestones
       
●
Process and handling of investigator agreements and payments
       
●
Project Reports including patient-specific tracking
       
●
Contingency Plan for the study to include: enrollment, safety, etc.
       
●
SOPs to be followed
               
 
2.
Periodically review actual progress of the study against the agreed standards and update the PMP as needed
               
 
3.
Oversee site start-up activities
               
     
a.
Site activation process
     
b.
Develop study documents:
         
1.
Operations Manual
         
2.
Site Initiation Visit ("SIV") Presentation
         
3.
Monitoring Plan
           
i.
specify the monitoring frequency and objectives of each visit,
           
ii.
provide templates for study required documentation, including monitoring visits reports and expectation for submission of monitoring reports.
           
iii.
identify standards, for example average number of Case Report Form ("CRF") modules monitored per monitoring visit day, maximum number of un-monitored modules at site at any one time.
               
     
c.
Regulatory Binder oversight and set up of each site with Clinical Research Associate ("CRA") and Clinical Project Coordinator ("CPC")
         
1.
Ensure CRA awareness of study specific information with education and training of the assigned CRAs for study
         
2.
Regulatory/IRB/IEC: Collaborate with the regulatory department in the completion of site specific documents required for Ministry of Health ("MOH") submissions and prepare site specific regulatory documents with study information: IEC, MOH, Financial Disclosures for PI and all subs; 1572
         
3.
Regulatory document collection
         
4.
Insurance Certificates for country submissions
         
5.
Investigational Medicinal Product Dossier ("IMPD")
 
 
4
 
 
         
     
d.
Work with site at all stages of regulatory document preparation and submission.
     
e.
Collect and review all regulatory of documents submitted to IRB/EC
     
f.
Complete site specific Critical Documents Checklist for sponsor (IP release)
         
 
4.
Recruitment /Maintenance Phase
         
     
a.
Oversight of CRAs
     
b.
Ensure consistency across sites
     
c.
CRA teleconferences for study updates
     
d.
Ensure Protocol compliance
     
e.
Track enrollment and site performance
     
f.
Work with sites on enrollment/retention of subjects in collaboration with the CRA
     
g.
Project Patient Visits per study schedule
     
h.
Communicate between the Site and assigned CRA on patient status and tolerance of Investigational Product after treatment
     
i.
Manage CRAs, in collaboration with the sites, to ensure Protocol compliance and Inclusion/Exclusion criteria adhered to, CRFs complete and up to date in order to meet study deliverables and monitoring visit schedule.
         
 
5.
Monitoring
         
     
a.
Review Monitoring Schedule for compliance to monitoring plan
     
b.
Review trip reports for consistency and quality and provide feedback
     
c.
Approve final trip report
     
d.
Ongoing training for study team and sites, as evidenced by report details and data management
     
e.
Assure Adverse Event reporting per regulations to IRB/EC
     
f.
Risk Management reporting, as applicable
     
g.
Communicate status of study monitoring and site management updates or issues to Actinium
         
The Project Manager and Lead CRA constitute the Project Management Team.
The overall Project Management Team will be responsible for the following tasks:
         
 
1.
Implementation and ongoing maintenance of the PMP
 
2.
Preparation and tracking of detailed timelines and deliverables
 
3.
Assurance that milestones are fully understood and met by the team
 
4.
Management of financial issues for assigned clinical study
 
5.
Capacity planning and review of resource allocation
 
6.
Coordination of team training
 
7.
Oversight of internal project team meetings
 
8.
Maintenance of project working files
 
 
5
 
 
 
9.
Assurance that effective communication between departments and project team members occurs with identification and resolution of critical issues (communication plan as outlined in the PMP)
 
10.
Recommendation of alternative approaches as necessary to ensure delivery of a timely and high quality project within budget (contingency planning)
 
11.
Reviewing monitoring reports
 
12.
Coordination and oversight of site monitoring activities, administrative interactions between investigators and Aptiv Solutions, and reporting to Actinium the sites' progress (monthly project progress reports)
 
13.
Enrollment tracking
 
14.
Implementation of all procedures and conducting the clinical program according to the agreed timelines, budget and in accordance with Good Clinical Practice and any applicable law.
         
Clinical Research Associates (CRAs)
         
The responsibilities of the CRAs include:
1.
collaboration for regulatory submissions for MOH and EC, site monitoring, site support and management, data tracking, data review,
2.
collaboration with the site for query resolution and assistance to the PM/Lead CRA in all study management related site issues, including but not limited to,
     
a.
informed consent design and IRB/IEC submissions.
   
3.
Aptiv Solutions currently assumes up to 3 CRAs to be assigned to the study. Every effort will be made to resource with as few staff as possible, allowing for language skills, travel, etc.
     
a.
Aptiv Solutions Full-time employees (FTEs) CRAs will be assigned preferentially. Aptiv Solutions may occasionally assign contracted CRAs who are extensions of the Aptiv Solutions team, held to the same standards as Aptiv Solutions employees and perform according to Aptiv Solutions SOPs.
         
4.
Study Initiation Visits (Sly)
         
The SIV will be conducted once all pre-study documents have been collected unless other arrangements are agreed with Actinium. It is estimated that site initiation visits will require one day of on-site time. The investigators and study personnel will be trained on all aspects of study procedures relating to patient screening, scheduling, evaluation, follow up, CRF completion, and drug use and accountability. The study regulatory binder (investigator site file) will be reviewed with the investigator. ICH/GCP requirements, including investigator responsibilities, will be reviewed.
         
5.
Interim Monitoring Visits
         
Aptiv Solutions will conduct initial interim site visit within two weeks after the first patient is enrolled at each site unless otherwise directed by Actinium; subsequent monitoring visits will be scheduled depending on enrollment rate and data quality. The frequency and length of visits will be adjusted as agreed upon by Actinium and Aptiv Solutions.
 
 
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Aptiv Solutions has assumed 12 one day (8 hours on-site) Interim Monitoring Visits per site. The monitoring plan can be written to allow the flexibility of more or fewer visits per site, as agreed upon with Actinium, as site-level enrollment warrants. The data quality will be reviewed after the first subject to identify any issues related to the protocol and retraining will occur, as applicable.
         
6.
During site visits, Aptiv Solutions CRAs will
     
a.
Assess investigator adherence to FDA regulations, GCP/ICH Practices, and local regulatory guidelines
     
b.
Verify informed consent and HIPAA authorization
     
c.
Review all source documentation in comparison to the CRFs
     
d.
Check for missing or incomplete data and inconsistencies
     
e.
Ensure resolution of all queries for data clarification
     
f.
Obtain documentation updates for pertinent documents
     
g.
Verify that the protocol is being followed with respect to eligibility, study-mandated procedures, and timetable.
         
Aptiv Solutions will inventory investigational materials and review accountability records. Problems with accrual, protocol compliance, any adverse event reporting and follow-up, as well as CRF accuracy, completeness, and timeliness will be documented and discussed. Should any problems require it, Aptiv Solutions, Actinium, and the site will jointly develop an action plan with timelines for resolution.
         
7.
Site Closeout Visits
         
Aptiv Solutions will perform the Site Closeout Visit once all Data Clarification queries have been resolved by the DM team and the Database Lock has occurred. Aptiv Solutions will review all patient files for completeness, review the study binder to assure all documentation is in place for FDA or other governing agency audit, perform final Investigational Product accountability, and authorize return or disposal of all unused study supplies.
         
8.
Site Communication
         
The Aptiv Solutions Lead CRA will be the primary contact for the study sites and the CRAs related to monitoring matters. The Lead CRA may designate a CRA to be the site's primary contact in an effort to establish continuity between the site and CRA. The Lead CRA will consult with the Project Manager and Project Team, Aptiv Solutions Management and Actinium as needed. Aptiv Solutions will document pertinent telephone contacts with the sites and will file documentation as appropriate in the Trial Master File.
         
Interim site communication will consist of routine contact and follow-up with the study sites by the Lead CRA and/or the assigned CRA to address any questions or issues raised at or between monitoring visits. Examples include pending site-specific MOH/IRB/IEC questions or Investigational Product supply and distribution issues, resolution of queries, etc.
 
 
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The Lead CRA or CRAs may also direct the Clinical Project Coordinator to contact the sites for missing Enrollment Logs and outstanding or deficient Regulatory Documents.
   
Clinical Project Coordinator (CPC)

1.
The CPC will be responsible for all administrative support to the study team throughout the duration of the study.
   
2.
The CPC is also responsible for all document management during the course of the study.
   
3.
A Trial Master File or Study File/Country File will be established for the study which will be maintained in the United States.
     
a.
All project documents and materials, excluding budgetary information, will be stored in the file.
     
b.
The CPC is responsible for the set up and the maintenance of the Study File (SF).
         
4.
In addition to the Study File, the CPC will set up and maintain the In-house Investigator Site Files (IHSF) for each individual site and respective country.
     
a.
The set up includes the initiation of the respective checklists for the country and each specific site
     
b.
ongoing maintenance and filing of all study documents to each respective section of the file.
     
c.
utilize the site checklists to reconcile the IHSF against the Investigator Site File throughout the course of the study and maintain a comprehensive list of all study documents filed at the site and Aptiv Solutions.
         
5.
At the end of the study, electronic correspondence with Actinium will be saved to disc, archived with the SF, and returned to Actinium.
     
a.
The active SF will be stored in locking file cabinets on Aptiv Solutions premises and the cabinets will be locked during non-business hours.
     
b.
Upon completion of the project, the Aptiv Solutions Trial Master File will undergo a final reconciliation, be archived and transferred to Actinium per Aptiv Solutions SOPs.
     
c.
If requested, files can be archived to an off-site storage facility at an additional cost.
         
6.
The CPC will support the entire study team including the PM, Lead CRAs, CRAs and other team members in the following tasks, including:
     
a.
Attending study TCs, taking notes, writing minutes, distributing minutes for internal review and feedback and then distributing final minutes.
     
b.
Set-up of the Trial Master File to include both the Study File (SF), the Country File (CF) and the Investigator Site Files(ISF)
     
c.
Creating a regulatory binder/Operations Binder for each site including printing the tabs, insertion of dividers and site documents.
     
d.
Creating the SF, CF and each ISF Checklist record that is maintained for all study documents as required per GCP, section 8.1
 
 
8
 
 
     
e.
Maintenance of the SF, CF and each ISF throughout the course of the study to include review of study documents for completeness and accuracy when submitted, and then updating the checklist and scanning and filing the document. If errors/omissions noted, works with the site and CRA to resolve the issue. Obtain ongoing updates, as applicable
     
f.
Schedule any Project Team meetings in collaboration with the PM/Actinium.
     
g.
Contact sites and F/U as required for missing documents, follow up on questions, etc.
     
h.
Creating all the shipping transmittals, per site, including the courier label for shipment.
     
i.
Assembling mailing with study documents, transmittals and notifying the courier. This would include the Regulatory Binder and Operations Manual
     
j.
Tracking receipt of mailing sent to the site through the return of the transmittal form
     
k.
Printing documents for CRAs for SIV/IMV, as requested
     
l.
Preparing required documents and checklists for the CRAs for monitoring visits
     
m.
Processing all monitoring trip reports into Study Management System by scanning, entering data and filing hard copy, once approved by Lead CRA.
     
n.
Running study reports as requested by PM. This would include the monitoring report and study progress report, and others, as requested
     
o.
Miscellaneous assigned tasks as requested by team members
         
7.
The CPC, in collaboration with the Lead CRA, will track monitoring visit reports and other visit related documents (e.g. confirmation, follow-up letters, and expense reports, regulatory documents, etc.) and enter these into the Study Management System (SMS) and Investigator Site File Checklist. The monitoring plan will be used as the quality check against the monitoring report to verify compliance with the study conventions. The CPC will maintain the SMS database, including entry and updating the system with site contact information and regulatory document information, etc throughout the course of the study. Study reports will be generated based on the data in the SMS.
         
Safety Management
         
Case managers are designated Clinical Safety Specialists (CSS) from our US office and Pharmacovigilence Scientists (PVS) from our EU office. In addition, the designated CSS or PVS will act as the safety project manager and will be the key contact for the Actinium on safety issues. They will also be responsible for the production of any contracted safety documents.
         
Case managers will:
     
 
1.
Receive SAE reports, process in EmpiricaTrace, assure completeness with sites
 
 
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2.
Development of narrative
 
3.
Distribute narratives to MM for review; incorporate in EmpiricaTrace
 
4.
Manage, maintain, and generate required reports from EmpiricaTrace
 
5.
Receive and process for completeness waiver requests; forward requests to MM; forward requests to Actinium
 
6.
Document significant interactions in e-log, if not otherwise documented in safety process
 
7.
Maintain shared FAQ log for medical issues, waivers granted, etc. for consistency and uniformity of response
 
Head of US / EU, Clinical Safety will:
 
1.
Maintain supervisory responsibility for safety specialist performance
 
2.
Respond to CSS issues, concerns, questions; document in e-log
     
The Clinical Safety Group at Aptiv Solutions will be responsible for receiving, tracking and entering SAEs in the database and for distribution to Actinium.
     
Expedited reports will be submitted to Regulatory Authorities by Aptiv Solutions; Aptiv Solutions will distribute copies of these reports to investigators.
     
Aptiv Solutions will provide a 24/7 fax line for receipt of SAE reports. Aptiv Solutions personnel will be available to further receive and process SAE reports according to Aptiv Solutions SOPs.
     
1.
Aptiv Solutions will provide written instructions to the clinical study sites regarding SAE reporting procedures.
2.
Serious adverse event reporting estimates are based on 10 total SAEs during the study.
3.
Aptiv Solutions assumes that, for each SAE, there will be an initial SAE report and one follow-up report.
4.
This budget does not include reconciliation of any separate Actinium SAE and clinical databases.
     
Medical Writing
 
Clinical Study Report
     
The Aptiv Solutions Medical Writer will be responsible for writing the study report based on an Aptiv Solutions report template and the statistical output. In addition, the Medical Writer can provide guidance with the protocol, ICF/IB, and statistical analysis plan as requested.
 
The Clinical Study Report will be written following ICH guidelines. Aptiv Solutions will prepare a Clinical/Statistical Report that consists of a summary of the clinical study with emphasis on clinical and statistical interpretations of the study. The report will describe
the rationale of the study, the study plan and design and the statistical methodology. The report will be structured according to document specifications and the word processing format requested by Actinium. A QC review will be performed to check the accuracy of the number transfer from the analysis tables and figures to the report.
 
 
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Preparation of the report also includes a Key Messages Meeting, which can be done via teleconference as needed. The purpose of this meeting is to discuss the results of the study in context of the objectives and endpoints stated in the protocol. This meeting also gives Actinium the opportunity to provide the "key messages" that should be developed in the report. Participants in the Key Messages Meeting include the Medical Writer and Actinium; the Medical Monitor/Advisor, and the PM. Other persons may participate as needed.
 
The report review process includes
 
1.
two rounds of Actinium review and the incorporation of comments.
 
2.
third version will be the final report delivered to Actinium.
 
3.
final deliverable: Aptiv Solutions will supply an electronic copy of the report text in Microsoft Word format that will include internal hyper linking to in-text tables.
 
Regulatory Affairs
The Regulatory Affairs Group will be responsible for writing, compiling and submitting clinical trial applications globally, in the countries where this project will be conducted. In addition, the Group will handle protocol amendments during the project and submission of annual safety reports, as needed.
 
Aptiv Solutions will collect and submit all appropriate country specific regulatory documents, as appropriate and in accordance with ICH/GCP guidelines, in each country involved and the local ethics submissions for each investigational site, e.g., FDA Form 1572, curriculum vitae, medical licenses, protocol signature, the initial financial disclosure statements, and laboratory normal ranges.
 
In the event any regulatory documents are deficient or missing, Aptiv Solutions will contact the site to secure the outstanding items and resolve issues. Aptiv Solutions will provide the necessary support to confirm acceptance of IRB/IEC approval for release of study drug.
 
Aptiv Solutions will forward all original regulatory documents to Actinium for filing, as requested. In addition, Aptiv Solutions will maintain complete and current in-house regulatory files during the course of the project. These documents will be stored in the Trial Master File.
 
 
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Legal Affairs
 
Aptiv Solutions will prepare a site agreement template based on the final protocol and discussions with Actinium. Note: site agreements are solely the responsibility of Actinium. This template will be charged at a fix fee. Alternatively, Aptiv Solutions will review and adapt a template provided by Actinium. Once this is finalized, Aptiv Solutions will adapt according to the requests from the individual sites and will submit, coordinate, negotiate and finalize the contracts with the participating institutions and/or physicians. In case of any translation, Aptiv Solutions can also provide and coordinate such services.
 
In case Actinium requires Aptiv Solutions to execute the final and approved site agreements, Aptiv Solutions can only carry out such work in the capacity as agent for and in the name of Actinium, and therefore, Actinium retains overall responsibility to the sites, and for payment matters. Aptiv Solutions will also provide administration of payment of investigator grants, hospital fees, and pharmacy fees, where appropriate, assuming advance funding has been provided by Actinium. The timing of such payments will be designed to compensate timely site performance at a rate to be agreed.
 
Aptiv Solutions will maintain invoice tracking to allow Aptiv Solutions to provide Actinium with a budget reconciliation of grant payments on a monthly basis.
 
Data Management and Statistics
 
Data Management & Statistics Team Leader (DMS-TL)
 
The Lead Data Manager will be assigned as the DMS-TL, and will coordinate data-management and statistical activities. The DMS-TL will be responsible for:
   
●
Implementation and ongoing maintenance of the data management plan
   
●
Preparation and tracking of detailed timelines and deliverables
   
●
Assurance that milestones are fully understood and met by the team
   
●
Capacity planning and review of resource allocation
   
●
Maintenance of project working files
   
●
Implementation of all procedures and conducting the clinical program according to the agreed timelines, budget and in accordance with Good Clinical Practice and any applicable law
 
Clinical Data Managers
 
A designated Clinical Data Manager will be responsible for data processing specifications, including validation checks specifications, discrepancy review, query handling, QC plan and data handling manual. The following CRF and Query flow involving Monitors and Data Management will be implemented.
 
   
●
CRF pages are collected by the CRA (by module.)
   
●
CRF pages received in Data Management are logged in on the tracking database.
 
 
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●
Copies of CRF pages are made (used as working copies by Data Managers.)
   
●
Validation checks run as overnight jobs and generate discrepancies.
   
●
Data discrepancies are reviewed by Data Managers. Relevant queries are generated as PDF files (Data Clarification Forms) and forwarded to the responsible monitor.
   
●
Resolves and signed Data Clarification Forms (DCFs) with signed resolved queries are sent by the monitor to Aptiv Solutions Data Management.
   
●
DCFs are tracked by data management in the tracking database and the ClintrialTM Database is updated accordingly.
   
●
Copies of DCFs are made and originals are filed and stored in fire-safe secure filing area with original CRFs.
   
●
All Data management status reports i.e. tracking, data entry, query management, will be updated and made available to the study team via H-System® Reports (Secure Internet.)
 
Clinical Database Programmers
 
 
1.
Programming
     
   
A Database Programmer and an independent database reviewer will develop and test the database. Highlights of the software development life cycle process include database development according to a validation protocol that documents the design requirements and specifications, database testing by programmers and end users using test CRF cases, and documented review and acceptance by end users. The database is considered validated when the expected results are the same as the actual results, and the end users verify that the database performs according to the requirements. The design procedures, testing results, and test CRF cases are filed in the Central Files.
     
 
2.
Maintenance
     
   
Database maintenance, including back-ups and off-site storage, will be provided throughout the study. All database modifications will be fully tested and documented in the same manner as above. Aptiv Solutions will run daily back-ups.
 
Statistician
A Lead/Senior Statistician will be assigned to this study and will be responsible for the implementation of the final statistical analysis plan (SAP) and production of all necessary statistical analyses including the statistical input for the study report. The SAP including tables and listing shells, will be produced by Aptiv Solutions and reviewed by Actinium. Before database closure a review meeting will be held to review all withdrawals, protocol deviations, and to define the populations to be analyzed. All tables and listings will be generated; Quality Control measures will be taken and reviewed according to Aptiv Solutions SOPs.
 
 
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Statistical (SAS) Programmers
The Statistical SAS Programmers will be responsible for programming statistical tables, listings and graphs as described in the SAP. The project biostatistician will provide statistical programming specifications. The Statistical Programmers will be working under the responsibility of the Statistician and will program and validate all data tables and listings according to the SAP, using SAS 9.1. Data tables programming validations will be performed by double programming by an independent SAS programmer.
 
Study Communications
Please refer to the Budget for further assumptions regarding frequency, duration, and attendees of study communications.
 
Method of
Communication
  
Key Participants
  
Frequency
  
Results
   
Actinium Project Team
  
One - at Kickoff
  
Detailed agenda with minutes/action items completed post meeting. Meeting Goal:
             
Face-to-Face Meetings
  
Aptiv Solutions Project Team: Project Manager Clinical Project Coordinator Data Management Biostatistician Medical Monitor Clinical Safety Specialist Actinium Project Team
  
Monthly
 
  
Define roles, responsibilities of the project team; establish study timelines and milestone achievements; detail study contacts at Actinium and Aptiv Solutions; identify site start up process and drug release for initiation, review safety issues and study operations; clarify all functional teams deliverables Minutes of items discussed during monthly teleconferences, action items if necessary
             
Aptiv Solutions-Actinium Project Team Teleconferences
  
Aptiv Solutions Project Team: Project Manager Clinical Project Coordinator Data Management Clinical Safety Specialist
        
             
Aptiv Solutions Team Meetings*
  
Aptiv Solutions Project Team:
Project Manager Regional CRAs Clinical Project Coordinator Medical Writer Data Management Clinical Safety Specialist Clinical Project Coordinator Medical Writer Data Management Clinical Safety Specialist
  
Monthly
  
Results of team meetings may contribute to agendas for monthly team teleconferences
 
 
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*Attendees at internal team meetings will vary depending upon the stage of the study (example: The Aptiv Solutions Project Manager would attend all team meetings throughout entire project, CRAs would attend during site setup and while sites are active through site closeout, Medical Writer may only attend later meetings as preparations for CSR writing are underway, etc.)
 
General Budget Assumptions:
 
1.
This budget is based on Protocol dated August 28, 2008 and amended on April 15, 2009.
2.
All work will be performed on a unit.
3.
Cost estimates are based on rates for Year 2011. An annual rate increase may be applied each January, to coincide with the fiscal year of Aptiv Solutions (up to 5%). Notification of the anticipated rate increase will be sent 30 days in advance of applying the rate increase each fiscal year.
4.
Actual costs will be billed monthly at the annual rate that corresponds with the year in which the work is performed.
5.
The budget cost estimate has been developed assuming 100% of sites are located in the US; 0% are located in Western Europe; and 0% are located in Central Eastern Europe. The budget is subject to revision if the site allocation is different than what is currently assumed.
6.
Travel expenses for project-related activities, including site visits, are not included in the Aptiv Solutions service budget and will be billed to Actinium as direct pass-through costs.
7.
Efforts relating to publication or presentation of results are not included in this budget.
8.
All deliverables that require Actinium sign-off will require no more than two rounds of review/revisions and each round of review will require no more than 5 business days. Extension of Actinium review time resulting in unreasonable delays may result in budget modifications.
9.
The budget covers only the services specified in this proposal.
10.
Any changes that impact the project time frame or costs (out-of-scope-activities) will be addressed by means of a written Change Order, which must be signed by both parties.
11.
Costs associated with Actinium requests for Aptiv Solutions attendance at scientific meetings, conferences and/or special presentations, or FDA meetings are not included in this budget; these efforts would be billed additionally.
12.
Costs for services outsourced by Aptiv Solutions to other vendors are not included in the Aptiv Solutions service budget and will be billed to Actinium as direct pass-through costs.
 
 
15
 
 
Milestones
    
Total
N Subjects
    
74
N sites
    
6
N Countries
 US only
  
1
N CRF Pages
 Per subject
  
70
N Unique CRF Pages
 Per subject
  
38
N Queries
 Per 100 CRF Pages
  
10
N Statistical Tables
 Unique/Non-Unique
  
30/0
N statistical Listings
 Unique/Non-Unique
  
0 I 20/0
N Statistical Figures
 Unique/Non-Unique
  
5/0
N CRAs
      
3
Start of Early Phase Activities
 0
  
June 2011
 
 Set Up IRBs, Pre study & initiation
    
Start of activities
 etc
  
June 2011
FPFV
    
TBD
LPFV
    
TBD
LPLV
    
TBD
LPLV
    
TBD
Database closure
 standard 6 weeks after LPLV
  
TBD
Final Close Out Visits
 4 wks after Database Closure
  
TBD
Final Tables, Listings, and
      
Figures
 6 wks after Database Closure
  
TBD
 
 6 weeks after provision of final
    
End of Activities: Final Study
 Sponsor-approved Tables,
    
Report Ready
 Listings, and Figures
  
TBD
Clinical Phase duration (months)
 Start of activities to Site Close Out
  
42
Biometrics Phase Duration
 Start of DM to production of final
    
(months)
 listings
  
40
 
 Start of activities to Final Study
    
Total Project duration (months)
 Report
  
44
 
 
16
 
 
Appendix C: Budget for Services and Pass-Through Budget
 
SUMMARY OF APTIV SOLUTIONS COSTS
    
USD
 
    
133,493
CLINICAL CONDUCT SERVICE COSTS    
683,983
PROJECT MANAGEMENT SERVICE COSTS    
336,000
CLINICAL ADMINISTRATION SERVICE COSTS    
258,396
DATA MANAGEMENT SERVICE COSTS    
246,087
BIOSTATISTICS SERVICE COSTS     72,448
DATA MONITORING COMMITTEE     0
STUDY REPORT
    36,782
OVERHEAD    
70,688
TOTAL APTIV COSTS    
1,837,876
 
 STUDY PREPARATION SERVICE COSTS
  
Unit Type
#
Units
Unit
Price
USD
 Project Plan
Project Plan Development and includes all sections (comm. Plan)
Per Plan
1
3,500
3,500
 
Ongoing
Maintenance of Project Plan:
Per Month
36
88
3,150
 CRF - Assumed Review only
45 minutes per unique CRF page, 10 minutes per non-unique CRF page,2 DM reviews at 6 minutes per CRF page per review, 2 DM updates at 6 minutes per CRF page per review, 2 Statistician
reviews at 6 minutes per CRF page per review, 1 hour Organisation Printing Subject Diary, 1 hour per page 2 rounds of PM/LCRA Clinical review.
Per Finalized CRF (Efforts based on Total/Unique Pages Assumed)
1
18,315
18,315
 
 
17
 
 
STUDY
PREPARATION SERVICE COSTS
  
Unit Type
#
Units
Unit
Price
USD
Critical Document Collection (sites)
Critical Document Collection at Site Start up US
Per Site
6
1,519
9,114
Investigator Brochure
Assumes Review only by the Medical Writer (approx. 10 hours)
Per IB
1
1,720
1,720
Patient Informed Consent (Review Only)
ICF Template Review Only:
Per Template
1
1,720
1,720
 
Review of Master version:
Per Review
1
688
688
US
Adapt for site requirements:
Per Site
6
172
1,032
 
Review by Lead CRA of site versions:
Per Site
6
172
1,032
Other Documents Writing/Review/Tra nslation
Monitoring Plan Development (Review only):
Per Plan
1
1,720
1,720
 
Monitoring Plan Maintenance:
Per Month
36
86
3,096
 
Study Operations Manual Writing (Review only):
Per Manual
1
1,720
1,720
 
Study
Operations Manual
Per Month
36
86
3,096
 
 
18
 
 
STUDY
PREPARATION SERVICE COSTS
  
Unit Type
#
Units
Unit
Price
USD
 
Maintenance:
        
Regulatory Affairs
RA - Reg Consultancy
Per Month
43
153
6,558
 
RA -IND & Amendments
Per IND
1
48,984
48,984
           
     
0
N/A
0
IRB/IEC
Submissions
US
Per
Submission/Si to
6
1,376
8,256
U.S. Investigator Meeting
Assumed a one day IM
Per Meeting
1
N/A
0
EU Investigator Meeting (EEU Sites Attend)
  
Per Meeting
1
N/A
0
Project Specific Training
Project review (protocol, CRFs, etc) for study team
Per
Study/Trainin g
1
19,792
19,792
Sub-total for study
preparation
        
133,493
 
 
 
19
 
 
CLINICAL CONDUCT SERVICE COSTS
  
Unit Type
#
Units
Unit
Price
USD
Pre-study Visit
Assumes no visits needed
        
Initiation Visit
1 visit per site.
        
6 sites US
1 hrs per visit prep, 7 hrs per visit on site, 3 hrs per visit for report writing and follow up, 9 hrs per visit travel US.
Per Visit
6
2,700
16,200
Monitoring Visit
12 Visits per site.
        
6 sites US
1 hrs per visit prep, 8 hrs per visit on site, 3 hrs per visit for report writing and follow up, 9 hrs per visit travel US.
Per Visit
72
2,835
204,120
Closure Visit
1 visit per site.
        
6 sites US
1 hrs per visit prep, 8 hrs per visit on site, 4 hrs per visit for report writing and follow up, 9 hrs per visit travel US.
Per Visit
6
2,970
17,820
Site Contact / Management
Units per Site per Month:
        
6 sites US
43 months.
Per Site * Per Month
258
389
100,440
Clinical Safety
Project Set-up
EmpiricaTrace Database request and set up (configuration - drug/reports), including QC/checking (including excel tracker). Safety Management Plan/Process Guideline development (including forms/completion guides) ­including one round of Actinium review (additional reviews fee-for-service).
Per Set-up
1
8,746
8,746
Clinical Safety Project
Maintenance
Database Maintenance (updating, license, upgrades, internal QC/QA checks). Monthly report (including compliance report). Project safety maintenance (general filing, regulatory updating, etc.).
Per Month
42
1,190
49,980
 
 
20
 
 
CLINICAL CONDUCT SERVICE COSTS
  
Unit Type
#
Units
Unit
Price
USD
 
Case
Management
Initial SAE processing: receipt, entry, coding, distribution, draft narrative creation, creation of CFF; follow-up SAE processing: receipt, entry, distribution and narrative revision. Medical review of SAEs by Safety Physician. SAE Follow-up management (2nd cycle ), assumes 1 additional cycle: Processing: Site queries, receipt, entry, (re-coding), narrative revisions, distribution. Medical review of SAEs by Safety Physician.
Per SAE
74
2,676
198,024
Expedited Activities - US
Analysis of similar events, Preparation of safety letters(MedWatch form/mail merge), Mailing and distribution to FDA, Mailing/distribution to sites.
Per
Expedited
7
1,258
8,806
End of Study Activities - Case Closure
Review case for
completeness and prepare for finalization. Complete, lock, close SAE case to further modification. SAE Reconciliation.
Per Case
74
339
25,049
End of Study - Archival
Packaging and shipping files to the Sponsor.
Per Study
1
1,480
1,480
Documentation Management:
TMF Startup
        
 
TOC Document (SF/CF/ISF)
Per Study
1
350
350
 
In-House Site File (IHSF) - Set Up electronic sites and Files/Folders including set­up of the checklist
Per Site
6
158
945
 
Investigator Site File (ISF)/Reg Binder - set-up folder/ship to site
Per Site
6
105
630
 
Study File (SF) Set-Up /Folders/electronic file and checklists
Per Study
1
525
525
 
 
21
 
 
CLINICAL CONDUCT SERVICE COSTS
  
Unit Type
#
Units
Unit
Price
USD
 
TMF (In-House Site File (ISF)) Maintenance
        
6 sites US, 42
months
 
Per Site * Per Month
Per Site * Per Monitoring Visit
72
313
22,536
 
TMF (Study File) Maintenance
        
 
Study File filing per month
Per Month
44
315
13,860
 
Quality Control
        
 
PM (periodic review of IHSF, CF, SF to ensure files are complete and request correction if necessary)
Per Month
44
175
7,700
 
TMF Close Out
        
 
Archive ISF reconciliation- transmittal completion
Per Study
6
697
4,182
 
Study File
Per Study
1
2,590
2,590
Sub-total for
clinical
conduct
        
683,983
 
PROJECT
MANAGEMENT SERVICE COSTS
  
Unit Type
#
Units
Unit
Price
USD
Project Management - US PM
40% FTE over set up phase
Per Month
3
11,200
33,600
Project Management - US PM
30% FTE during recruitment
Per Month
24
8,400
201,600
Project Management - US PM
20% FTE during treatment
Per Month
12
5,600
67,200
Project Management - US PM
30% FTE during close out for the US Project Manager.
Per Month
4
8,400
33,600
 
 
22
 
 
PROJECT
MANAGEMENT ANAGEMENT SERVICE COSTS
Unit
Type
#
Units
Unit
Price
USD
Sub-total for project
management
       336,000
 
CLINICAL
ADMINISTRATION SERVICE COSTS
Unit Type
#
Units
Unit
Price
USD
CPC Activities - US CPC
20% FTE over set up phase
Per Month
3
3,360
10,080
CPC Activities - US CPC
15% FTE during
recruitment
Per Month
24
2,520
60,480
CPC Activities - US CPC
7.5% FTE during treatment
Per Month
12
1,260
15,120
CPC Activities - US CPC
15% FTE during close out for the US CPC.
Per Month
4
2,520
10,080
           
           
Project Team Meeting
Assumes Monthly team meetings
Per Month
44
2,503
110,116
Actinium Meeting - Kickoff (Assumes 1 days in Duration)
Assumes one kick off meeting
Per Meeting
1
15,494
15,494
Actinium Meeting - Teleconferences
Assumes monthly calls
Per
Teleconference
44
842
37,026
Sub-total for clinical
administration
         258,396   
                                                                                                                  
DATA MANAGEMENT SERVICE COSTS
 Paper
Unit Type
#
Units
Unit
Price
USD
Biometrics Project Coordination
20 hours/month during DM startup and closeout.
Per Month
6
3,440
20,640
 
 
23
 
 
DATA  MANAGEMENT SERVICE COSTS
Paper
Unit Type
#
Units
Unit
Price
USD
 
4 hours/month during maintenance phase.
Per Month
35
688
24,080
Database Set up
4 hours per unique CRF page, 2 dictionaries set up, 3 hours per dictionary, 4 hours creation dummy patients, 38 hours testing, 1 day
documentation,                               4
hours Database set-up, 3 hours data transfer structure
Per Unique CRF Page
38
854
32,465
Database Maintenance
2 hours/month for maintenance and back up
Per Month
41
302
12,382
Data Handling Manual - Generation Maintenance & Filing
88 hours Data handling manual generation and maintenance.
Per Study
1
11,000
11,000
CRF Completion Guideline
30 min. per CRF page completion guidelines
Per CRF Page
70
63
4,375
Database Validation Checks Specification & Review
5 Checks per total CRF page, 15 Minutes per check specification and review; 2 reviews, 2 minutes per check per round of review, 4 updates, 4 hours per round of updates.
Per
Validation Check
350
45
15,875
Data Validation Checks
Programming & QC
5 Checks per total CRF page, 20 Minutes per check programming:, 12 Minutes per check testing, including dummy patient
Per
Validation Check
350
75
26,417
Data Entry & CRF Tracking & Archiving (All CRF driven costs assume 15% of patients (-11) will
250 pages per day per person double data entry. Assumes 15% of patients (-11) will only complete 50% of the CRF pages; 40 min per
Per CRF Page
4795
6.21
29,760
 
 
24
 
 
DATA                                    Paper
MANAGEMENT SERVICE COSTS
Unit Type
#
Units
Unit
Price
USD
only complete 50% of the CRF pages
100 CRF pages - CRF Tracking; CRF Archiving 10 min per 100 CRF pages;
        
Interim QC
2 interim QC day 2 days
Per QC
1
2,560
2,560
Final QC
3 final QC day 3 days.
Per QC
1
5,760
5,760
Data Import/Export
4 hours per data transfer, 3 transfers
Per
Transfer
3
604
1,812
Patient Profile Programming - General Listings & Report
4 days Patient Profile Programming
Per Listing
8
624
4,992
Discrepancy Review and Data Consistency Review
1 discrepancy per CRF page, 1.5min. per discrepancy. 0.5 min. per page Data consistency review.
Per CRF Page
4795
4.43
21,250
Query Management
10 Queries per 100 CRF pages, 12 min. per query.
Per Query
479.5
25.03
12,000
Lab Normal Management Per Site
8 hours per site, Lab normal Management.
Per Site
6
1,000
6,000
SAE Reconciliation
74 SAEs in total, 30 min per SAE reconciliation by DM.
Per SAE
74
63
4,625
Database Lock
18 hours for Database lock
Per DB Lock
1
2,250
2,250
Conmed Coding & Review
5 concomitant Medications per patient, 4 min. per term.
Per Coded Term
370
6.00
2,220
AE Coding & Review
5 adverse events per patient, 5 min. per term.
Per Coded Term
370
7.60
2,812
SAE Coding & Review
1 SAE's per patient, 5 min. per term.
Per Coded Term
74
8.00
592
Medical Condition
Coding & Review
5 medical conditions per patient, 4 min. per term.
Per Coded Term
370
6.00
2,220
 
 
25
 
 
DATA MANAGEMENT SERVICE COSTS
Paper
Unit Type
#
Units
Unit
Price
USD
Sub-total for data management       246,087   
 
BIOSTATISTICS SERVICE COSTS
Unit Type
#
Units
Unit
Price
USD
Statistical Analysis Plan Writing & Review
60 hours Statistician.
Per Plan
1
13,800
13,800
Unique Tables
30 tables, 6 hours per table.
Per Unique Table
30
936
28,080
Unique Listings
20 listings, 3 hours per listing.
Per Unique Listing
20
468
9,360
Unique Figures
5 Figures, 3.5 hours per Figure.
Per Unique Figure
5
562
2,808
Final Analysis
60 hours final analysis.
Per Final Analysis
1
13,800
13,800
Stat.Report Writing & Review
20 hours
Per Report
1
4,600
4,600
Sub-total for biostatistics
         72,448   
 
STUDY REPORT
Unit
Type
#
Units
Unit
Price
USD
Clinical Study Report
Write & QC Shell report, Incorporation of Sponsor comments and QC, Key Messages Report Meeting (preparation and attendance), Write fully integrated clinical trial report (assuming all tables, listings, patient narratives are provided by Clinical Safety) including all appendices, Medical Review, Quality control check of report (full check back to the raw data), Incorporation of Sponsor comments and QC, Collation of Electronic Appendices
Per Study Report
1
36,782
36,782
Sub-total for
Study report
         36,782
                                                                                                                  
 
26
 
 
OVERHEAD
        
 USD
Overhead 4% of Labor
         70,688
    Sub-total for Overhead         70,688
TOTAL
          
APTIV
          
COSTS
        
1,837,876

 
27
 
 
ESTIMATED PASS­THROUGH COSTS
USD
Qualification Visit Travel Expenses
Sites have been previously qualified
N/A
Initiation Visit Travel Expenses
6 Initiation Visits @ Est. 600/visit
3,600
Interim Monitoring Visit Travel Expenses
72 Interim Monitoring Visits @ Est. 600/visit
43,200
Closeout Visit Travel Expenses
6 Closeout Visits @ Est. 600/visit
3,600
IRB/IEC Fees
Estimated 3,000 per site
18,000
Regulatory Fees (HA Submissions)
Estimated 4,000 per country
4,000
Investigator Fees
Actinium will perform contracting and payment tasks for this project.
N/A
TOTAL ESTIMATED PASS- THROUGH COSTS
  
72,400

 
 
28
 
 
Appendix D: Payment Schedule
 
Initial Payment: USD$230,000, which is 12.5% of the Total Aptiv Solutions Services fees is due upon execution of this Project Agreement. Of this amount, Actinium Pharmaceuticals has already paid to Aptiv Solutions the amount of US$150,000 prior to execution of this Project Agreement which shall be credited against the Initial Payment referenced above. Upon execution of this Agreement and receipt of an appropriate invoice, Actinium Pharmaceuticals will pay Aptiv Solutions USD$80,000, being the difference between the total Initial Payment and the credited amount. The total Initial Payment of USD$230,000 will be credited against the final Project invoices.
 
In addition, 12.5% of the Pass Through Budget ($9,050) is due upon execution of this Project Agreement. This amount will be credited against the final invoices for Pass Through Costs.
 
Thereafter, invoices will be sent monthly for all work performed for the previous month on a unit basis in accordance with the annual rate that corresponds with the year in which the work is performed.
 
 
 29