Document:

f8k122812a1ex10xxi_cactus.htm

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

 

  

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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")

 

  

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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

 

  

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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

 

  

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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.

 

  

13

  

 

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

 

  

14

  

 

*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.

 

 

 29f8k122812a1ex10xxii_cactus.htm

Exhibit 10.22

 

	

 

Proposal for

 

Actinium Pharmaceuticals, Inc.

 

225Ac-Labeling of HuM195

 

March 30, 2007

 

Prepared by:

 

IsoTherapeutics Group, LLC 

1004 S. Velasco St. 

Angleton, TX 77515

 

	
IsoTherapeutics Group, LLC 

	CONFIDENTIAL 	Page 1 of 10

 

  

  

  

 

	Propodal for API	 3/30/2007

 

Table of Contents

 

	Purpose 	 3
	
Responsibilities 

	 3
	
API will provide 

	 3
	
ITG will provide 

	 3
	
Study Proposal — Executive Summary 

	 3
	
Study Proposal — Details 

	 6
	
Stage 1 — Review previous work 

	 6
	
Stage 2 — Complexation w/ DOTA 

	 6
	
Stage 3 — Complexation w/ BFC 

	 7
	
Stage 4 — Conjugation 

	 7
	
Stage 5 — Label HuM195 w/ 225Ac 

	 8
	
ITG Consultation Services 

	 8
	
Time Estimate 

	 8
	
Cost Estimate and Payment Schedule 

	 9
	
Cost Estimate 

	 9
	
Payment Schedule 

	 10
	
Signatures

	 10

 

	
IsoTherapeutics Group, LLC 

	CONFIDENTIAL 	Page 2 of 10

 

  

  

  

 

	Propodal for API	 3/30/2007

 

Proposal for Actinium Pharmaceuticals, Inc

225Ac-Labeling of HuM195

 

Purpose

 

This is a proposal by IsoTherapeutics Group, LLC (ITG) for Actinium Pharmaceuticals, Inc. (API) to work on the improvement of 225Ac-labeling of HuM195.

 

Responsibilities 

 

API will provide

●HuM195 monoclonal antibody and applicable information

●225Ac as required

●Applicable data from prior work

●Funding

 

ITG will provide

●     Supplies and materials

●Laboratory facility

●Labor

●Interim and final reports

●Consulting as as requested and authorized by API in writing

 

Study Proposal Executive Summary

 

The object of this work is to improve the overall yield of 225Ac labeling of HuM195 monoclonal antibody (mAb). The proposal is staged as indicated in the flow chart (Figure 1) and in the outline below. The proposal is intended to be flexible, with both parties reviewing the results of each Stage prior to initiation of the next Stage. The scope, deliverables, and estimated costs for the next stage will be adjusted as mutually agreed upon prior to initiation of that Stage. The estimated total cost to API for the entire proposal as outlined herein is $112,000. Details on the cost breakdown and payment terms are found in later sections.

 

In addition to the defined portions of this proposal, ITG will provide, at API's request, additional consulting as needed on matters outside the scope of this proposal. This will be done at an hourly rate of $200.

 

	
IsoTherapeutics Group, LLC 

	CONFIDENTIAL 	Page 3 of 10

 

  

  

  

 

	Propodal for API	 3/30/2007

 

	
Figure 1. Flow chart of stages proposal

 

	
 

The finished radiopharmaceutical is assembled from three parts, the mAb, the bifunctional chelant (BFC), and the 225AC. There are two stepwise ways of accomplishing this, conjugation followed by complexation:

 

1) mAb + BFC 4 mAb-BFC                                                       2) mAb-BFC + n5Ac mAb-BFC-225Ac

 

or complexation followed by conjugation:

 

1) BFC + 225AC --> BFC-225AC                                               2) mAb + BFC-225Ac 4 mAb-BFC-225Ac

 

The former method may be preferable from a manufacturing standpoint; however, the best results to date have been by the later approach. This proposal will explore both methods with the goal being maximization of 225Ac labeling yield.

 

In Stage 1, all available data from prior work will be reviewed. This includes work done by Memorial Sloan-Kettering Cancer Center (MSKCC), Oak Ridge National Laboratory (ORNL), and The Dow Chemical Company (Dow).

 

	
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In Stage 2, complexation conditions for 225AC will be optimized in a designed experiment using DOTA, a surrogate for the bifunctional chelating agent (BFC) SCN-Bz-DOTA. Additionally, 225AC will be purified and this purified "-*Ac will be complexed using the optimized conditions.

 

In Stage 3, the stability of the SCN-Bz-DOTA BFC will be evaluated under the conditions found to be optimum for 225AC complexation. If stability is an issue, i.e. if the BFC degrades under conditions required to obtain significant 225AC complex, then an alternative conjugation procedure involving the in situ formation of SCN-Bz-DOTA from NH2-Bz-DOTA will be investigated. Complexation of 225AC using the BFC(s) will be performed.

 

In Stage 4, the conjugation of the BFC will be optimized in a designed experiment. Finally, in Stage 5, process options will be prioritized and evaluated.

 

A brief outline of the stages in the plan is given below.

 

1. Stage 1 — Review previous work

a. MSKCC (McDevitt)

b. ORNL

c. Dow Chemical

 

2. Stage 2 — Complexation w/ DOTA

a. Purify 2z Ac

b. Complex ORNL 225AC w/ DOTA (designed experiment)

c. Complex purified 225AC w/ DOTA (optimum conditions)

d. Interim report

 

3. Stage 3 — Complexation with BFC

a. Stability of SCN-Bz-DOTA under optimum complexation conditions

b. Complex 225AC w/ SCN-Bz-DOTA or

c. Explore use of NH2-SCN-DOTA

d. Interim report

 

4. Stage 4 — Conjugation

a. Optimize BFC conjugation to HuM195 using tracelnLu

b. Interim report

 

5. Stage 5 — Label HuM195 w/ 225AC

a. Propose & prioritize process options

b. Evaluate proposed process(es)

c. Final report

 

	
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Study Proposal - Details

 

Additional detail for the staged proposal follows. Proposed deliverables for each Stage are listed. It is understood that, with mutual agreement, these details will evolve as the project progresses. Additionally, deliverables and funding will be agreed upon prior to the initiation of each stage.

 

Stage 1— Review previous work

 

In this stage, all available data from prior work on the optimization of 225AC labeling will be reviewed. The data will come from various sources; API, MSKCC, ITG, and Dow. It is understood, however, that ITG (former Dow employees who worked on this problem while at Dow) does not have direct access to Dow confidential information.

 

This stage will be performed at no charge and is, in fact currently underway.

 

Deliverables:

1. Defined plan to move forward

 

Stage 2 — Complexation w/ DOTA

 

In this stage, the complexation of 225AC will be optimized in a designed experiment. Parameters to be explored are pH, time, temperature, concentration, and buffers. DOTA will be used as a surrogate for the BFC SCN­Bz-DOTA. The BFC has a reactive isothiocyanate group (SCN-) to attach to a lysine residue on the mAb. The presence of this SCN- group would complicate the experiments on optimizing the complexation conditions. As can be seen from the structures in Figure 2 below, the chelating portion of the BFC is DOTA.

 

Consideration will be given to the potential sensitivities of the SCN- moiety (in the case of complexation first) or of the mAb (in the case of conjugation first) when optimum conditions are decided upon.

 

In parallel with this designed experiment, we will attempt to purify 225Ac of any metallic contaminants that could potentially interfere with the chelation. Metal-specific resins may be employed to accomplish this. The purified 225AC will then be complexed with DOTA and these results compared to those above with the unpurified 225AC. Alternate sources of 225Ac may also be examined. The estimated cost to API for Stage 2 is $37,000.

 

	
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Figure 2. Structures of DOTA and the BFC SCN-Bz-DOTA

 

 

Deliverables:

1. Optimum 225Ac-DOTA complexation conditions defined

2. Interim report

 

Stage 3 - Complexation w/ BFC

In this stage the stability of the BFC will be examined under the conditions determined to be optimum for complexation. This will be important if complexation is done prior to conjugation. If the SCN- survives these conditions, then 225AC will be complexed with the BFC to verify these conditions. If stability of the BFC is an issue, i.e. if the SCN- moiety is hydrolyzed to a significant extent under the complexation conditions, then the use of NH2-Bz-DOTA will be explored. This is the precursor to SCN-Bz-DOTA which can be made in situ during the conjugation reaction. The estimated cost to API for Stage 3 is $33,000.

 

Deliverables:

1. Assessment of SCN-Bz-DOTA stability

2. Complexation conditions for either SCN-Bz-DOTA or NH2-Bz-DOTA

3. Interim report

 

Stage 4 - Conjugation

Using 177Lu as a tracer, the conjugation conditions for the BFC (either SCN-Bz­DOTA or NH2-Bz-DOTA) will be optimized in a designed experiment. Parameters to be varied may include pH, time, temperature, concentration, and buffers. Consideration will be given to the known stability of the HuM195 mAb. Determination of immunoreactivity of the mAb (e.g. by ELISA) is not part of this proposal but may be optionally added.

 

	
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	Propodal for API	 3/30/2007

 

 

The trace 177Lu will allow the determination of conjugation yield and average loading value (ALV), i.e. the number of BFCs per mAb. Optionally, the conjugation yield and ALV can be determined using MALDI-TOF mass spectrometry. This is not a part of this proposal, but may be added with mutual agreement. The estimated cost to API for Stage 4 is $21,000.

 

Deliverables:

1. Optimum conjugation conditions

2. Interim report

 

Stage 5 - Label HuM195 w/22AC

In this stage, options for 225Ac labeling of HuM195 will be proposed and prioritized. These options include process order (complexation-conjugation or conjugation-complexation) and conditions for complexation and conjugation. The preferred process will be evaluated. The estimated cost to API for Stage 5 is $21,000.

 

Deliverables:

1. Defined process maximizing the 225Ac labeling yield

2. Final report

 

ITG Consultation Services

At the request of API, ITG is willing to provide consultation services in areas not specifically delineated in this proposal, e.g. technology transfer or manufacturing oversight. These services will be performed at an hourly rate of $200.

 

Time Estimate

The estimated time required for the various stages of this proposal is indicated in the Gantt chart in Figure 3 below. It is understood that this is an estimate and that scope changes and unforeseen issues may affect the timeline.

 

	
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Figure 3. Gantt Chart

 

 

Cost Estimate and Payment Schedule 

 

Cost Estimate

The cost estimate for the stages of this project is given in the table below. It is understood that, with mutual agreement, scope changes may result in modifications to this estimate.

 

	  	 	
M&S

	 	 	
Labor

	 	 	
Other

Expenses

	 	 	
Total

	 
	
1. Review previous work

	 	$	-	 	 	$	-	 	 	$	-	 	 	$	-	 
	
2. Complexation w/ DOTA

	 	$	2,000	 	 	$	30,000	 	 	$	5,000	 	 	$	37,000	 
	
3. Complexation w/ BFC

	 	$	2,000	 	 	$	28,000	 	 	$	3,000	 	 	$	33,000	 
	
4. Conjugation

	 	$	3,000	 	 	$	18,000	 	 	$	-	 	 	$	21,000	 
	
5. Label HuM195 w/ Ac-255

	 	$	-	 	 	$	21,000	 	 	$	-	 	 	$	21,000	 
	
Total

	 	$	7,000	 	 	$	 97,000 	 	 	$	8,000	 	 	$	1 112,000	 

 

Consultation work outside the above defined stages will be performed at a cost of $200/hour.

 

	
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Payment Schedule

Payment by API to ITG for each stage will be made as follows:

 

50% prior to initiation of each stage

50% upon completion of the final deliverable for that stage

 

Deliverables and cost will be mutually agreed upon prior to initiation of each stage. The final deliverable will be a report on the work done during that stage.

 

Fees for consultation services, if used, will be billed monthly. 

 

Payment is due on receipt of invoice.

 

Signatures

 

Agreed upon and accepted by:

 

	/s/ Howard S. Wachtler	Date	5/4/07	/s/ R. Keith Frank, Ph.D.	Date	1/26/07
	
HOWARD S. WACHTLER

PRESIDENT & CEO

	 	 	
R. Keith Frank, Ph.D.

PRESIDENT & CEO

	 	 
	Actinium Pharmaceuticals, Inc.	 	 	
IsoTherapeutics Group, LLC

	 	 

 

	
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