An Operating Division of Averion International Corp. *CONFIDENTIAL*

 

Millennix Oncology is pleased to provide a proposal to Actinium Pharmaceuticals Inc. (Sponsor) in support of a Phase I/II clinical trial.

 

Millennix Oncology, an operating division of Averion International Corp, provides expertise and experience in support of oncology clinical trials. Together with Averion which celebrates its 23nd anniversary in 2006, our history is driven by our commitment to our clients to maintain high standards of communication, quality, and accountability. Averion will keep Actinium current with project progress toward milestones. Our group has existing personnel, facilities, and resources to support all aspects of the project. Averion uses state-of-the-art software and hardware to support all projects while performing all work under industry-accepted SOPs. To date, we have supported 42 FDA approvals including 8 approvals in oncology.

 

Our proposal defines project task specifications for the services listed below.

Millennix Oncology will provide regulatory and clinical trial management services to Actinium Pharmaceuticals for the Phase I/II development of its study drug, 225Ac-HuM195 in patients with myeloid malignancies.

 

Millennix Oncology, a division of Averion International Corp., is a full-service CRO with 250 full-time employees including 35 data managers (including database developers, data managers, data entry specialists), 40 clinical affairs specialists (including Lead CRAs, regional CRAs, project managers, clinical assistants), 15 biostatisticians (including SAS programmers), 7 medical specialists (including physicians, nurses, safety specialists), IT support specialists, operations (supporting metrics, new technologies, resource management), and a quality assurance group (supporting quality systems, compliance, validation, audits). We have earned a reputation as a high quality CRO during our 22 year history.

 

Millennix Oncology offers many advantages to Actinium for supporting this pivotal study. We have extensive experiences with complex oncology indications, study populations and trial activity. Consequently we will be able to rapidly engage staff and quality systems to launch the study.

 

 

The inclusion/exclusion criteria are highly specific, and involve objective measures (e.g., leukemia classification, cell flow cytometry), medical history, and prior treatment. The sites will need to pay careful attention to these criteria, and monitors will go to the sites early on to assure proper implementation of the protocol.

 

Sites need to be adequately trained on the study procedures and methodology (e.g., marrow analysis). The bulk of this training will occur at the Investigator Meeting, though additional training will occur during the course of the study, particularly at site monitoring visits.

 

As several of the secondary endpoints may be patient-derived, the sites must adequately train patients to report symptoms and events.

 

Patient in this study will have a baseline of medical history and signs/symptoms. It will be important for sites to establish the patient's baseline (i.e., medical history), so that if the

 

frequency or severity of an event changes, the event can be proper characterized as an adverse event (AE). The definition of an AE will be clearly defined in the protocol so that an event that is part of the natural history is not being classified as an AE, especially not one associated with drug treatment.

 

Millennix was founded in 1997 and joined with Averion International in 2005. We have supported 45 FDA approvals to date. As illustration of our visibility, we helped gain five oncology approvals to date inclusive of drugs (Gleevec, Erbitux), biologics (Mylotarg, ONTAKT4) and devices (CA-125, PSA, Quadramet, and LUMA). We are well-known to the FDA review branches for oncology. We have extensive experience in all aspects of the desired services and are confident that we can meet high quality standards. Averion brings the following specific experiences in Prostate and other GU malignancy:

 

●	Strategic Assessment for Radiopharmaceutical Development

●	IND preparation/filing\

●	Implementation Phase I/IUIV Monoclonal Antibody (4 studies)

●	FDA-mandated Safety Registry

●	Post-transplant use

●	Side effect profile

●	US/EU Compassionate Access program

●	Field monitoring - STI571 - Imatinib Mesylate - Signal Transduction (TK) Inhibitor

●	Site recruitment & mgmnt - AML in elderly

●	Mucositis protectant - Phase III - Autologous transplant

●	Cytokine TP Prevention — MM, AML

●	IV Supplement — Chemotherapy Anemia — MM

●	Rescue Program — MM — Complex regimen

 

●	has comprehensive, FDA and Sponsor audited SOPs to govern all aspects of involved services

●	prospectively documents employee training and SOP mastery

●	has SAS based and Oracle-based 21 CFR Part 11 validated software for data management and file transfer

●	has systems to track the location and acceptance of each CRF page

●	has logic checks to identify inconsistencies or missing data including systems to track each reader review

●	has a firewall for maintaining data backup security and daily backup protection (Iron Mountain)

●	offers on-line data browsing capability to Actinium for checking data status at any time

●	has metrics for tracking site, reader, CRA, and staff performance

●	has a safety database and process for dealing with any issues (medical vs. device-related)

●	uses SAS for generation and validation of all analyses

●	pre-writes the integrated clinical and statistical report to speed ICSR completion

●	maintains central files to collect all study documents

●	conducts ongoing internal and external audits to ensure quality is achieved

●	keep Actinium current through conference calls, e-mails, and team meetings as desired.

 

This proposal and accompanying budget does not assume the use of electronic data capture (EDC) for this size study. We have worked with several EDC vendors, and have qualified preferred vendors for the appropriate situation.

Millennix Oncology has relevant clinical trials experience. Our leadership, line managers, and staff understand GCP and the requirements put forth in the RFP. Averion and its associates understand the Nocturia literature, can train sites and staff in a timely manner, will motivate the sites through frequent contact and site visits, will know the key monitoring issues, appreciate the study complexities, and will work collaboratively with the Sponsor and sites to complete the study in a timely manner. We look forward to the opportunity to work with Actinium Pharmaceuticals on this study.

4.

Site Qualification

 

If directed by the Sponsor, Millennix Oncology will conduct the site qualificationvisits to determine if: (1) the principal investigator and study personnel have adequate time and experience to conduct the study according to the protocol; and (2) the facility is acceptable, with secure areas for storage of the investigational product. Prior clinical trials experience of study investigators and support personnel will be assessed. Millennix Oncology will look for evidence of sufficient numbers of patients to meet accrual objectives and the duration of contact with these patients. GCP understanding will also be assessed.

 

5.

Study Initiation Visits

 

The initiation visit will be conducted once all pre-study documents have been collected. Millennix Oncology and Sponsor estimate 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 device use and accountability. The study regulatory binder will be reviewed with the investigator. GCP requirements, including investigator responsibilities, will be reviewed.

 

6.

Interim Monitoring Visits

 

Millennix Oncology will initially conduct site visits approximately two weeks after the first patient is enrolled at each site; subsequent monitoring visits will be scheduled depending on enrollment rate and data quality. It is estimated that one-day and two-day visits will be required. The frequency and length of visits will be adjusted as agreed upon by Sponsor and Millennix Oncology, based on patient enrollment and site quality.

 

During site visits, Millennix Oncology will check investigator adherence to FDA Good Clinical Practices, verify informed consent and HIPAA authorization, review all source documentation in comparison to the CRFs, check for missing or incomplete data and inconsistencies, obtain resolution of Data Clarification Forms, obtain documentation updates, and verify that the protocol is being followed with respect to eligibility, study-mandated procedures, and timetable. Millennix Oncology 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, Millennix Oncology, Sponsor, and the site will jointly develop an action plan. Completed CRF pages will be retrieved and forwarded to Millennix Oncology.

 

7.

Site Closeout Visits

 

Millennix Oncology will perform the Site Closeout Visit once all Data Clarification Forms have been resolved. Millennix Oncology will review all patient files for completeness, review the study binder to assure all documentation is in place for an FDA audit, perform final device accountability, and authorize return or disposal of all unused study supplies.

8.

Monitoring Coordination

 

The Millennix Oncology Lead CRA will be responsible for addressing site-emergent questions and problems. The Lead CRA will consult with the project team, management of Clinical Affairs, clinical study vendors, and Sponsor as needed. Millennix Oncology will inform Sponsor immediately of any issues requiring the sponsor's immediate attention (for example, serious adverse events).

 

The Lead CRA will work with Clinical Affairs Management to ensure all sites have an assigned CRA and that all CRAs assigned to the study have the appropriate training and will conduct ongoing study training as necessary. The Lead CRA will be responsible for managing the monitoring visit schedule and ensuring that all sites are being visited at the appropriate intervals.

 

The Lead CRA will review all monitoring visit reports and regulatory documents to ensure accuracy and completeness, and to ensure that the study is being conducted in accordance with GCP, the protocol, and the monitoring plan. The Lead CRA will also be responsible for providing study updates to the Project Manager and Actinium as needed (i.e., for monthly status reports or on an ad hoc basis).

 

The Clinical Project Coordinator will track monitoring visit reports and other visit related documents (e.g. confirmation, follow-up letters, and expense reports) under the direction of the Lead CRA to ensure all documents are completed and reviewed in a timely manner in accordance with the monitoring plan. The CPC will maintain the CTMS database, including entry and updating the system with site contact information and regulatory document information.

 

9.

Site Communication

 

The Millennix Oncology Lead CRA will be the primary contact for the study sites and the CRAs. The Lead CRA will consult with the Project Manager, Millennix Oncology Management and the Sponsor as needed. Millennix Oncology 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.

 

The Clinical Project Associate may also contact the sites for missing Enrollment Logs and outstanding or deficient Regulatory Documents.

 

10.

Contract/Budget Negotiation (Optional)

 

If directed by the Sponsor, Millennix Oncology will negotiate Investigator budgets based on agreeable rates determined jointly by Sponsor and Millennix Oncology. Millennix Oncology will obtain signed contracts/budgets from the clinical sites. All legal negotiations will be referred to the Sponsor.

E.

Medical Monitoring

 

A Millennix Oncology MD will discuss patient eligibility, discuss protocol deviations, interact with the project team, review documents (protocol, CRF, adverse events, clinical study report), and interact with the project team at Actinium. The Millennix Oncology Medical Director will be available during usual business hours. Additional back-up coverage can be arranged if requested by Actinium.

 

F.

Safety Review and Serious Adverse Event Reporting

 

1.

Safety Review

 

The Medical Monitor together with The Project Manager will conduct regular, ongoing review of adverse events and AE trends during the project lifetime. The results of this review will be forwarded in a quarterly report to Actinium with comment, notation or opinion as warranted.

 

2.

Serious Adverse Event Reporting

 

The Millennix Oncology Medical Monitor will be responsible for all SAE reporting to the sponsor and will prepare safety letters for IND filing as necessary in collaboration with Millennix Oncology Regulatory Affairs.

 

G.

Clinical Site Audits for Good Clinical Practice/Quality Assurance

 

1.

Audit Plan

 

Millennix Oncology can develop an initial site audit plan including site selection criteria, audit parameters and specifications, follow up, timelines, report format, etc. The plan can be provided to Actinium for review and approval.

 

2.

Good Clinical Practice/Quality Assurance Audits (GCP/QA)

 

Millennix Oncology can perform GCP/QA audits of clinical sites, including review of regulatory documents, study files, and data, as specified in the approved audit plan. Additional audits (routine, for-cause) or co-audits will be conducted as mutually agreed upon. Site audit tracking reports can be provided to Actinium in mutually agreed upon format and frequency.

 

3.

Good Laboratory Practice/Quality Assurance Audits (GLP/QA)

 

Millennix Oncology can perform a GLP/QA audit including review of standard operating procedures, documentation, study files, and data, as specified in the approved audit plan.

 

 

H.

Database Development

 

1.

Database Design

 

Millennix Oncology will develop a customized SAS-based/Oracle database including an automated audit trail, auto-encoding using industry standard electronic dictionaries and Case Report Form (CRF) and Data Clarification Form (DCF) tracking tables. A main menu will control the flow of data entry. The data entry screens will be "painted" in the image of the CRF. Valid ranges and field types (number, character, etc.) will restrict entry. The database will provide a "pop-up" window during second entry to display discrepancies for resolution.

 

a.

Audit Trail

 

A comprehensive automated audit trail will capture field level activity including initial entry, second entry, data clarification change, and logic check change. Current and previous data point values will be captured in the audit trail for all changes.

 

b.

CRF Tracking Table

 

Oracle tables will be developed to track the flow of CRFs within Millennix Oncology. CRF identification data and date will be captured for CRF receipt, first entry, second entry, data clarification forms sent out, data clarification forms received, and database edited/closed.

 

2.

Programming

 

A Database Programmer and an independent database reviewer will develop and test the database. Highlights of the software development lifecycle 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.

 

3.

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. Millennix Oncology will run daily back­ups.

 

4.

Imports of Electronic Data

 

Millennix Oncology will work out transfers of electronic data imports with the data import source. The medium, software, and schedule of merges will be mutually agreeable to Millennix Oncology and Sponsor.

 

Upon receipt at Millennix Oncology, the media will be logged and checked for viruses. The electronic data that is to be merged (in Oracle or SAS) with CRF data will be checked for integrity, and mismatched pairs will be identified for clarification. Millennix Oncology will resolve the mismatched pairs with the data import source. The data import source will be responsible for correcting and re­transmitting the data.

 

I.

Data Entry/Tracking

 

1.

CRF/DCF Tracking

 

CRF and DCF tracking tables in Oracle will be maintained to track the dates of CRF received, CRF first entered, CRF second entered, data clarification form sent, data clarifications resolved, and CRF closed. This data will be used by Millennix Oncology to generate monthly CRF/DCF status reports.

 

2.

Data Receipt Review

 

Prior to entry, Millennix Oncology will review the CRF for missing pages and any obvious data problems. These problems will be noted for review during generation of DCFs.

 

3.

Double Data Entry

 

Millennix Oncology will double enter the data; separate individuals perform each entry. Discrepancies between first and second entry will appear in a "pop-up" window to prompt the data entry specialist to either choose a correct value or enter a correct value. Any additional problems identified during entry will be flagged for review during DCF generation.

 

J.

Data Management

 

1.

Data Management Oversight

 

The Lead Data Manager provides project oversight to ensure staffing consistency and ongoing quality control. The Lead Data Manager will provide training to the Data Management staff assigned to the project, and will conduct frequent Data Management team meetings to ensure that pertinent project and subject-specific issues are identified and resolved in a timely fashion.

 

3.

Data Logic Check Definition

 

Logic checks will be defined by Millennix Oncology to identify missing key variables and discrepant data. These data checks will be based on the protocol and will include within field and between field checks. To ensure that appropriate checks are performed, the logic checks will be reviewed and approved by Sponsor prior to the commencement of programming.

 

4.

Logic Check Programming, Testing, and Execution

 

The data logic checks will be programmed using SAS version 8.02 or higher for UNIX. Millennix Oncology will test logic check programming. Millennix Oncology will create and enter test CRFs containing erroneous data, to confirm that the programming for each check is identifying errors correctly. Any problems with the logic checks will be reported to the SAS Programmers for correction. Testing will be considered complete when the logic checks correctly identify all erroneous CRF data. This process will be documented, signed, and filed in the Central File.

 

Logic checks will be run on all data received from the site. Each section of the case report form will be run through the SAS logic checks at least once. Updated records will be re-run through the logic checks to confirm that (1) the changes made corrected the original problem and (2) the changes made did not cause additional data discrepancies.

 

5.

Data Clarification Form Generation

 

Millennix Oncology will generate data clarification forms (DCFs) for each record that resulted in one or more data problems identified during manual review, entry, or logic check generation. DCFs will be sent to the monitors for resolution at site. These DCFs will outline (1) the patient record identification information (e.g. site, patient number/initials, and visit date), (2) the problem identified, and (3) the resolution. The resolution response will be left blank for the site to answer.

 

6.

Database Updates

 

Upon receipt of the completed DCFs, Millennix Oncology will make corrections to the database followed by manual verification of the corrections. Logic checks are then run again to verify that the database change corrected the original problem and did not cause any additional problems.

 

7.

Coding

 

Adverse events will be coded using MedDRA, and WHO-Drug will be used for coding concomitant medications. Following the auto-encoding execution, the Lead Data Manager will verify all assigned codes. Entries that are not an exact match will be manually coded by an experienced Data Manager and included in the thesaurus. Coded terms will be provided to Sponsor for review and approval.

 

 

 

 

 

 

 

 

 

Invoices will be sent monthly for all work performed for the previous month on a Fee for Service basis in accordance with the annual rate that corresponds with the year in which the work is performed. An initial payment of $150,000 is due upon contract execution and will be credited against the last invoice. If Sponsor terminates this project, Sponsor will reimburse Millennix Oncology for all reasonable costs to complete work in progress.

 

This Master Services Agreement ("MSA") is made by and between Averion International Corp. ("Averion"), with an address at 225 Turnpike Road, Southborough, MA 01772 and Actinium Pharmaceuticals, Inc. ("Client"), with an address at 25B Hanover Road, Florham Park, NJ 07932. The parties agree that this MSA shall govern any and all work to be completed by Averion for the Client.

 

As a "master" form of contract, this MSA allows Averion to work on one or more projects without having to re-negotiate the basic terms and conditions contained herein. This MSA will cover work assignments as well as consulting activities without formal work assignments.

 

Client shall engage Averion to provide and Averion shall provide consulting services as directed by the Client in writing or as specified in mutually agreed upon written Work Assignments as well as any mutually agreed upon written modifications (Amendment) to a Work Assignment. Each such Work Assignment and Amendment are governed by the terms and conditions of this MSA; provided, however, that in the event of a conflict between this MSA and a specific Work Assignment/amendment, the Work Assignment/Amendment shall control.

 

If Client wants to change a specific Work Assignment/amendment or to obtain additional services not identified in a Work Assignment, the Client must advise Averion and submit written specifications to Averion. Averion will then supply the Client with a written Change Order for the additional services. Upon written acceptance of the Change Order by the Client, these services will be performed subject to the terms of this MSA.

 

In the event the Food, Drug and Cosmetic Act, or any rule or regulation governing any Work Assignment, including without limitation any Good Clinical Practice regulation, is amended, revised or revoked during the term of any Work Assignment, the parties shall discuss the effect of such change on the Work Assignment. Any changes that Client determines to implement shall be handled as a Change Order, as above.

 

Client remains the sponsor of all studies and has not transferred any obligations to Averion pursuant to 21 CFR 312.52 unless specified in the Work Assignment. In any such instances, the obligations of Averion will be mutually agreed upon by Client and Averion in writing. Client will retain control of the relationship with the FDA unless specified in the Work Assignment.

 

Both parties agree that this MSA supersedes all prior proposals, letters, discussions, negotiations, and agreements of any nature, excluding any prior Confidentiality Agreement between the parties, which shall be replaced by this MSA on the effective date of this MSA. This MSA may be amended only in a writing signed by both the Client and Averion.

 

If one party believes the other has materially failed to perform as provided in this MSA or under any Work Assignment, it shall so notify the other in writing, stating in reasonable detail the nature of the deficiency. Within fifteen (15) business days, the breaching party shall respond in writing with a plan to cure which will specify the agreed upon time to effect a cure, which shall be approved by the non-breaching party, approval shall not be unreasonably withheld. No action arising hereunder may be instituted after one year from when the non-breaching party learns of, or should reasonably be expected to have learned of, the full facts upon which action would be based.

 

(a) Averion may submit to Client a written Work Assignment/Change Order proposal specifying objectives, tasks, assumptions, delivery, and estimated costs, as a proposed Work Assignment/Change Order. All work done by Averion and proposed to Client will be calculated on a fee for service basis with the base rates and estimated completion times specified in each Work Assignment/Change Order. If Client is not satisfied with the written Work Assignment/Change Order proposal, the parties shall use best efforts to resolve any such issues within sixty (60) days of receipt thereof. In any event, Client shall accept any proposed Work Assignment/Change Order by written notice to Averion within sixty (60) days of receipt of Averion's written proposal; otherwise the proposed Work Assignment/Change Order shall be deemed void. All labor rates and other direct costs to be used in Work Assignments and Change Orders are subject to change every January not to exceed 5% per year., The total cost of the project shall not exceed budgeted estimates described in Work Assignments and Change Orders unless scope of work changes or assumptions do not hold (e.g. study enrollment is extended, new sites are activated, additional analyses are required). In the event, Averion is authorized in writing by the Client to begin working on any Work Assignment/Change Order, while the Work Assignment/Change Order is under Client review, Averion will invoice Client on a Fee-for-service basis.

 

(b) Client and Averion will each designate one or more individuals to represent it with authority to make decisions with respect to this MSA and each Work Assignment proposal or Change Order. Each Work Assignment and Change Order must be signed by Client's authorized individual and Averion's authorized individual prior to going into effect.

 

(a) Averion will invoice Client monthly for services provided during the preceding monthly period.

Services performed under a Work Assignment/Change Order will be billed according to the terms of the Work Assignment/Change Order, while consulting without a signed work assignment will be invoiced on a fee for service basis according to the attached rate schedule (Appendix A). Any additional consulting outside a signed work assignment must be agreed to in advance in writing by the Client. Client agrees to pay Averion all charges related to services described in the invoices within 30 days of receipt of invoice. Thereafter, interest shall accrue and be payable at the rate of 12% per annum, calculated at the rate ,of 1% per month. In the event that Client disputes any portion of the invoice, Client shall notify Averion of such dispute within ten (10) business days of receipt and Client and Averion shall mutually agree upon a resolution of such dispute within ten (10) business days of receipt of the notice of dispute. Client will be responsible for payment for any amounts not in dispute, as stated herein. Client shall make all payments to Averion in United States Dollars ("US Currency"). Averion may suspend work on any assignment with thirty days advance notice if payment is in arrears and undisputed. All pass through costs invoiced to Client will be at actual cost with no mark-up for administration or overhead. In the event Averion incurs a pass through cost in a currency other than U.S. Dollars, the parties shall determine the amount payable based on the relevant conversion rate as reported in The Wall Street Journal on the invoice date.

 

(b) A normal business day is an eight-hour day. Partial days or additional hours worked during a 24-hour period will be billed by Averion as actual hours worked. Upon written approval in advance by Client, Client will reimburse Averion for travel and other direct costs incurred by Averion personnel, contractors, or consultants. Averion personnel, contractors or consultants required to travel out of state will bill Client for an 8-hour day for any partial days worked.

Averion personnel, contractors, and consultants are independent contractors and shall not be considered to be Client employees during the term of this MSA. Averion has the right to designate who will work on this project, provided that no contractors or consultants (collectively, "Third Party Contractors") will be designated without the prior written approval of the Client, which shall not be unreasonably withheld. Client can request reassignment of Averion staff or Third Party Contractors for any unsatisfactory performance that is unresolved to Client's satisfaction after written notice to Averion and after Averion has a reasonable opportunity to cure. In the event either party directly or indirectly solicits staff or contractors from each other, the soliciting party agrees to give immediate notice to the non-soliciting party. If either party hires staff or consultants, then the soliciting party agrees to pay 40% of the annual salary of that staff or contractors within three (3) months of the date of the hire to the other.

Representatives, employees, or agents of Averion will not be treated as an employee of Client for any purposes, including, but not limited to, those of FICA, Social Security, federal or state unemployment taxes, income tax withholding, or any other employment law or regulation. As the employer, Averion will: (i) supply only individuals legally authorized to work in the United States; (ii) complete and maintain 1-9 forms in compliance with the Immigration Reform and Control Act of 1986; (iii) conduct background checks to ensure its professionals have no felony convictions during the seven years prior to employment by Averion, nationally and by county of residence; (iv) maintain all necessary personnel and payroll records for its professionals; (v) calculate its employees wages and withhold applicable taxes, Social Security and other government-mandated charges; and (vi) remit such employment-related taxes and charges to the appropriate governmental entity.

 

(a) Averion warrants that its services shall be performed in a timely manner and be of professional quality in accordance with accepted industry standards. Any services provided by Averion which the Client claims are less than professional quality or do not substantially meet the stated performance standards, shall be promptly corrected by Averion without charge to Client provided that the Client provides Averion with a written notice of alleged poor quality at the earliest known opportunity; but in no event later than ninety (90) days after receipt of the final deliverable. Absent such notice, all services and deliverables are deemed accepted and conforming within one hundred eighty (180) days of such delivery. As Client's exclusive remedy and Averion's sole liability for any such defects, Averion shall timely cure such defects, at Averion's expense, such that performance and deliverables conform to the applicable specifications in effect at the time performance was due and without modification of said specifications.

 

(b) During the term of any Work Assignment/Change Order governed by this MSA, Averion, at its sole cost and expense, shall carry and maintain insurance in the amount of Three Million ($3,000,000) Dollars. Upon written request of Client, Averion shall provide Client with a Certificate of Insurance stating that such insurance policy is in full force and effect. In the event of any breach or default of the MSA or any applicable Work Assignment/Change Order that is not cured in accordance with the preceding paragraph, Client's monetary remedy shall be limited to the lesser of three (3) times the total fees associated with any Work Assignment/Change Order or $3,000,000 across all Work Assignments/Change Orders and Client agrees that this monetary remedy shall represent the total liability of Averion for all Work Assignments/Change Orders with Client that are governed by this MSA.

 

(c) EXCEPT AS EXPRESSLY STATED IN THIS SERVICESWARRANTY, AVERION MAKES NO OTHER WARRANTIES WITH RESPECT TO ITS PERFORMANCE HEREUNDER, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES WITH RESPECT TO THE OUTCOME OF ITS PERFORMANCE OR ANY ANALYSIS, THE VIABILITY OF PRODUCTS WHICH ARE THE SUBJECT OF ANY STUDY, WHETHER OR NOT THE PRODUCTS SHALL BE CLEARED BY THE FDA OR ANY OTHER REGULATORY AGENCY FOR THE STATED INDICATIONS OR IN ANY PARTICULAR TIME, WHETHER OR NOT ANY APPLICATION SHALL BE FILED, THAT THE PRODUCTS SHALL BE A COMMERCIAL SUCCESS, OR THAT THE CLIENT WILL OBTAIN ANY REVENUES OF ANY SIZE FROM ANY PRODUCT IN ANY STUDY.

 

(d) The Client acknowledges that the services to be provided by Averion are based on information supplied by the Client and other information in the public domain. Averion does not guarantee or warrant such services to any specifications, functions or other standards other than those supplied by Client. The sole remedy of the Client for any breach or default by Averion is the remedy specified herein or termination of this MSA as herein provided and in no event shall Averion be liable for damages to Client in excess of the amounts set forth in (b), above.

 

Client warrants that it has obtained all necessary governmental and regulatory approvals to conduct any study or clinical trial described any Work Assignment, including without limitation, all applicable FDA and IRB approvals; and that all approvals shall be in full force and effect during the relevant term of any Work Assignment. Unless expressly agreed in a Work Assignment, Client is solely responsible for interaction with regulatory agencies, including without limitation, the FDA. Client further warrants that the conduct of any studies or clinical trials under this MSA will not infringe any patents, trademarks or copyrights held by third parties.

(a) Client agrees to indemnify, defend and hold harmless Averion and its directors, officers, agents, employees and permitted subcontractors (collectively "Averion Indemnitees") from and against any and all costs (including reasonable attorneys' fees and expenses of litigation), expenses, damages, loss and liabilities incurred or imposed as a result of any third party claim, suit, action, demand or judgment ("Losses") arising from or attributable to the negligence, gross negligence, intentional misconduct or inaction of Client in the performance of any of its obligations under this MSA, including without limitation:

 

(1) personal injury and property damage suffered by a participant due to any drug, device, biologic, consent, procedure, or protocol arising out of or in connection with, any Work Assignment/Change Order under this MSA, including without limitation, injury and damage received as result of receiving medical care or as a result of medical malpractice;

 

(2) any harmful or otherwise unsafe effect, including without limitation, a claim based upon a person's use, consumption, sale, distribution, or marketing of any drug, device, biologic or procedure used in or resulting from any Work Assignment/Change Order under this MSA;

 

(3) Client's performance of or involvement with any drug, device, biologic or procedure used in or resulting from any Work Assignment/Change Order under this MSA or Client's negligent use of any data or information provided by Averion pursuant to this MSA;

 

(4) any violation of applicable law, rule or regulation for which Client bears responsibility for compliance; or

 

(5) otherwise resulting from Averion's proper performance of the services under this MSA and any Work Assignment/Change Order hereunder;

 

provided, however, that if any such Loss arises in whole or in part from the negligence, or intentional misconduct of any Averion Indemnitee(s), then the amount of such Loss for which Client shall indemnify the Averion Indemnitee(s) pursuant to this provision shall be reduced by an amount proportionate to the percentage of the responsibility of the Averion Indemnitees for such Loss.

 

(b) Averion agrees to indemnify, defend and hold Client and its directors, officers, agents, employees and subcontractors (collectively "Client Indemnitees") harmless from and against any and all Losses to the extent such Losses arise from or are attributable to, the negligence, gross negligence, or intentional misconduct of Averion or its directors, officers, agents or employees, permitted contractors, or consultants provided however, that if any such Loss arises in whole or in part from the negligence, gross negligence, or intentional misconduct of any Client Indemnitee(s), then the amount of such Loss for which Averion shall indemnify the Client Indemnitee(s) pursuant to this provision shall be reduced by an amount proportionate to the percentage of the responsibility of the Client Indemnitees for such Loss.

 

(c) As a condition of the indemnification provided herein, the indemnified parties shall promptly notify the indemnifying party in writing of any claim, action or proceeding potentially giving rise to indemnification hereunder. The indemnifying party shall have sole and absolute control of, and discretion in, the handling of any such claim, action or proceeding, including the selection of legal counsel. The indemnified parties shall fully cooperate with the indemnifying party in the defense and settlement of all such claims, actions and proceedings. The indemnifying party shall keep the indemnified entity reasonably informed concerning all said claims, actions or proceedings and shall not admit liability without the prior written consent of the indemnified entity.

 

This provision on indemnity shall survive termination or expiration of this MSA.

 

(a) Notwithstanding anything to the contrary in this MSA or in any Work Assignment, the parties agree Averion shall not be liable for: (1) the lack of efficacy or complications associated with any product under study outside of Averion control, or (2) the act of any principal investigator, sub-investigator, clinical research associate, nurse, nurse-practitioner, pharmacist, or any other employee or consultant licensed to practice medicine or employed by or under agreement with any hospital, clinic, nursing service, site management organization, or other entity which is contracted to be a site for any study conducted pursuant to this MSA, even if Averion shall pay, compensate, select, train, contract with or otherwise interact with any of the foregoing.

 

(b) NEITHER PARTY SHALL BE LIABLE TO THE OTHER PARTY OR ANY THIRD PARTY FOR ANY INDIRECT, SPECIAL, INCIDENTAL, PUNITIVE OR CONSEQUENTIAL DAMAGES OF ANY KIND (INCLUDING BUT NOT LIMITED TO LOST PROFITS) IN CONNECTION WITH THIS AGREEMENT, EVEN IF THE PARTY HAS BEEN ADVISED OF SUCH DAMAGES.

This limitation of liability shall survive termination or expiration of this MSA.

 

In order for Averion to provide services to the Client, confidential and proprietary information may be disclosed to Averion relating to Client's past, present, and future activities (collectively, "Confidential Information"). Averion and its personnel will preserve the confidential nature of information received from Client in accordance with Averion's established policies and practices, copies of which will be provided to Client. Confidential Information does not include 1) information in the public domain; 2) information previously known by Averion employees or consultants prior to the commencement of this MSA or any Work Assignment; 3) information given to Averion by a third party, not known to be violating Client confidentiality; or 4) information independently developed by Averion outside the scope of the project or this MSA, or without use of Client Confidential Information. Averion agrees to keep all Client Confidential Information confidential during the term of this MSA and for a period of five (5) years from the date of termination or expiration of this MSA. Nothing in this section will prohibit Averion from disclosing Confidential Information pursuant to regulation or court order, provided Averion gives the Client as much advance notice as practical prior to disclosure and Averion protects the Client Confidential Information to the same degree as Averion protects its own Confidential Information. The Client shall bear all costs if Client wishes to dispute the disclosure of its Confidential Information pursuant to regulation or court order.

 

(a) All tangible reports, tables, data analyses, figures, listings, and correspondence created by Averion pursuant to this MSA specifically for the Client (collectively "Work Product") other than the Averion Intellectual Property (defined below) belong to the Client and will not be disclosed by Averion to any third party except as required by any applicable federal or state law or regulation (and provided, in such event, that Averion shall notify the Client as soon as possible of such required disclosure). Averion hereby assigns, sells and transfers to client all of Averion's right, title and interest in and to all such Work Product and all intellectual property rights therein and Client shall provide Averion with a royalty-free non­exclusive license to use the Work Product worldwide throughout the term of this MSA for the purpose of performing its duties and obligations to Client under the MSA and Work Assignments or Change Orders.

 

(b) Averion owns all rights in and to its general use intellectual property related to its business, including without limitation, all software, algorithms, processes, systems, know-how, and all data collection, report generation, metrics, data checking, data quality checking, data analysis, data displaying and modeling based procedures that it uses in its general business (collectively, "Averion IP").

 

(c) Averion agrees not to disclose that the Client has specifically retained Averion for professional services unless the Client has specifically authorized in writing that such disclosure can be made.

 

All data and materials furnished by Client to Averion for use by Averion in connection with the services performed under this MSA or any Work Assignment or Change Order shall remain the sole property of the Client. Client may request the return of all data and confidential materials given to Averion and Averion will promptly ship all materials back to Client upon satisfactory negotiation of all invoices.

 

Client shall be entitled to one audit at no charge to Client per Work Assignment and subsequent Change Orders at the Client's discretion and upon reasonable advance notice to Averion. Audits are intended to monitor the operations of Averion hereunder, to examine standard operating procedures, facilities, books, records, papers, files and documentation, including computer files, data bases and records, at Averion's facilities, and, generally, to understand the manner in which tasks are being performed hereunder, determine the adequacy of records, ensure the tasks are being performed in accordance with this Agreement and applicable regulations. This audit shall be conducted during normal business hours and will be at no expense to the Client. Any additional audits conducted at the written request of client will be billed on a fee for service basis.

Client acknowledges that Averion will require from Client information, materials, and data in order to perform services properly. Averion is not responsible for errors, delays, or other consequences arising from the failure of Client to provide such data, records, or necessary background to permit Averion to perform services. Neither party will be liable for any delay or failure to perform as required under this MSA to the extent that such delay or failure to perform is caused by circumstances reasonably beyond either party's control, including, without limitation, labor disputes, accidents, any law, order or requirement of any governmental agency or authority, civil disorders or commotions, acts of aggression or terror, fire or other casualty, strikes, acts of God, explosions, material shortages, act required to comply with any laws of the United States or Massachusetts. Performance time will be considered extended for a period of time equivalent to the time lost because of any such delay or failure to perform, provided, however, that if any such delay extends for a period in excess of ninety days, then either party may terminate the applicable Work Assignment upon prior written notice to the other party.

 

Averion represents that it and its employees, affiliates and agents have never been (i) debarred or (ii) convicted of a crime for which a person can be debarred under Section 306(a) or 306(b) of the Generic Drug Enforcement Action of 1992. Averion represents that it has never been and, to the best of its knowledge after due inquiry, none of its employees, affiliates, or agents has ever been (1) threatened to be debarred or (2) indicted for a crime or otherwise engaged in conduct for which a person can be debarred, under Section 306(a) or (b). Averion agrees that it will promptly notify Client in the event of any such debarment, conviction, threat or indictment.

 

Neither party shall assign this MSA or any Work Assignment/Change Order without the prior written consent of the other party; provided, however a party may assign this MSA or any Work Assignment/Change Order without prior consent in the event of the sale of its business.

 

The waiver, forbearance or failure by either party to claim a breach of any provision of this MSA or any Work Assignment or Change Order pursuant hereto, or to exercise any right or remedy provided by this MSA, shall not be deemed to constitute a modification of any provision of this MSA, or a waiver or estoppel with respect to any subsequent breach or with respect to any provision thereof.

 

No changes or modifications of this MSA or any Work Assignment or Change Order shall be deemed effective unless in writing and executed by the parties hereto.

 

If any provision of this MSA or any Work Assignment/Change Order pursuant hereto shall be determined to be invalid or unenforceable, the validity and effect of the remaining provisions of this MSA or such Work Assignment/Change Order shall not be affected thereby.

 

(a) This MSA will be effective from the date of signature of the latter party to sign and will remain in

effect for a period of five years or until the last Work Assignment/Change Order is completed, whichever is longer. Notwithstanding the foregoing, either party may terminate this MSA and all open Work Assignments/Change Orders upon written notice in the event that the other party files for bankruptcy protection or seeks any similar relief from creditors, and Averion may terminate this MSA and all open work Assignments/Change Orders if Client fails to pay for work done as required. Upon termination of this MSA and payment in full for all work done through termination of any Work Assignment/Change Order, in addition to payments specified by any early termination clauses in a Work Assignment/Change Order. If so requested by the other party, each party will promptly return to the other all documents or data which are specified to contain Confidential Information, provided, however, that each party may retain one copy of such Confidential Information for documentation.

(b) If a study is stopped or put on hold for efficacy, safety, or site compliance in accordance with the applicable protocol, providing that such hold continues for longer than 6 consecutive months and the parties did not agree in writing to continue for a longer period based on analysis of the reasons for sioppage the Work Assignment/Change Order may be immediately terminated by either party and Averion will have thirty (30) days to wind-down the Work Assignment/Change Order. Alternatively, Client may terminate a Work Assignment/Change Order for any reason with ninety (90) days written notice. Upon such early termination of any Work Assignment/Change Order, Averion shall use commercially reasonable efforts to avoid incurring any additional costs and to fully cooperate in disengaging from any Work Assignment/Change Order and eliminating or minimizing all externally cancelable costs, damages, penalties and expenses connected with the termination of the Work Assignment/Change Order or this MSA. Averion shall comply with all applicable warranties during the wind-down period; provided however, that if the Client does not allow Averion to perform the applicable compliance-related activities (e.g., GCP, SOP or other applicable standard) during that period, then Averion shall promptly notify Client of Averion's inability to perform such compliance-related activities, provided Client with a budget estimate for any such compliance and within fifteen (15) days after any such notification, Client will agree to (i) accept the materials without a warranty for such compliance-related activities; or (ii) require such compliance in accordance with the budget estimate provided by Averion. However, nothing in the foregoing is intended to compromise patient safety in the event a study is suspended or terminated. Further, the parties shall cooperate with each other during such trial or project termination to safeguard patient safety and otherwise to comply with applicable laws and regulations.

 

Any heading used in this MSA or any Work Assignment/Change Order is inserted for convenience of reference only and shall not be construed to affect the construction or interpretation of any provision hereof.

 

This MSA and the rights and obligations of the parties hereunder shall be governed by and construed in accordance with the laws of the Commonwealth of Massachusetts, without regard to its conflicts of law rules.The parties hereby agree to submit any dispute arising hereunder to binding arbitration pursuant to the Commercial Arbitration Rules of the American Arbitration Association. The arbitration shall be conducted in New York, New York. The decision of the arbitrator or arbitration panel shall be final and binding upon the parties hereto and shall be enforceable by any court of competent jurisdiction.

 

Any notice to be given hereunder or under any Work Assignment/Change Order, unless otherwise specified in the relevant Work Assignment/Change Order, shall be in writing and shall be deemed given 3 days after being deposited in the United States certified mail (postage prepaid, return receipt requested), 1 day after being deposited with a nationally recognized overnight courier (shipping prepaid), or immediately upon acknowledged hand delivery or electronic confirmation of being sent by facsimile as follows (or to such other addressee as a party specifies from time to time via written notice as below):

 

If to Client:

Actinium Pharmaceuticals, Inc.

25B Hanover Road

Florham Park, NJ 07932

Attention: Howard Wachtler and Dragan Cicic

Fax: 973 ###-###-####

 

If to Averion:

Averion International Corp.

225 Turnpike Road

Southborough, MA 01772

Attention: Dr. Philip Lavin

Fax: 508 ###-###-####

Copy: Dr. Gene Resnick

800 Westchester Avenue, #N341

Rye Brook, NY 10573

Fax: 914 ###-###-####

In witness whereof, the parties intending to be legally bound, do hereby execute this MSA by their duly authorized representatives: