CLINICAL SERVICES MASTER AGREEMENT

CLINICAL SERVICES MASTER AGREEMENT

          THIS CLINICAL SERVICES MASTER AGREEMENT (this “Master Agreement”) is entered into as of this 1^st day of June, 2005, by and between ▇▇▇▇▇▇ Operations Pty Ltd ACN 093 317 367 (“Sponsor”) of ▇▇▇▇▇ ▇, ▇ ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇, Newstead in the state of Queensland, Australia and Omnicare CR, Inc., (“Omnicare CR”) a Delaware corporation.

          WHEREAS, Sponsor requires various clinical research services from time to time in support of various projects (individually, a “Project,” and collectively, the “Projects”), which shall be set forth in Exhibits to this Master Agreement; and

          WHEREAS, Omnicare CR and/or an affiliate entity (such entity being defined as an entity under direct or indirect beneficial common ownership as Omnicare CR’s; hereinafter referred to as “Affiliate Entity”) is willing and able to perform the services designated by Sponsor. Except for any references to invoicing or payment, any references to “Omnicare CR” shall be deemed to include “Omnicare CR and/or an Affiliate Entity”;

          NOW, THEREFORE, for good and valuable consideration, AND INTENDING TO BE LEGALLY BOUND, Sponsor and Omnicare CR hereby agree as follows:

1.

Scope of Master Agreement; Obligations

	1.1.		The specific responsibilities and obligations to be performed by Omnicare CR with respect to a Project (the “Services”), as set forth in the applicable Protocol(s), are expressly set forth in Exhibit(s) attached to this Master Agreement, which, together with the Exhibit(s) attached hereto, are incorporated by reference herein. No Exhibit will be attached to this Master Agreement or become effective without first being executed by duly authorized representatives of the parties hereto. To the extent any terms set forth in an Exhibit shall conflict with the terms set forth in this Master Agreement, the terms of this Master Agreement will take precedence unless the Exhibit expressly states that a conflicting term is intended to modify a specific term in this Master Agreement. The responsibility for the Services is being transferred to Omnicare CR in accordance with 21 C.F.R. §312.52. Those responsibilities and obligations not specifically transferred to and assumed by Omnicare CR in this Master Agreement or the Exhibit(s) as constituting part of the Services shall be and remain the sole responsibility of Sponsor.
	1.2.		Omnicare CR agrees that Omnicare CR will provide the Services in accordance with (a) all applicable federal laws and regulations, including standards of Good Clinical Practices; and (b) the standards and practices that are generally accepted in the industry and exercised by other persons engaged in performing similar services.
	1.3.		In the discharge of its duties, Omnicare CR shall comply with all reasonable directions of Sponsor as may be given in writing from time to time in respect of the Services.

	1.4.		Omnicare CR shall at all times provide sufficient appropriately-trained and qualified clinical research personnel on a given Project to meet the demands of said Project.
	1.5.		In the event that Sponsor or a third-party engaged by Sponsor performs an audit of the Project, Omnicare CR will respond in writing to the audit findings within thirty (30) days of receipt of same.
	1.6.		Omnicare CR shall use its commercially reasonable efforts, skills and abilities to promote the interests of Sponsor and to diligently and competently perform its duties under this Master Agreement.

2.

Payment

	2.1.		In consideration of the Services, Sponsor shall pay to Omnicare CR: (a) the Service Fees (as defined in Section 2.2); and (b) the Pass-Through Costs (as defined in Section 2.3).
	2.2.		As used in this Master Agreement, the term “Service Fees” means all amounts due for the Services, exclusive of the Pass-Through Costs. The estimated Service Fees and the payment schedule therefor are set forth in the Exhibit(s), and shall be increased to include: (a) the costs of any additional Services required as a result of Project changes by Sponsor; (b) any costs that arise out of or relate to a Force Majeure as outlined in Section 10 below, and (c) where a Project requires more time than allotted in the Exhibit(s), and the parties agree to continue such Project beyond the expected conclusion date, any additional costs that may be incurred in order to complete such Project, at the contractual rates set forth in the applicable Exhibit(s). All payments of Service Fees shall be made within thirty (30) days of receipt of invoice. If any payment of Service Fees is late by more than thirty (30) days, such payment shall be subject to a liquidated damages fee of 1.5% per month of the outstanding balance.
	2.3.		As used in this Agreement, the term “Pass-Through Costs” means all investigator, Institutional Review Board or other applicable pass-through costs actually and reasonably incurred by Omnicare CR under this Agreement or the Exhibit(s) in order to expedite successful completion of a Project, which costs are normal and routine to studies similar to such Project (e.g., advancing an investigator’s Institutional Review Board fee and investigator grant payments or reimbursing reasonable additional, unbudgeted patient expenses). In order to enable Omnicare CR to maintain a balance to be applied towards investigator-related Pass-Through Costs, Omnicare CR shall invoice Sponsor for all reasonably anticipated Pass-Through Costs (the “Estimated Pass-Through Costs”) in advance of the expected payment date therefor. Except with respect to investigator-related payments, which are payable upon receipt, all Pass-Through Costs shall be paid within thirty (30) days of receipt of invoice. If any payment Pass-Through Costs is late by more than thirty (30) days, such payment shall be subject to liquidated damages of 1.5% per month of the outstanding balance. The anticipated Pass-Through Costs and Estimated Pass-Through Costs and the payment schedule therefor are set forth in the Exhibit(s).

	2.4.		Where applicable, language pertaining to annual price increases will be included in each Exhibit.
	2.5.		Taxes (and any penalties thereon) imposed on any payment made by Sponsor to Omnicare CR will be the responsibility of Omnicare CR. Any sales tax, usage tax, Value Added Tax (VAT), or other similar taxes shall be the responsibility of the Sponsor.
	2.6.		Sponsor shall make payment direct to the following bank account nominated by Omnicare CR:

Omnicare CR Inc.
First Union National Bank
Philadelphia, PA
ABA # ****
Acct # ****

3.

Confidentiality

	3.1.		That certain Confidentiality Agreement by and between Omnicare CR and Sponsor dated as of 25th November 2004 (the “Confidentiality Agreement”) is hereby terminated and of no further force or effect.
	3.2.		In connection with the performance of the Services, Sponsor shall provide to Omnicare CR, and Omnicare CR shall have access to, Sponsor’s Confidential Information. As used in this Master Agreement, “Sponsor’s Confidential Information” means any (a) information provided by, or developed for, Sponsor within the framework of or in undertaking activity pursuant to this Master Agreement, the Exhibit(s) or the Confidentiality Agreement; or (b) data collected during a Project.
	3.3.		In connection with this Master Agreement, Sponsor will have access to, or become acquainted with, Omnicare CR’s Confidential Information. As used in this Master Agreement, “Omnicare CR’s Confidential Information” means any (a) information generated or obtained in connection with Omnicare CR’s pricing, proposals or contracts (including the provisions of this Master Agreement and the Exhibit(s)); (b) of Omnicare CR’s procedures, programs, guidelines or policies (including, without limitation, its Standard Operating Procedures); or (c) information designated in writing as “confidential.”
	3.4.		Neither Sponsor’s Confidential Information nor Omnicare CR’s Confidential Information (collectively, “Confidential Information”) shall include any information that:

(a)

was known by the receiving party at the time of disclosure to it by the disclosing party, or that is independently developed or discovered by the receiving party, after disclosure by the disclosing party, without the aid, application or use of any

			item of the disclosing party’s Confidential Information, as evidenced by written records;
	(b)		is now or subsequently becomes, through no act or failure to act on the part of the receiving party, generally known or available;
	(c)		is disclosed to the receiving party by a third party authorized to disclose it; or
	(d)		is required by law or by court or administrative order to be disclosed; provided, that the receiving party shall have first given prompt notice to the other party of such required disclosure.

	3.5.		Each party shall exercise due care to prevent the unauthorized use or disclosure of the other party’s Confidential Information, and shall not, without the other party’s prior written consent, (a) use the other party’s Confidential Information for any purpose other than performing its obligations under this Master Agreement and the Exhibit(s); or (b) disclose or otherwise make available, directly or indirectly, any item of the other party’s Confidential Information to any person or entity other than those employees, independent contractors, agents or investigators of such party and/or its affiliate entities (collectively, “Representatives”) who reasonably need to know the same in the performance of such party’s obligations under this Master Agreement (including the Exhibit(s)), or in order to make decisions or render advice in connection therewith. For the convenience of the parties, each party acknowledges that unless precluded in writing by the other party, Confidential Information may be transmitted to a party and/or its Representatives via the Internet. Each party shall advise its Representatives who have access to the other party’s Confidential Information of the confidential nature thereof, and agrees that such Representatives will be bound by terms of confidentiality and restrictions on use with respect thereto that are at least as restrictive as the terms of this Section 3.
	3.6.		The provisions of this Section 3 shall survive for a period of five (5) years from the date of any expiration or termination of this Master Agreement, however caused.
	3.7		Omnicare CR acknowledges that in accordance with Section 1043A of the Corporations Act of the Commonwealth of Australia:

	(a)		Omnicare CR may from time to time as a consequence of the services provided hereunder possess confidential information which may have a material effect on the price or value of the securities of Sponsor and may therefore constitute “inside information” for the purposes of the Corporations Act; and
	(b)		as an insider one must not (whether as principal or agent in possession of such inside information):

	•		apply for, acquire or dispose of such securities, or enter into an agreement to apply for, acquire or dispose of any such securities; or
	•		procure another person to apply for, acquire or dispose of, or to enter into an agreement to apply for acquire or dispose of, any such securities.

and acknowledges further that:

	(c)		once in possession of confidential information, a party may be subject to the ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇ restrictions imposed by the Corporations Act and may be prohibited from trading in the securities (as noted above) and / or communicating the confidential information to any other person who would be likely to subscribe for, purchase or sell securities, or procure a third person to do the same until such date when this confidential information has been made “public” in terms of the requirements of the Corporations Act; and
	(d)		it must seek its own legal advice on its responsibilities under the Corporations Act and that neither party purports that the comments in this clause are either advice or a comprehensive description of the provisions of the Corporations Act.

4.

Property of Sponsor

	4.1.		All (a) of Sponsor’s Confidential Information (including, without limitation, all original Project records and reports), (b) unused clinical supplies provided by Sponsor, and (c) complete and incomplete Case Report Forms, which in any case are in Omnicare CR’s possession, shall be and remain Sponsor’s property; provided, however, that Omnicare CR may retain one copy of Sponsor’s Confidential Information in its files for archival purposes, as a means of determining any continuing obligations under this Master Agreement (including the Exhibit(s)).
	4.2.		All inventions, improvements in know-how, new uses, processes and compounds involving the study drug(s) and/or product(s) covered by this Master Agreement and/or the Exhibit(s) that are conceived or reduced to practice as a direct result of the Project(s) (“Inventions”) shall be and remain the sole property of Sponsor. Omnicare CR shall cooperate with Sponsor in obtaining, at Sponsor’s sole cost and expense, any patent protection as may be available for the Inventions, and shall execute all documents reasonably deemed necessary by Sponsor for purposes of procuring such patent protection. Omnicare CR agrees that Omnicare CR shall endeavor to ensure contractually the prompt disclosure to Sponsor by any investigator, employee or other individual retained by Omnicare CR for a Project of any Inventions, as well as the cooperation of such persons in securing patent protection as set forth herein.
	4.3.		Notwithstanding the foregoing, Sponsor acknowledges that Omnicare CR and their respective professional staff currently possess certain inventions, processes, know-how, trade secrets, methods, approaches, analyses, improvements, other intellectual properties and other assets including, but not limited to, clinical trial management analyses, analytical methods, procedures and techniques, computer technical expertise and proprietary software, and technical and conceptual expertise in the area of conducting clinical trials, all of which have been developed independently by Omnicare CR without the benefit of any information provided by Sponsor (collectively, “Omnicare CR Property”). Sponsor agrees that any Omnicare CR Property which is used, improved, modified or developed by Omnicare CR under or

during the term of this Master Agreement shall be and remain the sole and exclusive property of Omnicare CR.

5. Restrictions on Announcements

Omnicare CR shall not make any announcement, oral presentation or publication relating to any Project without Sponsor’s prior written consent (which consent shall not be unreasonably withheld), except as required by law or by court or administrative order. Neither Omnicare CR nor Sponsor shall employ or use the name of the other party in any publication or promotional material or in any form for public distribution, without the prior written consent of the other party, except as required by law or by court or administrative order.

6. FDA Inspection

In the event that Omnicare CR receives a Notice of Inspection (a “Notice”) from the Food and Drug Administration (“FDA”) which relates to any Project Omnicare CR shall: (a) notify Sponsor promptly of such Notice; (b) keep Sponsor informed of the progress of the inspection; and (c) provide to Sponsor a copy of any documents produced to the FDA pursuant to such Notice. Sponsor acknowledges that it is Omnicare CR’s obligation to respond to a Notice directed to Omnicare CR and that Omnicare CR must respond to the Notice without advice from, or consultation with, Sponsor concerning the contents thereof.

7. Access to Facilities and Records

	7.1.		Sponsor’s authorized representatives may visit Omnicare CR’s site and facilities at reasonable times and with reasonable frequency during normal business hours and upon reasonable advance written notice, to observe the progress of any Services. All such visits shall be subject to Omnicare CR’s restrictions and procedures relating to safety, security and protection of Confidential Information, and in connection therewith, Sponsor’s authorized representatives may be required to sign a confidentiality agreement, or an access agreement for special access-controlled areas.
	7.2.		During the term of this Master Agreement, Omnicare CR shall maintain all materials and all other data obtained or generated by Omnicare CR in the course of providing the Services hereunder, including all computerized records and files. Omnicare CR shall cooperate with any reasonable internal review or audit by Sponsor and make available to Sponsor for examination and duplication, during normal working hours and at mutually agreeable times, all documentation, data and information relating to a Project.
	7.3.		Upon the expiration or termination of this Master Agreement, all materials and all other data and information obtained or generated by Omnicare CR as a direct result of providing the Services hereunder will, at Sponsor’s option and cost and expense, be (i) delivered to Sponsor’s offices at the address provided herein in such form as is then currently in the possession of Omnicare CR, (ii) retained by Omnicare CR for Sponsor for a period of two years, or (iii) disposed of as directed in writing by Sponsor, unless such materials are otherwise required to be stored or maintained by

Omnicare CR under applicable law. In no event shall Omnicare CR dispose of any materials or data or other information obtained or generated by Omnicare CR as a direct result of providing the Services without first giving Sponsor sixty (60) days prior written notice of its intent to dispose same. Notwithstanding the foregoing, Omnicare CR may retain copies of any such materials, data and information as is reasonably necessary for regulatory purposes or to demonstrate the satisfaction of its obligations hereunder, all subject to the confidentiality obligations set forth herein.

8. Indemnification

	8.1.		Sponsor agrees to indemnify, defend and hold harmless Omnicare CR and its Affiliate Entities, and their respective officers, directors and employees from and against any and all claims, demands, investigations, suits or actions (each a “Claim”) for any and all liabilities, losses, damages, penalties, costs or expenses of every kind whatsoever (including but not limited to court costs, legal fees, awards of settlements) arising out of, in connection with or related to this Master Agreement and/or the Exhibit(s); provided, however, that Sponsor’s indemnity obligations under this Section 8 shall not apply to any Claim to the extent arising directly from Omnicare CR’s negligence or willful malfeasance.
	8.2.		Omnicare CR agrees to indemnify, defend and hold harmless Sponsor and its respective officers, directors and employees from and against any and all Claims for any and all liabilities, losses, damages, penalties, costs or expenses of every kind whatsoever (including but not limited to court costs, legal fees, awards or settlements) arising out of, in connection with or related to any breach of this Master Agreement and/or the Exhibit(s) by Omnicare CR, including any breach of warranties, or any willful, unlawful or negligent act or omission of Omnicare CR.
	8.3.		Each person or entity seeking indemnification under this Section 8 (the “Indemnified Party”) shall, as a condition thereto, notify the other party within twenty (20) days after the receipt of notice of the Claim; provided, however, that the other party shall not be released from its obligations under this Section 8 if the failure to notify that other party within twenty (20) days does not materially prejudice the defense of such Claim. That other party shall have the right to select defense counsel and to direct the defense or, with the consent of the indemnified party (which consent shall not be unreasonably withheld) settlement of, any Claim. In the event that representation of an Indemnified Party and the other party by the same counsel would be a conflict of interest for such counsel, the Indemnified Party may select its own independent counsel without relieving the other party of its obligations under this Section 8. Under no circumstances shall an Indemnified Party settle or otherwise compromise any Claim without the other party’s prior written consent.
	8.4.		This clause shall survive the expiration or termination of the Master Agreement and/or the Exhibit(s).

9. Termination

	9.1.		Either party may terminate this Master Agreement and/or any Exhibit at any time and for any reason upon a minimum of thirty (30) days’ prior notice, provided that Omnicare CR may only terminate under this sub-clause in the event that there are no active Exhibits, ie, all tasks under all Exhibits have been completed.
	9.2.		Without limiting the generality of any other clause in this Master Agreement or the remedies available to either party, either party may terminate this Master Agreement immediately by notice in writing if:

	(a)		the other party is in material breach of any terms of this Master Agreement or any Exhibit and, where such breach is remediable, such party fails to remedy such material breach or establish a corrective action plan to cure such material breach (which plan shall outline actions to be taken and relevant dates) acceptable to the non-breaching party within fifteen (15) days of receiving notice to do so from the non-breaching party;
	(b)		the other party is in serious and/or presistent breach of any terms of this Master Agreement or any Exhibit. Failure to perform in accordance with the corrective action plan outlined above shall be deemed a serious breach; or
	(c)		the other party becomes, threatens to become or is in jeopardy of becoming insolvent.

	9.3.		Upon receipt of any notice of termination, a party shall avoid or limit, to the extent practicable, incurring any futher commitments, obligations or costs which would otherwise result in Service Fees and Pass-Through Costs.
	9.4.		Upon any early termination, Sponsor shall pay to Omnicare CR all Service Fees and Pass-Through Costs due and owing based upon Services completed and costs incurred through the effective date of termination, including costs for materials and/or services previously acquired or contracted for which will not be used for the Services as a result of such termination.
	9.5.		Any funds held by Omnicare CR which by contract definition or amendment are deemed unearned (including, without limitation, any Estimated Pass-Through Costs not used to satisfy Pass-Through Costs) shall be returned to Sponsor within sixty (60) days after conclusion or termination of the Project(s) set forth in the applicable Exhibit(s).
	9.6.		Following completion or termination of any Project, Omnicare CR shall forward all original Project records and reports to Sponsor (or to a repository designated by Sponsor in writing) at Sponsor’s sole cost and expense. Thereafter, Omnicare CR shall retain any documentation related to such Project in compliance with Omnicare CR’s corporate policy on retention and destruction of records.

10. Force Majeure

If either party’s performance of this Master Agreement or any Exhibit is prevented, restricted or delayed (either totally or in part) by reason of any cause beyond the reasonable control of the parties, such as acts of God, explosion, disease, weather, war, insurrection, civil strike, riot or power failure, the party so affected shall, upon giving notice thereof to the other party, be free and be excused from such performance to the extent of such prevention, restriction or delay; provided, that the affected party shall use its commercially reasonable efforts to avoid or remove such causes of non-performance and shall continue performance with the utmost dispatch whenever such causes are removed; and provided further, that nothing herein shall relieve either party from the obligation to pay promptly in full all payments that may be due to the other party under this Master Agreement or the Exhibit(s). In addition to the above, the affected party shall be free from any liabilities, losses, damages, penalties, costs or expenses arising out of or related to such cause beyond the reasonable control of such affected party. If such cause for non-performance exceeds or is likely to exceed thirty (30) days, a party other than the affected party may immediately terminate the Master Agreement and/or the Exhibit(s).

11. No Conflict

Each party represents and warrants that it is authorized to enter into this Master Agreement, that it is not prevented from or impeded in carrying out its obligations under the Master Agreement and/or the Exhibit(s) by way of any agreement, arrangement or understanding that it may have with any other person and that the terms hereof are not inconsistent with or a violation of any other legal obligation to which it is subject.

12. Limitations

	12.1.		Sponsor acknowledges that the results of the Project(s) are inherently uncertain and that, accordingly, there can be no assurance, representation or warranty by Omnicare CR that the study drug(s) and/or product(s) covered by this Master Agreement and/or the Exhibit(s) can, either during the term of this Master Agreement or thereafter, be developed sucessfully or, if so developed, will receive the required approval(s) from the FDA orther regulatory agency or authority.
	12.2		Both parties acknowledge that the Services constitute research and development. Accordingly, Sponsor’s sole remedy for any breach or default hereof by Omnicare CR shall be termination of this Master Agreement or the applicable Exhibit as herein provided or a return of any Service Fees paid to Omnicare CR for Services improperly performed or not performed. In no event shall Omnicare CR be liable for any special, indirect, incidental or consequential damages (whether in contract or tort).

13. Non-Debarment

13.1.

Omnicare CR represents and warrants that Omnicare CR has not been nor is currently:

(a)

an individual who has been debarred by the FDA pursuant to 21 U.S.C. §335a (a) or (b) (a “Debarred Individual”) from providing services in any capacity to a

			person that has an approved or pending drug product application, or an employer, employee or partner of a Debarred Individual; or
	(b)		a corporation, partnership, or association that has been debarred by the FDA pursuant to 21 U.S.C. §335a (a) or (b) (a “Debarred Entity”) from submitting or assisting in the submission of an abbreviated new drug application, or an employee, partner, shareholder, member, subsidiary or affiliate entity of a Debarred Entity.

13.2.

Omnicare CR further represents and warrants that Omnicare CR has no knowledge of any circumstances which may affect the accuracy of the representations and warranties set forth in Section 13.1 including, but not limited to, FDA investigations of, or debarment proceedings against, Omnicare CR or any person or entity performing, or rendering assistance related to, the Services. Omnicare CR will notify Sponsor promptly upon becoming aware of any such circumstances during the term of this Master Agreement.

14. Independent Contractor

The status of the parties under this Master Agreement is that of independent contractors, and, except as specifically set forth herein, or in the Exhibit(s), neither party has any authority to bind or act on behalf of the other party without its express written consent.

15. Notices

Any notices, requests or other communications given under this Master Agreement shall be in writing and shall be given by, personal delivery, or sent by (a) facsimile transmission (with message confirmed during normal business hours); (b) first class mail, postage prepaid; or (c) Federal Express (or equivalent nationally recognized overnight delivery service), delivery charges prepaid. All notices shall be given to a party at its respective address set forth below, or at such other address as such party from time to time may specify by notice in accordance with this Section 15. A notice shall be deemed given when actually received; provided, that if any facsimile notice is received after 5:00 P.M. local time at the place of receipt, it shall be deemed to have been given as of the next following business day.

If to Omnicare CR:		Omnicare CR, Inc.
		▇▇▇ ▇▇▇▇▇▇▇▇▇ ▇▇▇▇
		▇▇▇▇ ▇▇ ▇▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
		Attention: Global Client Contracts
If to Sponsor:		▇▇▇▇▇▇ Operations Pty Ltd
		▇▇▇▇▇ ▇, ▇ ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇
		▇▇▇▇▇▇▇▇
		▇▇▇ ▇▇▇▇
		▇▇▇▇▇▇▇▇▇

Attention: Dr ▇▇▇▇▇ Welbum

16. Entire Agreement

This Master Agreement, together with all corresponding Exhibits, Amendments or Change Orders, constitutes the entire agreement between Sponsor and Omnicare CR with respect to the subject matter hereof, and replaces and supersedes any and all prior and contemporaneous agreements and/or understandings, whether oral or written, between Sponsor and Omnicare CR with respect to the subject matter hereof. This Master Agreement (including the Exhibit(s)) may be amended or modified only by a written instrument executed by a duly authorized officer of each party.

17. Construction of Agreement

The descriptive headings of the Sections of this Master Agreement are for convenience only and shall not affect the meaning or construction of any of the provisions of this Master Agreement. The failure of either party to enforce any provision of this Master Agreement (including the Exhibit(s)) shall not be construed as a waiver or limitation of that party’s subsequent rights to enforce and compel strict compliance with every provision of this Master Agreement. To the extent any provision of this Master Agreement or the application thereof is found by a proper authority to be invalid or unenforceable, it shall be considered deleted herefrom, and the remainder of this Master Agreement shall continue in full force and effect.

18. Assignment and Sub-contracting

Neither Sponsor nor Omnicare CR may assign this Master Agreement or any rights hereunder or delegate the performance of any duties hereunder without the prior written approval of the other party, which approval shall not be unreasonably delayed or withheld; provided, however, that without such consent, either party may assign this Master Agreement in connection with the transfer or sale of all or substantially all of its assets, stock or business, or its merger, reorganization, consolidation or combination with or into another entity; provided, further, however, without such consent, Omnicare CR may assign any rights hereunder to an Affiliate Entity and Sponsor may assign any rights hereunder to its parent company or a subsidiary of said parent company without the consent of Omnicare CR. Omnicare CR shall not sub-contract any Services under an Exhibit to any legal entity other than an Affiliate Entity without the prior written consent of Sponsor, such consent not to be unreasonably withheld. Subject to the foregoing, this Master Agreement shall be binding upon, inure to the benefit of and be enforceable by the parties and their respective successors and permitted assigns.

19. Timely Review

Sponsor acknowledges that Omnicare CR will require, among other things: (a) timely review of Omnicare CR’s work product; and (b) timely supplies of documents, data, records, and investigational drug product(s) from Sponsor in order to properly perform the Services hereunder and that Omnicare CR are not responsible for errors, delays or other consequences arising from the failure of Sponsor to provide such review and/or materials. Sponsor therefore agrees that it will: (a) promptly review Omnicare CR’s work product where such review is required and/or

necessary; and (b) provide all documents, data, records, investigational drug product(s) and other materials necessary for completion of Omnicare CR’s tasks and Services in a timely manner and in accordance with the schedule or timeline for the applicable Project.

Sponsor agrees to reasonably extend all deadlines hereunder due to delays (by Sponsor or contractors under its control) in (a) reviewing Omnicare CR’s work product; and (b) providing documents, data, records and investigational drug product(s) and other materials needed for the completion of Omnicare CR’s tasks and Services.

20. Restriction

For the period commencing on the date of execution of the last party to sign this Master Agreement and continuing for a period of one (1) year after the termination or expiration of this Master Agreement, each party agrees that it shall not knowingly solicit (as defined below) any of the other party’s or any of the other party’s affiliates’ then current personnel, whether employees or independent contractors under agreement with that other party. As used in this Section 20, “solicit” means the initiation of a contact with any of the other party’s or any of the other party’s affiliates’ then current personnel for the purpose of offering employment to such personnel, but shall not include the circumstance where any such personnel initiate a contact with the party for the purpose of obtaining employment with that party, whether in response to a general advertisement of employment placed by that party or otherwise, or where such contact is initiated by a third party who was not instructed to contact such personnel by that party. In the event a party breaches the terms of this Section, that party agrees to pay the other party as liquidated damages and not as a penalty a sum equal to twenty-five percent (25%) of the starting salary of such employee.

21. Survival

Any terms of this Master Agreement which by their nature extend beyond its performance, expiration or termination (including, without limitation, Sections 2 through 5, 8 through 10, 12, 20 and this Section 21) shall remain in effect indefinitely until fulfilled in accordance with their terms.

22. Governing Law

This Agreement will be governed by and construed in accordance with the laws of the State of Queensland in Australia without giving effect to any choice of law principles that would require the application of the laws of a different jurisdiction.

23. Signatories

This Master Agreement may be executed in counterparts, each of which, when executed and delivered, shall be deemed to be an original, and all of which, when joined, shall together constitute one and the same agreement. Any photocopy or facsimile of this Master Agreement, or of any counterpart, shall be deemed the equivalent of an original.

     IN WITNESS WHEREOF, the parties have executed this Master Agreement by their duly authorized officers as of the date first above written.

▇▇▇▇▇▇ Operations Pty Ltd						Omnicare CR, Inc.
By:		/s/ ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇				By:		/s/ ▇▇▇▇▇ ▇. ▇▇▇▇▇
Name:		▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇				Name:		▇▇▇▇▇ ▇. ▇▇▇▇▇
Title:		Director				Title:		Senior Vice President Global Marketing & Business Development
								APPROVED
								LEGAL DEPT.
		29-July-05						28-July-05

Exhibit I to the Clinical Services Master Agreement
between ▇▇▇▇▇▇ Operations Pty Ltd. and Omnicare CR, Inc.,
dated June 1, 2005.

          THIS EXHIBIT I is entered into this 21^st day of June 2006, by and between ▇▇▇▇▇▇ Operations Pty Ltd. (hereinafter “Sponsor”) and Omnicare CR, Inc. (hereinafter “Omnicare CR”).

          WHEREAS, Sponsor and Omnicare CR entered into a Clinical Services Master Agreement, dated June 1, 2005 (hereinafter the “Master Agreement”), wherein Omnicare CR agreed to provide clinical services; and

          WHEREAS, Omnicare CR and/or an affiliate entity (such entity being defined as an entity under direct or indirect beneficial common ownership as Omnicare CR’s; hereinafter referred to as “Affiliate Entity”) is willing and able to perform the services designated by Sponsor. Except for any references to invoicing or payment, any references to “Omnicare CR” shall be deemed to include “Omnicare CR and/or an Affiliate Entity”; and

          WHEREAS, Sponsor and Omnicare CR agree that Omnicare CR shall provide the services set forth in this Exhibit I, subject to the terms and conditions set forth in the Master Agreement;

          NOW, THEREFORE, for good and valuable consideration, AND INTENDING TO BE LEGALLY BOUND, Sponsor and Omnicare CR agree as follows:

I. Project Plan

Based on the Project Specifications, Omnicare CR has provided a description of services to be performed for Sponsor’s “A multi-center, randomized, double-blind, double-dummy, vehicle-controlled sequential cohort study to determine the safety of PEP005 0.025% and 0.05% topical gel in patients with actinic keratoses” (hereinafter “the Project”) and associated costs. Changes made in the Project scope, at any time during the Project, will result in a corresponding adjustment to the Project costs.

II. Project Timeline

The parties acknowledge and agree that Omnicare CR commenced performance of the Services under the letter of intent dated May 25, 2006. The projected timeline for this Project is as follows:

Major Milestones		Projected Timeline
Study Start		****
First Patient In		****
Last Patient In		****
Last Patient End of Treatment		****
Last CRF to Data Management		****
Database Close		****
Statistical Analysis		****
Study Close/Report		****
Total Study Duration		****

III. Omnicare CR Services

Services provided by Omnicare CR and the assumptions upon which associated costs were determined are based on the Project specifications provided by Sponsor, and are outlined below. It should be noted, however, that the timeline and costs presented in this budget for these services are estimated pending review of the final specifications, protocol and case report form (CRF).

A. Study Management

          Project Director

The Project Director will act as a single point of contact for the Sponsor during the course of this study. The Project Director is responsible for the generation of detailed project timelines and ensures that these milestones are met. The Project Director will provide on-going project status reports as directed by the Sponsor and will proactively identify and resolve critical project issues. The Project Director is also responsible for managing the study budget and addresses all out-of-scope items with the Sponsor.

           Clinical Trial Manager

The Clinical Trial Manager will be dedicated to managing the day-to-day clinical trial activity. The Clinical Trial Manager is responsible for overseeing all site and clinical research associate (CRA) activity for the Project. The Clinical Trial Manager is also responsible for developing case report form completion and monitoring guidelines; overseeing regulatory document management for each investigational site and for reviewing and tracking the Project CRA activities which include the scheduling of site visits, site visit reports, monitoring logs and follow-up correspondence.

           Project Administrative Coordination

The Project Coordinator provides the necessary administrative support to the Project Director and to the rest of the Project Team with all administrative related tasks.

           Draft Informed Consent Review

The Omnicare CR Project Management Team will review the draft of the Informed Consent and will evaluate whether it is in accordance with IRB and Ethic committee requirements. The Project Management Team will provide feedback to Sponsor as required.

B. Clinical Trial Initiation

          Setup & Maintenance of Study Master File

Omnicare CR will establish and maintain the Study Master File in accordance with Omnicare CR’s Standard Operating Procedure (SOP). The study wide, individual investigator files, and patient CRFs will be maintained in a locked, limited access, controlled file room.

           Investigator Document Plan

An Investigator Document Plan will be developed for the Sponsor. The purpose of the Investigator Document Plan is to define the project-specific review criteria for essential documents, the investigational product shipment approval procedure, the investigator site binder content and essential document file maintenance.

          Investigator Essential Document Management-Regulatory Document Collection

Once Sponsor has signed the Investigator Documentation Plan, essential document packages, with letters of instruction, will be mailed to qualified investigative sites. Document collection will cover all criteria required under the principles of Good Clinical Practices (GCP) and International Committee for Harmonization (ICH) guidelines, as well as Omnicare CR SOPs.

Omnicare CR will track the retrieval of documents on an ongoing basis and provide updates to Sponsor as requested. The fee for essential document collection, processing, and tracking is based upon the number of sites required for the Project. All sites that drop from the study for any reason will be billed based on percentage of work completed prior to notification of the drop. A submission ready regulatory document package for each investigator will be forwarded to Omnicare CR Regulatory prior to drug shipment and site initiations. Omnicare CR Regulatory will review the packages.

Once all essential documents and approvals are received, the essential documents are copied and an Investigator Site File is created. An Investigator Site File Binder will be sent to each investigator.

          IRB Submissions

Omnicare CR will work with investigational sites, Sponsor and the IRBs to obtain regulatory approval for sites participating in this study. Omnicare CR will submit to the Central IRB on behalf of those sites using the Central IRB.

          Protocol Amendments and IND Safety Reports and Investigator Brochure Updates

Protocol amendments will be billed at an additional processing fee. IND safety reports and revised Investigator Brochures will be sent to sites at an additional fee.

           Regulatory Document Renewals and Updates — Annual Site Maintenance

Throughout the study, Omnicare CR will collect updated essential documents. The updating of essential documents (medical licenses, lab certifications, and changes to FDA form 1572 fee will be based on the site’s date of drug shipment through the site’s first IRB re-approval date. For studies lasting greater than one year, the annual renewal and update fee will be charged based on the site’s subsequent IRB re-approval dates.

           Investigator Agreement Negotiation

Omnicare CR will be responsible for the following activities related to negotiating the investigator agreements:

	•		Create all investigator agreement templates and patients budget template with the Sponsor
	•		When possible, set up pre approved alternative language and budget parameters in anticipation of site negotiation
	•		Negotiate all investigator agreements that satisfy Sponsor requirements on behalf of the Sponsor
	•		Incorporate changes using pre-approved alternative parameters and if changes are outside parameters and secure approval by the Sponsor
	•		Obtain signatures from investigators, institutions, facilities, site management organizations on all investigator agreements as needed
	•		Collect IRS Form W9 and payment information sheets from sites
	•		Track documentation and communication between the sites, Omnicare CR Project Management and the Sponsor.

           Agreement Negotiation for Institutional Sites

Omnicare CR will also be responsible for the above activities related to negotiating the investigator agreements for academic medical centers and large hospitals. Negotiation of investigator agreements for these types of sites tends to be very involved due to legal staff at these institutional sites reviewing and negotiating the investigator agreements.

           Investigator Agreement Amendments

Protocol and study amendments, which require investigator agreement revisions, amendments and/or re-negotiation, will be billed as needed at an additional processing fee per unit. (See budget.)

           Facility Letters and other Investigator Notices

Facility letters are shortened versions of the investigator agreements intended to apprise the facilities where study procedures are going to be performed that a study is taking place on their premises. A facility letter also outlines duties and obligations of the facility during the course of the study. Facility letters are used when investigators have privileges at one Institution where

most of the study procedures are performed and grant payments are sent but some other procedures will occur at another facility. Facility letters are also common when investigators are affiliated with SMOs. If an SMO is involved and the Institution refuses to be apart of the main agreement, the facility where the study will be performed will accept and sign the facility letter. Facility letters are billed as noted in the budget. Facility letters are created, negotiated, and tracked like investigator agreements.

Examples of miscellaneous investigator notices and documentation are: termination letters, transfer letters, or any notices related to the Protocol that affects the agreements. Notices without any negotiation and without site signature involved will be billed as noted in the budget. These notices involve drafting the template, tailoring the templates for each site, preparing them for delivery, and sending to the sites. If additional work is required such as follow-up or negotiation these will be billed at the amendment letter rate per unit.

           Letters of Indemnification

Letters of Indemnification are often required by sites to be on Sponsor letterhead and signed by the Sponsor outlining how they will be indemnified and what they are indemnifying for during the course of a study. The letters of indemnification are negotiated and issued as needed and site and Sponsor signature is obtained. Letters of Indemnification are created, negotiated and tracked like investigator agreements.

           Vendor Service Agreements

Vendor Agreements are separate agreements between a vendor and Omnicare CR on behalf of the Sponsor. Vendor agreement terms and conditions are negotiated separately from investigator agreements and related documents.

           Project Team Training

Omnicare CR, in conjunction with the Sponsor, will provide specific therapeutic area training and orientation to the protocol and the CRF prior to study initiation and on an ongoing basis. This training will be designed to ensure that all Team members are familiar with the Project requirements and their role within the Team. Items discussed at these meetings will include, but will not be limited to:

	•		Therapeutic are and clinical development background
	•		Protocol and CRF
	•		Discussion of therapeutic implications for this study
	•		Monitoring guidelines
	•		Data handling rules from Data Management Plan

           Investigator’s Meeting Coordination

Omnicare CR’s Meetings Coordinator will coordinate arrangements associated with the investigators’ meeting(s) for the Project. Omnicare CR’s Meetings’ Coordinator has extensive experience in conducting investigators’ meetings, including but not limited to, organizing and scheduling the meeting, making cost-effective travel arrangements for participants, and providing on-site coordination services.

The Meeting Coordinator will manage all logistics of the meeting including:

	•		Identify appropriate location(s) for the meeting
	•		Negotiate, organize, and make hotel arrangements (e.g. meeting space and lodging)
	•		Secure discounted travel arrangements and issue tickets to investigators and study coordinators
	•		Prepare meeting materials (e.g. Welcome letters/packets, and name badges)
	•		Arrange meal functions and off-site events
	•		Manage administrative aspects associated with the meeting
	•		Provide on-site assistance at the meeting (the coordinator will arrive at the location prior to the meeting and will stay after the meeting to manage any outstanding arrangements such as shipping meeting materials
	•		Provide post meeting service including reconciliation of outstanding meeting bills

           Investigators’ Meeting Preparation

The Omnicare CR Project Team will prepare slides, educational handouts, meeting materials, etc. according to Omnicare CR’s plan for training investigators to successfully conduct this study.

	•		Assist in defining meeting requirements and outlining a meeting agenda
	•		Preparing necessary meeting materials (e.g., annotated CRFs, presentation materials, etc.)
	•		Coordinating presentations
	•		Conducting presentations and/or workshops on protocol, CRF, study conduct issues, and reporting of serious adverse events

           Investigators’ Meeting Attendance

Omnicare CR’s clinical trial management staff assigned to the Project will be available on-site to assist during the meeting. They will arrive at the location prior to the meeting to assist Omnicare CR and/or attendees with any last minute details that may arise.

C. Clinical Trial Management

          CRA activities and Site Responsibilities

Omnicare CR CRAs perform comprehensive site management and monitoring activities to include the following types of monitoring visits:

	•		Pre study selection visits
	•		Initiation visits
	•		Interim monitoring visits
	•		Close out visits

All activities are performed in accordance with ICH-GCP guidelines to ensure all investigational sites are compliant with all applicable regulations and protocol requirements.

The paramount responsibility of Omnicare CR CRAs is to ensure patient rights, safety and data integrity. This is accomplished through ongoing review of the following:

	•		Informed consent process
	•		IRB/IEC approval
	•		Ensuring proper AE and SAE reporting and documented follow up
	•		Adherence the protocol
	•		100% source documentation verification and data query clarification
	•		Investigational product administration and accountability
	•		Protocol Compliance
	•		Site training and support

Omnicare CR CRAs ensure ongoing site compliance via the continual review of the following:

	•		Site staff qualifications and experience
	•		Site staffing, facilities, storage and equipment
	•		Accessibility and eligibility of subjects
	•		Review and retrieval of regulatory documents (i.e. FDA 1572, protocol signature page, curricula vitae, medical licenses, certification of investigators’ financial disclosure, etc.)
	•		Accurate and timely completion of all CRF and source data

In addition to on-site responsibilities, each CRA is responsible for site management documentation and follow-up activities to ensure that site staff remains motivated and focused. These activities include the following:

	•		Site Visit Report and follow-up letters
	•		Providing site training and support through communications
	•		Generation of status reports
	•		Maintenance of tracking tools/logs
	•		Facilitation of DCF resolution

Omnicare CR CRAs complete comprehensive site visit reports and follow-up letters which are provided to the Omnicare CR Project Management Team within 10 working days of the visit however all urgent issues are immediately reported to Project Management. The visit reports provided by the CRAs include detailed action plans for all issues identified and all issues are tracked through to resolution.

           Site Qualification (Pre-Study Visits and Phone Calls)

Omnicare CR’s site management and monitoring procedures will be performed in accordance with ICH-GCP guidelines to ensure each investigative site’s compliance with regulations and protocol requirements, and to enhance expeditious enrollment of appropriate patients into the clinical study. Regulatory documents will be reviewed by the CRA on an ongoing basis during the study conduct phase, including verification of signed informed consent forms and investigator IRB notifications.

The Omnicare CR CRA will review the following information at the pre-study site visit:

	•		Latest version of the Protocol for this study
	•		Consent form process
	•		AE and SAE reporting procedures and contact information

	•		Case report form completion and maintenance
	•		Source documentation requirements
	•		Drug accountability requirements

In addition, to ascertain that an identified investigational site is qualified to perform this study to Omnicare CR’s expectations, the CRA will review the following issues at the study site and report this “study profile” in a site visit report to Omnicare CR and the Sponsor:

	•		Principal investigator qualifications and experience
	•		Site staffing, facilities, storage and equipment
	•		Adequacy of and accessibility to subject population
	•		Access to source documentation
	•		Status of regulatory documentation (i.e. FDA 1572, protocol sign-off page, curricula vitae, medical licenses, certification of investigators’ financial disclosure, etc.)
	•		IRB and ethics committee issues
	•		Laboratory and pharmacy certifications and normal ranges (if applicable)
	•		Investigator agreement and indemnification issues
	•		Recommendations for investigational site approval or exclusion from the study

Sites that have recently had a pre-study site visit performed by the Sponsor or have worked with Omnicare CR in the preceding 12 months may be exempt from a pre-study site visit. The Sponsor will provide Omnicare CR with a list of any exempt investigators for this study.

           Site Initiation

Once all regulatory documents and approvals are received, a site initiation visit will be scheduled. During this visit, the CRA will review the following with the principal investigator and his/her staff as appropriate:

	•		Study goals and obligations
	•		Investigator brochure
	•		Protocol procedures with particular attention to inclusion/exclusion criteria, enrollment goals, adverse events, primary efficacy variables and GCP compliance)
	•		Informed consent procedure
	•		Randomization procedure
	•		AE/SAE reporting
	•		CRF completion and error correction/need for adequate source documentation
	•		Maintenance of the investigator binder and site visit log
	•		Laboratory sample/photography sample handling procedures and results reporting procedures
	•		Clinical supply dispensation, accountability and storage procedures

                Site Interim Visits

Omnicare CR CRAs will perform 100% source document verification of CRF data for accuracy and completeness. CRFs will be retrieved during each monitoring visit. Pages and information for patients who fail screening will be reviewed and monitored.

The following issues are addressed at each interim visit as appropriate:

	•		Source document verification
	•		CRF completion
	•		Expedient data retrieval and query resolution
	•		Drug accountability
	•		Check and review of the regulatory binder and its contents
	•		Clinical supply inventory
	•		SAE reporting
	•		Enrollment issues and targets
	•		Protocol amendments
	•		Significant protocol deviations
	•		Acceptability of facilities
	•		Personnel changes
	•		Updated regulatory documentation
	•		Laboratory sample/photography sample handling

Following each monitoring visit, Omnicare CR will complete follow-up letters and site visit reports within two weeks of each visit. These follow-up letters and monitoring reports will be available to the Sponsor via Omnieview.

           Site Closeouts

At the conclusion of the study, after all completed CRFs have been returned to Omnicare CR for logging and tracking, and after all unused CRF binders have been returned to Omnicare CR for destruction, the Omnicare CR CRA will perform a close-out visit.

The following issues are evaluated and/or reviewed with the investigator and his/her staff at the close-out visit:

	•		Reason for termination (if study is not complete)
	•		Reconciliation and removal of clinical supplies per The Sponsor’s requirements (including hazardous materials)
	•		All original CRFs retrieved from the site at the previous visit
	•		Signed informed consents retained by investigator
	•		Record retention requirements
	•		Notification to IRB or ethics committee of study termination
	•		Collection of randomization codes for return to The Sponsor
	•		Resolution of all data queries
	•		Investigator binder contents (complete and updated)
	•		Informed consent log
	•		Financial agreements and disclosure (filed separately)
	•		Signature log and screening log
	•		Site visit and subject enrollment log
	•		Laboratory certification and renewals
	•		Summary/discussion of study from investigator and/or staff

           Site Maintenance

Omnicare CR maintains a minimum of bi-weekly contact with investigational sites via telephone, facsimile, e-mail and/or mail correspondence, based on the requirements of each investigational site.

Activities that are performed in-house between monitoring visits include, but are not limited to:

	•		Discussion of study protocol and any amendments to the protocol
	•		Inclusion/exclusion questions or issues
	•		Review of clinical laboratory results
	•		New staff or team member orientation
	•		Additional site training
	•		Clinical supply activities or issues
	•		Enrollment updates (via weekly fax updates)
	•		AE and SAE updates
	•		Data query resolution
	•		Scheduling activities

Included in Site Maintenance activities, Omnicare CR CRAs will assist the Sponsor in resolving data queries for data from investigational sites, which are unclear, conflicting or incomplete.

           CRA Teleconferences

Omnicare CR’s CRAs will participate in conference calls with the Sponsor as warranted by the Project.

           Sponsor Meeting Attendance

Omnicare CR assigned Project Team will attend face-to-face meetings with the Sponsor’s clinical team throughout the Project.

           Clinical Grants Administration

Omnicare CR’s Investigator Grant staff will administer the clinical grant payments to the site. Included in their responsibilities are following:

	•		Processing financials records for all of the patients in the study
	•		Issue initial and interim payments for each investigator
	•		Reconciling all payments to each of the investigators prior to final payments
	•		Tracking account administration with Omnicare CR’s finance group
	•		Maintaining IRS W-9 forms and all relevant and government reports
	•		Reporting excess grants from sites at study end

Activities included in Clinical Grants Administration include the following:

           Investigator Grant Start-up Administration

Investigator Grant Start up Administration includes two activities: Contract Review which includes protocol/contract evaluation, investigator/site budget drafting, and telephone contact with the investigator and Grant Set-up which involves evaluating and entering site specific information. Confirm with the site representative(s) the correct name of the payee and that the site representative(s) understand how payments will be made. Identify correct payee by verifying contract information with IRS W-9 and site profile; follow-up calls and correspondence may be needed to clarify discrepancies. Set-up directories, site, and study specific spreadsheets to perform the tracking payments/invoices to the sites. Set up binders/files for hard copy files of site profiles and order checks (i.e. in addition to setting up an account for each payee).

           Grant Management

Grant Management includes review and verification of source payment tracking data, data entry, and tracking and follow-up clarification with the Project Management staff and site contacts/site communications, managing ongoing investigator inquiries regarding payments and follow-up. Grant Management occurs after the site “set up” until 60 days after final payment (note: actuals will be billed). Grant Management also includes determining when grant payments are due per contract (i.e. site payment status), re-designing tracking spreadsheets as study parameters change, reconciling tracking logs with general ledger, and making adjustments from previous payment cycle and at study completion. Also includes re-issuing checks as needed (due to sites not cashing or lost checks), completing Sponsor specific reconciliation (as needed) and completing a final reconciliation of all payments made throughout the study.

The following are the types of ongoing payments which are required/performed during the course of a clinical trial: multiple IRD payments/fees (for initial & amendment submissions), patient enrollments (i.e. payments based on completed CRFs, visits or procedures performed and may include, coordinator fees, and investigator fees). Other types of separate payments include screen failure payments, incentive fee payments, specialized equipment payments, specialized study specific supply payments, and sub-study payments.

In addition, participating sites will be analyzed with Project Managers for the future enrollment to determine grant payment projections. Time will be allocated to complete the grant payment reconciliation process with Omnicare CR’s business administration office.

           Payments

As payments are processed the following are generated: payment/check request form, payment detail and letters (by Sponsor request) to accompany checks. In addition, Omnicare CR will update site-specific logs and study-specific summary logs as well as the log for tracking payments sent to sites. The payment process includes mailing and photocopying expenses.

Investigator grants, with parameters defined by the Sponsor, will be passed through at cost. Invoices submitted for payment to Sponsor for estimated grant funds will be payable upon the receipt of the invoice. Any remaining funds will be carried forward to the next payment cycle and additional invoices will be generated as needed. A grant administration fee will be applied, based on the number of sites and payments to be managed throughout the duration of the study.

           Site Refund Checks

Additional costs may be incurred if the Sponsor requests site refunds. Letter will be sent to sites that do not enroll patients in a study, etc. A letter from Investigator Grants is generated to the site requesting the return of funds for a stated reason. This is sent via preferred carrier or by certified mail. Follow up with the site contact will occur up to three times. Regardless of the outcome, the service will be considered rendered if either of the following occurs. (1) A refund is received, (2) a letter and 3 follow up calls have been completed or (3) an agreement is reached between the Sponsor and the principal investigator.

If the site objects to refunding the monies, the site sends a detailed letter stating reasonable start up costs. A copy of the letter is forwarded to the Project Manager and or Sponsor to determine the outcome and action needed. Otherwise, the site returns a check payable to Omnicare CR for the amount stated in the refund letter. The check is returned to Investigator Grants and then is forwarded to Account Receivable Department to be deposited and credited to the study. Refund service fees are not calculated in advance as part of any grant administration budget item.

D. Safety and Medical

          Medical Monitoring (during business hours)

The medical aspects of The Sponsor’s clinical program will be overseen by one of Omnicare CR’s staff physicians who will be assigned to the study during business hours as the Project’s Medical Monitor. In addition to acting as medical advisor to the Project Team, the Medical Monitor is responsible for the following:

	•		Addressing medical inquiries, internal or external
	•		Reviewing of clinical documentation (protocol, draft CRF, sample informed consent form)
	•		Project-specific medical training
	•		Evaluating patient eligibility (in conjunction with the Medical Director of the Sponsor)
	•		Participating in team meetings
	•		Review of Safety Data, such as laboratory results, ECGs, SAEs, AE Listings
	•		Reviewing study reports, regulatory submissions and study manuscripts

           Safety Coordinator

The Coordinating Safety Officer assigned to the Project will coordinate all activities relating to safety. These activities include attendance of internal and external team meetings, safety training of Project staff or sites, communication of safety information to Omnicare CR Project Management and Data Management departments as well as the sponsor, and tracking the flow of safety information for the life of the Project. The Coordinating Safety officer will also be responsible for the generation of, and any required revisions to, the Study Safety Plan, a comprehensive document, which defines the process and flow for contracted safety services. Safety coordination also includes assistance with the SAE reconciliation process, and completion of sponsor derived queries of the sites.

          SAE Reporting- (with initial descriptive summaries)

Omnicare CR can provide initial descriptive summaries for all identified serious adverse events. The descriptive summaries will be written from information provided by the investigator on the SAE report forwarded to Omnicare CR at the time of the event. If significant follow-up information becomes available, the narrative will be updated accordingly.

           SAE Reporting (Follow-up/Revision Reports>2)

Updates or revisions to an initial SAE report greater than two (2) will be billed per unit based upon the actual number of additional reports required. The Coordinating Safety Officer tracks all initial and follow-up reports.

           Safety Database

Omnicare CR will develop the safety database for the Project. The database platform is the current version of the **** system. The system is fully validated and compliant with all regulatory requirements for electronic storage of adverse event data. Additionally, the system is capable of generating adverse event files in electronic format according to the definitions set in ICH E2B. Omnicare CR is able to perform electronic submission of serious, unexpected, suspected adverse reactions (‘SUSARs’) to regulatory authorities as mandated by the European Clinical Trials Directive.

E. Clinical Data Management

A Data Management team will be assigned to this project to carry out all of the activities defined in the bid specifications. The team will consist of a Lead Data Manager, Lead CDA, Database Programming staff, Dictionary Manager and specialists, Clinical Data Analysts and Data Technicians. Team recourses for the project will be developed by the Data Manager and will be based on the patient enrollment plan along with the Case Report Form retrieval plan. Adjustments will be-made as needed as the study progress.

The Data Management team will work together under the leadership of the Lead Clinical Data Manager to ensure the meeting of all project quality deliverables along with a successful and timely database closure.

           Data Manager

The Clinical Data Manager assigned to this project will oversee all Data Management activities throughout the life of the project. This dedicated Clinical Data Manager will act as the primary liaison for all Data Management activities. Some of the Clinical Data Manager’s activities are listed below:

	•		Overseeing and supporting the Lead CDA throughout the completion of setup and completion of all data management activities
	•		Review and approval of the Data Management Plan. The Data Manager will assure the receipt of the Sponsor’s approval prior to the initiation of any tasks outlined in this plan
	•		Supporting the development of the CRF completion guidelines

	•		Maintain ongoing communication with Sponsor team members and Omnicare CR’s Project Team Members
	•		Development of resource and contingency plans to ensure appropriate project staffing throughout the study, based on the Data Retrieval Plan provided by the CTM.

           Lead Clinical Data Analyst

Based on the deliverables for the Project, Omnicare CR has assigned a Lead Clinical Data Analyst. The Lead Clinical Data Analyst will provide additional team oversight for the Project Data Technicians and Clinical Data Analysts. The Lead Clinical Data Analyst will assist the Clinical Data Manager with the following activities in relation to the page-related staff:

	•		Prioritize of Clinical Data Management tasks
	•		Direct the daily Clinical Data Management team task assignments
	•		Monitor the status of task and work load
	•		Oversee Project training for Clinical Data Management team members.
	•		Liaise with Clinical Trial Managers to ensure expectations for recording data accurately are communicated to the Project Team and the study site
	•		Manage the query generation and final resolution
	•		Proactively address data quality issues to reduce query generation
	•		Liaise with the Clinical Trial Managers for timely query resolution
	•		Ensure high quality and timely data management deliverables
	•		Provide feedback to the Clinical Monitoring staff on query trends
	•		Provide backup support to the Clinical Data Manager
	•		Ensure a cohesive team that maintains high quality and data consistency
	•		Provide status updates to both the Omnicare CR internal Project Team and the Sponsor team members

           Data Management Plan

The Lead CDA will develop the Data Management Plan. The Data Management Plan will include descriptions of the following Data Management activities:

	•		Project data flow
	•		Database development overview
	•		Edit specifications
	•		Data entry guidelines
	•		Data handling guidelines
	•		Study assumptions (Level 1)
	•		SAE reconciliation process
	•		External data load procedures / External Data Cleaning parameters / Discrepancy identification flow
	•		Dictionary coding guidelines and processes
	•		Database closure procedures

Prior to the start of Data Management activities, the Data Management Plan and edit specifications must be agreed to and signed by the Omnicare CR designee and Sponsor representative. It is expected that the Sponsor will respond to requests for comments (on draft documents) or approval (on final documents) within two (2) weeks of receipt of document. The agreement to all data handling rules will ensure an accurate and timely final database lock leading to a successful data analysis. It is assumed that all portions of the Data Management Plan related to any specific task will be agreed upon prior to the start of those activities.

           CRF Design and CRF Completion Guidelines

Upon approval of a final protocol by the Sponsor, a draft CRF to record pertinent study data will be prepared with input from Omnicare CR’s Data Management, Project Management, and Biometrics. A draft document / CRF is provided to Sponsor for review. It is expected that the Sponsor will respond to requests for comments (on drafts documents) or approval (on final documents) within two (2) weeks of receipt of documents. Upon receipt of the final draft comments, the final printable version of the CRF is prepared and provided to Sponsor for approval signature. Sponsor will be provided with either “camera-ready” CRFs for printing or with ready-to-use multicopy carbonless forms.

Any requests for Clinical Data Management to supply the CRF Completion Guidelines will follow the same process. These guidelines need to be finalized prior to the start of monitoring, preferably prior to the investigator meeting.

           Database Creation and Testing

Omnicare CR’s Data Management Department uses Oracle Clinical for a standardized, validated approach to database design, edit development, data collection and storage. Several benefits for using this approach include an integrated query system directly linked to the clinical database. Omnicare CR’s Programming group will develop data entry screens using Oracle Clinical® version 4.5 software running on Solaris Unix. The data entry screens (i.e. CRF data module designs) will mimic the flow of the CRF, thereby improving the ease and integrity of the data entry process.

Database creation will be initiated upon the receipt of the final Case Report Form.

A series of standard metric reports will be provided to the Project Team and the Sponsor. These standard CRF and query status reports are listed in Section “Reports.” Omnicare CR provides flexible and a ‘can do’ customer service approach to all aspects of Omnicare CR’s work and can create customized Sponsor reports if requested.

           Data Tracking and Data Entry

The dual data entry strategy will be utilized for numeric and/or text fields. Data will be entered by one member of the data entry staff and re-entered on-line by a second member of the staff. Omnicare CR assumes the CRFs for screen failure patients will not be received in-house, unless otherwise specified.

All CRF and ancillary data received from the investigative sites are logged into a tracking database on a page-by-page basis. Each page is identified by type of page and date received. Working copies will be maintained in Clinical Data Management and used for any annotations during processing and cleaning as appropriate. All original (white) CRF and query pages will be immediately sent for filing in the Project Master File.

           Data Review and Query Processing

Following the data handling rules and edits specifications listed in the Data Management Plan, the Clinical Data Analyst team will be responsible for:

	•		Reviewing the CRF data for obvious corrections and potential queries via the electronic Edit checks and the Manual review checks listed in the Data Management Plan
	•		Applying any agreed upon self evident corrections or study assumptions
	•		Transmitting queries to investigative sites with a copy forwarded to Project Management
	•		Logging queries (issued and resolved) into Oracle Clinical Discrepancy Management System
	•		Working with the Clinical Trials Manager to ensure all Data Clarification Forms (DCFs) are signed by the investigator and received in house via fax or mail.

On a continual basis, Clinical Trial Manager and the Clinical Data Manager working together will evaluate the number and type of queries being generated by Clinical Data Management, in order to proactively manage the retrieval of quality data on these studies. The team will frequently inspect the data for trends and identification of issues, providing feedback to both the Project Team and the site. This will begin as soon as sufficient CRF pages are received to identify the trends.

           Quality Control Review of the Database

It is Omnicare CR’s policy to perform a QC of the final database ensuring the error rate is within an acceptable range. Each CRF will be printed as a data listing with 100% QC of adverse events and the protocol identified primary efficacy parameters against the hard-copy CRF. Also, a random sample subset of the patients will under go a 100% QC of all data points vs. the CRFs, to ensure the estimate of the error rate for the database is within acceptable limits prior to declaration of clean database. The processes and outcomes of these QC procedures will be documented, with the findings corrected within the timeframe identified within the Data Management Plan. Omnicare CR believes that these strategies will ensure the following results with respect to these studies:

	•		Quality data
	•		On-time delivery of Final Clean Clinical Study Databases
	•		No surprises when preparing for data analysis

           Edit Checks

The edit specifications identified in the Data Management Plan require Sponsor approval prior to the initiation of the programming of the edit checks. It is Omnicare CR’s goal and in the Project’s best interest to have all edits programmed and tested prior to any CRF data being submitted to Data Management. This will ensure there are no delays in reviewing and querying

the data. Omnicare CR suggests a periodic review of the edit specifications and data review guidelines to ensure that the rules and edit checks meet the Project needs. It is expected that the Sponsor will respond to requests for comments (on draft documents) or approval (on final documents) within two (2) weeks of receipt of documents. The Sponsor will be billed on the actual number of edit checks defined and approved by the Sponsor.

           Dictionary Coding

Omnicare CR is proficient in coding to both MedDRA and the WHO-Drug dictionaries. Additional dictionaries can also be accommodated.

Omnicare CR Clinical Data Management will:

	•		Design and maintain the clinical database with Omnicare CR’s current version (at time of database build) of MedDRA for coding Adverse Events and Medical History terms, and WHO-Drug for coding Medications
	•		Utilize standard coding conventions as listed in the Data Management Plan for the mapping procedures. If Sponsor requires specific coding guidelines they must be provided prior to the start of the coding work and will be included in the Data Management Plan
	•		Utilize an automated process using Oracle TMS to map literal text to the corresponding term in the dictionary
	•		Research, code and review unmapped terms with a dedicated team

The Dictionary team will provide standard reports of all automated and manually coded terms/medications for periodic review and to Sponsor at soft lock of the database. Sponsor feedback and final approval is requested prior to hard lock of the database.

Sponsor is required to have a MedDRA license prior to receipt of any MedDRA coded terms.

Sponsor is required to have a WHO-Drug license prior to receipt of any WHO-Drug coded medications.

           Dictionary Mapping of the WHO-Drug ATC Level

Omnicare CR will map all medications to the WHO-Drug ATC level to the matching medication indication reported on the CRF, utilizing both the medication indication and medication route.

           Reconciliation of the Safety and Clinical Database

On a monthly basis (weekly during final month), Omnicare CR will receive a cumulative SAE listing of the Omnicare CR Safety database to compare against the clinical database. The qualifiers identified in the Data Management Plan will be reconciled, and a site query will be generated in order to resolve discrepancies. Clinical Data Management will update Omnicare CR’s Safety department with the DCF responses and Safety will update Sponsor on the changes.

           Reports

The standard Omnicare CR CRF and DCF reports will be provided to Sponsor and Omnicare CR’s Clinical Trial Manager on a monthly basis and more frequently approaching a database lock.

The standard reports are as follows:

	•		Cumulative CRF / DCF Status
	•		Cumulative CRFs by Site
	•		Outstanding DCFs by Site
	•		Resolved DCFs by Site
	•		Weekly Metrics: Data Processing

Nonstandard reports can be accommodated at an additional per diem cost. This would include reports for data metrics, data quality, and ad hoc data reports requested by the Sponsor.

           Standard Data Transfers

At the conclusion of the study, Omnicare CR will transfer the Project database to Sponsor in standard Omnicare CR SAS data sets using Omnicare CR standard naming conventions and format. Omnicare CR recommends an initial test transfer, an interim transfer when 50% of patients are entered, and a final transfer when 100% of patients have been entered and the database is soft locked and then again at hard-lock.

Customized data transfers, or interim data closures and transfers can be accommodated on request at an additional fee.

           Protocol Deviation Log Load

Omnicare CR will develop an additional Oracle Clinical module in order to load Sponsor’s log of protocol deviations into the clinical database. This includes development of the DCM/DCI module, loading the spreadsheet database, and quality control of received data.

F. Biometrics Analysis

          Biometrics Team Manager

Omnicare CR recognizes that statistical and programmatic services are critical to Sponsor achieving timelines and objectives for the Project. All of Omnicare CR’s biostatisticians are Master’s or Ph.D. level prepared, with an average of **** (****) years of ****, ****, or **** experience. Both the biostatistician and lead programmer assigned to Sponsor’s Project will meet with you during Project initiation and throughout the clinical phase, and will serve as Sponsor’s main point of contact for technical communications for the duration of the study. The frequency of communication will be determined at the kick off meeting, at a minimum communication should be scheduled for every other or every week depending on the complexity of the deliverables. In addition Omnicare CR Biometrics Senior Management meet together on a weekly basis to review staffing needs and forecasting. At this weekly meeting

management communicates with individual Project Team leaders to monitor the success factor of the team.

In addition, the Biometrics Team Leader will serve as local liaison to the Sponsor for technical issues, as the main point of contact for both clinical data management and biometrics services.

           Project Data Setup

The primary software product used for statistical analysis is SAS Version 8 or higher. SAS version 6 is available as a prior version. Omnicare CR’s standard SAS macros are globally accessible, validated according to current software development practices and Omnicare CR SOPs, and are compliant with FDA industry guidance documents. Every programming project environment is created with both a development and production area. Version control software tracks all changes made to production files once files are ‘checked in’ from the development environment. Prior to programming actual data displays (data listings, summary tables and graphics), Omnicare CR will perform the following:

	•		Initialize an internal Quality Control project tracking system which tracks the status of the program, the validation of the program output, the owners of the files and the dates that the events were completed
	•		Customize project specific macros and header files for program development
	•		Create a cross reference file for data displays to SAS program files
	•		Review of client programming style guidelines if applicable and incorporate into programming specifications if applicable
	•		Hold at least one internal kick-off meeting for the Biometrics team members

After approval of the prototype data display formats by Sponsor and the Omnicare CR Project Team, the programming staff will develop the programs required to generate each data display. Any changes to data display formats after approval and programming initiation could result in additional charges.

           Statistical Plan

A statistical analysis plan, including operational definition of endpoints to be analyzed, definition of patient subsets (evaluable and intent-to-treat), visit windows, rules for data handling, and a detailed description of statistical methodology, will be prepared for each study. By default the plan follows Omnicare CR SOP’s which incorporate all ICH and FDA guidance. If the Sponsor has a standard statistical analysis plan template then this can be used instead. This plan will be submitted to Sponsor for review and approval prior to closing the database for analysis or after receiving the final protocol and CRF if Sponsor is providing the database. It is expected that the Sponsor will respond to requests for comments (on draft documents) or approval (on final documents) within two (2) weeks of receipt of documents.

           Sample Size/Power Determination

Omnicare CR will estimate the required sample size according to the study design specified in the protocol and clinical assumptions of effect size and variability provided by Sponsor. In cases where clinical assumptions are not available or are not considered reliable, power curves will be provided for various scenarios for review by Sponsor.

           Randomization Schedule

The Project statistician will generate a randomization schedule according to the study design specified in the protocol. Electronic copies of the randomization will be created for loading into the clinical database at the time of database closure. Electronic and paper copies of the randomization are stored in a secured location in accordance with Omnicare CR SOPs. Fees include verification and review by a senior biostatistician.

           Design of Table Shells (Mocks)

The statistical plan will include a set of formatted shells for all data displays (data listings, summary tables and graphics) planned for the study, which will be prepared with input from the Clinical Writing Department. If formatted data displays are not required, a detailed table of contents of SAS generated data displays will be included.

           Programming/QC of Data Displays

The process to programming actual data displays (data listings, summary tables and graphics) at Omnicare CR is methodical and stepwise in description.

The process begins with the rules and requirements stated in the Protocol, Statistical Analysis Plan and Mock Data Displays. The annotated mocks drive the specifications for derived datasets definitions document, the programming of those datasets and the development and production of the data displays. The derived dataset specifications document follows the format presented by the FDA guidance concerning regulatory submissions in electronic format. Derived dataset structures can be created to client specifications. If specifications are not provided then programming defaults to CDISC standard structures in SAS transport file format. As the mocks is the specification for all programming output, any changes to data display formats or raw database after approval and programming initiation could result in additional charges.

The biometrics staff will use a combination of independent programming, hand tabulations from supporting listings, and programming verification to ensure the accuracy and completeness of tables, listings, and statistical results. Products developed in SAS are validated for accuracy through a double programming process and these processes are outlined in the departmental SOPs and guidelines. The status of a SAS program’s development is monitored through an internal tracking system which stores the individuals involved with a given product, comments for program and output issues, when the programmed files are ready for QC and when the person validating the results states that the product has passed QC. All report data displays will be verified for accuracy and internal consistency among data displays. A quality control binder, including the quality control strategy for each data display and audit trail, will be included in the Project file.

           Programmatic Evaluability/Outcome

Patient evaluability criteria and relevant algorithms will be developed for the study by Omnicare CR and presented to Sponsor for review and approval. These algorithms will be programmed using SAS to identify evaluable patients. Biostatisticians will verify the accuracy of the output with independent programming and review of individual patient data. Final decisions regarding patient evaluability will require approval by the Sponsor; patient evaluability is performed once for each patient in the study.

Data listings for each patient’s evaluability status and supporting data will be prepared and submitted to Sponsor for classification prior to breaking the blind. Data classification meetings may be held either in person or via teleconference.

           Statistical Analysis

Omnicare CR staff biostatisticians will perform statistical analysis, in accordance with the approved statistical analysis plan. The analysis includes verification of assumptions needed for statistical inference, determination of investigator-by-treatment interaction, and examination of outlying data points.

Statistical findings which may not be appropriate for the body of the clinical report (e.g., tests for interaction, data distribution issues, etc.), deviations from the planned analyses, and additional exploratory analyses will be included in a statistical appendix to the clinical report.

The Project statistician will also review the clinical report to ensure appropriate representation of statistical methodology and inference.

           FDA Item 11

Additional data definition documentation for all derived datasets can be provided to support the FDA requirements for submitting to the agency. The file produced would be named define pdf matching the guidance titled Regulatory Submissions in Electronic Format; New Drug Applications. Datasets are provided in SAS version 5-transport format.

           Standard Data Transfer

At the conclusion of the study, Omnicare CR will transfer, the Project database to Sponsor in standard Omnicare CR SAS data sets using Omnicare CR standard naming conventions and format. Customized data transfers, or interim database closes and transfers, can be accommodated on request at an additional fee.

           Data Safety Monitoring Board

A Data Safety Monitoring Board (DSMB) will be formed according to Omnicare CR’s operating procedures and will be solely responsible for evaluating the interim results of the study. One (1) organizational meeting and one (1) interim analysis evaluation meeting are planned.

Omnicare CR and Sponsor will jointly develop guidelines for membership of the DSMB, and for conduct of DSMB meeting to be documented in the DSMB Charter. The DSMB members will be recruited by Omnicare/Sponsor. Members of the DSMB will neither have previous involvement with Sponsor’s studies in this area, nor be currently involved in clinical trials of competing therapies.

The DSMB will have a written charter that will be produced by a Project Director which will define the responsibilities and will maintain records of all meetings. The written charter will also include a statistical appendix that will document the requirements and guidelines for analyzing and interpreting the interim safety results.

Omnicare CR’s biometrics team will prepare mock data displays specific to the DSMB charter. A senior statistician, otherwise unrelated to the study, will be responsible for the development of the data displays defined by the DSMB to ensure interim data accuracy and summaries are produced. These data displays will be programmed and validated by biometrics staff. The validation will be performed through a combination of individual patient data review and independent programming.

When the blind is ready to be broken, the DSMB statistician will perform the final run of the DSMB data displays and prepare for the DSMB.

For each DSMB meeting, the database will be extracted and the data listings and summary tables will be rerun. If the DSMB requests data clarification or further information, Omnicare CR will re-extract the data and rerun the listings and tables on the new data.

G. Clinical Writing

          Clinical Study Report — Phase II/III

The Clinical Writing Department has experience in the production of integrated statistical and clinical study reports covering a wide range of therapeutic areas. It will be the responsibility of the assigned Clinical Writer to ensure delivery of an integrated statistical and clinical study report for this program. The integrated clinical and statistical summary will be prepared in accordance with ICH guidelines on the “Structure and Content of Clinical Study Reports”, appropriate agency regulations, and Omnicare CR’s SOPs and clinical study report format. A draft clinical report will be generated within **** (****) weeks after receipt of source material and final summary tables and patient data listings.

The designated Omnicare CR clinical writers will liaise closely with the statistician and other team members. All clinical documents will receive, two levels of quality control reviews before they are released. There will be a QC review by an independent clinical writer for accuracy and consistency, and a review by the writing manager for accuracy, client format consistency, and appropriate regulatory and clinical perspective. The first draft will then be provided to the Sponsor for review.

The second draft clinical study report will be produced after receipt of one set of collated comments from the Sponsor. It is Omnicare CR’s experience at Omnicare CR that this can be facilitated, more speedily, by holding a draft review meeting (optional) between a Sponsor representative and the Omnicare CR clinical writer. The second draft will be reviewed within the Clinical Writing Department at Omnicare CR to ensure that all Sponsor comments are addressed and that all changes are consistent with the supporting data. Following the Sponsor’s second review, minor revisions will be made and the report finalized.

Omnicare CR Biometrics will provide up to **** tables and **** listings that will be summarized in the clinical study report. This fee includes **** major and **** minor revision. **** major revision of the draft report is considered to be up to **** (****) days of requested changes and a minor revision is up to **** (****) day of requested changes. Patient narratives will be drafted from final patient data listings. Omnicare CR Writing will prepare patient narratives for SAEs and, discontinuations due to adverse events based upon a $**** per narrative fee. The fee for the study report does not include study report appendices (including TLs).

           Clinical Writing Input to Statistical Analysis Plan

Omnicare CR’s Clinical Writing will review the draft statistical analysis plan and mock summary tables and data listings for consistency with the protocol and ICH guidelines for clinical study reports. Clinical Writing will provide feedback on the table design and format to facilitate the use of the data in the clinical study report.

H. Technology

Omnicare CR recognizes the importance of accurately tracking clinical study data and processes throughout the life of a study. Our secure clinical trial portal, OmnieView and OmnieTrack our clinical trial management system, allow study teams to communicate via a secure internet site, 24 hours a day, 7 days a week from anywhere. Sponsors can view the progress of their study by going to one centralized location. Because all team members have access to the same portal, communications can be more-timely, trial progress is known more quickly, and centralization allows everyone to see the same current information. Examples of information available on OmnieView include trial progress reports and metrics., reference and training materials, newsletters and other communications, contact listings, templates/forms and lots more.

OmnieTrack is Omnicare CR’s global Clinical Trial Management System (CTMS), which provides the ability for study personnel to plan, track and control all aspects of the clinical trial process for the duration of a study. OmnieTrack utilizes “web-enabled’’ technology to enable dispersed sites and Omnicare CR locations to communicate in real time through a central “hub”, transcending time zones worldwide.

OmnieTrack includes process and workflow automation, which includes task notification, issues escalation, and comparative analysis between actual and projected data. It also has enhanced capabilities including electronic trip reports and automated study projections. Key features and functionality of OmnieTrack are,

	•		Investigator Recruitment / Essential Document Tracking
	•		Patient Enrollment (patient accrual) by site and by trial projected and actual
	•		Monitoring Statue and Monitor Visit Scheduling
	•		CRF pages ready for review at site (projected/actual), CRF pages collected as related to patient and monitoring visit schedules
	•		Trip Reporting — electronic trip reports

OmnieTrack is able to provide you with ongoing, reliable and accurate information regarding specific studies via OmnieView and can deliver information to you in real time, summarized or detailed deliveries from the modules listed above. Status reports and trip report formats can be customized to meet your requirements (fees apply).

Omnicare CR works with each study team to assess what technologies and features should be used on a clinical trial to maximize the benefit of the solutions. Omnicare CR also works with sponsors to identify other technical requirements such as interfaces, secure connections, and customized reports. Fees are determined after the full requirements are known.

I. Regulatory Services

          Filing and Reconciliation of CRFs in the Study Master File

After logging in Clinical Data Management, completed CRFs are transferred to the Study Master File. Fees reflect time required to verify CRF and ancillary pages received against the Clinical Data Management tracking log and filing of CRFs. The Sponsor will be billed for the actual number of pages filed.

           Study Master File and CRF Return

Omnicare CR will return the Study Master File in hard copy format in accordance with Omnicare CR’s SOPs, within three (3) months of final study deliverable. A final review of the study wide and individual investigator files is completed by Project Management for completeness and accuracy. Sponsor will be billed for the actual number of sites returned.

           Compilation of Appendices to Clinical Study Report

Omnicare CR has included cost to compile and collate the Clinical Study Report electronic to hard-copy appendices in accordance with ICH guidelines. It is assumed that the Clinical Study Report appendices without hyper links will be prepared. Deliverables include electronic-to-paper publishing, with all required formatting, utilizing a validated environment and formatting check. Hardcopies requested by the Sponsor can be provided for an additional charge. PostScript files will allow for subsequent printing needs of Sponsor (one CD-ROM). Publishing of the appendices with hyper links applied is available for an additional charge.

J. Clinical Quality Assurance

Independent CQA audits provide additional verification to Sponsor that all contracted processes and procedures have been followed. As part of Omnicare CR’s contracted service, a CQA Project Leader will attend Omnicare CR and Sponsor Project Team meetings, conduct and manage the audit program, and proactively address any issues that may arise during the clinical development program.

In addition to contracted audits, CQA may, at its discretion, audit any aspect of a clinical trial. As these are internal audits intended to support the overall quality of Omnicare CR’s work, reports generated as a result of the audits are submitted to the management of Omnicare CR. Although the audit report is not provided to the Sponsor, CQA will inform Sponsor of any observations that affect the integrity of the study. CQA also provides an Audit Certificate for inclusion in the Project Master File.

An Executive Summary will be generated at the end of each study, documenting the quality status over the complete duration of the study. The Executive Summary will summarize all of the pertinent issues for all audits conducted in a concise, easy-to-read format. The findings will be listed by audit types and by categories and will be evaluated for their impact on the GCP compliance of the study. The Executive Summary also will document the corrective actions taken to achieve resolution of the findings.

Together with the Executive Summary, a Summary Audit Certificate will be issued for each audit conducted during the study.

           Quality Plan

The CQA Project Leader will develop a customized Project-specific Quality Plan in partnership with Sponsor. Ideally this contact person will be a CQA representative within Sponsor. The Quality Plan describes the approaches and methodology for the audits and as such, is a component of the Global Project Management Process (GPMP). The plan will include details such as the percentages of sites/patients/data to be audited, the timeline of audits, and the plan for generation of individual Audit Reports and Certificates. Sponsor will be requested to review and sign off on the plan and any necessary amendments to the original plan, prior to implementation.

           Investigator Site Audits

Typically, **** percent (****%) of the sites in a project are selected for audit. In the case of multinational trials, one site should be audited in each country. Audits will typically be performed at sites with high enrollment of subjects to identify whether study site performance, site documentation and facilities are in compliance with regulatory obligations and the requirements of the protocol, SOPs and ICH GCP. Typically more than one site will be selected for audit in countries with larger numbers of sites. Other criteria may also be used for selection of sites to be audited, e.g. issues identified by monitors or other members of the Project Team.

Study site audits will include an audit of the “in-house” investigator files for each site to be visited, as well as the audit at the study site itself. On-site auditing activities include 100% review of essential documents, including all informed consent documents and serious adverse event reporting compliance. In addition, for approximately ****% of subjects at each study site, CRF data will be audited against source documents with an emphasis on critical efficacy and safety data; drug accountability will also be verified for these subjects.

Each audit will conclude with a debriefing session with the site’s study personnel. Critical or urgent issues will be discussed at this time and recommendations for improved compliance will be offered. Should any observations arise that affect the integrity of the study, the CQA auditor will immediately alert Sponsor’s representative and the Omnicare CR Project Leader.

Specifics will be defined in the Quality Plan. An Audit Report, which documents the audit results as well as suggestions for corrective actions, will be generated. Upon receipt and acceptance of the responses, the Audit Report along with written responses will be sent to Sponsor. The Audit Report will summarize all of the pertinent issues in a concise, easy-to-read format, and will also list the findings by categories. In addition, an Audit Certificate will be provided.

K. Clinical Supplies Management

          General Service Description

Sponsor will provide study drug to Omnicare CR’s central dispensing pharmacy located in Perrysburg (Ohio). Sponsor will provide Omnicare CR with a MSDS and any special handling procedures for storage and distribution.

Upon approval of the proposal by Sponsor, Omnicare CR will assign a Study Drug Coordinator. The role of this Coordinator is to oversee the study drug management aspects of the project. The Coordinator’s responsibilities are to ensure that all cGMP/GCP requirements and all relevant local guidelines are followed for storage and distribution activities associated with the project.

Omnicare CR will be responsible for central storage, distribution to sites and Returned Drug Management, including drug destruction, of study drugs from all sites. Storage (assumed 4 months) and distribution of study drug to sites will be performed at cold store. Omnicare CR assumes up to **** shipments per site and an overall number of **** sites.

           Ordering, Receipt and Inventory Setup

Clinical supplies and other project related supplies/material would be ordered and/or received by Omnicare CR. Upon receipt, all items will be inspected and transferred to Omnicare CR’s “Quarantine” area until released. Upon a visual inspection and paperwork release, drug product will be placed into inventory.

           Storage for Distribution

Until shipment, clinical supplies will be stored in a segregated limited access area. Temperature and humidity are continuously monitored and recorded for the storage area. Products for this study will be stored in dedicated storage units or on designated shelves. The current inventory status of clinical supplies can be provided to Sponsor upon request during the study.

           Distribution

A written request (i.e. fax) for shipment to clinical sties will be received from Sponsor or designee. Study Drug will be shipped to investigational sites by overnight courier. It is assumed that each investigational site will require up to **** shipments throughout the duration of the trial. It is Omnicare CR’s assumption that supplies to be distributed to investigational sites will be stored pre-kitted, require no additional preparation or assembly prior to shipment and that **** hour shipping notice will be given by Sponsor. A Shipping Note including an acknowledgement of receipt section will accompany each clinical supply shipment. Prior to distribution, each shipment will be QC checked and inventory records will be adjusted.

           Returned Drug Management

Each site will return study drug back to Omnicare CR’s distribution facility. Upon receipt (assume one receipt per site), the returned study drug will be inspected and transferred to Omnicare CR’s rejected material area until released for destruction. Omnicare CR, will notify Sponsor before and after destruction of returned drug. Omnicare CR will document the receipt of each shipment from investigational sites. Returns from each site will be tracked and stored separately (at room temperature). The current inventory status of returned Study Drug can be provided to Sponsor, upon request, during the study.

           Documentation/Quality Assurance and Project Management/General Study Drug Issues

Omnicare CR will generate, review and approve documentation to ensure compliance with cGMP/GCPs. All documentation will be filed in a project-specific pharmacy file. Upon Project completion, Omnicare CR will provide all original Study Drug Management Documentation associated with the receipt, storage, shipping and returns to Sponsor, unless arrangements are made with Sponsor to archive originals at Omnicare CR.

IV. Budget

A. Estimated Project Budget

Omnicare CR, Inc. Clinical Budget for:
Sponsor:		▇▇▇▇▇▇
Compound:		PEP005 Topical Gel
Study:		A multi-center, randomized, double-blind, double-dummy, vehicle-controlled sequential cohort study to determine the safety of PEP005 0.025% and 0.05% topical gel in patients with actinic keratoses
PCN:		KO1605

Unit

Estimated

Estimated

Services

Unit

# Units

Cost

Fees

Pass-Thru

Total Cost

A. Study Management

•

Project Director — Americas (assumes ****% FTE)

Days

****

****

****

****

****

•

Project Administrative Support/Coordination - Americas (includes support for all functional areas) (assumes ****% FTE)

Days

****

****

****

****

****

•

Draft Informed Consent Review

Review

****

****

****

****

****

Sub-Total Study Management

****

****

****

B. Clinical Trial Initiation

•

Site Screening and Identification (assumes ▇▇▇▇▇▇ will perform this task)

> Zone 1

Site

****

****

****

****

****

•

Site Recruitment (assumes ▇▇▇▇▇▇ will perform this task)

> Zone 1

Site

****

****

****

****

****

•

Study Master File

> Americas: **** sites for **** months

Site Months

****

****

****

****

****

•

Regulatory Document Collection

> Zone 1

Site

****

****

****

****

Central IRB (pass-throughs are estimates only; actual fees will be billed based on specific IRB fees)

Site

****

****

****

****

****

Local IRB (pass-throughs are estimates only; actual fees will be billed based on specific IRB fees)

Site

****

****

****

****

****

•

Protocol Amendments — excluding ICF change

> ▇▇▇▇ ▇

▇▇▇▇▇▇▇▇▇▇/▇▇▇▇

****

****

****

****

****

•

Protocol Amendments — including ICF change

> ▇▇▇▇ ▇

▇▇▇▇▇▇▇▇▇▇/▇▇▇▇

****

****

****

****

****

		Page 29

Unit

Estimated

Estimated

Services

Unit

# Units

Cost

Fees

Pass-Thru

Total Cost

•

Investigator Agreement Negotiation — Standard (actuals will be billed)

> Americas

Site

****

****

****

****

****

•

Investigator Agreement Negotiation — Complex (actuals will be billed)

> Americas

Site

****

****

****

****

****

•

Investigator Agreement Amendments — Standard

> Americas

Amendments/site

****

****

****

****

****

•

Letters of Indemnification (US sites only)

Site

****

****

****

****

****

•

Facility Letters

># Standard Facility Letters

Site

****

****

****

****

****

># Complex Facility Letters

Site

****

****

****

****

****

•

Notice Letters

Site

****

****

****

****

****

•

IND Safety Report

>Zone 1

Reports/Site

****

****

****

****

•

Investigator Brochure Updates

>Zone 1

IB Updates/Site

****

****

****

****

****

•

Collect Financial Disclosure at Site Closeout

>Zone 1

Site

****

****

****

****

****

•

Vendor/Lab Service Agreements — Americas

Project

****

****

****

****

****

•

Investigators’ Meeting Coordination (pass-through is for investigator travel only-other pass-throughs are indicated below)

> Coordination, Meeting ▇ ▇▇▇▇▇ ▇▇▇▇▇▇▇

Meeting

****

****

****

****

****

> Per Attendee, Meeting 1 North America

Attendee

****

****

****

****

****

•

Investigators Meeting Preparation

Days

****

****

****

****

****

•

Investigators’ Meeting Attendance (OCR attendees x days)

Project Director — Americas

Days

****

****

****

****

****

CTM — Americas

Days

****

****

****

****

****

Medical Monitor — Americas

Days

****

****

****

****

****

Project Coordinator

Days

****

****

****

****

****

CRA Attendees

>Zone 1: **** CRAs

Days

****

****

****

****

****

Client Attendee Travel

Attendee

****

****

****

****

****

Meeting Coordinators

Attendee

****

****

****

****

****

Sub-Total Clinical Trial Initiation

****

****

****

		Page 30

C. Clinical Trial Management

•

Clinical Trial Manager - Americas (assumes ****% FTE)

Days

****

****

****

****

****

•

Clinical Monitoring

>Site Qualification Visit

>Zone 1: **** hrs on-site, **** hrs for prep, follow-up, and reports, and **** hrs for travel

Visits

****

****

****

****

****

>Site Initiation Visit

>Zone 1: **** hrs on-site, **** hrs for prep, follow-up, and reports, and **** hrs for travel

Visits

****

****

****

****

****

>Site Interims Visit

>Zone 1: assume **** visits/site, **** hrs on- site, **** hrs for prep, follow-up, and reports, and **** hrs for travel

Visits

****

****

****

****

****

>Additional Day Interim Visits (based on **** hour day; visits are total per zone; actuals will be billed)

>Zone 1: assume **** days for Zone pool of visits

Visits

****

****

****

****

****

>Site Close-out Visit

>Zone 1: **** hrs on- site, **** hrs for prep, follow-up, and reports, and **** hrs for travel

Visits

****

****

****

****

****

•

Site Maintenance for **** hrs/month/site (**** sites x **** enrollment and treatment months)

>Zone 1: **** sites

Site Months

****

****

****

****

****

•

CRA Monthly Teleconferences

>Zone 1: **** CRAS

Months

****

****

****

****

****

•

Project Team Training (To be held in conjunction with Investigator Meeting)

Project Director - Americas

Days

****

****

****

****

****

CTM — Americas

Days

****

****

****

****

****

Medical Monitor - Americas

Days

****

****

****

****

****

Project Coordinator

Days

****

****

****

****

****

CRA Attendees

Days

>Zone 1 CRAs: **** CRAs

Days

****

****

****

****

****

•

Sponsor Meeting Attendance (assumes **** face-to-face meetings and **** one-hour teleconferences, not all positions participate in all meetings; ▇▇▇▇ on actuals)

Project Director - Americas

Days

****

****

****

****

****

CTM — Americas

Days

****

****

****

****

****

Data Manager — Int’l

Days

****

****

****

****

****

Statistician — Int’l

****

****

****

****

****

Sr. Writer — Americas

Days

****

****

****

****

****

Project Coordinator

Days

****

****

****

****

****

Clinical Data Analyst

Days

****

****

****

****

****

Programmer

Days

****

****

****

****

****

•

Project Team Teleconference Attendance (assumes **** meetings; not all positions participate in all meetings; ▇▇▇▇ on actuals)

Project Director - Americas

Days

****

****

****

****

****

CTM — Americas

Days

****

****

****

****

****

Data Manager — Int’l

Days

****

****

****

****

****

Medical Monitor - Americas

Days

****

****

****

****

****

Safety Officer - Americas

Days

****

****

****

****

****

Statistician — Int’l

Days

****

****

****

****

****

Sr. Writer — Americas

Days

****

****

****

****

****

CQA Manager- Americas

Days

****

****

****

****

****

Study Initiation Manager

Days

****

****

****

****

****

Project Coordinator

Days

****

****

****

****

****

Clinical Data Analyst

Days

****

****

****

****

****

Contract Negotiator

Days

****

****

****

****

****

Programmer

Days

****

****

****

****

****

•

Clinical Grants Administration

>Grant Payment Set-up

>Zone 1

Sites

****

****

****

****

> Grant Management (takes place for active sites from site set-up through **** days after site close-out; estimated amounts; actuals will be billed based on number of active sites set up)

>Zone 1

Site Quarters

****

****

****

****

>Payment Processing (estimated based on **** payments/site; actuals, including investigator and site related payment and any miscellaneous payments, actuals will be billed; pass through costs are related to photocopying and postage)

>Zone 1: **** sites

Payments

****

****

****

****

****

>Estimated Investigator Grants (Includes Administrative, Study Coordinator, and Investigator fees; excludes tests in the synopsis that will be performed by the central laboratory; estimate based upon draft synopsis provided and may change upon review of the final protocol)

Patient

****

****

****

****

****

Screen Fail Patient - Americas

****

****

****

****

Enrolled Patient — Americas

****

****

****

****

•

Refund Checks (if needed; actuals will be billed)

Refund

****

****

****

****

****

•

Central Laboratory Services (**** passthroughs)

Project

****

****

****

****

•

**** (based upon **** Sites)

Project

****

****

****

Sub Total Clinical Trial Management

****

****

****

D. Safety and Medical

•

Medical Monitoring availability during business hours (flat fee of **** hours per month from first patient in through last patient out)

>Americas

Months

****

****

****

****

****

Greater than **** hours per month will be billed at hourly rate (from first patient in through last patient out); Billed on actuals

>Americas

Hours

****

****

****

****

****

•

Medical Monitoring during Study Start Up and Study Close-out (Billed on actuals)

>Americas

Hours

****

****

****

****

****

•

Safety Coordinator

>Americas — assumes **** day per month for **** months

Days

****

****

****

****

****

•

SAE Reporting (with initial descriptive summary) Billed on actuals

Report

****

****

****

****

****

•

SAE Reporting (Follow-up/Revision Reports >****) Billed on actuals

Report

****

****

****

****

****

> Data Entry into **** (actuals will be billed)

SAE

****

****

****

****

****

•

Medical Review of Protocol (▇▇▇▇ on actuals)

Days

****

****

****

****

****

Sub-Total Safety and Medical

****

****

****

E. Clinical Data Management

•

Clinical Data Management Oversight — Int’l (CDM Manager assumes ****% FTE x **** months for Start-up, ****% FTE for **** months for Duration, and ****% FTE for **** months for Close-out)

Days

****

****

****

****

****

•

Lead CDA — Int’l (assumes ****% FTE x **** months, ****% FTE x **** months, and ****% FTE for **** months)

Days

****

****

****

****

****

•

Development of Data Management Plan (includes **** major and **** minor revision; add’l revisions will be billed at per diem rates)

Days

****

****

****

****

****

•

CRF Design (assumes **** page CRF, **** unique CRF pages); includes **** major and **** minor revision

Project

****

****

****

****

****

•

Database Development, Testing and Maintenance (assumes **** page CRF, **** unique CRF pages)

Project

****

****

****

****

****

•

Estimated Data Entry (actuals will be billed)

> Pages in Int’l

Pages

****

****

****

****

****

•

Estimated Data Review and Query Resolution (assumes **** issue per **** CRF pages, **** manual checks and the application of **** study assumption for **** CRF pages); assumes **** CRF pages per enrolled patient, **** pages per screen failure patient and **** pages per drop out patient. Pages will be billed on actuals.

> CRF Pages

Page

****

****

****

****

****

•

Quality control check — critical items

Patient

****

****

****

****

****

•

Quality control check — full case

Patient

****

****

****

****

****

•

Edit Development (actuals will be billed)

Edits

****

****

****

****

****

•

CRF Tracking (includes all ancillary pages; actuals will be billed)

Page

****

****

****

****

****

•

Dictionary Med remapping — ATC Meds (actuals will be billed)

Term

****

****

****

****

****

•

Dictionary Coding of Adverse Event terms to MedDRA(estimated to be **** per patient; actuals will be billed)

Term

****

****

****

****

****

•

Dictionary Coding of

Term

****

****

****

****

****

Medication Terms (estimated to be **** per patient; actuals will be billed)

•

External Vendor — Initial Load (actuals will be billed)

Initial Load

Load

****

****

****

****

****

>Subsequent Load

Loads

****

****

****

****

****

(actuals will be billed)

Lab Visit Verification

Visits

****

****

****

****

****

(**** visits x **** patients; actuals will be billed)

•

Reconciliation of the

SAE

****

****

****

****

Safety and Clinical Database (actuals will be billed)

•

Interim Database Close (assumes clean database; based on # patients in close — actuals will be billed)

•

>1st Interim Close

Patients

****

****

****

****

****

•

Protocol Deviation Log

Project

****

****

****

****

****

Load

Sub-Total Clinical Data Management

****

****

****

F. Biometrics Analysis

•

Biometrics Team Manager

Days

****

****

****

****

****

•

Biometrics CRF Review

Days

****

****

****

****

****

•

Statistical Input into

Days

****

****

****

****

****

Protocol

•

Project Data Setup

Project

****

****

****

****

****

•

Statistical Plan

Project

****

****

****

****

****

•

Sample Size/Power

Days

****

****

****

****

****

Determination

•

Randomization Schedule

Project

****

****

****

****

****

•

Design of Table Shells

Project

****

****

****

****

****

(Mocks)

•

Programming/QC of Data Displays (actuals will be billed).

Unique Tables

Table

****

****

****

****

****

Repeat Tables

Table

****

****

****

****

****

Unique Listings

Listing

****

****

****

****

****

Repeat Listings

Listing

****

****

****

****

****

Unique Figures

Figure/Graph

****

****

****

****

****

Repeat Figures

Figure/Graph

****

****

****

****

****

•

Custom Derived Data Sets

>Initial (Assumes ****

Project

****

****

****

****

****

datasets)

>Subsequent

Dataset

****

****

****

****

****

(Assumes **** datasets)

•

Programmatic Evaluability/Outcome

>Regular or Advanced

Project

****

****

****

****

****

•

Statistical Analysis

>Regular

Project

****

****

****

****

****

•

FDA Item 11

Project

****

****

****

****

****