CLINICAL TRIAL AGREEMENT

Exhibit 4.53

 

Certain portions of this Exhibit have been omitted pursuant to a request for "Confidential Treatment" under Rule 24b-2 of the Securities and Exchange Commission.  Such portions have been redacted and bracketed in the request and appear as [*] in the text of this Exhibit.  The omitted confidential information has been filed with the Securities and Exchange Commission.

 

CLINICAL TRIAL AGREEMENT

 

THIS Agreement is entered into on March 18 ^th 2005 by and between AMARIN NEUROSCIENCE LIMITED , a limited company incorporated in Scotland with offices located at Kings Park House, Laurelhill Business Park, Stirling, UK, FK7 9PQ (“Sponsor”) and the UNIVERSITY OF ROCHESTER (“Institution”), a not-for-profit educational institution established under the laws of New York State, with business offices located at 5 ^th Floor Hylan Building, RC Box 270140, Rochester, NY 14627.

 

RECITALS

 

A.            Sponsor is engaged in the business of (inter alia) the development of pharmaceutical products, and the Institution is engaged in the business (inter alia) of providing clinical research and development services, including the provision of investigators who conduct clinical trials for the pharmaceutical industry, the management of clinical trials, clinical data management and statistical analysis.

 

B.              Sponsor desires Institution to study the safety and/or efficacy of Miraxion ™ (formerly Lax-101)(“Study Drug”) via a Phase III Clinical program and Institution is willing to perform a clinical study of the Study Drug; and

 

C.              The Study (as defined below) is of mutual interest and benefit to Sponsor and Institution, and will further the Institution’s instructional and research objectives in a manner consistent with its status as a not-for-profit tax-exempt educational institution;

 

Now therefore, in consideration of the promises and mutual covenants herein contained, Sponsor and Institution hereby agree as follows:

 

1.                STATEMENT OF WORK .

 

1.1                                  The Institution shall exercise best efforts to carry out or to facilitate the carrying out of the clinical trial research study set forth in the research protocol dated 2005 and entitled  “A Multi Center, Double Blind, Randomized, Parallel Group, Placebo-Controlled Trial of (ethyl-EPA) Miraxion ™ in Patients with Mild to Moderate Huntington’s Disease” (the “Study”), which is attached hereto as Exhibit A (the “Protocol”) and hereby incorporated into this Agreement by reference.  The Study shall be conducted under the direction of Dr. Ira Shoulson as principal investigator and Dr. Christopher Ross and Dr. Blair Leavitt as Co-Principal

 

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Investigators (together the “Principal Investigators”) in accordance with this Agreement.  The Institution shall procure that each of the Principal Investigators enters into an agreement containing the provisions set out in Exhibit D (as may be amended by mutual agreement as between the Institution and the Sponsor) prior to the commencement of the Study.

 

1.2                                  The Institution shall perform the services described in Exhibit B to this Agreement (the “Services”). All obligations which Sponsor desires to delegate to Institution are specified in Exhibit B under Assignment of Responsibilities and Institution shall assume the responsibility for such delegated obligations as Sponsor under the Federal Food, Drug and Cosmetic Act.  Any obligation not delegated to Institution pursuant to this Agreement and its Exhibits shall be retained by the Sponsor.

 

1.3                                  Institution acknowledges that time shall be of the essence in relation to the timetable set out as part of the Budget attached hereto as Exhibit C.

 

Notwithstanding the above, Sponsor acknowledges that the Institution ’s activities may be delayed by events or circumstances outside of its control, including, but not limited to: delays in Study Drug supply; changes to the Protocol or other related Study documents; regulatory or audit issues; and competing enrollments in the geographic areas served by investigators conducting the Study.

 

1.4                                  In the event that Sponsor requires for any reason to add to or vary the scope of the Services it shall notify Institution in writing to that effect and Institution shall, within ten business days of receipt of such notice, submit its proposals, including revised costings and timelines, as appropriate, for the performance of such Services.  If acceptable to Sponsor, the parties shall amend the Exhibits to this Agreement accordingly.

 

1.5                                  In performing the Services, the Institution shall (where appropriate), and the Institution agrees to be responsible for ensuring that its investigators (the “Investigators”), comply with and procure compliance with the following:

 

1.5.1                         the Protocol and any subsequent amendments;

 

1.5.2                         the ICH Harmonised Tripartite Guideline for Good Clinical Practice or its local equivalent (“GCP”);

 

1.5.3                         part 312 Title 21 of the Code of Federal Regulations issued by the U.S. Food and Drug Administration (“FDA”);

 

1.5.4                         the standard operating procedures of Institution to be agreed in advance by Sponsor ;

 

1.5.5                         all applicable national and local laws, rules and regulations, including but not limited to the U.S. Federal Food, Drug and Cosmetic Act and

 

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Regulations of the FDA, and those promulgated by any relevant regulatory authority, and relevant professional standards;

 

1.5.6                         all reasonable  written and verbal instructions of Sponsor;

 

and the Institution shall ensure that:

 

1.5.7                         the Investigators will permit monitoring, auditing or inspection of their activities by or on behalf of the Sponsor and the regulatory  authorities;

 

1.5.8                         the Investigators  will permit direct access to case report forms (“CRFs”), source data and  documentation (including patient notes) to persons performing trial-related  monitoring, audits, ethical review or regulatory inspection.  The expected frequency of monitoring visits will be as agreed between the parties from time to time;

 

1.5.9                         Investigators understand any persons delegated trial related duties are  suitably qualified and aware of the requirements of the Protocol, ICH GCP and the appropriate regulatory requirements and are adequately informed  about the Study Drug;

 

1.5.10                   the Investigators have adequate facilities, resources  and time are available to conduct the Study;

 

1.5.11                   adequate drug  storage facilities and drug accountability procedures are in  place;

 

1.5.12                   Study CRFs and other relevant Study documents are completed on an ongoing basis throughout the duration of the Study and are completed accurately and legibly and are consistent with the source documents;

 

1.5.13                   Investigators notify all adverse events and serious adverse events  (including suspected unexpected serious adverse events) occurring during the course of the Study to Institution, the Sponsor and any company contracted by the Sponsor to manage the reports and ensure onward reporting to Regulatory Authorities;

 

1.5.14                   the Investigators assist in the preparation of ethics submissions and  ensuring that local ethical approvals are in place;

 

1.5.15                   the storing of essential Study documents (as defined by ICH GCP) is in a suitable  archive for the period required by ICH  GCP guidelines;

 

and that all such responsibilities will be contained in a written agreement  between the Institution and its Investigators in a form approved by the Sponsor in writing.

 

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1.6                                  Institution shall perform the Services with reasonable care and skill and shall ensure that personnel engaged by it in the provision of the Services are competent and have appropriate professional qualifications, training and experience.

 

1.7                                  Each party shall from time to time by notice to the other nominate (a) representative(s) for primary liaison relating to the Services, which from the date of this Agreement shall be as follows:

 

For Sponsor:	Bimmie Strausser MD
	Consultant
For Institution	Dr. Ira Shoulson
	Principal Investigator

 

1.8                                  Institution agrees that all personnel performing the Services shall be employees or sub-contractors of Institution and that nothing in this Agreement shall be deemed to create a contract of employment between Sponsor and any employee or sub-contractor of Institution.

 

1.9                                  Sponsor agrees to provide in good time to Institution all data, advice and information reasonably necessary for the performance of the Services in accordance with this Agreement.

 

1.10                            Institution agrees (provided Sponsor has given it adequate notice in advance) to allow Sponsor to attend the site(s) where the Services are being conducted for the purpose of monitoring and reviewing the performance of the Services at times and dates mutually acceptable to all parties and to give Sponsor its full co-operation in this regard.

 

1.11                            In the event of any inconsistency between this Agreement and the Protocol, the terms of this Agreement shall govern.  Changes in the Protocol may be made only through prior written agreement between the Sponsor and the Institution.

 

1.12                            The Institution agrees to screen sufficient numbers of patients into the Study to allow for 300 patients to be randomised into the Study.

 

1.13                            The Sponsor reserves the right to amend in writing the numbers of patients to be randomised as set out in Article 1.12, in accordance with the provisions of Article 1.4.

 

2.                PERIOD OF PERFORMANCE .

 

The Period of Performance under this Agreement shall commence on the date of this Agreement and shall remain in force (subject to earlier termination pursuant to Article 14) until the completion of the Services in accordance with the terms of this Agreement. The Study may not in any event begin until approval is received from the Institution’s Institutional Review Board (“IRB”) and Regulatory Authority.

 

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3.                PAYMENT .

 

3.1                                  Sponsor shall pay the Institution in accordance with the budget and milestone schedule attached hereto as Exhibit C and incorporated herein by reference (the “Budget”).  The parties estimate that the payments provided for in the Budget will be sufficient to support the Study, but Institution may submit to Sponsor and/or the Sponsor may request a revised budget in the event that costs may reasonably be projected to exceed or be less than the Budget.  Except as otherwise provided in this Agreement, Sponsor will not be required to make any payment in excess of the Budget without Sponsor’s prior written approval.

 

3.2                                  Regardless of whether it is included in the Budget, the Sponsor understands and agrees that it is responsible for paying the Institution’s nonrefundable Institutional Review Board fees and for reimbursing to the Institution any Institutional Review Board fees payable to any third party in respect of any site taking part on the Study, and shall pay such fees within thirty (30) days of the date of receipt of the invoice except as otherwise provided in the Budget.

 

3.3                                  Sponsor shall in addition reimburse Institution for reasonable and necessary pre-approved travel and other out-of-pocket expenses properly and necessarily incurred in the performance of the Services as set out in Exhibit B(the “Expenses”), provided that the Institution produces copy invoices or other substantiating documentation and, in the case of any individual item of expenditure exceeding the sum of $500, Sponsor’s prior written approval has been given to such expenditure.

 

3.4                                  Institution shall render invoices in respect of installments of the Budget and in respect of Milestones (once achieved), when payable, and monthly invoices in arrears in respect of the Expenses. Payment shall be due within 30 days of the date of receipt of the Institution’s invoice.

 

3.5                                  Checks shall be made payable to the University of Rochester and sent to:

 

University of Rochester

Clinical Trials Coordination Center

1351 Mt. Hope Avenue, Suite 223

Rochester, NY  14620

ATTN:   Finance Department.

 

3.6                                  For purposes of identification, each payment shall include the title of the project and the name of the Principal Investigator.

 

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3.7                                  Payments will be made by the Sponsor to the Institution and from the Institution to participating Study sites upon (i) completion of CRF’s for evaluable patients, and (ii) inclusion of such CRF’s in the Study database.

 

4.                SUPPLIES .

 

Sponsor will provide Institution, at no charge, with a sufficient quantity of the Study Drug and matching placebo necessary to conduct the Study, as well as any other compounds, materials, equipment, and information, which the Protocol specifies as being provided by Sponsor to Institution, or which Sponsor and Institution deem necessary to conduct the Study.  All such Study Drug, compounds, materials, and equipment remain the sole property of Sponsor, unless otherwise designated.

 

5.                INVESTIGATOR’S ASSURANCE .

 

5.1                                  The Institution acknowledges that the Principal Investigator agrees to undertake certain obligations as prescribed in Exhibit B and as required by applicable government regulations.

 

5.2                                  Sponsor acknowledges that the responsibility to comply with and perform under the provisions of Exhibit B where indicated as being the responsibility of the Principal Investigator shall rest with the Principal Investigators as required by the Food and Drug Administration (FDA).

 

6.          NOTICES .

 

Any notices related to this Agreement or required herein shall be in writing and delivered by first class mail, postage prepaid, or by facsimile (facsimile notice to be confirmed by letter posted within 24 hours of transmission) to the address of the other party as set out below (or such other address as may have been notified in writing to the other party), and any such notice shall be deemed to have been served at the time of delivery (if delivered) or upon the expiration of 96 hours after posting (if sent by post) or upon the expiration of 12 hours after transmission (if sent by facsimile)

 

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INSTITUTION Gunta J. Liders, Associate VP for Research Administration University of Rochester Office of Research & Project Administration 5 th Floor Hylan Bldg. Rochester, NY 14627 Phone: (585) 275-4031 FAX: (585) 275-9492

SPONSOR General Counsel & Company Secretary  Amarin Corporation plc; 7 Curzon Street; Mayfair; London W1J 5HG U.K Phone +44 (0)20 7907 2447 FAX: +44 (0)20 7499 9004

 

7.                INDEPENDENT CONTRACTOR .  The Institution is an independent contractor and not an agent, joint venturer, or partner of Sponsor.

 

8.                INDEPENDENT RESEARCH .  Nothing in this Agreement shall be construed to limit the freedom of the Principal Investigators and/or Institution, its employees and agents, whether paid under this Agreement or not, to engage in similar inquiries made independently under other grants, contracts or agreements with parties other than Sponsor.

 

9.                CONFIDENTIAL INFORMATION .   All information designated at the time of disclosure, in writing, by either party as confidential (“Confidential Information”) shall not be used by the other party other than for purposes of this Agreement.  Each party agrees to treat Confidential Information received from the other party with the same degree of care with which it would treat its own Confidential Information of a similar nature and further agrees not to disclose such Confidential Information to a third party without prior written consent of the other party, for a period of five (5) years following disclosure.  The foregoing obligations of non-disclosure do not apply to Confidential Information which:

 

(a)           is in the public domain at the time of disclosure;

(b)          was known to the other party prior to disclosure;

(c)           was received from a third party not under an obligation of confidence to Sponsor;

(d)          is required to be disclosed by law or at the request of a governmental authority, but only to the extent that such disclosure has been so directed or requested and provided that Sponsor has been given sufficient advance notice of any such proposed disclosure in order to enable it to take appropriate measures to protect the confidentiality of the Confidential Information; or

(e)           is disclosed by either party to its employees and sub-contractors who reasonably require access to it and use of it for the purpose of carrying out that party’s rights and obligations under this Agreement, and who have a contractual obligation to that party to (i) protect the confidentiality of information such as the Confidential Information on terms no less onerous than as set out in this Agreement; and (ii) to assign all

 

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Intellectual Property (as defined below) arising from such individuals work on behalf of that party to that party upon request.

 

10.          DATA OWNERSHIP AND INTELLECTUAL PROPERTY .  The Institution agrees that all data, inventions and discoveries generated by any party (to include for the avoidance of doubt any Subcontractor or Investigator) during the course of the activities described in the Exhibits hereto shall be the sole and exclusive property of Sponsor.  The Institution shall execute any documents or undertake any further actions if requested by Sponsor to evidence transfer of title thereto.  Sponsor shall reimburse the Institution, Principal Investigators or Subcontractors for any reasonable expenses incurred at Sponsor’s request to secure title or legal protection for any such Inventions.  Notwithstanding the above, the Institution and its Subcontractors may retain a copy of the data, inventions and discoveries for their own education and non-commercial research purposes.  The Institution shall also own the copyright to all of its standard forms previously created by the Institution, including those modified for use by Sponsor.

 

11.          PUBLICATION .   Sponsor acknowledges that Institution is dedicated to free scholarly exchange and to public dissemination of the results of its scholarly activities.  Therefore, Institution shall have the right at its reasonable discretion to publish in writing, material resulting from or related to the Study.  The Institution shall furnish Sponsor with a copy of any proposed written publication or presentation of such material at least thirty (30) days prior to the submission for publication. Within said period, Sponsor shall review such proposed publication for any designated proprietary information and, by written notice to the Institution, identify with specificity the sentence(s) or figure(s) in the proposed publication which Sponsor contends contains such proprietary information or which cannot be disclosed for legal or administrative reasons so that the proposed publication shall be edited appropriately by the Institution to remove it/them before publication.  If the Sponsor determines that the proposed publication contains patentable subject matter which requires protection, the Sponsor may require delay of submission for publication for a period of time not to exceed sixty (60) days for the purpose of filing patent applications.  The Institution shall give the Sponsor and /or Sponsor’s personnel appropriate credit and / or recognition for co-authorship in accordance with academic standards for any direct contribution made by them, subject to their prior consent.

 

12.          SITE MONITORING AND AUDITING Sponsor and the Institution acknowledge that routine site monitoring is not included in the Institution’s Work Scope, attached as Exhibit B, and will be performed by a sub-contractor of Sponsor. Should Sponsor elect to conduct additional audits, inspections or reviews of the Investigators and/or sites participating in this Study (“quality assurance”, “validation” or other Sponsor related audits) over and above routine monitoring, which places an undue burden on the relevant Investigators and/or sites participating in this Study then Sponsor agrees that a reasonable fee shall be due and owing to the Investigator/site so audited.  This fee shall not apply in the event of an FDA or Sponsor

 

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“for cause” inspection and shall not in any event exceed $1,000 where such audit, inspection or review is two days or less.

 

13.          PUBLICITY .  Neither party shall use the name of the other in connection with any products, promotion, or advertising related to this Study without the prior written permission of the other party save to the extent as is properly required to be disclosed by law or at the request of a governmental authority.  This does not include the existence of the Agreement for internal reporting requirements.

 

14.          TERMINATION .

 

14.1                            This Agreement may be terminated without cause by either party at any time during the term of the Agreement on ninety (90) days prior written notice to the other party.  In the event that Agreement is terminated for any reason by the Institution, the Institution will use its best efforts to promptly conclude and/or upon Sponsor’s request, transfer the responsibility for the Study to Sponsor or their designee. Sponsor will use its best efforts to accept the transfer of responsibility from Institution in a timely fashion.  The Institution will take all necessary steps to accomplish the orderly transfer of Study responsibilities and to minimize disruption of day-to-day Study activities, particularly those activities involving Study participants.  At Sponsor’s request, the Institution shall promptly deliver to Sponsor or their designee all data, information, materials and any and all documentation relating to the work or the services performed or to be performed hereunder.

 

14.2                            Either party shall be entitled forthwith to terminate this Agreement by notice to the other if:

 

14.2.1                   that other party commits any material breach of any of the provisions of this Agreement and, in the case where the breach is capable of remedy, fails to remedy the same within thirty (30) days of receipt of notice from the party seeking to terminate, specifying the breach and requiring it to be remedied; or

 

14.2.2                   the other party compounds or makes arrangements with its creditors or is adjudged insolvent or goes into liquidation (other than for the purposes of a bona fide reconstruction) or has a  receiver appointed over most of its property or assets or any event occurs in any jurisdiction in relation to that party which is analogous to the foregoing events.

 

14.2.3                   in the reasonable judgment or the parties and the Principal Investigators, the Institution’s IRB, or the Food and Drug Administration it is determined to be inappropriate, impractical, or inadvisable to continue due to a safety issue.

 

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14.3.                         The exercise of the rights to terminate this Agreement given by this Article 14 shall not prejudice legal rights or remedies either party may have against the other in respect of any breach of the terms of this Agreement.

 

14.4                            All provisions of this Agreement that by their terms require performance by one or both parties following expiration or termination of this Agreement shall survive such expiration or termination.  Such provisions shall include, but not be limited to, Articles, 3, 5, 6, 9, 10, 11, 13, 15,17 ,24, 25 ,26 and 27.

 

15             POST TERMINATION CONSEQUENCES

 

15.1                            In the event of termination for any reason of this Agreement pursuant to Article 14 above:

 

15.1.1                   the parties shall promptly meet in good faith to discuss and endeavour to agree on the steps required to effect an orderly closure of all outstanding Services;

 

15.1.2                   to the extent that any part of the fee for the Services has been paid in advance and such fee is recoupable in accordance with any relevant agreement, the Institution shall promptly re-pay such fee to Sponsor, having made deduction only of a sum representing payment for the Services calcul