AGREEMENT Between BioCancellTherapeutics Ltd. BeckScience Center, 8 Hartom St. Jerusalem97775, Israel (Hereinafter:BioCancell) Andbetween

 

1.1.

The preface and appendices to this Agreement constitute an integral part hereof.

 

1.2.

Titles of the sections in this Agreement shall be used for terms of reference only, and could not be used for the interpretation of this Agreement.

 

1.3.

This Agreement contains the entire understanding of the Parties and the Principle Investigator with respect to the subject matter hereof, and supersedes all prior or pre-existing negotiations, declarations, presentations, commitments and/or agreements, whether written or oral, whether explicit or implied, between the Parties and the Principle Investigator, with respect to such subject matter.

 

1.4.

In the event of a contradiction between this Agreement and any of the terms of its appendices, the terms and conditions of this Agreement shall prevail.

 

1.5.

Anything in this Agreement denoting the singular shall also denote the plural, and anything denoting the feminine gender shall also denote the masculine gender, and vice versa, insofar as no other meaning is inferred by the context.

 

2.1.

Appendix A: The Trial Protocol

 

2.2.

Appendix B: The Trial Personnel Clearance

 

2.3.

Appendix C: The Consideration

 

2.4.

Appendix D: Schedule 4 of the Guidelines.

 

2.5.

Appendix E: The Trial Documents and Related Activities.

 

4.1.

The approval of the Trial Protocol by the Medical Center Helsinki Committee and the MOH, if such latter approval is required by the Guidelines; and

 

4.2.

The approval of the Agreement in general, its budget and Appendix C in particular, by the MOH and the committee of engagement with commercial companies in accordance Section 9 of the Guidelines; and

 

4.3.

The approval of the Trial Protocol, Investigator Brochure and related documents by the FDA

 

5.1.

Zohar A. Dotan MD, PhD of the Medical Center (hereinafter: “the Principal Investigator”) has agreed to serve as the principal investigator of the Trial

 

5.2.

The Principal Investigator undertakes to perform the Trial in compliance with the following: (a) the Trial Protocol, (b) the Guidelines, (c) the instructions and the terms specified in the approval of the Medical Center Helsinki Committee, (d) the ICH-GCP, (e) the Helsinki Declaration, (f) the applicable laws, rules and regulations regulating such studies which are applicable in Israel, (g) written instructions and prescriptions issued by BioCancell regarding the Trial and/or the Product; all as may be amended from time to time, and (h). the requirements in accordance with the FDA Form 1572 “Statement of Investigator.” Every PI at each site must sign this form for submission to the FDA

 

5.3.

The Principal Investigator has declared that he holds the professional ability and credentials required for performing the Trial in accordance with the Trial Protocol and any applicable laws, rules, regulations and guidelines, all as detailed above.

 

5.5.

In the event of the replacement of the Principal Investigator, as described under this Section 5, the Principal Investigator shall have no claim towards BioCancell and/or the Fund and/or any third party acting on their behalf in direct or indirect connection with such replacement.

 

6.1.

The Fund represents that it has the requisite skills, knowledge, experience and human resources to undertake and conduct the Trial in accordance with the provisions of this Agreement

 

6.2.

The Fund undertakes to perform the Trial in compliance with the following: (a) the Trial Protocol, (b) the Guidelines, (c) the instructions and the terms specified in the approval of the Medical Center Helsinki Committee, (d) the ICH-GCP, (e) the Helsinki Declaration, (f) the applicable laws, rules and regulations regulating such studies which are applicable in  Israel, and (g) written instructions and prescriptions issued by BioCancell regarding the Trial and/or the Product; all as may be amended from time to time.

 

6.3.

The Medical Center hereby undertakes to furnish BioCancell, the Principal Investigator and all of the Trial Personnel with the facilities and personnel necessary for the adequate performance of the Trial according to the terms and conditions of the Trial Protocol, and to fully collaborate with the Principal Investigator, BioCancell, and/or any other third party nominated by BioCancell, with regard to performing its duties hereunder.

 

7.1.

BioCancell hereby undertakes to allow the Principal Investigator to use the BioCancell Data, exclusively for the purpose of performing the Trial, during the Term of This Agreement and according to the terms and conditions of this Agreement.

 

7.2.

BioCancell shall remunerate the Fund, according to the terms of Appendix C hereto, for all services rendered.

 

9.1.

BioCancell will, at its own expense, supply to the Fund all necessary quantities of the drugs to be used in the Trial, and only for the purposes as described in the Protocol. Any surplus shall be returned to BioCancell without delay, upon completion of the Trial or termination of this agreement for any reason whichever is the earlier.

 

9.2.

The Fund will ensure that the Product is managed and stored in accordance with GCP and with any special instructions issued by BioCancell. The Fund will maintain proper records of receipts, dispensing and returns of the Product.

 

9.3.

BioCancell will continue to supply the Product after the termination of the Trial and/or Agreement to the patients participating in the trial in accordance with Appendix D.

 

10.1.

The Fund and the Principal Investigator hereby undertake to exercise their best efforts so that the Trial Personnel shall abide by: (a) the Trial Protocol, (b) the Guidelines, (c) the instructions and the terms specified in the approval of the Fund Helsinki Committee, (d) the ICH-GCP, (e) the Helsinki Declaration, (f) the applicable laws, rules and regulations regulating such studies which are applicable in Israel, and (g) written instructions and prescriptions issued by BioCancell regarding the Trial and/or the Product; all as may be amended from time to time.

 

10.2.

The Trial will also be conducted in accordance with the “Statement of Investigator” (FDA form no. 1572).

 

10.3.

Trial Personal Clearance:

 

11.1.

The Fund and the Principal Investigator hereby undertake to perform the Trial in accordance with the budget of the Trial, as such term is derived from Appendix C hereto (hereinafter: “the Trial Budget”) and not to deviate therefrom without the prior written approval of BioCancell in relation thereto.

 

11.2.

The Fund hereby undertakes that any deviation from the Trial Budget without the prior written consent of BioCancell shall be born by the Fund.

 

11.3.

The Fund and the Principal Investigator hereby undertake to fully cooperate with any and all sub-contractors nominated by BioCancell for the purpose of the Trial, including, inter alia, clinical research organizations, logistics companies, laboratories, etc.

 

12.1.

The Principal Investigator shall prepare and submit the Trial Documents.

 

12.2.

The Principal Investigator shall perform all the activities specified in Appendix E hereto.

 

12.3.

Any and all amendments to the Trial Protocol shall be performed only after securing the approval of BioCancell and the competent regulatory authority.

 

13.1.

The Parties and the Principal Investigator hereby agree and undertake that they are aware that the BioCancell Data and the Trial Data (hereinafter, jointly and severally “the Confidential Information”) are confidential information, and that BioCancell has disclosed such Confidential Information to the Fund and Principal Investigator for the sole purpose of conducting the Trial.

 

13.2.

The Parties and the Principal Investigator hereby agree and undertake that they are aware that the Confidential Information is the sole and exclusive property of BioCancell and/or any other company from the BioCancell Group. Accordingly, The Principal Investigator shall retain the Confidential Information under the strictest safeguarding and not use, disclose or divulge the Confidential Information in part or in whole, directly or indirectly, for a period of seven (7) years.

13.4.

The Fund and the Principal Investigator hereby further undertake to limit access to the Confidential Information to the Trial Personnel and any third parties on a “need to know basis” only, and cause such Trial Personnel and third parties to accept, in writing, the undertaking of the Principal Investigator in relation to the Confidential Information under this Agreement, as a condition precedent for receipt of any part of the Confidential Information.

13.5.

At the request of BioCancell, the Fund and the Principal Investigator shall forthwith return to BioCancell the Confidential Information or any part thereof.

13.6.

The Fund and the Principal Investigator hereby state that they are aware of the fact that any unauthorized disclosure or use of the Confidential Information shall cause immediate and/or irreparable injury to BioCancell, and that BioCancell cannot be adequately compensated for such injury in monetary damages. Thus, in order to safeguard BioCancell from any possible breach of confidentiality, the Principal Investigator and the Fund hereby undertake that BioCancell would be permitted to obtain, from any Court or Tribunal, any temporary or permanent injunction relief, necessary to prevent such unauthorized disclosure or use or peril thereof, and hereby renounce filing and/or submitting any objection to any request by BioCancell or by any company from the BioCancell Group, relating to such temporary or permanent injunction.

13.7.

For the avoidance of any doubt, it is hereby clarified that such an undertaking is supplementary to and will not prejudice any right or remedy, which is or shall be available to BioCancell under any applicable law or agreement.

14.1.

The Fund and the Principal Investigator hereby acknowledge that the idea and initiative for the Trial were exclusively those of BioCancell, and that the involvement of the Fund and the Principal Investigator in the Trial is strictly the consequence of their nomination by BioCancell.

14.2.

The Parties and the Principal Investigator hereby irrevocably agree and undertake that the Confidential Information, except for medical records of the Subjects, is the exclusive property of BioCancell, may be freely utilized by BioCancell in any manner it sees fit. Notwithstanding the above, BioCancell shall have the right to review Subjects’ medical records to verify entries in the CRF’s. BioCancell hereby undertakes full responsibility to ensure the safekeeping of patients’ confidentiality and personal data and shall be fully responsible for taking every measure to apply this commitment.

15.1.

The Fund and the Principal Investigator hereby, undertake to allow the Monitors to perform monitoring visits in all sites related to the Trial, during or after the Trial, and assist the Monitors in their duties. For the avoidance of doubt, it is hereby clarified that the Monitors shall be entitled to monitor and/or inspect among others the Trial Documents and Trial Data as well as to insure compliance with the Trial Protocol.

15.2.

The Fund and the Principal Investigator hereby undertake to allow the Inspectors to perform inspections of all sites related to the Trial, during or after the Trial (and each such inspection shall hereinafter be referred to as: “an Inspection”), and to assist the Inspectors in their duties, if and to the extent requested to do so by the Inspectors.

15.3.

The Fund and the Principal Investigator shall immediately inform BioCancell in the event of an Inspection and/or upon gaining knowledge of any intention to perform an Inspection. The Fund and the Principal Investigator shall provide BioCancell with copies of any inquiries, correspondence or communications to or from any such Inspectors.

 

16.1 

BioCancell covenants that it will not at any time, without first obtaining the consent in writing of the Medical Center (which consent may by refused or granted in its absolute discretion), use the Medical Center’s name or the name of the Principal Investigator or otherwise disclose the fact of their involvement in the performance of the Trial in any advertising, publicity or publication. However, BioCancell may use the name of the Fund and/or the Principal Investigator for listing the Trial on clinicaltrials.gov.

 

16.2 

Publication of the Trial and/or its results, in whole or in part, shall be within the sole and absolute discretion of BioCancell. The Fund, the Principal Investigator or the Trial Personnel, and any employees and/or officers and/or representatives of any of the foregoing shall not publish or refer to the Trial and/or its results, in whole or in part, without obtaining the prior consent BioCancell in writing. BioCancell reserves the right to reject any such request, at its sole discretion. For the avoidance of doubt BioCancell has the right, at all times, to publish any article or data generated from the services rendered under this Agreement. Without derogating from this Section 16, BioCancell hereby undertakes to abide by the rules of publications issued by the MOH and set forth in Section 2 of Appendix D attached hereto.

17.1.

The Fund and the Principal Investigator hereby undertake to submit the Reports to BioCancell and/or to competent authorities, whether Israeli or foreign.

17.2.

The Fund and the Principal Investigator hereby undertake to disclose in the Reports any and all data provided to them by BioCancell, in accordance with any applicable laws, rules, regulations and guidelines, including, inter alia, safety data.

17.3.

The Fund will cause the Principal Investigator to provide BioCancell, within 45 (forty five) days of the end of each period of three (3) months during the period of the Trial, with a written report on the progress of the Trial in the said period.

17.4.

45 (forty five) days following the End of the Trial, the Principal Investigator shall submit to BioCancell a summary report, which shall include, in a full and detailed manner, a declaration regarding the activities performed during the Trial and the results obtained therein.

18.1.

In the event one or more of the Subjects sustains any Serious Adverse Event related to the Trial, the Principal Investigator shall inform BioCancell and the Fund Helsinki Committee and/or the Fund management and/or the authorized national health authorities.

18.2.

The Principal Investigator shall report such Serious Adverse Event in the timetable and manner prescribed in the Trial Protocol and Guidelines.

18.3.

In the occurrence of a Serious Adverse Event the Principal Investigator and the Fund Helsinki Committee shall be entitled to immediately cease the performance of the Trial, pending a prior notice of at least 24 hours to BioCancell regarding such decision and its execution.

18.4.

In the occurrence of a Serious Adverse Event BioCancell will immediately take all measures at their disposal to evaluate the risk to the other patients and will instruct the Principal Investigator which measures to take with regard to that risk.

18.5.

BioCancell has an obligation, as the trial sponsor, to notify each investigator of any Serious Adverse Events that are reported by any site during the trial that are submitted to the FDA in a safety report. Each Principal Investigator is obligated to provide these reports to the appropriate Helsinki Committee.

18.6.

19.1.

The Parties and the Principal Investigator hereby agree that the relationship between BioCancell, on one hand, and the Fund and the Principal Investigator, on the other hand, are that of a client and an independent contractor, with the Fund and the Principal Investigator lacking any capacity whatsoever to legally bind BioCancell to a relationship of employer-employee, principal-agent or any other legal relationship differing from that of a client and an independent contractor.

20.1.

This Agreement shall be in full force and effect as of the latter of either: (a) the date of its execution by the last Party or (b) the date the Approvals have been granted; and until the End of the Trial (and the period in which this Agreement shall be in full force and effect shall be referred to in this Agreement as “the Term of this Agreement”).

 

20.3.

In the event of termination of this agreement the Parties and the Principal Investigator shall bring the Trial to an end as follows:

 

20.4.

The obligation of the Parties and the Principal Investigator pursuant to sections 13, 14, 16, 17, and 21 shall survive termination of this Agreement.

 

21.1.

BioCancell has agreed to insure, in accordance with the terms and conditions set forth in Appendix D attached hereto, the Subjects, the Trial Personnel, the Principal Investigator and the Fund.

21.2.

BioCancell has agreed to indemnify the Trial Personnel the Principal Investigator, Medical Center and the Fund according to the terms of Sub-Section 21.3 below (hereinafter each of them shall also be referred to as: the “Indemnitee”) for damages arising as a direct result of their involvement in the performance of the Trial (hereinafter: the “Damages”), provided that the damages are not as a result of an expected side effect of the Products and subject to the conditions detailed herein:

21.3.

Promptly after receipt by the Indemnitee of a notice of the commencement of any claim, action, suit, proceeding or investigation in respect of which indemnity may be sought pursuant to this Section 21 (hereinafter: the “Claim”), the Indemnitee shall provide a notice to BioCancell, in writing, describing in reasonable detail the facts and circumstances upon which the asserted Claim for indemnification is based, and shall thereafter keep BioCancell reasonably informed with respect thereto, BioCancell shall have the right to assume the defense of any Claim, at its sole discretion. In any event, the Indemnitee shall cooperate with BioCancell in the defense of any Claim for which BioCancell assumes the defense. BioCancell shall not be liable for the settlement by the lndemnitee of any Claim affected without the consent of BioCancell. BioCancell shall be entitled to enter into any settlement of a Claim at its sole discretion.

22.1.

Notices to be given by one Party to another shall be in the English language, and shall be deemed properly given if reduced to writing and transmitted to the Party’s address appearing on the first page of this Agreement, by air courier or by certified registered mail - all to be effective 3 (three) days after their sending date, or by facsimile with confirmation receipt - to be effective at the first business day following the date of transmission.

22.2.

However, a notice shall be considered properly given, only in case a copy thereof was communicated as follows:

22.3.

The addresses of the Parties, listed in page 1 of this Agreement, shall be subject to any change of such address notified in writing by one Party to the other, according to the procedure stipulated in this Section.

23.1.

Expenses of the Parties. Each Party and the Principal Investigator shall bear all its own expenses, including the expenses of its attorneys, in connection with the negotiation, execution and performance of this Agreement.

23.2.

Waiver and forbearance. No rights of any Party shall be prejudiced or restricted by any indulgence or forbearance, to any other person or entity, and no waiver by any Party in respect of any breach shall operate as a waiver in respect of any subsequent breach.

23.3.

Governing law and jurisdiction. This Agreement shall be exclusively governed by the Laws of the State of Israel. Any and all disputes arising hereunder shall be resolved by a competent court having jurisdiction over such matters in the Tel-Aviv Jaffn District, Israel

23.4.

Assignment. This Agreement shall not be assigned, without the prior written consent of all of the other Parties, save for an assignment of rights by BioCancell to any company within the BioCancell Group

23.5.

Counterparts. This Agreement and any amendment hereto may be executed in multiple counterparts, each of which shall be deemed an original agreement and all of which shall constitute one and the same agreement.

23.6.

Amendments. Modification or amendment to this Agreement shall only be valid if performed by a written instrument, signed by all Parties to this Agreement.

23.7.

Severability. If any provision of this Agreement is determined by a court of competent jurisdiction to be invalid, illegal, or unenforceable, that determination shall not affect any other provision of this Agreement, and each such other provision shall be construed and enforced as if the invalid, illegal, or unenforceable provision were not contained herein.

 

2.1.

In consideration for the performance, in good faith, by the Principal Investigator and the Fund, of all of their undertakings under  this Agreement, BioCancell hereby undertakes to pay to the Fund the following amounts:

 

3.1.

For the avoidance of doubt, it is hereby declared and agreed that BioCancell shall not pay any additional payments or any other amounts, which are not clearly mentioned and specified in section 2 above.

 

3.2.

It is further clarified that the amounts specified in section 2 above include payment by BioCancell for all services rendered from the Fund including but not limited to office services, Trial Personal required for performing the Trial including the Principal Investigator, physicians, nurses, receptionists and study coordinator, use of the Fund’s facilities, and all tests, procedures, examinations and evaluations as detailed in the Trial protocol.

 

3.3.

The considerations do not include cost of analysis of hematology and chemistry samples which will be performed by BioCancell’s sub-contractor/s.

 

4.1.

The Fund shall send an invoice at the end of each calendar quarter (31/3, 30/6, 30/9, and 31/12) detailing the Complete Screening, Complete Treatment Visits and Complete Evaluation Visits (together hereinafter: “Complete Visits”) performed as well as on which Subjects or Participating Subjects the relevant Complete Visit was performed.

 

4.2.

Payments detailed in section 2 shall be conditioned upon payment for Complete Visits and shall be included in the first invoice sent by the Fund.

 

4.3.

Payment shall be maid by BioCancell within 30 (thirty) days of receipt of the Fund’s invoice.

 

6.1.

No payment would be performed for any activities performed by the Principal Investigator and/or by the Fund, prior to the commencement of the Trial.

 

6.2.

Without derogating from any right of BioCancell, in the event that no Completed CRF’s are provided to BioCancell, regarding a Subject, in relation to which BioCancell has performed payments to the Fund, BioCancell shall be entitled to perform one of the following three, according to its absolute discretion:

 

6.3.

No advance payments would be performed by BioCancell to the Fund.

 

1.1.1.

Responsibility for the safety and good order of the investigational product;

 

1.1.2.

Supply of information regarding the trial;

 

1.1.3.

Notice to the Ministry of Health regarding the performance of a multicenter trial in Israel;

 

1.1.4.

Monitoring the trial process;

 

1.1.5.

Safety reports;

 

1.1.6.

Accountability in respect of the investigational product;

 

1.1.7.

Retention of documents.

2.

The Sponsor undertakes that if it shall decide to publish the results of the clinical trial in scientific literature, it shall publish them in full and without taking matters out of their context.

 

3.1.

The Sponsor undertakes to insure its legal liability pursuant to the laws of the State of Israel against claims that may be filed by subjects in the clinical trial and/or third party claims - all in connection with the clinical trial, whether in the period of conducting the clinical trial or thereafter. The insurance shall be extended to include the legal liability of the medical institution and/or the clinical trial personnel and/or the Principal Investigator (hereinafter referred to as “the parties conducting the trial”) deriving from their involvement in the conduct of the clinical trial, subject to an exception of an act committed negligently or an intentional deviation from the clinical trial protocol.

 

3.2.

The Sponsor shall be given notice of any claim or any potential claim immediately after such comes to the knowledge of the medical institution or the Principal Investigator.

 

3.3.

The Principal Investigator, the medical institution and its employees shall give the Sponsor, upon its written request, reasonable support in any event of a claim that may be filed against it as aforesaid.

4.

The Sponsor undertakes to supply the medical institution with the investigational product throughout the period of the clinical trial until the conclusion thereof, free of charge. Furthermore, the Sponsor undertakes to pay all additional costs deriving from the conduct of the clinical trial, provided that such costs do not derive from the regular medical treatment of the sickness.

5.

If after the termination of the clinical trial it is ascertained and recommended by the Principal Investigator that the welfare of the patient participating in the clinical trial necessitates continuation of his treatment with the investigational product and there is no other appropriate alternative medical treatment, the Sponsor undertakes to also continue supplying the investigational product, without charge, after the termination of the clinical trial for a period of three years, except in one of the following cases:

 

5.1.

The investigational product was approved for marketing in the State of Israel after its registration for its requested scope and it can be obtained from the sick fund with which the patient is insured.

 

5.2.

The development of the product was discontinued or the results of the clinical trials were unsuccessful.

 

5.3.

The administration of the investigational product for the said protracted period is likely to harm the patient’s health, since there is insufficient information regarding the safety of the product administered over the long term.

 

5.4.

Where the investigational product is not a medical preparation, such as: cosmetic products / food / food additive / herbal remedy.

6.

The continued administration of the investigational product after termination of the clinical trial is subject to the following terms and conditions:

 

6.1.

The continued treatment shall be given within the context of an orderly monitoring protocol that shall be written by the Principal Investigator and approved by the Sponsor and the Helsinki Committee.

 

6.2.

The Principal Investigator is responsible for continuing to routinely monitor the subject’s medical condition and to report to the Helsinki Committee any exceptional events that occur during the ongoing treatment, as is the norm in clinical trials.

7.

This Appendix constitutes an integral part of the agreement between the company sponsoring the clinical trial and the medical institution.

1.

The executed signature page of the Trial Protocol; and

2.

Investigator Brochure; and

3.

The current curriculum vitae of the Principal Investigator; and

4.

The list of all sub-investigators, all of which necessarily being listed on either the FDA form no. 1572, or on the Principal Investigator’s Statement Form; and

5.

The written approval of the Medical Center Helsinki Committee, indicating that it has reviewed and approved the Trial Protocol; and

6.

The written approval of the MOH with regards to the content of all publicity and advertisements, related to the Trial, which are to be performed prior to the commencement of the Trial; and

7.

A list of all participants in the Helsinki Committee, convened in relation to the Trial (hereinafter: “the Helsinki Committee”); and

 

7.1.

Should the Principal Investigator be a member of the Helsinki Committee, the written Statement of the chairman of the Helsinki Committee confirming that the Principal Investigator did not participate in the voting, relating to the Trial, during the hearing of the said Helsinki Committee; and

 

7.2.

A financial disclosure form, confirming that the Principal Investigator holds no financial interests in BioCancell.

1.

A review of all the Trial Documents and verification the accuracy and completeness thereof in relation to the source documents, on which the above documents were based; and

2.

Report to the Medical Center Helsinki Committee of any Severe Adverse Events, as such terms are defined in the Trial Protocol, to the Subject(s), in accordance with the Guidelines; and

3.

Report to the Medical Center Helsinki Committee of any deviation from the Trial Protocol; and

4.

Maintain adequate records of Subjects identification, clinical observations, as well as study drug receipt and dispensation (hereinafter: “the Records”), in accordance with any applicable laws, rules, regulations and guidelines, as amended from time to time. In any event, the Principal Investigator and BioCancell shall maintain the Records for a period of no less than 15 (fifteen) years following the end of the Trial.

5.

Compare the data in the CRF with the source documents relating to each subject participating in the Trial, and confirm the accuracy of the CRF; and

6.

Maintain a log, documenting the Product(s) provided to each subject during the Trial; and

7.

Report no later than 7 (seven) days before additional quantities of Product(s) are required to proceed with the Trial.

8.

Complete all CRFs

9.

Re-validate the approval of the relevant Helsinki Committee to the Trial, within a reasonable time prior to its expiration date.

10.

A written detailed periodic report on the progress of the Trial in the said period (section 17.3 of the Agreement).

1.

All Completed CRFs;

2.

A summary report, which shall include, in a full and detailed manner, a declaration regarding the activities performed during the Trial and the results obtained therein (section 17.4 of the Agreement).