CLINICAL STUDY AGREEMENT IND 75,807 AV-101

 

A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Pharmacokinetics

of Single Doses of AV-101 in Healthy Volunteers

 

Protocol Number VSG-CL-001

 

Sponsor:       

VistaGen Therapeutics, Inc.

384 Oyster Point Boulevard #8 South San Francisco, CA 94080

 

Institution:     

Progressive Medical Concepts, LLC

dba, Progressive Medical Research 5111 Ridgewood Avenue Suite 301

Port Orange, FL 32127

 

 

THIS CLINICAL STUDY AGREEMENT ("AGREEMENT"), made and entered into as of April 15, 2010, with an effective date of April 14, 2010 (the "EFFECTIVE DATE") between Progressive Medical Concepts, LLC, a Florida limited liability corporation doing business as Progressive Medical Research, located at 5111 Ridgewood Avenue, Suite 301, Port Orange, FL 32127 ("INSTITUTION"), and VistaGen Therapeutics, Inc., a California corporation, ("SPONSOR"), shall govern the conduct of a clinical investigation (as described in Section 1 hereof, the "STUDY") of SPONSOR'S proprietary product, AV-101 ("PRODUCT").

 

WHEREAS, SPONSOR and AvivoCHn Clinical Services, LLC ("AVIVOCLIN"), previously collaborated on a portion of the STUDY pursuant to that certain Clinical Study Agreement, dated October 16, 2009, between SPONSOR and AVIVOCLIN (the "AVIVOCLIN AGREEMENT"); and

 

WHEREAS, AVIVOCLIN ceased operations and SPONOSR terminated the AVIVOCLIN AGREEMENT for cause on April 14, 2010; and

 

WHEREAS, SPONSOR and INSTITUTION wish to collaborate to complete the STUDY such that INSTITUTION shall perform services related to the STUDY in the manner contemplated to be performed by AVIVOCLIN pursuant to the AVIVOCLIN AGREEMENT; and

 

WHEREAS, Alexander White, MD, with appropriate privileges at AVIVOCLIN and INSTITUTION to conduct the STUDY, was the sole investigator for the STUDY pursuant to the AVIVOCLIN AGREEMENT and has agreed to continue to , serve as sole investigator ("INVESTIGATOR") for the STUDY pursuant to this AGREEMENT.

 

NOW, THEREFORE, in consideration of the mutual promises, benefits, rights, and obligations set forth below, the parties agree as follows:

 

 

INSTITUTION and INVESTIGATOR shall conduct the STUDY in accordance with:

 

(i) industry standards;

(ii) the conditions and timelines specified in the PROTOCOL and in the Institutional Review Board/Independent Ethics Committee ("IRB/IEC") approval;

 

(iii) all applicable federal, state and local laws, regulations and guidelines, including any requirement of the United State Food and Drug Administration ("FDA") (or any successor or replacement entities thereof) and any other governmental department, agency or commission and, to the extent applicable, the Good Clinical Practices ("APPLICABLE LAW");

 

(iv) the STUDY procedures manual supplied by SPONSOR, as updated from time to time;

 

(v) any additional STUDY instructions that may be provided by SPONSOR from time to time, and

 

(vi) all terms and conditions contained with Notice of Grant Award 2R44DA08515-02.

 

 

INSTITUTION and/or INVESTIGATOR shall also supply, if not already provided, the following to SPONSOR within five (5) business days of the Effective Date:

 

 

 

 

 

 

Any withdrawal of INVESTIGATOR'S privileges, sanctions against INSTITUTION or INVESTIGATOR or the like shall be reported by INVESTIGATOR in writing immediately to SPONSOR.

 

4.  FDA REVIEW AND IRB/IEC APPROVAL. SPONSOR has provided to the FDA, INVESTIGATOR and the applicable local IRB/IEC, adequate information (e.g., Investigator's brochure and the PROTOCOL) to obtain approval to begin the STUDY, and the STUDY is ongoing as of the Effective Date. INVESTIGATOR shall be responsible for maintaining all approvals from the local IRB/IEC and INVESTIGATOR shall keep SPONSOR fully appraised of the progress of submissions and shall, upon request, provide SPONSOR with all correspondence relating to any submissions; provided that INVESTIGATOR shall not consent to any change in the PROTOCOL requested by the IRB/IEC without the prior written consent of SPONSOR. INSTITUTION and INVESTIGATOR hereby acknowledge and represent that they have been provided with a copy of the IRB/IEC approval to conduct the STUDY. Said approval, amongst other things, indicates the date it was given, contains the name and signature of the Chairperson or Secretary of the IRB/IEC, states the names, qualifications and professions of the members, and confirms that only those IRB/IEC members who are independent of INVESTIGATOR and SPONSOR voted or provided their opinion on the STUDY. INVESTIGATOR shall confirm that an Informed Consent Form ("ICF") has been created by INVESTIGATOR and approved by SPONSOR. Any withdrawal of IRB/IEC approval shall be reported immediately by INVESTIGATOR to SPONSOR.

 

 

 

(a) a fully executed and completed copy of this AGREEMENT;

 

 

 

INSTITUTION and each of its employees participating in the STUDY shall conduct this STUDY in accordance with industry standards, the conditions specified the PROTOCOL, the conditions specified in the IRB/IEC approval, the current market authorization for the PRODUCT, all APPLICABLE LAWS, the STUDY procedure manual supplied by SPONSOR, as updated from time to time, and any additional STUDY instructions that may be provided by SPONSOR from time to time.

 

 

Use of off-site laboratories not listed in the PROTOCOL to perform analyses shall be pre-approved in writing by SPONSOR. INVESTIGATOR and INSTITUTION shall be responsible for ensuring that all data obtained from off-site laboratories shall be provided to INSTITUTION to be made part of the recruited subject medical records.

 

The STUDY is to be conducted as a blind trial. SPONSOR shall, free of charge, provide INSTITUTION with sufficient quantities of investigational or marketed product, or placebo, used as a reference in the STUDY, to enable INSTITUTION to undertake the STUDY, the use of which by INSTITUTION and INVESTIGATOR shall be subject, mutatis mutandis, to the terms and conditions applicable to the PRODUCT. INSTITUTION shall not perform any independent assays for the purpose of unblinding treatment assignment. INSTITUTION and INVESTIGATOR shall (i) use all methods possible to ensure that the blind is preserved and promptly document and explain to SPONSOR any premature unblinding (e.g., accidental unblinding, unblinding due to a severe adverse event or serious adverse event) of the PRODUCT; (ii) follow the STUDY'S randomization procedures, if any; and (iii) ensure that the code is broken only in accordance with the PROTOCOL. Upon conclusion or ten-nination of the STUDY, INSTITUTION or INVESTIGATOR shall provide SPONSOR with the randomized codes that are related to the STUDY.

 

All specimens collected by or on behalf of INSTITUTION shall be delivered to SPONSOR or its designee by INSTITUTION in a timely manner throughout the performance of the STUDY in accordance with the PROTOCOL, or as otherwise provided by SPONSOR, or when SPONSOR otherwise requests delivery of the specimens. INSTITUTION shall not collect specimens for use in any research without prior written permission from SPONSOR.

 

 

 

 

 

 

 

 

(e) INVESTIGATOR'S brochure.

 

The MASTER FILE shall:

 

 

 

 

The foregoing source documents and records shall be made available for inspection and copying at routine clinical monitoring visits. INSTITUTION and INVESTIGATOR shall cooperate with SPONSOR or SPONSOR'S designee during monitoring visits or for the resolution of questions regarding records or clinical data generated throughout the performance of this AGREEMENT.

 

INSTITUTION and INVESTIGATOR shall retain records in accordance with APPLICABLE LAW and, at a minimum, for a period of two (2) years after the latter of the following: the date on which all investigational studies using the PRODUCT are terminated or completed or the date SPONSOR receives notice from the FDA of the approval of the PRODUCT for commercialization.

 

Names of subjects shall not be divulged unless the record requires more detailed study or if a reason exists to believe the record does not contain actual results. INSTITUTION and/or INVESTIGATOR shall maintain detailed lists identifying recruited subjects.

 

 

 

 

 

Adverse events and/or laboratory abnormalities identified in the PROTOCOL as critical to the safety evaluations should be reported by INVESTIGATOR to the Medical Monitor of the STUDY and/or SPONSOR and its designee Cato Research Ltd. according to the reporting requirements and within the time periods specified by SPONSOR in the PROTOCOL.

 

For reported deaths, INVESTIGATOR should supply the Medical Monitor of the STUDY, the SPONSOR, the SPONSOR designee Cato Research Ltd., and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).

 

 

 

In addition, at the request of SPONSOR and/or SPONSOR designee Cato Research Ltd, INSTITUTION and INVESTIGATOR shall provide to the Medical Monitor of the STUDY, SPONSOR designee Cato Research Ltd, and/or the SPONSOR in writing:

 

(a) periodic progress reports,

 

 

 

 

SPONSOR and/or SPONSOR designee shall prepare all reports required for submission to FDA. INSTITUTION and/or INVESTIGATOR agree, upon request by SPONSOR and/or SPONSOR designee Cato Research Ltd, to conduct a complete, accurate and timely review and provide comments on any such report before its submission by SPONSOR to-the FDA.

 

 

 

INSTITUTION'S compensation shall be paid pursuant to the Clinical Trial Compensation Schedule set forth in Exhibit B hereto pursuant to invoices sent by INSTITUTION.

 

The maximum amount to be earned for subjects who complete the entire STUDY is set forth in Exhibit C, Budget of Per Subject Clinical Trial Costs.

 

The parties shall negotiate changes to the budget that may be necessitated by amendments to the PROTOCOL, if any.

Payments shall be made payable to: Progressive Medical Concepts LLC, dba Progressive Medical Research

and shall be addressed as follows:

 

Progressive Medical Research c/o Alexander White, MD 128 S.Halifax Dr. Ormond Beach, FL 32176 Wiring Instructions: Bank of America ABA #026009593

For Further Credit to Progressive Medical Concepts, LLC Account #5564148128

Swiss Code (for international wires) BOFAUS3N

 

SPONSOR acknowledges that INSTITUTION maintains the status of a not-for-profit/tax-exempt institution for which no withholding should be required. It is agreed, to the extent required by APPLICABLE LAW that SPONSOR shall report any payments to INSTITUTION and be allowed to withhold any applicable taxes from INSTITUTION'S payment.

 

 

 

INSTITUTION and INVESTIGATOR agree:

 

 

 

 

 

The furnishing of CONFIDENTIAL INFORMATION under this AGREEMENT shall not constitute any grant, option or license to INSTITUTION or INVESTIGATOR under any patent or other rights now or hereafter held by SPONSOR. Neither INSTITUTION nor INVESTIGATOR shall acquire any rights of any land whatsoever with respect to the PRODUCT as a result of this AGREEMENT or otherwise.

 

AH original recruited subject records are the sole and exclusive property of the respective subjects, to be retained by INSTITUTION as required by Section 9 of this AGREEMENT and all other APPLICABLE LAW. All data, information and results generated by performance of this AGREEMENT shall be and are the exclusive property of SPONSOR, and shall be delivered to SPONSOR and/or SPONSOR designee in a timely fashion, and in no event later than ten (10) days after: any date required by the PROTOCOL, receipt of SPONSOR'S or SPONSOR designee's written request for the data, termination of the STUDY, and/or termination of this AGREEMENT.

 

Upon request of SPONSOR or SPONSOR designee, at the completion or earlier termination of the PROTOCOL, all CONFIDENTIAL INFORMATION and any copies thereof shall be returned to SPONSOR, except that one record copy may be retained in INSTITUTION's/INVESTIGATOR's legal files solely for purposes of determining future compliance with the terms of this AGREEMENT.

 

In the event INSTITUTION or INVESTIGATOR is ordered to provide CONFIDENTIAL INFORMATION by a lawful judicial or government order, INSTITUTION shall promptly inform SPONSOR designee and SPONSOR and shall permit SPONSOR to oppose such order of disclosure and shall assist in such defense to the extent permitted by law.

 

The obligations of confidentiality, non-disclosure and non-use hereunder shall survive expiration or early termination and continue until the relevant CONFIDENTIAL INFORMATION falls within the exceptions provided for in paragraph (b) above.

 

 

At SPONSOR'S request, INVESTIGATOR and INSTITUTION shall provide SPONSOR with assistance as is reasonable to obtain and secure the intellectual property rights in and to any INVENTIONS, including, the execution of the legal documents related thereto and perform any and all acts necessary to assist SPONSOR in preparing, filing, and enforcing its rights in any patent applications or in otherwise perfecting its rights thereto; provided that all expenses related thereto shall be paid by SPONSOR.

 

 

INSTITUTION agrees that the PRIMARY PUBLICATION coordinated by SPONSOR shall be the first publication to present the STUDY results. Following the PRIMARY PUBLICATION, or if the PRIMARY PUBLICATION is not submitted for publication within eighteen months of completion of the STUDY (meaning completion of analysis of the pooled and locked database), the INSTITUTION and INVESTIGATOR may publish or present materials related to the STUDY upon SPONSOR'S written consent.

 

In the event SPONSOR permits INSTITUTION to conduct additional research as described in Section 7 above, INSTITUTION and INVESTIGATOR shall not publish or make presentations with respect to such research without written authorization by SPONSOR until after the PRIMARY PUBLICATION is published or publicly presented, or if the PRIMARY PUBLICATION is not published within two years of completion of the STUDY (meaning completion of data analysis of the pooled and locked database).

 

If INVESTIGATOR wishes to make a submission for presentation or publication subject to the paragraphs above, INVESTIGATOR must submit all manuscripts, written or oral presentations to SPONSOR at least thirty (30) days prior to the date on which such submission is proposed to be made and SPONSOR shall provide timely review of such materials. INVESTIGATOR shall give due consideration to all comments received from SPONSOR.

 

SPONSOR may cause the presentation or submission to be delayed for up to thirty (30) additional days if, upon review of the presentation or submission, SPONSOR reasonably determines and notifies INVESTIGATOR within the initial thirty (30) day period that the presentation or submission contains patentable material or SPONSOR'S CONFIDENTIAL INFORMATION. INSTITUTION and/or INVESTIGATOR agree to provide to SPONSOR and its representatives such assistance in the preparation and filing of any patent application(s) as SPONSOR may reasonably request and to cooperate with SPONSOR with regard to such measures as are reasonably necessary to protect the CONFIDENTIAL INFORMATION.

 

INSTITUTION shall give SPONSOR the option of receiving an acknowledgement in manuscripts, written, or oral presentations in recognition of its sponsorship of the STUDY.

 

 

INSTITUTION and/or INVESTIGATOR shall notify SPONSOR in writing immediately upon becoming aware of a PROCEEDING for which SPONSOR has indemnification obligations and agree to cooperate with and to authorize SPONSOR to carry out the sole management and defense of such PROCEEDING. SPONSOR agrees, at its own expense, to defend any such PROCEEDING whether or not such PROCEEDING is rightfully brought or filed.

 

Neither INSTITUTION, its trustees, officers, agents or employees, INVESTIGATOR, nor associated staff shall compromise or settle any PROCEEDINGS without the prior written approval of SPONSOR.

 

SPONSOR agrees to (i) carry sufficient liability insurance in amounts not less than One Million Dollars (51,000,000) per incident and One Million Dollars (S1,000,000) annual aggregate toto cover its indemnification obligations under this AGREEMENT or (ii) to provide evidence to the satisfaction of INSTITUTION of self insurance in respect of its liability under this Agreement. Such coverage may not be changed or terminated except upon at least forty-five (45) days prior written notice to INSTITUTION.

 

INSTITUTION shall, to the extent permitted by law, secure and maintain in full force and effect throughout the performance of the STUDY insurance coverage for (a) Employer's Liability, (b) General Liability, and (c) Automobile Liability, as well as Professional Medical and Nursing Indemnity in amounts appropriate for the conduct of INSTITUTION'S business.

 

 

 

(a) to SPONSOR addressed:

 

VistaGen Therapeutics, Inc. 384 Oyster Point Boulevard #8 South San Francisco, CA 94080

 

Attention: Ralph Snodgrass, Ph.D., CSO

(b) to INSTITUTION addressed:

Progressive Medical Concepts LLC

 

dba Progressive Medical Research 5111 Ridgewood Ave., Ste. 301 Port Orange, FL 32127

 

Attention: Alexander White, M.D.; and

 

(c) to INVESTIGATOR addressed:

 

Alexander White, MD 128 S. Halifax Dr. Ormond Beach, FL 32176

 

 

SPONSOR reserves the right to advise INSTITUTION to discontinue recruiting subjects for the STUDY at any time. SPONSOR reserves the right to terminate this AGREEMENT at any time with or without cause upon notice to INSTITUTION and INVESTIGATOR. Any verbal notification of termination shall be confirmed in writing within thirty (30) days. Upon receipt of initial notice from SPONSOR, the clinical investigation of the PRODUCT and the recruitment of further subjects into the STUDY shall cease. The collection of data and the preparation of CRFs for subjects who received the PRODUCT prior to notice shall continue pursuant to written instruction of SPONSOR or SPONSOR'S designee Cato Research Ltd. SPONSOR shall reimburse INSTITUTION for all reasonable and uncancelable obligations resulting from the termination upon receipt by SPONSOR of an itemized listing of such obligations unless SPONSOR has terminated this AGREEMENT for cause.

 

INSTITUTION may terminate this AGREEMENT if SPONSOR materially breaches this AGREEMENT and SPONSOR fails to cure such breach within thirty (30) days from the receipt of prior written notice from INSTITUTION, or if INSTITUTION believes that the continuation of the PROTOCOL is detrimental to the health and/or safety of subjects) participating in the PROTOCOL.

 

INSTITUTION shall immediately notify SPONSOR if INVESTIGATOR ceases to be employed by or associated with INSTITUTION, and shall use reasonable endeavors to find a replacement acceptable to both SPONSOR and INSTITUTION. If no mutually acceptable replacement can be found either party may terminate this AGREEMENT.

 

SPONSOR reserves the right to extend the AGREEMENT upon showing of clinical need or to comply with APPLICABLE LAW.

 

21. PUBLICITY.

 

(b)  Press Releases. INSTITUTION and SPONSOR shall obtain written permission from each other before using the name, symbol and/or marks of the other in any form of publicity in connection with the STUDY. This shall not include legally required disclosure by SPONSOR or INSTITUTION that identifies the existence of the AGREEMENT. Further, SPONSOR'S use of the name, symbols, and/or marks of INSTITUTION, or names of INSTITUTION'S employees, shall be limited to identification of INSTITUTION as a research site and the research staff as participants of the STUDY.

 

 

 

 

 

 

INVESTIGATOR warrants and represents that he/she has never, is not and shall not during the term be debarred by FDA, NIH, or any federal agency and has not and is not involved in any regulatory or misconduct litigation or investigation by regulatory authorities (Canadian or foreign). No data produced by him/she in any previous clinical study has been rejected because of concerns as to its accuracy or because it was generated by fraud.

 

 

24. MISCELLANEOUS PROVISIONS.

 

 

 

 

 

 

 

 

 

 

 

OR ITS USE. SPONSOR DISCLAIMS ALL IMPLIED WARRANTIES OR CONDITIONS, EXPRESS OR IMPLIED, BY OPERATION OF LAW OR OTHERWISE WITH RESPECT TO THE PRODUCT OR ITS USE, INCLUDING ANY WARRANTY OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, VALIDITY, SCOPE, ENFORCEABILITY OR PATENTABILITY OF THE INTELLECTUAL PROPERTY RIGHTS OR NON­INFRINGEMENT OF THIRD PARTY PROPRIETARY RIGHTS OF ANY KIND.

 

OR IN CONNECTION WITH THIS AGREEMENT, EVEN IF A PARTY HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH DAMAGES. THE PARTIES AGREE THAT THE LIMITATION OF LIABILITY SET FORTH IN THIS SECTION IS A REASONABLE ALLOCATION OF RISK AND A FUNDAMENTAL PART OF THE BASIS OF EACH PARTY'S BARGAIN HEREUNDER, AND NEITHER PARTY WOULD ENTER INTO THIS AGREEMENT ABSENT SUCH LIMITATIONS. This Section shall not apply to the extent that APPLICABLE LAW specifically requires liability despite the foregoing exclusions and limitation.

 

 

Title: President Date:

 

INVESTIGATOR hereby confirms that he has (i) read and understands each and every provision of this AGREEMENT; (ii) had the opportunity to obtain advice from legal counsel of his choice in order to understand any and all of its provisions; (iii) had the opportunity to ask questions about its contents, and any of such questions have been answered to his satisfaction; and (iv) been given a copy of this AGREEMENT.

 

Furthermore, I hereby agree to be personally bound by the terms and conditions  this AGREEMENT.

Signature:

 

Print Name:    Alexander White. MP

Date:

 

 

 

 

 

Clinical Trial Compensation Schedule

 

 

 

The following schedule will be adhered to with regard to compensation for conduct of the STUDY. Compensation requests should be sent to SPONSOR pursuant to written invoices as contemplated by the AGREEMENT.

 

5. Upon database lock, a payment of $500 will be made for records storage.

 

 

Exhibit C