EXHIBIT 10.15
CONTRACT RESEARCH ORGANIZATION SERVICES AGREEMENT
AGREEMENT effective as of AUGUST 11, 1999 ("EFFECTIVE DATE") by and
between Therapeutic Management, THE STONEHOUSE, 0000 XXXX XXXXXXX XXXXXX,
XXXXX 000, XXXXXXXX, XX 00000 ("CRO" and Entropin, Inc., 00000 Xxxxxx Xx.,
Xxxxx 000, Xxxxxxxx Xxxxx, XX 00000 ("ENTROPIN"). (CRO and Entropin are
individually referred to as a "PARTY" and collectively as the "PARTIES.")
PURPOSE
WHEREAS, Entropin desires to obtain the services of CRO to assist in
the development of, and /or to conduct a MULTI-CENTER clinical drug
evaluation study (the "STUDY") to research the Entropin pharmaceutical
product ESTEROM(R) (the "STUDY DRUG"); and the non-active ingredient as
defined in the protocol for comparative purposes (the "VEHICLE").
WHEREAS, CRO possesses the requisite expertise and personnel to
conduct, assist, and/or develop the Study.
NOW THERFORE, in consideration of the mutual promises and obligations
contained herein, the Parties agree as follows:
ARTICLE I
TRANSFER OF RESPONSIBILITIES AND OBLIGATIONS
--------------------------------------------
1.1 UNITED STATES FOOD AND DRUG ADMINISTRATION REGULATIONS. The Parties
enter into this Agreement for the express purpose of transferring from
Entropin to CRO the responsibilities and obligations of Entropin to
conduct, coordinate, manage, and/or develop the Study in accordance
with United States Food and Drug Administration ("FDA") regulations
set forth in 21 CFR Section 312, Subpart D, as such may be amended
from time to time. Accordingly, Entropin hereby transfers and CRO
hereby assumes the compliance responsibilities and obligations for the
services set forth in APPENDIX A, attached hereto and made a part of
hereof, to conduct, coordinate, manage and/or develop the Study
pursuant to the Protocol (as that term is defined in Article 1.2A.
(collectively, the "SERVICES").
1.2 PROTOCOL.
A. Protocol Title. CRO, when requested, shall assist to modify when
necessary Entropin protocol entitled:
ESTEROM 99-02-01 CONTRACT PAGE 1 OF 20 AUGUST 11, 1999
PROTOCOL NO: Esterom 99-02-01
-----------------------------
"A STUDY TO DETERMINE THE EFFECTIVENESS AND SAFETY OF TOPICALLY
APPLIED ESTEROM(R) VERSUS VEHICLE IN PATIENTS WITH IMPAIRED RANGE
OF MOTION ASSOCIATED WITH PAINFUL SHOULDER.
(the "PROTOCOL") attached hereto as APPENDIX B and made a part
hereof, in accordance with the Project Specification Sheet
attached hereto as APPENDIX C and made a part hereof, and CRO
shall conduct the Services and/or the Study in accordance with the
Protocol, which Protocol may be amended or revised from time to
time by Entropin.
1.3 ENTROPIN REPRESENTATIVE. Any and all deliverables due as a result of
the performance of the Services and/or Study by CRO hereunder, including,
without limitation, any and all reports and/or copies of tables
(collectively, "DELIVERABLES"), shall be delivered by CRO, in the manner
mutually agreed by the Parties, to Entropin project physician and/or
project manager ("ENTROPIN REPRESENTATIVES"). In no event shall any
Deliverables, or any copies thereof, in whole or in part, be given to any
other party including, without limitation, any other Entropin individual,
without the express prior consent of the Entropin Representative.
ARTICLE II
ENTROPIN RESPONSIBILITIES
-------------------------
2.1 ENTROPIN RESPONSIBILITIES
A. PROVISION OF INFORMATION. Entropin shall provide all necessary
information to CRO as reasonably required to assure initiation
and completion of the Study in accordance with APPENDIX G.
B. APPROVAL. Entropin shall approve all copy, layouts, and Study
elements in a timely fashion so as to allow CRO to meet its
obligations hereunder.
2.2 Term. This Agreement shall commence on the Effective Date and remain
in full force and effect until such time as the Services have been
satisfactorily completed (the "TERM"), unless sooner suspended pursuant to
Article 2.6 or terminated pursuant to Articles 2.3, 2.4 or 2.5.
2.3 EXTENSION OF MODIFICATION OF THE TERM. Subject to Suspension of the
Term as set forth in Article 2.6, the Term may only be extended or modified
in accordance with a written amendment signed by the Parties as set forth
in Article XX.
2.4 TERMINATION BY ENTROPIN. This Agreement may be terminated by Entropin
for any reason and at any time upon thirty (30) days' written notice to
CRO. In the event this agreement is for a human study, if thirty (30)
days' notice is reasonably determined by Entropin to be insufficient based
upon evaluation of risks to subject(s) enrolled in the Study (the "STUDY
SUBJECT(S)"), the Parties will cooperate to withdraw the Study Subject(s)
safely from the drug treatment over a mutually agreeable period of time,
ESTEROM 99-02-01 CONTRACT PAGE 2 OF 20 AUGUST 11, 1999
however, in no event shall Entropin's obligation to supply Study Drug
hereunder extend beyond a period determined to be reasonable by Entropin.
Notwithstanding the foregoing, in the event Entropin believes that
immediate termination is necessary due to Entropin's evaluation of risks to
Study Subject(s), Entropin may terminate this Agreement immediately.
A. ENTROPINS' OBLIGATIONS UPON TERMINATION. Upon termination,
Entropin's sole obligation to CRO shall be to pay CRO any
equitable pro-rated monies due for work actually performed and/or
expenses actually incurred up to the effective date of
termination. To the extent that such actual costs and expenses
shall be less than the total monies previously paid to CRO by or
on behalf of Entropin, CRO shall promptly refund to Entropin any
and all such excess funds.
B. CRO'S OBLIGATIONS UPON NOTICE OF TERMINATION. Upon the delivery
of notice of termination by Entropin, CRO shall cease the Study
in accordance with Article2.3. CRO will return to Entropin all
Confidential Information (as defined in Article 4.1) and transfer
and assign all property and materials (including unused
materials) in CRO's possession or control that belong to
Entropin, including, but not limited to, the right, title, and
interest in and to the Inventions (as described in Article 14.1)
and patent applications and patents thereon. Following the
receipt of such notice of termination, CRO shall not incur any
additional expenses with respect to the Study, except those
expenses that are documented in detail and are necessary in order
to terminate the Study.
2.5 TERMINATION BY CRO
A. MATERIAL BREACH. CRO shall have the right to immediately
terminate this Agreement in the event Entropin commits a material
breach hereof and fails to cure such material breach within
thirty (30) days of receipt of written notice thereof.
B. CRO'S OBLIGATIONS UPON TERMINATION. Upon CRO's termination of
this Agreement, it shall cease the Study in accordance with
Article 2.3. CRO will return to Entropin all Confidential
Information (as defined in Article 4.1) and transfer and assign
all property and materials (including unused materials) in CRO's
possession or control that belong to Entropin, including, but not
limited to, the right, title and interest in and to the
Inventions (as described in Article 14.1) and patent application
and patents thereon. Following the notice of such termination to
Entropin, CRO shall not incur any additional expenses with
respect to the Study, except those expenses that are documented
in detail and are necessary in order to terminate the Study.
C. ENTROPIN'S OBLIGATIONS UPON TERMINATION. Upon termination,
Entropin's sole obligation to CRO shall be to pay CRO any
equitably pro rated monies due and owing it for work actually
performed and/or expenses actually
ESTEROM 99-02-01 CONTRACT PAGE 3 OF 20 AUGUST 11, 1999
incurred up to the effective date of termination; to the extent
that such actual costs and expenses shall be less than the total
monies previously paid to CRO by or on behalf of Entropin, CRO
shall promptly refund to Entropin any and all such excess funds.
2.6 BANKRUPTCY. Both Parties shall have the right to immediately
terminate this Agreement in the event the other Party makes (i) a general
assignment for the benefit of its respective creditors, (ii) has a
custodian, receiver, or trustee appointed for either it or a substantial
part of its assets, (iii) commences a voluntary proceeding under either the
Federal Bankruptcy Act or any state law relating to insolvency or (iv) a
court having jurisdiction over it enters a Decree of Order for Relief in an
involuntary case under any applicable bankruptcy or insolvency law and such
Decree or Order continues unstayed and in effect for a period of sixty (60)
days or more
2.7 DELAY IN TERM. The Term may be delayed, suspended and/or put on hold
by Entropin for any reason upon thirty (30) days' written notice to CRO
("SUSPENSION OF THE TERM"). The Term may be suspended by CRO pursuant to
Article 3.1.
2.8 SURVIVAL. Neither the expiration or termination of this Agreement
shall relieve the Parties of their respective obligations pursuant to
Articles IV, 5.4, 7.3, IX, X, XI, XII, XIX, XXI, XXV, XXVII, and XXVIII.
ARTICLE III
COMPENSATION
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3.1 TOTAL STUDY COST. The estimated total cost for the Study and all
services (the "TOTAL STUDY COST") is detailed in APPENDIX D attached hereto
and made a part hereof. Notwithstanding Article 3.3, the Total Study Cost
shall not exceed the estimate for any reason without the prior written
approval of Entropin. Cost increases greater than 10% of the Total Study
Cost will require an amendment to this Agreement. In the event the prior
written consent of Entropin is not obtained or an amendment to the
Agreement has not been executed, CRO will suspend all Services prior to
exceeding the estimated Total Study Cost to the extent there are no risks
to the Study Subjects.
3.2 TOTAL STUDY COST PAYMENT SCHEDULE. The Total Study Cost shall be
payable in accordance with the terms of this Agreement and APPENDICES D AND
E attached hereto and made a part hereof.
3.3 ENTROPIN-REQUESTED CHANGES TO THE PROTOCOL AND/OR STUDY. Entropin
reserves the right to request CRO to perform services ("ADDITIONAL
SERVICES") in addition to the services set forth in APPENDICES A, C AND D.
Subject to the last sentence of this Article 3.3, in the event Entropin
does request CRO in writing to perform Additional Services and to the
extent that the performance of such Additional Services by CRO will
actually incur documentable charges in addition to the Total Study Cost,
Entropin and CRO shall mutually agree on the cost for such Additional
Services prior to CRO being obligated to undertake such Additional
Services. Any costs incurred by CRO under this Article 3.3, which cause
the Total Study Cost to be exceeded without Entropin's prior written
approval, shall not be reimbursed. Notwithstanding anything to the
contrary set forth in
ESTEROM 99-02-01 CONTRACT PAGE 4 OF 20 AUGUST 11, 1999
this Article 3.3, CRO shall perform without any increase in the Total Study
Cost, Additional Services including, without limitation, those services
necessitated as a result of changes to the Study and/or Protocol, provided
that such Additional Services are, or would have been, reasonably expected
to be within the scope of the Study as determined by industry standards.
3.4 REDUCTION IN THE TOTAL STUDY COST. In the event any agreed upon
reduction in either the scope of the Study or amount of Services requested
by Entropin reduces the Total Study Cost such that the total amount
previously paid exceeds the reduced Total Study Cost, the difference shall
be returned to Entropin by CRO in full at the end of the Term.
3.5 MONITORING/MEETING EXPENSE. Entropin shall reimburse CRO for all
monitoring/meeting expenses actually incurred by CRO in accordance with
Entropin's Reimbursement Policy attached hereto as Appendix F and made part
hereof. As a prerequisite to reimbursement under this Article CRO shall
maintain and have readily available appropriate documentation on file in
accordance with Entropin's Reimbursement Policy which may be audited at any
time upon request by Entropin.
3.6 ADDITIONAL POSTAGE. Entropin shall be invoiced on a monthly basis and
at CRO's net costs for all necessary next day mail and/or courier services
related to the administration of the Study. For expedited shipments,
economy two-day delivery is the preferred method. CRO will use discretion
when shipping by Standard Overnight delivery and will use Priority
Overnight delivery only when absolutely necessary. Invoices for the latter
should be accompanied by an explanation justifying use.
3.7 FINAL RECONCILIATION OF THE TOTAL STUDY. CRO shall provide Entropin
with a final reconciliation of the Total Study Cost within thirty (30) days
of either the expiration or termination of this Agreement.
ARTICLE IV
CONFIDENTIALITY
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4.1 CONFIDENTIAL INFORMATION. CRO acknowledges that, in the course of
performing its obligations hereunder, it shall receive information which
will be communicated orally and/or in writing which Entropin wishes to
protect from public disclosure ("CONFIDENTIAL INFORMATION"). In addition
to the foregoing, Confidential Information shall include but is not limited
to, Entropin's physician lists, all data, information, reports and
correspondence related to the Study or performance of this Agreement.
4.2 USE OF CONFIDENTIAL INFORMATION. CRO agrees to retain in confidence
during the Term and thereafter for a period of ten (10) years all
Confidential Information disclosed to it by or on behalf of Entropin, and
that it will not, without the written consent of Entropin, use Confidential
Information supplied hereunder for any purpose other than indicated herein.
This restriction shall not apply to Confidential Information (i) which is
or becomes public knowledge (through no fault of CRO); (ii) which is
lawfully made available to CRO by an independent third party; (iii) which
is already in CRO's possession at the time of
ESTEROM 99-02-01 CONTRACT PAGE 5 OF 20 AUGUST 11, 1999
receipt from Entropin (and such prior possession can be properly
demonstrated by CRO); or (iv) which is required by law, regulation, rule,
act or order of any governmental authority or agency to be disclosed by
CRO; PROVIDED, HOWEVER, that CRO gives Entropin sufficient advance written
notice to permit it to seek a protective order or other similar order with
respect to such Confidential Information and thereafter discloses only the
minimum Confidential Information required to be disclosed in order to comply.
4.3 LIMITATIONS ON DISCLOSURE. CRO shall limit disclosure of Confidential
Information received hereunder to only those of its officers, employees,
and/or CRO Agents (as defined in Article 5.1) who are directly concerned
with the performance of this Agreement. CRO shall advise such officers,
employees, and /or CRO Agents, upon disclosure to them of any Confidential
Information, of the proprietary nature thereof and CRO shall thereafter use
its best efforts to prevent unauthorized disclosure by such officers,
employees, and/or CRO Agents of Entropin's Confidential Information. CRO
shall comply with the requirements under Article 5.4 in the event CRO
discloses Confidential Information hereunder to any CRO Agent.
4.4 NON-DISCLOSURE OF THE AGREEMENT. CRO agrees that the existence and
nature of this Agreement is proprietary to the business and operations of
Entropin and will not disclose the fact that this Agreement exists, or any
of the terms or conditions contained herein, without the express written
consent of Entropin. CRO shall not demonstrate, exhibit, show, illustrate,
or disclose any part of the Services and/or Study to any other party
without the express written consent of Entropin, which consent may be
withheld for any reason.
4.5 NON-ADVERTISING; USE OF NAME. CRO agrees that it shall not in any
manner advertise, publish or release for publication any statement (i)
referencing or identifying the Study Drug or Study, or (ii) using
Entropin's name or the name of any Entropin affiliate, without prior
written consent of Entropin.
4.6 RETURN OF CONFIDENTIAL INFORMATION. Other than as required by law or
regulation, upon the expiration or termination of this Agreement, CRO shall
return to Entropin all Confidential Information received from or on behalf
of Entropin, shall destroy all copies of same and its notes and/or
memoranda referring or relating to such information, and shall execute a
certification that it has performed these acts.
ARTICLE V
STAFF REQUIREMENTS/CRO AGENTS
-----------------------------
5.1 DEBARMENT CERTIFICATION. CRO represents and warrants that it did not
and will not use in any capacity the services of any person debarred under
subsections (a) or (b) of Section 306 of the Federal Food , Drug, and
Cosmetic Act, as amended, 21 U.S.C. Section 335a(a) and (b), in connection
with its performance of this agreement.
5.2 AFFILIATES SUBSIDIARIES, SUBCONTRACTORS, AND CONSULTANTS. Without the
prior written consent of Entropin, and subject to the provisions of Article
XVII, CRO shall not (i) contract with, nor permit, anyone other than CRO
employees to perform the Services or
ESTEROM 99-02-01 CONTRACT PAGE 6 OF 20 AUGUST 11, 1999
(ii) assign material aspects of the Services, or any material portions
thereof, to any outside investigator, affiliate, subsidiary, subcontractor,
and/or consultant (collectively, "CRO AGENT(S)").
5.3 CHANGE OF STAFF. Any change in the personnel performing Services, or
any portion thereof, shall be communicated in writing to Entropin at least
30 days prior to such change by CRO. Such written communication shall be
accompanied by written documents describing the proposed personnel,
including, without limitation, CURRICULUM VITAE; provided that CRO shall
provide Entropin with any additional materials concerning such proposed
personnel as Entropin shall reasonably request within three days of such
request. CRO shall remove and replace any employee and/or CRO Agent whose
performance and/or qualifications are deemed unsatisfactory by Entropin (in
the sole opinion of Entropin).
5.4 CONFIDENTIALITY AND COMPLIANCE. CRO will ensure that every CRO Agent
approved in accordance with article 5.1 will (i) execute a confidentiality
agreement containing the same provisions set forth in the Article IV and
(ii) adhere to the terms and conditions of this Agreement. CRO will
provide a copy of all such agreements to Entropin in accordance with
Article XIII hereof following their execution.
5.5 CRO AGENTS COSTS AND/OR FEES. CRO shall bear sole responsibility for
any costs, fees, and/or expenses to be paid to any CRO Agent.
5.6 CRO EMPLOYEE DOCUMENTATION. CRO agrees that it will create, maintain,
and provide to Entropin within fifteen (15) days of the execution of this
Agreement a document containing the following information with regard to
each CRO employee providing Services hereunder: Full Name, Title, Services
provided, and sample of employee's initials. CRO further agrees that it
will update this document, maintain updated versions and provide to
Entropin following any change in CRO employees and/or Services provided by
such employees pursuant to this Agreement.
ARTICLE VI
TIME TABLE
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6.1 TIME SCHEDULE. The timetable for the Services and the Study is set
forth in APPENDIX G attached hereto and made a part hereof. Entropin shall
be immediately notified by CRO, in accordance with Article XIII, of any
anticipated or actual delays with respect to the Services and/or the Study.
ARTICLE VII
STUDY DRUG
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7.1 SUPPLY. Entropin will assure that the Study Drug and comparative
agent(s), if applicable, and placebo(s) if applicable, collectively
referred to as "VEHICLE" are provided on a timely basis and at no charge to
CRO in amounts Entropin deems adequate to accommodate the patient treatment
period as specified in the Protocol.
ESTEROM 99-02-01 CONTRACT PAGE 7 OF 20 AUGUST 11, 1999
7.2 STUDY DRUG SHIPMENT. Entropin will assure that all Study Drug and
Vehicle(s), if applicable, shall be shipped to the location(s) and/or
persons(s) identified by CRO.
7.3 RETRIEVAL OF UNUSED STUDY DRUG. CRO represents and warrants that it
will use its best efforts to (i) retrieve and identify all unused Study
Drug and comparative agent(s), if applicable, and placebo(s), if
applicable, from each investigator, (ii) identify each lot, physician, and
patient number, and (iii) log and record the foregoing information for
Entropin review.
7.4 ADVERSE EVENT REPORTING.
A. CRO AGREEMENTS. CRO will enter into an agreement with each
research center and/or principal investigator that the following
adverse events will be reported to CRO immediately by telephone
from the investigator: (i) those events which are defined by the
Protocol as "serious", including events which a) result in death,
severe or permanent disability, cancer, congenital anomaly, or
overdose, b) are considered life-threatening, and/or c) which
result in hospitalization or prolongs an existing hospitalization
and, (ii) those events which are defined by Protocol as
"unexpected," meaning any event which is not identified in
nature, severity, or frequency in the investigator brochure.
B. REPORTS TO ENTROPIN BY CRO. Adverse events shall be defined as,
any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and
which does not necessarily have a casual relationship with this
treatment. An adverse event can therefore be any unfavorable and
unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a
medical (investigational) product, whether or not related to the
medicinal (investigational) product, and will be reported by CRO
to Entropin.
C. PATIENT TREATMENT BY INVESTIGATOR(S). Any investigator, if
properly qualified, shall have the right to provide reasonable
and customary treatment to any Study Subject who exhibits
symptoms of an adverse reaction. Such properly qualified
investigator shall advise CRO in advance of such treatment,
whenever reasonably possible, or as soon thereafter if prior
notice is not possible.
D. PAYMENT OF COSTS. If in the opinion of the investigator and
Entropin, the Study Subject's reaction directly resulted from the
use of the Study Drug, placebo provided in conjunction with the
Study, if applicable, or other required procedures involved in
the Study, then Entropin shall reimburse patients for all
reasonable and customary costs associated with the diagnosis and
treatment provided, to the extent such costs are not reimbursed
by medical insurance of Study Subjects. In the event that a
suspected adverse reaction is not, in the opinion of the
investigator and Entropin, Study related, Entropin shall provide
reimbursement for diagnostic work-up costs
ESTEROM 99-02-01 CONTRACT PAGE 8 OF 20 AUGUST 11, 1999
only. Entropin's obligations to pay the foregoing costs is
limited to incidents when the Study Drug was administered (a) in
accordance with applicable law, accepted medical practice, the
Protocol and any other written instructions, precautions, and/or
indications furnished by or on behalf of Entropin, and (b)
without negligence, recklessness, or willful misconduct or
omission of the investigator or the Study Subjects.
ARTICLE VIII
REPRESENTATIONS AND WARRANTIES
------------------------------
8.1 REPRESENTATION AND WARRANTIES OF CRO
A. STAFF AND EXPERTISE. CRO represents and warrants that it has the
facilities, professional, technical, and clerical staff,
experience and expertise sufficient in quality and quantity to
perform the Services and the Study pursuant to the Protocol
within the time frame set forth in APPENDIX G.
Further CRO represents and warrants that it did not and will not
use in any capacity the services of any person debarred under
subsections (a) or (b) of Section 306 of the Federal Food, Drug,
and cosmetic Act, as amended, 21 U.S.C. Section 335a (a) and (b),
in connection with its performance of this agreement.
B. COMPLIANCE WITH LAWS. CRO represents and warrants that all the
Services performed and provided by CRO, its employees and CRO
Agents shall fully comply with all applicable federal, state, and
local laws, rules and/or regulations.
C. INCONSISTENT OBLIGATIONS. CRO represents and warrants that the
responsibilities and obligations assumed by CRO on behalf of
Entropin hereunder are not in conflict with any other obligations
CRO might have.
D. INDUSTRY STANDARDS. CRO hereby agrees that it will perform, and
cause its employees and CRO agents to perform the Services in a
manner commensurate with the highest professional standards
applicable to its industry.
E. FINANCIAL STABILITY. CRO shall at all times during the Term of
this Agreement have sufficient financial resources to perform its
obligations hereunder.
ESTEROM 99-02-01 CONTRACT PAGE 9 OF 20 AUGUST 11, 1999
8.2 REPRESENTATIONS AND WARRANTIES OF ENTROPIN.
A. COMPLIANCE WITH LAWS. Entropin represents and warrants that all
Study Drug supplied pursuant to this Agreement shall fully comply
with all applicable federal, state and local laws, rules and
regulations.
B. FDA APPROVALS. Entropin represents and warrants that it has or
will obtain the necessary protocol approvals and/or amendments
relative to the Study.
ARTICLE IX
COMPLIANCE
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9.1 PERFORMANCE. CRO will perform the Services and the Study in
accordance with the current state of Good Clinical Practices, the Protocol,
and all applicable Entropin SOPs which Entropin will provide to CRO. CRO
will also comply with all federal, state, local laws, rules and regulatory
requirements applicable to its performance under this Agreement.
9.2 COMPLIANCE CHANGES. In the event currently applicable federal, state,
or local laws, rules and/or regulations are changed or new applicable laws,
rules and/or regulations are promulgated, CRO shall comply with such
change(s) and/or additions. In the event that compliance with such new
requirements necessitates change(s) in the Services and/or the Study, CRO
will submit to Entropin a revised technical and cost proposal for Entropin
review and acceptance prior to CRO making any changes in the Services
and/or the Study. The continuation of the Study shall be subject to
Entropin's written approval of such changes and the related costs.
ARTICLE X
RECORDS, AUDIT AND INSPECTION
-----------------------------
10.1 RECORD INSPECTIONS. Entropin or its designated representatives shall
have access to, and be permitted to review, during normal business hours
and upon reasonable advance notice during the Term (including any Delay of
the Term in accordance with Article 2.6), all papers, correspondence,
books, records, data, information, instructions, receipts, and/or reports
relating to the Study and/or Services (collectively, "RECORDS") performed
by or on behalf of CRO pursuant to this Agreement including, but not
limited to, those Records concerning the Study and/or Services which may be
either in the possession of CRO or located at the investigator site(s).
Records shall include Study-related financial records with respect to
monitoring/meeting expenses, payments to CRO Agents and when applicable,
investigator Study grant payments(i.e., honoraria)
10.2 MAINTENANCE OF THE RECORDS. CRO shall preserve the Records, without
additional compensation therefor, during the Term and thereafter for a
period of five (5) years (or longer if required by law) (the "RETENTION
PERIOD"). CRO shall notify Entropin in writing at least sixty (60) days
prior to the expiration of the Retention Period of such expiration.
Entropin shall bear all costs of removal. Upon receipt of such
notification, Entropin shall
ESTEROM 99-02-01 CONTRACT PAGE 10 OF 20 AUGUST 11, 1999
instruct CRO with respect to the removal of the Records from the CRO
facility with any removal costs passed directly through to Entropin with
receipts. Once the Records have been satisfactorily removed in accordance
with Entropin's instructions, Entropin shall be solely responsible for the
storage of Records.
10.3 SITE MONITORING VISITS. Entropin and/or its representatives may,
during the Term, visit CRO's and /or CRO Agents' facilities and
laboratories at reasonable times and with reasonable frequency during
normal business hours to (i) observe the progress of the Study, (ii)
monitor the accuracy and completeness of the Services, including but not
limited to, quality control and assurance, and/or (iii) review the
responsibilities and/or performance obligations of CRO and/or CRO Agents.
CRO will assist Entropin in scheduling such visits and will make Records
and any other relevant information available to Entropin and/or
representatives.
10.4 AUDIT AND/OR INSPECTION. CRO shall notify Entropin immediately upon
being notified or becoming aware of any planned, scheduled or ongoing FDA
audit and/or inspection of any study site, the CRO, and/or CRO Agents
during the Term and thereafter for a period of five (5) years.
ARTICLE XI
INSURANCE
---------
11.1 REQUIRED INSURANCE. CRO will, at its own cost and expense, obtain and
maintain in full force and effect, the following insurance during the term
of this Agreement.
A. Workers' Compensation Insurance in accordance with the statutory
requirements of the state in which the Services are to be performed;
B. Employers Liability Insurance with minimum coverage of One
Million Dollars ($1,000,000);
C. Comprehensive General Liability Insurance including a products
liability coverage endorsement, covering all of CRO's operations
under this Agreement including broad contractual liability
coverage, with minimum coverage of Two Million Dollars
($2,000,000) per occurrence, and Four Million Dollars
($4,000,000) in the aggregate.
11.2 CERTIFICATE (S) OF INSURANCE. CRO agrees to provide within fifteen
(15) days of execution of this Agreement, an original signed Certificate(s)
of Insurance evidencing all coverage required pursuant to this Article XI.
The Certificate(s) must provide that thirty (30) days' prior written notice
of cancellation will be given to Entropin.
11.3 REQUIREMENTS FOR CRO AGENTS. CRO will not permit any CRO Agent to
perform Services unless such CRO Agent is and remains insured in accordance
with the insurance requirements outlined in this Article XI. CRO shall
indemnify Entropin for any loss suffered by Entropin for the failure of any
CRO Agent to be so insured.
ESTEROM 99-02-01 CONTRACT PAGE 11 OF 20 AUGUST 11, 1999
ARTICLE XII
INDEMNIFICATION
---------------
12.1 ENTROPIN INDEMNIFICATION OF CRO
A. PROPER PERFORMANCE AND STUDY DRUG CLAIMS. Entropin agrees to
indemnify, defend and hold harmless CRO and its officers,
directors and employees ("Indemnitee") from and against any loss
which Indemnitee becomes legally obligated to pay on a claim made
against Indemnitee by any independent third party ("Loss") to the
extent that such Loss (i) is a direct result of administration of
the Study Drug or (ii) directly arises out of the activities or
procedures required to be carried out in this Study of Protocol;
provided that any such Loss resulting from (a) the negligence of
Indemnitee or CRO Agents, (b) the willful malfeasance or
nonfeasance by Indemnitee or CRO Agents, (c) any non-compliance
or violation by Indemnitee or CRO agents of this Agreement,
including, but not limited to, Articles IV (Confidentiality),
VI(Time Table), 7.4 (Adverse Event Reporting), 8.1
(Representations and Warranties of CRO), IX (Compliance) or the
Protocol, (d) any non-compliance or violation by Indemnitee or
CRO Agents of any applicable local, state, or federal law(s) ,
rule(s), or regulation(s) including, but not limited to ,
applicable FDA regulations and other governmental requirements or
(e) any FDA approved drug, is excluded from this agreement to
indemnify and hold harmless; provided further that for purposes
of the Section 12.1 any CRO Agent is deemed not to be an Indemnitee.
B. CONDITIONS OF INDEMNITY OBLIGATIONS. As condition precedent to
indemnification under Article 12.1 (A), Indemnitee agrees to
notify Entropin in writing within ten (10) days of Indemnitee
becoming aware of any claim threatened, asserted, made, brought
or instituted against it that could or may result in a Loss.
Whenever the Indemnitee has information from which it may
reasonably conclude that any incident of bodily injury, sickness,
disease or death has occurred (an "Incident") to a study subject
during the study, Indemnitee shall immediately notify Entropin of
all pertinent data surrounding such Incident. Indemnitee shall
cooperate fully in assisting Entropin with respect to gathering
information concerning the time, place and circumstances of such
potential or actual claim(s) and in obtaining the names and
addresses of the injured parties and all available witnesses.
Indemnitee agrees to cooperate with and to authorize Entropin to
control the defense of such claim(s) (including all decisions as
to legal counsel, litigation, settlement and appeal). No
Indemnitee or CRO Agents (approved in accordance with Article
5.1) shall compromise or settle any claim(s) without the prior
written approval of Entropin.
12.2 CRO INDEMNIFICATION OF ENTROPIN. In addition to the indemnification
requirements set forth in Article 11.3, CRO hereby agrees to the following:
ESTEROM 99-02-01 CONTRACT PAGE 12 OF 20 AUGUST 11, 1999
A. BODILY INJURY OR PROPERTY LOSS. CRO agrees, at its own cost and
expense, to indemnify, defend and hold harmless Entropin,
Entropin's affiliates and their respective officers, directors
and employees from and against any loss, including but not
limited to attorneys' fees, cost of suit, judgments and
settlements, which such person has become legally obligated to
pay on a claim made against such person by an independent third
party resulting from any bodily injury sustained, including
death, and/or for damage to or loss of any property incurred
during or as a result of CRO's, its officers', directors',
agents', or employees' or CRO Agent's acts, omissions, and/or
performance under this Agreement. For any such injury sustained
and/or damage or loss incurred, CRO agrees to release and waive
all rights to subrogation against Entropin possessed by CRO's
insurers. Notwithstanding anything to the contrary set forth in
this Article 12.2 (A), to the extent that Entropin has expressly
directed CRO to engage certain investigator(s) to carry out the
Study and/or perform Services, CRO shall be relieved of its
indemnification obligations under this Article 12.2 (A) but only
with respect to such investigator(s).
B. BODILY INJURY, PROPERTY DAMAGE AND CONSEQUENTIAL LOSSES. CRO
agrees, at its own cost and expense, to indemnify, defend and
hold harmless Entropin, Entropin's affiliates and their
respective officers, directors and employees ("Indemnitees") from
and against any claims, suits, actions or demands made against
any such Indemnitee by any independent third party, including
attorneys' fees and costs of suits, judgements and settlements,
resulting from any bodily injury, damage to or loss of any
property, or consequential loss of damage incurred due to CRO's,
its officers', directors', agents', or employees' or CRO's
Agent's (i) acts, omissions, performance, or non-compliance
under, or violation of, this Agreement, including but not limited
to, Articles IV (Confidentiality), VI ( Time Table), 7.4 (Adverse
Event Reporting), 8.1 (Representations and Warranties of CRO)(,
IX (Compliance) or the Protocol; (ii) negligence or willful
malfeasance or nonfeasance; and (iii) non-compliance or violation
of any applicable local, state or federal law(s), rule(s), or
regulation(s), including, but not limited to applicable FDA
regulations and other governmental requirements. For any such
claim, suit, action or demand asserted, CRO agrees to release and
waive all rights to subrogation against Entropin possessed by
CRO's insurers, and to hold Entropin harmless and indemnify it
against any such subrogation claim.
ARTICLE XIII
NOTICES
-------
Any report or notice required or permitted to be given hereunder shall
be effective when sent. All notices shall be in writing and given
personally or by prepaid certified mail, return receipt requested, or sent
by telex, telegram, expedited delivery service of facsimile transmission
(with written confirmation by certified mail, return receipt requested)
addressed to the Parties at their respective addresses as follows.
ESTEROM 99-02-01 CONTRACT PAGE 13 OF 20 AUGUST 11, 1999
If to Entropin: Entropin, Inc.
00000 Xxxxxx Xx., Xxxxx 000
Xxxxxxxx Xxxxx, XX 00000
Attention: Xx. Xxxx Xxxxxx
Telephone: (000) 000-0000
Telefax: (000) 000-0000
If to CRO: Therapeutic Management, Inc.
The Stonehouse
0000 Xxxx Xxxxxxx Xxxxxx, Xxxxx 000
Xxxxxxxx, XX 00000
Attention: Xxxxxxx Xxxxxx, Director of US Operations
Telephone: (000) 000-0000
Telefax: (000) 000-0000
ARTICLE XIV
INTELLECTUAL PROPERTY
---------------------
14.1 ENTROPIN PROPERTY. Any and all materials, information, documents,
inventions, discoveries and improvements whether or not patentable, which
(i) are prepared, made or developed by CRO, its employees and/or any CRO
Agent (ii) and/or were conceived, made or reduced to practice by CRO, its
employees or any CRO Agent and/or (iii) as a result of Confidential
Information (collectively, the "INVENTIONS") shall be promptly disclosed to
Entropin and shall be the sole and exclusive property of Entropin.
CRO will, upon request of Entropin, promptly execute and will cause its
employees and CRO Agents to execute any and all applications, assignments
or other instruments which Entropin shall reasonably deem necessary or
useful in order to apply for and/or obtain patent protection worldwide for
the Inventions, and/or in order to assign and convey to Entropin the sole
and exclusive right, title and interest in and to the Inventions, patent
applications and patents thereon. CRO shall ensure that its contractual
arrangements with its employees and/or CRO Agents provide for their
automatic assignment to Entropin of all such Inventions, patent
applications and patents. Entropin will bear the costs of preparation and
filing of all patent applications with respect to the Inventions.
14.2 PRESERVATION OF ENTROPIN PROPERTY. All materials and documents
prepared, purchased or furnished by CRO on Entropin's account in connection
with the Study shall belong to Entropin, and shall be preserved by CRO in
accordance with Article 10.2 and in compliance with regulatory requirements
for delivery to Entropin upon its request. Except as set forth in the
Protocol, Entropin retains the title to and exclusive right to publish all
documentation, research data, records, raw data, other work product, data,
and./or results generated with respect to the Services and/or Study ("WORK
PRODUCT"). Such Work Product will be retained in the CRO's archive in
compliance with regulatory requirements and Article 10.2.
ESTEROM 99-02-01 CONTRACT PAGE 14 OF 20 AUGUST 11, 1999
14.3 EXPIRATION OR TERMINATION. Notwithstanding anything to the contrary
set forth in Article 10.2, upon the expiration or termination of this
Agreement, CRO shall transfer, assign and make available to Entropin, if
Entropin so requests, all property and materials in CRO's possession or
control belonging to Entropin including, without limitation, the right,
title and interest in and to the Inventions and patent applications and
patents thereon. CRO shall cooperate in obtaining the consents of third
parties in interest, if any.
ARTICLE XV
RELATIONSHIP OF THE PARTIES
---------------------------
15.1 NATURE OF RELATIONSHIP. CRO agrees that, in its relationship with
Entropin hereunder, it is acting in the capacity of an independent
contractor and that it has no authority to create or assume in Entropin's
name or on Entropin's behalf any obligation, expressed or implied, or to
act or purport to act as Entropin's agent or legally empowered
representative for any purpose whatsoever, except as expressly provided
herein, without Entropin's prior written consent. Accordingly, CRO shall
perform the Study as an independent contractor and shall have complete and
exclusive control over its employees and/or CRO Agents.
15.2 NON-LIABILITY. Entropin shall not be liable to any third party in any
way for the engagement, obligation, commitment, contract, representation,
transaction or for any negligent act of or omission to act by CRO, except
as expressly provided in Article XII.
ARTICLE XVI
FORCE MAJEURE
-------------
16.1 EXCUSE. If the performance or observance of this Agreement by either
Party or if any of either Party's respective obligations under this
Agreement are prevented or delayed by reason of an act of God, civil
commotion, storm, fire, riots, strikes, legal moratorium, war, revolution
or action by government, the Party so affected shall, upon prompt notice of
such cause being given to the other Party, be excused from such performance
or observance to the extent of such prevention or during the period of such
delay provided that the Party so affected shall use its best efforts to
avoid or remove the cause(s) of non-performance and observance with utmost
dispatch.
16.2 REPERFORMANCE. In the event that any part of the Study is rendered
invalid as a result of claiming excuse pursuant to Article 16.1, CRO shall,
after written authorization from Entropin to proceed and at Entropin's sole
cost and expense, reperform that part of the Study affected by such claim
of excuse.
ESTEROM 99-02-01 CONTRACT PAGE 15 OF 20 AUGUST 11, 1999
ARTICLE XVII
ASSIGNMENT
----------
CRO shall not, in whole or in part, assign its interests and/or
obligations under this Agreement, including performance of any monies due
hereunder, to any person, firm, partnership, corporation or other entity
(including by operation of law, judicial process, or otherwise) without the
prior written consent of Entropin, which consent may be withheld for any
reason. Entropin may assign this Agreement to any of its affiliates
(including by operation of law, judicial process or otherwise) without the
prior written consent of CRO.
ARTICLE XVIII
NON-WAIVER OF RIGHTS
--------------------
No failure or delay on the part of a Party in either exercising or
enforcing any right hereunder will operate as a waiver of, or impair, any
such right. No single or partial exercise or enforcement of any such right
will preclude any other or further exercise or enforcement thereof or the
exercise or enforcement of any other right. No waiver of any such right
will have effect unless given in a signed writing. No waiver of any such
right will be deemed a waiver of any other right hereunder.
ARTICLE XIX
BURDEN OR BENEFIT
-----------------
This Agreement and all the rights, obligations, duties,
representations, warranties and covenants of each Party shall inure to the
benefit, and be the burden of, and shall be binding upon their respective
affiliated, successors (including by operation of law), and lawful assigns,
and other legal representatives.
ARTICLE XX
AMENDMENTS
----------
This Agreement may neither be amended nor any of the provisions
contained herein rescinded, altered, or modified except by writing executed
by the Parties.
ARTICLE XXI
GOVERNING LAW AND JURISDICTION
------------------------------
It is understood and agreed that no provision of this Agreement shall
be construed so as to be in conflict with the laws of the State of
Colorado. It is further agreed that this Agreement is deemed to be
consummated in the State of Colorado, and that the terms and provisions of
this Agreement shall be construed and interpreted pursuant to the laws of
Colorado, without regard to the conflict of laws rules or principles
thereof. The state or federal courts located in the State of Colorado are
the agreed-upon forum for the resolution of all disputes hereunder, and the
Parties, their officers and employees hereby consent to (i) the
jurisdiction and venue of the aforesaid courts for the purpose of resolving
all such
ESTEROM 99-02-01 CONTRACT PAGE 16 OF 20 AUGUST 11, 1999
disputes and (ii) service for process by registered mail, return receipt
requested, or any other manner consistent with federal or Colorado law.
Any dispute arising between CRO and Entropin concerning this Agreement
or its interpretation shall be resolved by submission to arbitration in
Denver, Colorado in accordance with the rules of the American Arbitration
Association then in effect. Any award made by such arbitrators shall be
binding and conclusive for all purposes hereof, may include injunctive
relief, and may be entered as a final judgement in any court of competent
jurisdiction. The costs and expenses of such arbitration shall be borne in
accordance with the determination of the arbitrators.
ARTICLE XXII
SEVERABILITY
------------
In the event any portion of this Agreement shall be held illegal,
void, or ineffective, the remaining portions hereof shall remain in full
force and effect. If any of the terms or provisions of this Agreement are
in conflict with any applicable statute or rule of law, then such term(s)
or provision (s) shall be deemed inoperative to the extent that they may
conflict therewith and shall be deemed to be modified to conform with such
statute or rule of law.
ARTICLE XXIII
HEADINGS
--------
The headings contained in this Agreement are for convenience for
reference only and shall not affect or alter the meaning of effect of any
provision hereof.
ARTICLE XXIV
COUNTERPARTS
------------
This Agreement may be executed simultaneously in one or more
counterparts, each of which shall be deemed to be an original, but all of
which together shall constitute one and the same instrument.
ARTICLE XXV
ENTIRE AGREEMENT
----------------
This Agreement, together with Appendices A, B, C, D, E, F, and G set
forth all of the promises, agreements, understandings, covenants,
warranties and representations by and among the Parties and there are no
other promises, agreements, understandings, covenants, warranties, or
representations, oral or written, express of implied, between them with
respect to the subject matter addressed herein. This Agreement, together
with the attached Appendices, is intended by the Parties to be an
integration of any and all prior agreements and understandings, oral or
written, with respect to the subject matter addressed herein.
ESTEROM 99-02-01 CONTRACT PAGE 17 OF 20 AUGUST 11, 1999
ARTICLE XXVI
CONTROLLING TERMS
-----------------
No term, condition, or other provision of any attachment(s),
appendices, and/or addenda to this Agreement shall supersede any term,
condition or other provision of this Agreement and with respect to any
inconsistency or ambiguity, this Agreement shall control.
ARTICLE XXVII
ATTACHMENTS/ADDENDA
-------------------
Any attachment(s) or addenda referred to herein to be delivered and
the acts to be performed at or subsequent to the Effective Date, including,
without limitation, Protocol (collectively, "ITEMS") are incorporated
herein and expressly made a part of this Agreement as fully as though
completely set forth herein, and all references to this Agreement herein or
in any such Items shall be deemed to refer to and include all said Items.
ARTICLE XXVIII
YEAR 2000 COMPLIANCE
--------------------
CRO represents, warrants and covenants to and, for the benefit of, Entropin
that:
A. All hardware, software, operating systems, mechanical devices,
electronic devices, and any other components or items of CRO's
computer system which are used to produce reports and data for
Entropin's use (collectively, "CRO's Computer Equipment"), and
all data provided to Entropin under this Agreement shall be "Year
2000 compliant" and shall be free of bugs, viruses, and errors.
"Year 2000 Compliant" means that all of CRO's Computer Equipment,
and all data provided to Entropin under this Agreement:
(a) Shall be free of bugs, viruses and errors that may
materially adversely affect the performance or operation of
CRO's Computer Equipment on or following January 1, 2000 or
cause material delays in the services (including, but not
limited to, reports and data) to be provided by CRO's to
Entropin under this agreement before and/or after January 1,
2000; and
(b) Shall operate in the same manner and will have the same
functionality in all respects before and after January 1,
2000' and
(C) Shall operate without interruption in all respects from the
effective date of this Agreement continuously though January
1, 2000, and afterwards; and
ESTEROM 99-02-01 CONTRACT PAGE 18 OF 20 AUGUST 11, 1999
(D) Shall successfully process without interruption data
consisting of or relating to dates from the date of
installation continuously through January 1, 2000, and
afterwards; and
(E) Shall operate without interruption in all respects from the
effective date of this agreement continuously through
January 1, 2000; and
(F) Shall operate such that all features and functionality
containing or calling on a calendar function, including
without limitation, any function indexed to a CPU or other
clock, and any function providing specific dates or days, or
calculating spans of dates or days, shall record, store,
process, provide, and, where appropriate, insert, true and
accurate dates and calculations for dates in spans including
and following January 1, 2000; and
(G) Shall have no lesser functionality with respect to records
containing dates both, or either, before of after January 1,
2000, that with respect to dated prior to January 1, 2000,
only; and
(H) Shall not crash, fail, cause data to be corrupted, or cause
any of Entropin's hardware or software to crash, fail, or
cause data to be corrupted as a result of operating up to
and beyond January 1, 2000, or as a result of processing
data consisting of or relating to dates from the effective
date of this Agreement continuously though January 1, 2000,
and afterwards; and
(I) Has successfully been tested for Year 2000 Compliance as set
forth herein, and as to any greater operating requirements
as specified by the relevant hardware or software
manufacturer(s).
B. If CRO discovers or learns at any time subsequent to the
execution of this agreement that any of CRO's Computer Equipment
or any data provided to Entropin or to be provided to Entropin
under this agreement does not comply with paragraph A above
('non-compliant"), CRO shall notify Entropin of this fact within
ten days of dicovering or learning of said non-compliance. CRO's
notification shall set forth, with specificity, the following:
(a) A detailed description of the specific hardware, software,
and/or other components or data that CRO has discovered or
learned are non-eompliant, and the manner in which the are
non-compliant; and
(b) A detailed description of the problems that will occor on or
after January 1, 2000, as a result of non-compliance; and
(c) A detailed description of the method(s) by which CRO will
make the non-compliant components or data compliant, and the
date by
ESTEROM 99-02-01 CONTRACT PAGE 19 OF 20 AUGUST 11, 1999
which CRO will provide such solutions to Entropin in order
to bring the components or data into compliance.
C. If CRO discovers or learns at any time subsequent to the
execution of this agreement that any of CRO's Computer Equipment
or any data provided to Entropin or to be provided to Entropin
under this agreement is non-compliant, CRO shall cure the non-
compliance at CRO's sole expense within 30 days of discovering or
learning of said non-compliance. If CRO fails to cure the non-
compliance, in addition to and without waiving any other rights
or remedies provided under the law and/or under this agreement,
Entropin may terminate this agreement, and Entropin's obligation
to pay conultant for any outstanding invoices shall be waived
until such time as the non-compliance is cured, and CRO shall
refund amount of any invoiced paid by Entropin representing work
product that is non-compliant and not cured within a reasonable time.
The Parties hereby execute this Agreement on the dated set forth below.
THERAPEUTIC MANAGEMENT ENTROPIN, INC.
By: /s/ XXXXXXX XXXXXX By: /s/ XXXXXX XXXXXX
--------------------------- ---------------------------
Xxxxxxx Xxxxxx
Title: Title: Chief Executive Officer
--------------------------- -------------------------
Director of US Operations
Date: August 12, 1999 Date: August 16, 1999
--------------------------- -------------------------
ESTEROM 99-02-01 CONTRACT PAGE 20 OF 20 AUGUST 11, 1999
APPENDIX A
Transfer of Sponsor's Obligations
to a Contract Research Organization
APPENDIX A IS CONFIDENTIAL IN ITS ENTIRETY AND HAS BEEN
OMITTED AND FILED SEPARATELY WITH THE COMMISSION.
APPENDIX B
PROTOCOL NO: ESTEROM 99-02-01
"A Study to Determine the Effectiveness and Safety of Topically Applied
Esterom(R) versus Vehicle in Patients with Impaired Range of Motion
Associated with Painful Shoulder"
APPENDIX B IS CONFIDENTIAL IN ITS ENTIRETY AND HAS BEEN
OMITTED AND FILED SEPARATELY WITH THE COMMISSION.
APPENDIX C
Project Specification Sheet
APPENDIX C IS CONFIDENTIAL IN ITS ENTIRETY AND HAS BEEN
OMITTED AND FILED SEPARATELY WITH THE COMMISSION.
APPENDIX D
Total Study Cost
APPENDIX D IS CONFIDENTIAL IS ITS ENTIRETY AND HAS BEEN
OMITTED AND FILED SEPARATELY WITH THE COMMISSION.
APPENDIX E
Total Study Cost Payment Schedule
APPENDIX E IS CONFIDENTIAL IN ITS ENTIRETY AND HAS BEEN
OMITTED AND FILED SEPARATELY WITH THE COMMISSION.
APPENDIX F
CRO/Vendor/Consultant
Monitoring/Meeting Guidelines and Reimbursement Policy
APPENDIX F IS CONFIDENTIAL IN ITS ENTIRETY AND HAS BEEN
OMITTED AND FILED SEPARATELY WITH THE COMMISSION.
APPENDIX G
Study Time Table
APPENDIX G IS CONFIDENTIAL IN ITS ENTIRETY AND HAS BEEN
OMITTED AND FILED SEPARATELY WITH THE COMMISSION.
