Exhibit 6.8
CONTRACT
This Agreement effective October 24,1996 ("Effective Date") sets forth the
terms under which Innapharma, Inc., 00 Xxxxxxxxxxxx Xxxx, Xxxxx Xxxxxx Xxxxx, XX
00000 (hereinafter referred to as "Innapharma,") will conduct a multicenter
clinical study on behalf of NexMed, Inc., 0000 Xxxxxxxx Xxxxx, Xxxxxxxx, XX
00000 (hereinafter referred to as "NexMed").
1. Innapharma will be responsible, in consultation with NexMed, for the
conduct of the NexMed PGE-1 Cream Study entitled: "Development and
validation of safety and efficacy for a topically applied prostaglandin
E-1 preparation in a Chinese population of men suffering from
impotence", as set forth in Scope of Work (Exhibit "A").
2. The Contract stipulates that Innapharma personnel will make one site
selection visit to each Ministry of Health (MOH) approved study site.
It is agreed that NexMed personnel may accompany Innapharma personnel on
such site visit. NexMed shall provide Innapharma with reasonable notice
of its intention to attend a site visit or to visit sites separately.
3. Innapharma shall promptly notify NexMed of any MOH or other inspection of
which it becomes aware, and NexMed shall have the right to be present at
any such inspection.
4. All clinical study data generated by clinical investigators or Innapharma
in connection with the study shall be the property of NexMed and is
subject to audit by NexMed, during regular business hours, at NexMed's
discretion and upon reasonable notice to Innapharma.
5. Innapharma will keep strictly confidential all information transmitted to
it by NexMed for use with the study and will require all clinical
investigators to do the same. This obligation of confidentiality shall
remain in effect for five (5) years after delivery of the data transfer
to NexMed (see Exhibit "A"). All such information will be returned
promptly to NexMed upon the completion of the project, upon termination
of this Agreement or at any time at the request of NexMed.
Notwithstanding the foregoing, Innapharma may keep in its possession a
reasonable but limited number of such documents as may be required for
regulatory, legal, insurance or record keeping purposes or which contain
information deemed by Innapharma to be privileged and/or proprietary to
Innapharma.
Information belonging to Innapharma which it designates in writing to be
confidential shall be protected from disclosure by NexMed with at least
the degree of care as used by NexMed in dealing with NexMed confidential
information.
Any and all discoveries and/or inventions by Innapharma (whether or not
patentable) relating to PGE-1 Cream Study during or within six (6)
months after delivery of the final data transfer shall be the sole and
exclusive property of
NexMed. Innapharma shall promptly notify NexMed of any such event and
assist NexMed in the protection of NexMed's proprietary rights to such
discoveries and/or inventions. Notwithstanding the foregoing,
Innapharma's software, programs, policies, procedures, methods,
manuals, materials, and related information developed prior to
or during the study shall remain the exclusive proprietary property of
Innapharma.
6. NexMed shall hold harmless and indemnify Innapharma, its
agents and its subcontractors as approved by NexMed from all
liabilities and cost (including reasonable attorneys' fees) arising
out of or relating to Innapharma's or said agents or
subcontractors' performance of contracted services under this
Agreement including liability for adverse experiences to subjects
in the study, except to the degree such liabilities or costs are
caused by the fault or negligence of Innapharma or said agents or
subcontractors. For the purpose of this section, "Subcontractor"
and "Agents" shall be defined to mean any third party which
provides services in support of the study including, but not
limited to Printing Services, Local IRBs, clinical research
associates and clinical investigators.
7. The estimated budget for this study is set forth in Exhibit
"B" attached hereto and entitled "Budget Estimate". NexMed will
make payments in accordance with the attached Exhibit "C" entitled
"Schedule of Payments".
8. Innapharma may terminate this agreement on thirty (30) days
written notice if NexMed materially breaches this agreement;
provided, however, that NexMed shall have the right to cure such
breach within thirty (30) days after receipt of such written notice
of Innapharma's intention to terminate.
NexMed may terminate this agreement on thirty (30) days
written notice with or without cause. In the event of termination
by NexMed for reasons other than default by Innapharma actions or
recommendations of the MOH or other involving regulatory
authorities, NexMed's liability shall include the total study
budget amount listed in Exhibit B, with the only exception, the
unearned portion of the Investigator grant agreement up to the date
of receipt of termination notice, and all additional costs
associated with the termination itself.
In the event that the termination of the study is due to
default by Innapharma, NexMed's liability shall be limited to all
sums owed to Innapharma but unpaid for work performed to date of
receipt of termination notice as described in paragraph above.
In the event that the termination of the study is due to
actions or recommendations of the MOH or other involving regulatory
authorities, NexMed's liability shall be limited to all sums owed
to Innapharma but unpaid for work performed to date of receipt of
termination notice and all costs associated with termination
itself, such as for the close-out of study sites, completion of the
database, etc., as described in the two paragraphs above.
2
In the event of termination requiring close-out, Innapharma
shall use its best efforts to terminate all arrangements with
investigators and other obligations, as soon as possible, to avoid
additional expenses.
9. This Agreement shall take effect upon execution by both
parties and shall continue until all obligations of the parties are
completed unless previously terminated. Sections 4, 5, 6, 7 and 8
shall survive termination of this Agreement.
10. The parties acknowledge that NexMed is relying on the
expertise of Innapharma both for the conduct of the study and also
for not exceeding the budget set forth in Exhibit "C". Innapharma
warrants and represents that it will maintain strict budgetary
controls and that it will not exceed any of the itemized costs or
the total study cost figure contained in Exhibit "C" without the
written approval of NexMed.
The parties shall review, on a monthly basis, actual Direct
and Indirect ("Pass Through") costs associated with the ongoing
performance of the clinical trial. As necessary the parties shall
make reasonable adjustments to the budget, the payment schedule,
the scope of the work, and to this contract so as to insure that
the study is adequately funded and to promote the best interests of
the clinical trial. All changes in the scope or budget will require
the written authorization of NexMed prior to the commitment of any
Innapharma resources.
The final payment (Exhibit D) will be made upon NexMed's
acknowledgment that the data included in the final data transfer
are complete and acceptable, and it is agreed that the format meets
with NexMed's prior specifications. This acknowledgment shall take
place within 30 days of receipt of the final data transfer. After
acceptance of the final data transfer, actual project costs
incurred and payments made shall be reconciled. Any outstanding
balance as there may be after final reconciliation shall be paid
within thirty (30) days.
11. The parties stipulate and agree that 500 patients shall be
enrolled and approximately 3 Investigator sites shall participate
in this clinical trial.
12. Any change or modifications to this Agreement shall be in
writing and approved by Xxxx X. Xxxxx, Ph.D, for Innapharma and X.
Xxxxxx Mo, Ph.D. for NexMed or by their designees.
13. Any required notices shall be provided in writing, certified mail,
return receipt requested to the following individuals:
If to Innapharma:
Xxxx X. Xxxxx, Ph.D
Corporate Vice President
Clinical & Nonclinical Operations
Innapharma, Inc.
00 Xxxxxxxxxxxx Xxxx
Xxxxx Xxxxxx Xxxxx, XX 00000
3
If to NexMed:
X. Xxxxxx Mo, Ph.D
NexMed, Inc.
President
0000 Xxxxxxxx Xxxxx
Xxxxxxxx, XX 00000
14. The transfer of obligations from NexMed as Sponsor to
Innapharma as Contract Research Organization as required by the US
Code of Federal Regulations Section 21-312.52 is described in
detail in Scope of Work Section (Exhibit A).
This Agreement is not assignable and the obligations
hereunder cannot be delegated in whole or in part without the prior
written consent of NexMed. Innapharma will be an independent
contractor and not an employee of NexMed.
15. With respect to this contract and this study only,
Innapharma agrees not to use or imply the NexMed name or logo for
advertising, promotional purposes, raising capital, recommending
investments, or in any way that implies endorsement by NexMed.
NexMed or Innapharma may publicly disclose, in a news context, the
fact that an Agreement has been entered into, including the name of
NexMed or Innapharma and the general nature of the project covered
by this Agreement. The party seeking such public disclosure shall
advise and provide the other party with a copy of the proposed
release and obtain proper written approval of said release.
16. No party will be liable for failure or delay in performing the
obligations set forth in this Agreement if such failure or delay is
due to any causes beyond the reasonable control of such party.
17. This Agreement shall be governed by the laws of the State of New Jersey.
4
CONTRACT SIGNATURE PAGE
NexMed, Inc.
By: /S/ Xxxxxx Xxx
--------------------------------
Xxxxxx Xxx
Vice President
Date: 10/30/96
--------------------------------
Innapharma, Inc.
By: /S/ Xxxx X. Xxxxx
----------------------------------
Xxxx X. Xxxxx, Ph.D.
President
Date: 10/24/96
----------------------------------
5
EXHIBIT A
Scope of Work for
PROSTAGLANDIN E-1 FOR MALE IMPOTENCE STUDY
EXECUTIVE SUMMARY
NexMed, Inc. has requested that INNAPHARMA provide a contract agreement and
budget encompassing management of all activities required to initiate and a 500
patient trial in China including monitoring through final statistical report in
conjunction with NexMed's Prostaglandin E-1 for male impotence.
INNAPHARMA has prepared this contract agreement in two parts which allows
NexMed to proceed with several GO- NO/GO decision points while incurring only
minimal costs. An outline of the scope of work has been provided including
timeline and cost estimates which can be found in Exhibits E, B and D.
The first part of obtaining Clinical Trial Registration in China (permission
to conduct the trial) involves the information gathering and clinical strategy
development stage. Innapharma will assist NexMed in obtaining an expert in China
in the area of Prostaglandin's / Impotence. Innapharma will schedule a meeting
with the Ministry of Health. Innapharma and the Chinese medical expert will
pre-assess the proper approval pathway for the Prostaglandin product in China.
Innapharma will prepare a feasibility report based on information obtained from
China allowing NexMed to make educated Go -No/Go decision.
The costs for this stage are included in the Clinical Registration costs
listed in the budget (Exhibit B), and include the identification of a Chinese
Medical Expert as well as a meeting with the Minister of Health.
CONCEPT SUMMARY
INNAPHARMA CONTACT
Primary Liaison: Xxxxxx Xxxxxx
Sr. Dir. Worldwide Clinical Operations
Phone: 000-000-0000 Ext. 652
Fax: 000-000-0000
6
PROTOCOL INFORMATION
Objective: To confirm safety and efficacy of a topically applied
prostaglandin E-1 preparation in a Chinese population of men
suffering from impotence.
Design: Open Label, multicenter safety and efficacy study
Patients: Five hundred men (500), 18-75 years of age.
Expected
enrollment
period: 3 months
Total study
duration: 6 months
Number of
sites: 3 sites
Key inclusion
criteria: Psychogenic origin of erectile dysfunction
Have had erection sufficient for intercourse within the last year
No prostrate surgery
Have not been on injection therapy for erectile dysfunction
Key exclusion
criteria: Psychogenic origin of erectile dysfunction
History of past or concomitant hormonal therapy
History of hypogonadism or hyperprolactinemia
Concomitant drugs not allowed:
Yohimbine, antidepressants, vasodilators,
alpha blockers, monamine oxidase inhibitors
Type I diabetes mellitus
Unstable angina
Uncontrolled hypertension
Hypotension, or any cardiovascular abnormalities.
Alcohol or drug abuse
7
Scope of Work (cont'd)
I. CLINICAL TRIAL REGISTRATION--CHINA
This is the process of assembling, summarizing and
translating all pre-clinical and clinical information relating to
prostaglandin E-1 from the literature as well as from NexMed's
trials and submitting this package to the Ministry of Health. Upon
review of this package, the Ministry will issue Clinical Trial
Registration Approval allowing the trial to Commence or advise us
as to the proper pathway.
The assumption has been made that this clinical trial will
be conducted under U.S. Good Clinical Practice conditions and the
data from the trial will be able to be used worldwide to augment
other submissions
All work both in US and in China to prepare this package is
covered by one charge as indicated in Exhibit B and listed as
"Clinical Trial Registration Process".
II. PREPARATION OF STUDY MATERIALS
INNAPHARMA assumes that there will be further modifications
to the protocol submitted to the Chinese regulatory authorities.
Innapharma will work with the Chinese regulatory authorities to
produce a final Protocol that satisfies all parties. Innapharma
will develop and design the case report forms (annotated in
Chinese). It has been assumed that the clinical supplies will be
produced, packaged and shipped to investigative sites by NexMed.
III. INITIATION OF STUDY
Innapharma will work with the Ministry of Health to select
the most qualified and experienced investigative sites for this
study. Innapharma will negotiate all investigator grants and
provide a duly constituted local IRB. Innapharma will conduct
pre-study qualification visits to all sites. Upon satisfactory
approval each site will be shipped a pre-study package of documents
to prepare and submit to Innapharma as per GCP.
INITIATION VISITS I SITE COORDINATOR TRAINING
During the initiation visits study coordination training
sessions to review protocol / CRFs will be developed and conducted
by INNAPHARMA
8
personnel at study initiation visits for all
investigative sites involved in the clinical trial.
IV. CONDUCT OF STUDY
PATIENT GRANTS
Innapharma will manage grant payments to all investigators.
STUDY MONITORING
INNAPHARMA will select study monitors from the Innapharma
China Monitor Network. All monitors are medical doctors. Monitors
will be chosen based on therapeutic experience as well as location.
INNAPHARMA will utilize local monitors whenever possible to
minimize travel time and costs.
ONGOING REPORTS
SERIOUS ADVERSE EVENTS
Serious adverse event reports will be forwarded to the
sponsor within 24 hours of receipt by INNAPHARMA. INNAPHARMA will
work with the investigative site to gather any additional detail on
serious adverse events required. Adverse events (serious or
non-serious) will be coded, tracked and reported to the sponsor.
PROJECT MANAGEMENT
A dedicated project manager will be assigned to this
project. The project manager will coordinate the project team,
track timelines, and monitor financial activities. The project
manager works in cooperation with the project team to ensure
timelines of the study are met and ongoing communications with
NexMed are maintained. Monthly status reports will be provided
to provide the following information:
1. Subject enrollment
2. Serious Adverse Events log
V. DATA MANAGEMENT
DATA COLLECTION
Data fields consisting of subject demographic, medical
history, physical exam, adverse events, and laboratory data will be
collected on NexMed
9
CRFs for each subject. In addition, the efficacy data collected for
subjects will be entered into a data base.
DATA ENTRY
Prior to data entry, all CRFs will be coded and reviewed for
completion. Coding of data will utilize the WHO dictionary unless
otherwise specified by NexMed. All data will be double-key entered
and checked against the designated ranges. It is anticipated that
12 unique CRFs (of an estimated 20 total CRF's) will be processed
per subject.
Computerized edit checks will be performed on the data on an
ongoing basis. Tracking spreadsheets will be created to account for
all data collection documents received and keyed by Data Entry.
DATABASE PROGRAMMING AND STARTUP
Based on the CRF design, a database design will be developed
and programmed. INNAPHARMA will create the trial database using
customized range checks for flagging data outliners for review, and
process the data utilizing documented coding guidelines.
TABLES, LISTINGS, AND PROFILES
Final table formats, listings, and profiles will be
developed in collaboration with NexMed. All table programming will
be validated and checked prior to final reports.
VI. STATISTICS
INNAPHARMA will perform the statistical analyses for the clinical trial
as per the final protocol analysis plan.
VII. EDITORIAL SERVICES
INNAPHARMA will produce a final study report including all statistical
tables.
VIII. PROJECT TIMELINES
See attached schedule (Exhibit E)
10
IX. BUDGETS
See attached schedule (Exhibit B)
Proposed payment schedule (Exhibit C)
Investigator grant estimate (Exhibit D)
11
BUDGET ESTIMATE
EXHIBIT B
Duration of project (in months):......................................... 6
Duration of clinical trial (enrollment & study time)..................... 3
Number of sites:......................................................... 4
Number of patients:...................................................... 500
Cost per patient:........................................................ 30
# of payments to investigator:........................................... 4
Number of CRF's:......................................................... 20
Number of unique CRF's:.................................................. 12
Number of patient diary cards............................................ 4
Investigator's / CRA Meeting:
number of investigators/coordinators:............................... 8
number of CRA's:.................................................... 2
number of Innapharma employees:..................................... 2
CRA's Conference Call:
number of investigators/coordinators:............................... 0
number of CRA's:.................................................... 0
number of Innapharma employees:..................................... 0
Number of monitoring visits:............................................. 4
(do not include Initiation Visit)
IRB:
Local IRB--number of sites.......................................... 4
Central IRB--number of sites........................................ 0
Project Management:...................................................... 6
(estimated number of hrs per week)
# of investigator's newsletters:......................................... 2
# of data transfers to sponsors.......................................... 2
Sponsors Name: NEXMED, INC. (prostaglandin E-1)
12
BUDGET ESTIMATE
EXHIBIT B
TASK NAME INNAPHARMA COST RESPONSIBILITY
---------------------------------------------------------------------------- ---------------- --------------
Preparation of Study Materials
Clinical Trial Registration Process......................................... 10,000
CRF development............................................................. 1,200
assemble / print CRF........................................................ x
ship CRF's to Sponsor from Innapharma
patient diary development................................................... 320
print patient diaries....................................................... x
clinical supplies -- shipping............................................... x
Total:................. $ 11,520
Initiation of Study
recruit investigator's...................................................... 160
negotiate grants with investigator's........................................ 160
payments to investigator's.................................................. 160
Local IRB:.................................................................. 800
prestudy visit--CRA time.................................................... 240
prestudy visit--CRA expenses................................................ 1,400
initiation visit--CRA time.................................................. 400
initiation visit--CRA expenses.............................................. 120
Total:.................. $ 3,440
Conduct of Study
investigator site grant..................................................... 15,000
monitoring visits--CRA time................................................. 1,600
monitoring visits--CRA expenses............................................. 480
provide status reports -- monthly........................................... 480
SAE's reporting / follow up................................................. 200
project management.......................................................... 1,000
Total:................. $ 18,760
Data Management
initial CRF / protocol review............................................... 360
develop coding guidelines................................................... 600
establish edit specs / query program / list................................. 56
design / set-up database, including labs, diaries........................... 1,200
program data edit checks.................................................... 200
database validation / 100% check on fields.................................. 366
logging in of CRF's......................................................... 500
CRF coding.................................................................. 750
installation of on-line dictionaries, format libraries...................... 300
encoding of AE's, con meds, etc. ........................................... 1,000
13
BUDGET ESTIMATE
EXHIBIT B
TASK NAME INNAPHARMA COST RESPONSIBILITY
---------------------------------------------------------------------------- ---------------- --------------
single data entry........................................................... 200
double data entry........................................................... 458
double key comparison check................................................. 500
Fax/ or e-mail transfer of first 50 pts to USA.............................. 200
clean lab data / query lab data file........................................ 340
track data entry / queries / resolution..................................... 450
generate queries............................................................ 350
resolve queries............................................................. 456
perform OC on 100% of CRF's (key variables)................................. 456
program custom listings, summaries, profiles................................ 600
generate listings........................................................... 40
transfer data to sponsor.................................................... 56
Total:................. $ 9,438
Statistical Analysis
prepare mock tables......................................................... 400
program SAS datasets........................................................ 250
perform statistical analysis................................................ 1,500
write statistical report.................................................... 1,500
Total:................. $ 3,650
Medical Writing
Final study report.......................................................... 500
Total:................. $ 500
Grand Total:........... $ 47,308
14
EXHIBIT C
PROSTAGLANDIN E-1 STUDY
PROPOSED PAYMENT SCHEDULE
PAYMENT # MILESTONE ESTIM. DATE AMOUNT
--------- ----------------------- ----------- ------------
1 Contract finalization 11/1/96 $ 7,308.00
2 Clinical trial approval 12/15/96 $ 10,000.00
3 First patient in 12/31/96 $ 10,000.00
4 Last patient out 1/29/97 $ 10,000.00
5 Final report 3/13/97 $ 10,000.00
TOTAL............. $ 47,308.00
15
EXHIBIT D
Investigator Grant Estimate
Prostaglandin E-1 Study
Visit 1
Explanation of study $ 15.00
Informed consent
Brief history
Dispensation of drug + diaries
Visit 2 Pt. interview / CRF completion $ 10.00
Collection of diaries
Patient stipend $ 5.00
(Transportation)
Per patient........... $ 30.00
Total patient number............. $ 500.00
------------------------------------------------------------------------------
Total investigator grant......... $15,000.00
16
EXHIBIT E
NexMed Prostaglandin E-1
China Study Timeline
ID TASK NAME DURATION START FINISH
--------- -------------------------------------------------------------------------- ------------- --------- ---------
1........ PRELIMINARY MEETINGS/CONTRACT 42d 9/5/96 11/1/96
2........ Initial meeting NexMed / Innapharma 0d 9/5/96 9/5/96
3........ Bid proposal sent 0d 9/20/96 9/20/96
4........ Contract agreement signed 5d 10/28/96 11/1/96
5........ INFORMATION/STRATEGY STAGE 14d 11/4/96 11/21/96
6........ Medical expert identified 10d 11/4/96 11/15/96
7........ Meeting with Minister of Health 1d 11/18/96 11/18/96
8........ Clinical strategy approved by MOH 3d 11/19/96 11/21/96
9........ NexMed's GO/NO GO DECISION 0d 11/21/96 11/21/96
10....... CLINICAL REGISTRATION PROCESS 55d 11/22/96 2/6/97
11....... Assembly of all NexMed data 10d 11/22/96 12/5/96
12....... Assembly of all literature to date 10d 12/6/96 12/19/96
13....... Finalization of Clin. Reg. Package 5d 12/20/96 12/26/96
14....... Translation of Package to Chinese 10d 12/27/96 1/9/97
15....... Submission to MOH 0d 1/9/97 1/9/97
16....... Approval of Clinical Registration 20d 1/10/97 2/6/97
17....... CLINICAL TRIAL 80d 2/7/97 5/29/97
18....... site / investigation selection 5d 2/7/97 2/13/97
19....... Pre-study evaluation visit 1d 2/14/97 2/14/97
20....... Case Report form development 10d 2/17/97 2/28/97
21....... IRB selection 3d 3/3/97 3/5/97
22....... Study initiation visit 1d 3/6/97 3/6/97
23....... Enrollment and treatment time 24d 3/7/97 4/9/97
24....... Clinical trial complete 1d 4/10/97 4/10/97
25....... Data entry complete / data base clean 15d 4/11/97 5/1/97
26....... Statistical analysis 15d 5/2/97 5/22/97
27....... Final stat. Report sent to NexMed 5d 5/23/97 5/29/97
17
